Transition-metal-free variant of Glaser- and Cadiot-Chodkiewicz-type Coupling: Benign access to diverse 1,3-diynes and related molecules

Article abstract of DOI:10.1016/j.tetlet.2020.151775

Efficient and transition-metal-free transformations towards the synthesis of 1,3-diynes have been described from their corresponding terminal acetylenes or 1,1-dibromo-1-alkenes. The efficiency of molecular iodine as catalyst in aqueous medium, driven the transformation to afford 1,3-diynes in moderate to good yields. The developed reaction conditions revealed appreciable functional group tolerance in aqueous medium. Further, the scope of the transition-metal-free approach for the synthesis of 1,3-enynes has been investigated using terminal alkynes as easy available precursors.

Full text of DOI:10.1016/j.tetlet.2020.151775

Journal Pre-proofs
Transition-Metal-Free Variant of Glaser- and Cadiot-Chodkiewicz-Type Cou-
pling: Benign Access to Diverse 1,3-Diynes and Related Molecules
Dhananjaya Kaldhi, Nagaraju Vodnala, Raghuram Gujjarappa, Arup K. Kabi,
Subhashree Nayak, Chandi C. Malakar
PII:
S0040-4039(20)30207-0
DOI:
https://doi.org/10.1016/j.tetlet.2020.151775
TETL 151775
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 January 2020
20 February 2020
23 February 2020
Please cite this article as: Kaldhi, D., Vodnala, N., Gujjarappa, R., Kabi, A.K., Nayak, S., Malakar, C.C., Transition-
Metal-Free Variant of Glaser- and Cadiot-Chodkiewicz-Type Coupling: Benign Access to Diverse 1,3-Diynes and
Related Molecules, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151775
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Tetrahedron Letters
journal homepage: www.elsevier.com
Transition-Metal-Free Variant of Glaser- and Cadiot-Chodkiewicz-Type
Coupling: Benign Access to Diverse 1,3-Diynes and Related Molecules
Dhananjaya Kaldhi ǂa, Nagaraju Vodnala ǂa, Raghuram Gujjarappa a, Arup K. Kabi a, Subhashree Nayak
b, Chandi C. Malakar*a
a Department of Chemistry, National Institute of Technology Manipur, Langol, Imphal - 795004, Manipur, India.
b Department of Chemical Sciences, National Institute of Science Education and Research (NISER), Jatani, Bhubaneswar, Odisha - 752050,
India.
ǂ D. K. and N. V. contributed equally to this work.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Efficient and transition-metal-free transformations towards the synthesis of 1,3-
diynes have been described from their corresponding terminal acetylenes or 1,1-
dibromo-1-alkenes. The efficiency of molecular iodine as catalyst in aqueous
medium, driven the transformation to afford 1,3-diynes in moderate to good yields.
The developed reaction conditions revealed appreciable functional group tolerance
in aqueous medium. Further, the scope of the transition-metal-free approach for the
synthesis of 1,3-enynes has been investigated using terminal alkynes as easy
available precursors.
Available online
Keywords:
1,3-diynes,
terminal alkynes
1,1-dibromo-1-alkenes
1,3-enynes
2009 Elsevier Ltd. All rights reserved.

2
Introduction
The conjugated 1,3-diynes and poly-ynes are witnessed as well-perceived molecular architecture because of their on-
growing recognitions in multidisciplinary fields of research.1 These moieties are well-understood as decisive constituent
of talented bio-molecules, such as natural products and pharmaceuticals.2 The complex compounds embodied with 1,3-
diynes have found wide attentions as anti-inflammatory, anti-fungal, anti-HIV, anti-bacterial and anti-cancer agents.2
Moreover, their application has been greatly acknowledged in material science towards engineering of advanced
optoelectronic materials,3 polymers,4 supramolecular materials5 and “high-tech” smart materials, such as liquid crystals,
electrically conductive and high strength fibers.6 In addition, the conjugated 1,3-diyne moieties are revealed as fruitful
precursors for the synthesis of pivotal heterocyclic scaffolds and organometallic compounds.7 Hence, development of
novel and diverse tools for their preparation remain as peering assignment in the area of C-C bond forming reactions.1
These molecules are traditionally synthesized by Glaser-type (Scheme 1a)8 and Cadiot-Chodkiewicz (Scheme 1b)1b,
9 coupling reactions in the presence of Cu-salts as promoters. However, these methods rely on the use of stoichiometric
Cu-sources, toxic and rigid organic bases, high reaction temperature and excess of alkynes. Referring the noteworthy
earliest reports,8-9 the urge towards evolving more practical, eco-friendly and cost effective reaction conditions have
acquired a renewed concern in the area of catalytic oxidative coupling to form C(sp)-C(sp) bonds. Therefore, the
extensive revival of the original conditions based on metal-catalysts and ligands have secured a landmark contribution
towards the development of a spectrum of efficient methods in homogeneous catalysis (Scheme 1a,b).1,10
Scheme 1. Overview of previous and present reports.
Among the remarkable modifications on catalytic systems, the reactions using Pd-salts are endorsed as
most facile approaches in homogeneous catalysis for the homo-coupling of terminal alkynes. These reactions are
11
well-executed and shown to be effective due to the need of low-catalyst loading and mild conditions.10d,
However, the merits of the well-documented Pd-catalyzed homo-coupling processes suffer from barriers such as
poor selectivity, high cost of reagents, use of sensitive and environmentally-unfriendly phosphine ligands and
amine reagents. Therefore, considering the economic and environmental perspective, the versatility of both
homo- and hetero-coupling processes are well-investigated under heterogeneous catalysis.12 In this regards, the
heterogeneous systems based on Cu,10g-h, 13 Pd,11, 14 Ni15 and Au10t, 16 are studied extensively to facilitate high
selectivity in product formation. Admitting the leading breakthrough realized by several researchers over past 148
years that shares an ample platform for the useful applications of these protocols; nevertheless, few reported
methods accord with the similar hurdles such as use of metal/bimetallic catalysts, toxic reagents, ligands, complex
reaction conditions and the use of excess alkynes. On the other hand, the typical substrates 1-haloalkynes those
used in Cadiot-Chodkiewicz coupling (Scheme 1b) and in their self-coupling reactions (Scheme 1c) are traditionally
prepared under highly basic conditions and are normally unstable.17 These limitations lead to the narrow practical
applications in large scale synthesis of conjugated 1,3-diynes. Improvements of the methods using surrogates of
1-haloalkyne precursors are not well-explored so far. Recently, 1,1-dibromo-1-alkenes are effectively employed

3
as substrates instead of 1-haloalkynes for the synthesis of conjugated 1,3-diynes (Scheme 1d).18 These reactions
are investigated using metal-catalyst under harsh reaction conditions. Thus, the rising concern towards novel and
eco-friendly surrogate approaches for C(sp)-C(sp) cross-coupling reactions that avoids use of metals and toxic
reagents remains important.
Recently, the transition-metal-free transformations are envisioned as most powerful tools and have
emerged considerable attention due to their uniqueness in terms of high atom-economy and low waste disposal.19
A number of synthetic strategies are devised for C-C and C-heteroatom bond formations to serve effective
preparation of complex molecules and the success of these methods rely on high selectivity and well investigated
functional group tolerance under relatively mild conditions.19 The transition-metal-free approaches towards the
synthesis of 1,3-diynes from terminal alkynes are rarely investigated and the reported methods have not
completely explored the synthetic utility of reaction conditions.19d-e The transition-metal-free protocols are
restricted by the usage of expensive reagents or the use of strong bases.19d Here, we represent two distinct
transition-metal-free approaches for the synthesis of 1,3-diynes based on (i) transition-metal-free oxidative
coupling of terminal alkynes (Scheme 1e) and (ii) organocatalytic oxidative dimerization of 1,1-dibromo-1-alkenes
(Scheme 1f).
We commenced with the experiments by investigating the homo-coupling reaction of phenylacetylene
(1a) (Table 1). To our delight, after having a short optimization, the desired homo-coupling product 1,4-
diphenylbuta-1,3-diyne (2a) was formed in highest yield of 93%, when using 30 mol% of molecular iodine as
catalyst and 3.0 equiv. of piperidine as base in water at 100 °C (Table 1, Entry 18). To identify these suitable
conditions, we have subsequently screened the effect of various catalysts, oxidants, bases and solvents. Initially,
TBAI was investigated as a catalyst for this transformation. It was observed that when phenylacetylene (1a) was
reacted using catalytic amounts of TBAI and in presence of 2.5 equiv. TBHP; the corresponding terminal iodinated
product has been formed in 31% yield under solvent free conditions at ambient temperature after 12 h (Table 1,
Entry 1).
Table 1. Screening of reaction conditions for the transition-metal-free
Glaser-type coupling of phenyl acetylene (1a).a
Entry
Catalyst
(mol%)
Oxidant/Base (Equiv.),
Solvent, Temperature
2a %
yieldb
3a %
yieldb
1
2
TBAI (30)
TBAI (30)
TBAI (30)
PIDA (30)
NIS (30)
KI (30)
TBHP (2.5), neat, 25 °C
TBHP (2.5), DMSO, 100 °C
TBHP (2.5), DMF, 100 °C
TBHP (2.5), DMSO, 100 °C
TBHP (2.5), DMSO, 100 °C
TBHP (2.5), DMSO, 100 °C
TBHP (2.5), DMSO, 100 °C
K2CO3 (2.5), DMSO, 100 °C
n-BuLi (2.5), THF, 25 °C
0c
33
37
0d
0c
0
3
0
4
0d
0
5
23
35
51
<5
19
26
11
0
6
0
7
I2 (30)
0
8
I2 (30)
0
9
I2 (30)
0
10
11
12
13
I2 (30)
LiHMDS (2.5), THF, 25 °C
KOtBu (2.5), DMSO, 100 °C
KOtBu (0.2), DMSO, 50 °C
DABCO (2.5), DMSO, 100 °C
0
I2 (30)
0
TEMPO (5)
I2 (30)
79
0
<5

4
14
15
16
17
18
19
20
I2 (30)
I2 (30)
I2 (30)
I2 (30)
I2 (30)
I2 (30)
I2 (15)
Et3N (3), DMSO, 100 °C
Morpholine (3), DMSO, 100 °C
Piperidine (2.5), DMSO, 100 °C
Morpholine (3), H2O, 100 °C
Piperidine (3), H2O, 100 °C
Piperidine (3), H2O, 50 °C
17
67
55
81
93
<5
61
0
0
0
0
0
0
0
Piperidine (3), H2O, 100 °C
a All reactions were performed using 1.0 mmol 1a in 2 mL solvent for 12 h.
b Isolated yields. c Terminal iodinated product was isolated in 31% yield. d
1,2-diiodo product was isolated in 22% yield.
Interestingly, the similar reaction delivered the homocoupling product 1,3-diyne 2a in low yield, when
the transformations were carried out in presence of DMSO and DMF as solvents at 100 °C (Table 1, Entries 2-3).
Next, various iodine-based reagents like PIDA (phenyliodine(III) diacetate), NIS (N-iodosuccinimide), KI and I2 were
examined as catalysts. It was realized that using PIDA the transformation did not lead to the desired product 2a,
rather the reaction favoured the formation of 1,2-diiodo derivative in 22% yield (Table 1, Entry 4). Among the
other catalysts tested, NIS and KI revealed low efficiencies under the reaction conditions towards formation of the
product 2a (Table 1, Entries 5-6). Moreover, 30 mol% molecular iodine as catalyst in presence of 2.5 equiv. TBHP
as oxidant in DMSO at 100 °C delivered the product 2a in 51% yield (Table 1, Entry 7). Inspired by these results,
we further attempted to screen the conditions using molecular iodine as catalyst. Several organic and inorganic
bases were investigated for this transformation (Table 1, Entries 8-11 and 13-15). Among the tested bases,
inorganic bases like K2CO3, n-BuLi, LiHMDS and KOtBu were inefficient towards the conversion of 1a into 2a (Table
1, Entries 8-11). Surprisingly, when the reaction was performed using catalytic amounts of KOtBu in presence of
TEMPO, the formation of 1,3-enyne 3a in 79% yield was observed (Table 1, Entry 12) On the other hand, DABCO
and triethylamine as bases furnished low yields of the product 2a (Table 1, Entries 13-14). Interestingly,
morpholine and piperidine as bases showed the considerable efficacies towards the successful conversion of 1a
into 2a with 67% and 55% yields respectively in DMSO at 100 °C (Table 1, Entries 15-16). Surprisingly, when DMSO
was replaced with H2O as solvent, both morpholine and piperidine mediated reactions accomplished the
transformation with 81% and 93% yield of the product 2a respectively (Table 1, Entries 17-18). It was also realized
that reducing the reaction temperature and catalyst amounts, the yield of the reaction decreased drastically (Table
1, Entries 19-20). Hence, the reaction using 30 mol% of molecular iodine and 3.0 equiv. of piperidine in H2O at 100
°C for 12 h was considered as optimal conditions towards the formation of 1,4-diphenylbuta-1,3-diyne (2a) (Table
1, Entry 18).

5
Scheme 2. Substrate scope of terminal alkynes towards the
synthesis of 1,3-diynes 2.
After attaining the best reaction conditions to obtain 1,3-diynes 2, the transformations of a broad
range of terminal alkynes 1 bearing different synthetically useful functional groups were examined under the
standard conditions (Scheme 2). In general, all the investigated starting materials were successfully reacted
under the developed conditions and the corresponding products 2 were obtained in high yields. Terminal
alkynes with mono- and di- functional groups on the aromatic ring such as methyl (–CH3), methoxy (–OCH3),
amino (–NH2), chloro (–Cl), bromo (–Br), fluoro (–F) and trifluromethoxy (–OCF3) at various positions were well
tolerated under the reaction conditions and leading to the corresponding products 2b-n in high yields despite
the electronic nature and substitution pattern. Terminal alkynes embedded with naphthyl ring also delivered
the product 2o in good yield using the developed method. Interestingly, it was investigated that the scope of
the protocol could be successfully extended to terminal alkyne with alkyl substituent with moderate isolated
yield of the product 2p.
Scheme 3. Control experiments to establish the plausible
reaction mechanism.
Next, we determined to establish a plausibe reaction mechanism for this transition-metal-free
approach. In this regard, we have carried out several control experiments to depict the plausible reaction
mechanism. To begin with, the reaction of 1a was carried out using standard reaction conditions under N2
atmosphere. The reaction conditions gave an unsatisfactory result with less than 10% isolated yield of 2a from a
complex reaction mixture (Scheme 3, Eq. 1). It is thus believed that the reaction conditions require sufficient
amounts of aerial oxygen towards completion of the transformation. Then, we carried out the reaction of 1a using
standard reaction conditions under the influence of radical scavengers like TEMPO (2,2,6,6-tetramethylpiperidine
1-oxyl) and BHT (butylated hydroxytoluene) (Scheme 3, Eq. 2 and Eq. 3). To our disappointment, we found the
trace amount of product 2a in both the above mentioned cases. From the obtained results, it was concluded that
the mechanism follows a radical pathway to afford the desired product 2a. To further realize about the mechanistic
pathway, we have performed the reaction of terminal iodinated acetylene 1aa under standard reaction conditions.
Surprisingly, the reaction conditions were successful towards the formation of 1,3-diyne 2a in 75% yield (Scheme
3, Eq. 4). Simultaneously, we have also carried out the reaction of terminal iodinated acetylene 1aa with
phenylacetylene (1a) under the standard reaction conditions, which is leading to the formation of 1,3-diyne 2a in
68% yield (Scheme 3, Eq. 5).
Finally, to have better understanding about the plausible reaction mechanism, we were influenced to
carry out the reaction of phenylacetylene (1a) ([M]+ = 102.1, [M + H]+ = 103.1) under standard reaction conditions.
The course of the reaction was inspected and analyzed by gas chromatography-mass spectrometry (GC-MS) after
an interval of 3 h, 6 h and 9 h. The mass-spectroscopic data disclosed that the mechanism could proceed via the

6
formation of intermediate 1aa ([M]+ = 228.03) to obtain the desired product 2a ([M]+ = 202.1, [M + H]+ = 203.3)
(details of mass spectra are given in Figure 1, SI).
Having these informations from the above experiments and literature evidences, we were able to
20
propose a plausible mechanism (Scheme 4).10l, According to the proposed mechanism, iodopiperidinium
iodide (B) can be in situ formed from iodine and piperidine (A).20a The intermediate B further acts as an
iodinating agent to deliver intermediate 1aa from 1a. It is believed that after obtaining the intermediate 1aa,
the reaction may proceed in two pathways. According to path A; the intermediate 1aa adds on to another
molecule of phenylacetylene (1a) via radical pathway resulting in product 2a. In accordance to the path B; the
intermediate 1aa via self-dimerization of phenylacetylene radical leading to the formation of desired product
2a. It is presumed that molecular iodine can be regenerated from hydrogen iodide in presence of aerial
oxygen.20b
Scheme 4. Plausible mechanism for 1,3-diyne 2 formation.
After establishing Glaser-coupling reaction for the synthesis of 1,3-diynes under iodine-mediated protocol, we
envisioned to establish the transition-metal-free variant for the synthesis of conjugated 1,3-diynes using 1,1-
dibromo-1-alkenes 4 as starting materials. In this regards, we have strived the optimization of the reaction
conditions towards the formation of 1,4-diphenylbuta-1,3-diyne (2a) using (2,2-dibromovinyl)benzene (4a) as
starting material.
Table 2. Screening of reaction conditions for the transition-metal-free
coupling of 2,2-dibromovinyl)benzene (4a).a
Entry
Catalyst (mol%)
Base (Equiv.), Solvent,
Temperature
2a %
yieldb
1
2
3
4
5
6
7
8
9
I2 (10)
Piperidine (3.0), H2O, 100 °C
Cs2CO3 (3.0), DMSO, 100 °C
NaOtBu, (3.0), DMSO, 100 °C
Cs2CO3 (3.0), DMSO, 120 °C
Cs2CO3 (3.0), DMSO, 120 °C
Cs2CO3 (3.0), DMSO, 120 °C
Cs2CO3 (1.0), DMSO, 120 °C
Cs2CO3 (0.5), DMSO, 120 °C
Cs2CO3 (1.0), MeCN, 120 °C
0
TEMPO (10)
63
57
51
55
69
86
47
23
TEMPO (10)
Thiourea (10)
Niacin (10)
3-nitropyridine (10)
3-nitropyridine (10)
3-nitropyridine (10)
3-nitropyridine (10)

7
10
11
3-nitropyridine (10)
3-nitropyridine (10)
Cs2CO3 (1.0), diglyme, 120 °C
Cs2CO3 (1.0), DMSO, 70 °C
49
Trace
a All reactions were performed using 1.0 mmol 4a in 2 mL solvent for 12 h.
b Isolated yields.
Initial reaction conditions using 10 mol% I2 in presence of 3.0 equiv. of piperidine in water at 100 °C were inactive
to deliver the product 2a (Table 2, Entry 1). Surprisingly, when 10 mol% TEMPO was used as catalyst in addition
with 3.0 equiv. of Cs2CO3 or 3.0 equiv. of NaOtBu in DMSO at 100°C, the formation of product 2a was observed in
63% and 57% yield respectively (Table 2, Entries 2-3). Replacing TEMPO with thiourea or niacin as catalyst, the
product 2a was obtained with similar yields under identical reaction conditions (Table 2, Entries 4-5). Further
investigation revealed that catalytic amounts of 3-nitropyridine in presence of base showed maximum efficacy
towards this transformation (Table 2, Entries 6-7). Among the tested bases, 1.0 equiv. of Cs2CO3 accomplished the
transformation with 86% yield of the product 2a (Table 2, Entry 7). It was also described that with decreasing
amounts of base, changing the solvent and reaction temperature leading to the unsuccessful transformation
(Table 2, Entries 8-11). Hence, the reaction using 10 mol% of 3-nitropyridine and 1.0 equiv. of Cs2CO3 in DMSO at
120 °C for 12 h was considered as optimal conditions towards the formation of 1,4-diphenylbuta-1,3-diyne (2a)
(Table 2, Entry 7).
Further, the scope of (2,2-dibromovinyl)arenes 4 was explored towards the preparation of 1,3-diynes 2. It was
observed that the (2,2-dibromovinyl)arenes 4 containing both electron donating and electron withdrawing
substituents on aromatic rings in various positions leading to the formation of the corresponding 1,3-diynes
2a-c, e-g, i-k, o in good yields. However, the transformation remains inactive using the corresponding (2,2-
dibromovinyl)alkenes as the substrates (Scheme 5).
Scheme 5. Scope of 1,3-diyne 2 from (2,2-dibromovinyl)arenes 4.
Subsequently, to know the mechanistic insights, we were wilful of carrying out the control experiments.
To begin with, the reaction of 4a was performed in the presence of 1.0 equiv. of Cs2CO3 in DMSO at 120 °C for 8
h. The reaction conditions gave the terminal brominated acetylene 4aa in 86% and phenylacetylene (1a) in 10%
isolated yield (Scheme 6, Eq. 1). Then, the intermediate 4aa was subjected to a reaction with 10 mol% 3-
nitropyridine in DMSO at 120 °C for 12 h. Delightfully, the reaction conditions gave 2a in 74% isolated yield
(Scheme 6, Eq. 2). Similarly, to know the role of aerial oxygen, we were encouraged to carry out the reaction of
intermediate 4aa under above mentioned conditions in the presence of N2 atmosphere. The reaction conditions
were found inefficient and provided the product 2a in only 22% yield (Scheme 6, Eq. 3). At last to inquire about
the radical pathways, a reaction of 4aa was performed with 10 mol% of 3-nitropyridine in DMSO at 120 °C for 12
h in the presence of 1.1 equiv BHT as radical scavenger. To our realization, the reaction conditions offered desired
product 2a with an unsatisfactory yield of 26% (Scheme 6, Eq. 4).
Finally, to realize the feasible reaction mechanism, we were guided to carry out the reaction of 2,2-
dibromovinyl)benzene (4a) ([M]+ = 259.88) under the standard reaction conditions. The course of the reaction was
monitored and studied by gas chromatography-mass spectrometry (GC-MS) after an interval of 40 min, 2 h, 4 h, 6
h, 8 h and 10 h. The mass-spectroscopic data revealed that the mechanism could progress via the formation of

8
intermediate 4aa ([M]+ = 180.13), 1a ([M]+ = 102.1) to obtain the desired product 2a ([M]+ = 202.1) (details of mass
spectra are given in Figure 2, SI).
Scheme 6. Control experiments and plausible mechanism for
formation of 1,3-diyne 2 from (2,2-dibromovinyl)arenes 4.
With this much information, we proceeded to propose a plausible mechanism based on the
experimental and literature evidences (Scheme 6).21-23 According to the proposed mechanism, the base
mediated dehydrohalogenation of 4a takes place to deliver the terminal brominated acetylene 4aa.21 During
the reaction monitoring, it was observed that the phenylacetylene (1a) was also forming in lower
concentration. Hence, we put up two pathways to generate phenylacetylene radical C either from
intermediate 4aa or 1a under 3-nitropyridine-N-oxide F catalyzed protocol. It is reported that the intermediate
F can be generated from 3-nitropyridine by in situ generated H2O2 under aerobic conditions.22-23 Finally, the
intermediate C involves in self-dimerization to obtain the desired product 2a.
Scheme 7. Scope of 1,3-enyne 3 from aryl acetylenes 1.

9
More surprisingly during our screening experiments (Table 1), we have observed that when,
phenylacetylene (1a) was reacted in presence of catalytic amounts of TEMPO and KOtBu, the unexpected
formation of 1,3-enyne product 3a was observed with higher E-selectivity (Table 1, Entry 12).24 This
serendipitous finding was scrutinized and obtained the suitable optimal conditions (The additional optimization
of reaction conditions are provided in SI). The maximum yield of 1,3-enyne 3a was obtained when the reaction
of 1a was carried out in presence of 5 mol% TEMPO and 20 mol% KOtBu in DMSO at 50 °C for 12 h. To explore
these serendipitous findings, we have investigated the brief substrate scope of this approach (Scheme 7). It
has been described that the terminal aryl acetylenes 1, despite the electronic nature of the substituents in
various positions were well tolerated to deliver the corresponding products 3a-d in high yields ranging from
69-79% (Scheme 7).
Scheme 8. Control experiments and plausible mechanism for
formation of 1,3-enyne 3 from aryl acetylenes 1.
We were fascinated in establishing the plausible reaction mechanism for this unexpected finding. In
pursuing this objective, we have carried out few control experiments. The reaction of 1a was carried out under
the standard reaction conditions in the presence of N2 atmosphere to obtain the product 3a in 21% yield
(Scheme 8, Eq. 1). Next, we performed the reaction of 1a under standard reaction conditions in presence of
1.1 equiv. BHT. The reaction conditions gave a disappointing yield of 3a in 17% (Scheme 8, Eq. 2). Hence, from
above performed reactions we could assume that the reaction may proceed via radical pathway in the
presence of aerobic conditions. Additionally, we have carried out the reaction of 1a under the standard
reaction conditions and the course of the reaction was examined and analyzed by gas chromatography-mass
spectrometry (GC-MS) after an interval of 1 h, 3 h, 6 h and 9 h (details of mass spectra are given in Figure 3,
SI). From GC-MS data we could not identify the formation of any intermediate, but we could monitor the
disappearance of starting material 1a ([M]+ = 102.1) and increase in percentage of product 3a ( ([M]+ = 204.24)
formation at regular intervals. With this much information we decided to describe the plausible mechanism.
The fact may be explained as the generation of potassium acetylide G in the presence of KOtBu. The
intermediate G undergoes single electron transfer in presence of TEMPO ((2,2,6,6-tetramethylpiperidin-1-
yl)oxyl) to form the phenylacetylene radical C.25 The generated intermediate C adds on to another molecule
of 1a via anti-approach leading to the formation of 1,3-enyne radical H. Finally, subsequent protonation of H
from tert-butanol to obtain the desired 1,3-enyne 3a. It is presumed that TEMPO anion could transfer an
electron to tert-butoxide radical and results in TEMPO radical and tert-butoxide anion respectively (Scheme
8).
In summary, we have developed the benign transition-metal-free approach towards the synthesis of 1,3-
diyne from their corresponding terminal acetylenes or 1,1-dibromo-1-alkenes under iodine or 3-nitropyridine
catalyzed reaction conditions respectively. The described strategies holds good for wide range of substrates bearing
different functional groups. Additionally, we also have investigated a mild approach towards the synthesis of E-

10
selective 1,3-enyne under transition-metal-free reaction conditions. The proposed mechanism were validated by
using relevant control experiments and mass-spectroscopic investigations.
Acknowledgments
CCM appreciate Science and Engineering Research Board (SERB), New Delhi and NIT Manipur for financial support
in the form of research grant (ECR/2016/000337). We sincerely thank Prof. Anil Kumar, Vikki N. Shinde and Shiv
Dhiman from BITS Pilani for sample analysis and research support. We also thank Dodla Sivanageswara Rao from
Department of Chemistry, Malaviya National Institute of Technology, Jaipur and Mostakim SK from Department of
Chemistry, Indian Institute of Technology, Guwahati for NMR and HRMS analysis. DK, NV, RG and AKK grateful to
Ministry of Human Resource and Development (MHRD), New Delhi for fellowship support.
Supplementary Material
A detailed supporting information is available which includes the purity and source of the reagents, copies of GC–
MS for investigation of the reaction mechanism, experimental procedures, 1H NMR and 13C NMR of the final products.
Supplementary material for this article can be found in online version, at doi……...
Experimental Section
General Method: All starting materials were purchased from commercial suppliers (Sigma-Aldrich, Alfa-Aesar, SD fine chemicals, Merck, HI
Media) and were used without further purification unless otherwise indicated. All reactions were performed in a 10 mL reaction vial with
magnetic stirring. Solvents used in extraction and purification were distilled prior to use. Thin-layer chromatography (TLC) was performed on
TLC plates purchase from Merck. Compounds were visualized with UV light (λ = 254 nm) and/or by immersion in KMnO4 staining solution
followed by heating. Products were purified by column chromatography on silica gel, 100-200 mesh. Melting points were determined in open
capillary tubes on EZ-Melt automated melting point apparatus and are uncorrected. All the compounds were fully characterized by 1H and
13C NMR and further confirmed by EI-HRMS analysis. All HRMS are recoreded in EI-QTOF method and GC-MS are recorded in EI method in
methanol solvent. 1H (13C) NMR spectra were recorded at 600 (150) MHz, 500 (125) MHz and 400 (100) MHz on a Brucker spectrometer using
1
CDCl3 as a solvent. The H and 13C chemical shifts were referenced to residual solvent signals at H/C 7.26/77.28 (CDCl3) relative to TMS as
internal standards. Coupling constants J [Hz] were directly taken from the spectra and are not averaged. Splitting patterns are designated as
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), overlapped and br (broad).
General experimental procedure for the synthesis of 1,3-diynes 2a-p using terminal acetylenes 1a-p: A 10 mL reaction vial was charged
with a terminal acetylenes 1a-p (1.0 mmol), piperidine (3.0 mmol), H2O (1 mL) and 30 mol% molecular iodine. The reaction vial was then
heated at 100 °C for 12 h. After completion of the reaction (progress was monitored by TLC; SiO2, Hexane/EtOAc = 9.5:0.5), the mixture
was diluted with ethyl acetate (15 mL) and water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was
washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and the remaining residue
was purified by column chromatography over silica gel using hexane / ethyl acetate (9.5:0.5) as an eluent to obtain the desired products
2a-p in high yields.
1
1,4-diphenylbuta-1,3-diyne (2a)17h: White solid, Rf = 0.75 (SiO2, Hexane/EtOAc = 9.5:0.5); m.p = 84-85 °C (Lit17h 86-87 °C); H NMR (400
MHz, CDCl3) δ = 7.54-7.51 (dd, 3J = 7.8 Hz, 4H; 1-H, 5-H), 7.37-7.31 (m, 6H; 2-H, 3-H and 4-H) ppm; 13C NMR (100 MHz, CDCl3) δ = 132.59
(C-1 and C-5), 129.3 (C-2, C-4), 128.53 (C-3), 121.88 (C-6), 81.64 (C-7), 74.4 (C-8) ppm; HRMS (EI, [M + H]+): calculated for C16H11: 203.0860;
found: 203.0858.
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Graphical Abstract
Leave this area blank for abstract info.
Transition-Metal-Free Variant of Glaser- and
Cadiot-Chodkiewicz-Type Coupling: Benign Access to
Diverse 1,3-Diynes and Related Molecules
Dhananjaya Kaldhiǂa, Nagaraju Vodnalaǂa, Raghuram Gujjarappaa, Arup K. Kabia, Subhashree Nayakb, Chandi C.
Malakar*a

13
Declaration of Interest Statement
Transition-Metal-Free Variant of Glaser- and Cadiot-Chodkiewicz-Type Coupling:
Benign Access to Diverse 1,3-Diynes and Related Molecules
Dhananjaya Kaldhi, Nagaraju Vodnala, Raghuram Gujjarappa, Arup. K. Kabi, Subhashree Nayak and
Chandi C. Malakar*
Authors have NO conflict of interest to declare on the above cited manuscript.
 Transition-metal-free approach towards Glaser- and Cadiot-Chodkiewicz-type Coupling.
 Regioselective synthesis of 1,3-diynes and 1,3-enynes.
 Chemical transformations were possible in aqueous medium.
 Organocatalyzed chemical transformations.
 Broad substrate scope with high yields of the products.