Visible light promoted coupling of alkynyl bromides and Hantzsch esters for the synthesis of internal alkynes

Article abstract of DOI:10.1039/c8ob02912a

A metal-free visible light promoted C(sp³)-C(sp) coupling reaction of alkynyl bromides and Hantzsch esters was developed, giving internal alkynes with primary, secondary, tertiary alkyl or other functional groups in good to high yields.

Full text of DOI:10.1039/c8ob02912a

Organic &
Biomolecular Chemistry
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Visible light promoted coupling of alkynyl
bromides and Hantzsch esters for the synthesis of
internal alkynes†
Cite this: Org. Biomol. Chem., 2019,
17, 181
a,b
Zhi-Yong Song,a,b Chun-Lin Zhanga and Song Ye
*
Received 22nd November 2018,
Accepted 3rd December 2018
A metal-free visible light promoted C(sp3)–C(sp) coupling reaction of alkynyl bromides and Hantzsch
esters was developed, giving internal alkynes with primary, secondary, tertiary alkyl or other functional
groups in good to high yields.
DOI: 10.1039/c8ob02912a
rsc.li/obc
scope. In 2015, Li et al. reported a pioneering metal-free coup-
ling of an alkyne and alkyl iodide under ultraviolet irradiation
Introduction
Alkynes are essential structural motifs and ubiquitous inter- (Scheme 1, reaction (c)).13
mediates in synthetic transformations for building fine
Recently, Hantzsch esters (HEs)14 have been extensively
chemicals, pharmaceuticals and polymeric photo-/electronic used in transfer-hydrogenation reactions and transfer-alkyl-
materials.1 The past several decades have witnessed tremen- ation reactions, especially in photoredox reactions.15 In 2011,
dous development of alkyne synthesis in organic chemistry. Nishibayashi and coworkers reported the first visible-light-
The general approaches via the C(sp3)–C(sp) bond formation induced reaction of HEs via alkyl radicals.16 After that, the
rely on the addition reaction with organometallic reagents,2 reactions of HEs have been successfully used for the
and transition-metal-catalyzed coupling reactions using Pd,3 C(sp3)–C(sp3)17 and C(sp3)–C(sp2)18 bond formation. Very
Cu,4 Co,5 Ni,6 Ag7 and Fe8 complexes (Scheme 1, reaction (a)).
However, the tedious reaction conditions and the use of rela-
tively expensive metals led chemists to explore alternative pro-
tocols under mild conditions in an environmentally benign
manner.9
The visible-light-induced catalysis is becoming a fascinating
methodology in modern organic synthesis,10 including those
for C(sp3)–C(sp) coupling reactions (Scheme 1, reaction (b)).
For example, in 2014, Chen et al. reported a visible-light-
induced deboronative alkynylation reaction with [Ru(bpy)3]
(PF6)2/BI–OH.11 This reaction worked with alkyl trifluorobo-
rates or boronic acids to generate substituted alkynes. In 2015,
Hashmi et al. reported a gold-catalyzed radical C(sp3)–H alky-
nylation of tertiary aliphatic amines using readily available
1-iodoalkynes as a radical alkynylation reagent in the presence
of [Au2(μ-dppm)2]2+ under photocatalysis conditions.12 The
reaction shows excellent regioselectivity and good functional-
group compatibility. However, these reactions require expen-
sive transition metals/ligands and limitations of the substrate
aBeijing National Laboratory for Molecular Sciences, CAS Key Laboratory of
Molecular Recognition and Function, CAS Research/Education Center for Excellence
in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China. E-mail: songye@iccas.ac.cn
bUniversity of Chinese Academy of Sciences, Beijing 100049, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02912a
Scheme 1 Synthesis of internal alkynes via C(sp3)–C(sp) coupling.
Org. Biomol. Chem., 2019, 17, 181–185 | 181
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recently, Cheng and co-workers reported the alkynylation of 4–8), and K3PO4 performed best compared to other inorganic
HEs with benziodoxole-activated alkynes under oxidative con- and organic bases (entries 8–12). Evaluation of photocatalysts
ditions (Scheme 1, reaction (d)).19 In this paper, we report a showed that Ir- and Ru-based photocatalysts only afforded the
visible-light-induced radical C(sp3)–C(sp) coupling of alkynyl product with a slightly increased yield (entries 13 and 14),
bromides and Hantzsch esters for the synthesis of internal while the organic photocatalyst of 10-methyl-9-mesitylacridi-
alkynes (Scheme 1, reaction (e)). Our work provides a photo- nium gave only a trace amount of product (entry 15).
catalytic approach from readily available alkynyl bromides Considering the environmental benignity of organic photoca-
without any additional oxidant, which leads to good tolerance talysts compared to transitional metals, the metal-free photo-
of functional groups.
catalyst 4CzIPN was chosen for the reaction. A higher yield was
achieved when the loading of Hantzsch ester 2a was increased
to two equivalents (entry 16). It is worth noting that the reac-
tion using alkynyl chloride (1a′) or sulfone (1a″) instead of
bromide (1a) resulted in some loss of yield (entries 17 & 18).
With the optimized reaction conditions in hand, we then
investigated the substrate scope. A variety of arylethynyl bro-
mides worked well for the reaction (Table 2). Both electron-
donating groups (1b–1f) and electron-withdrawing groups
(1g–1m) were tolerated at the ortho-, meta- or para-position,
giving the internal alkynes 3aa–3ma in good to high yields
(entries 1–13). All arylethynyl bromides with 4-phenyl or
α-naphthyl and heteroarylethynylbromide derived from indole
or thiophene worked as well (3na–3qa) (entries 14–17).
Notably, the ester and ketone were also tolerable for the reac-
tion to give the corresponding product (3ra) and estrone-
derived alkyne (3sa) in good yields (entries 18 &19). The reac-
tion of a series of 4-alkyl Hantzsch esters is shown in Table 3.
It was found that benzyl, acyclic and cyclic secondary alkyl
could be easily coupled with the alkynyl bromides to give the
products (3db–3ld) in good to high yields (entries 1–4). More
importantly, the tertiary alkyl, which is difficult to introduce
by the classical nucleophilic substitution reaction, worked best
due to the relative stability of their radicals (3ae–3qe) (entries
5–11). It should be noted that Meyer nitrile 2e 20 was used
instead of Hantzsch esters due to the difficulty in their syn-
thesis. Furthermore, the reaction of the piperidine-derived
Hantzsch ester went smoothly to give product 3df in 65% yield
(entry 12).
Results and discussion
Initially, the reaction of 1-bromo-2-phenylacetylene (1a) with
4-cyclohexyl Hantzsch ester (2a) was investigated under photo-
catalysis (Table 1). We were encouraged to find that the
desired cyclohexyl alkyne (3aa) was obtained in 19% yield
when the reaction was carried out with 2 mol% of 4CzIPN
(2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile) as the photo-
catalyst in dichloromethane at room temperature for 12 h
under the irradiation of blue LEDs (entry 1). The yield was
increased to 66% when the reaction time was prolonged to
36 h (entry 2). The addition of a silver salt showed no apparent
improvement (entry 3). Screening of solvents and bases
revealed that 1,2-dichloroethane is the best choice (entries
Table 1 Optimization of the alkynylation reactiona
Entry
1
PC
Base
Solvent
Yieldb (%)
1c
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a′
1a″
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
fac-Ir(ppy)3
Ru(ppy)3Cl2
Mes-Acr-Me
4CzIPN
4CzIPN
4CzIPN
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
NaOAc
t-BuOK
DBU
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
CH2Cl2
CH2Cl2
CH2Cl2
DMF
DMSO
MeCN
Acetone
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
19
66
67
Trace
45
55
57
70
60
51
NR
22
71
76
3d
4
The scale-up reaction using 1.05 g (5 mmol) of alkynyl
bromide 1e gave product 3ea in 78% yield (Scheme 2).
5
6
7
8
The photocatalytic alkynyl–alkyl coupling reaction is
believed to proceed via a radical intermediate.21 Control
experiments revealed that the reaction was completely sup-
pressed with no desired product detected when TEMPO
(2,2,6,6-tetramethyl-1-oxylpiperdine) was added as the radical-
trapping reagent (Scheme 3).
The plausible mechanism for the reaction is shown in
Fig. 1. The readily available photocatalyst 4CzIPN is
irradiated under blue LEDs to the photoexcited state
9
10
11
12
13
14
15
16e
17e
18e
3
83(75)f
(45)f
(21)f
(4CzIPN*), which features
a
high redox potential
ðPC* =PC•ꢀÞ
ðE1=2
¼ þ1:43 vs: SCEÞ 22 (PC = 4CzIPN) to promote the
a Unless otherwise specified, 1a (0.2 mmol), 2a (0.3 mmol), photo-
catalyst (2 mol%), base (0.6 mmol), solvent (4 mL, [0.5 M]), rt. b Yields
determined by 1H NMR (400 MHz) spectroscopy with CH2Br2 as the
internal standard. c The reaction was terminated after 12 h. d AgNO3
(0.2 mmol) was added as an additive. e 2a (0.4 mmol) was used.
f Isolated yields in parentheses. DCE = 1,2-dichloroethane, 4CzIPN =
2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile, ppy = 2-phenylpyridine,
Mes-Acr-Me = 10-methyl-9-mesitylacridinium.
photooxidative reaction. The substituted Hantzsch esters
(E
= +1.08 V vs. SCE)17a were cleaved by the oxidation of
red
1=2
photoexcited 4CzIPN* to generate the alkyl radical I and
radical anion II. The addition of alkyl radical I to arylethynyl-
bromide affords the bromoalkenyl radical III,23 which is
collapsed to give alkylalkyne 3 and a bromine radical.24 The
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Table 2 Scope of alkynyl bromides
Table 3 Scope of 4-alkyl Hantzsch esters
Entry
1
1
2
3
Yield (%)
92
Entry
1
3
Yield (%)
1d
1
2
3
4
5
6
7
8
1a (X = H)
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
75
87
77
84
85
64
76
55
69
81
74
93
70
79
1b (X = 2-Me)
1c (X = 3-Me)
1d (X = 4-Me)
1e (X = 4-MeO)
1f (X = 4-t-Bu)
1g (X = 2-F)
1h (X = 3-F)
1i (X = 4-F
1j (X = 2-Cl)
1k (X = 4-Cl)
1l (X = 4-Br)
1m (X = 4-CF3)
2
3
4
1d
1k
1l
2c
2c
3dc
3kc
89
72
91
9
10
11
12
13
14
3ja
3ka
3la
3ma
5
6
7
8
9
10
11
1a
1e
1l
1m
1n
1r
2e
2e
2e
2e
2e
2e
2e
3ae (X = H)
3ee (X = MeO)
3le (X = Br)
3me (X = CF3)
3ne (X = Ph)
3re (X = CO2Me)
91
89
91
63
89
99
51
15
16
53
62
1q
12
1d
65
17
18
45
66
19
56
Scheme 2 Gram-scale experiment.
Scheme 3 Radical-trapping reaction.
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and 4 mL of DCE were injected. Then the solvent was degassed
3 times. The reaction mixture was stirred for 36 h at room temp-
erature and irradiated by 24 W blue LEDs. After the completion
of the reaction, the mixture was diluted with H2O and extracted
with DCM 3 times. The combined organic layers were washed
with brine, dried over Na2SO4, filtered and evaporated under
reduced pressure. The residue was purified by chromatography
on silica gel to give the desired coupling product 3.
Radical-trapping experiment
To a solution of alkynyl bromides 1e (42 mg, 0.2 mmol) in a
10 mL reaction tube were added Hanzsch ester 2a (134 mg,
0.4 mmol, 2.0 equiv.), 4CzIPN (3.15 mg, 0.004 mmol, 2 mol%),
TEMPO (2,2,6,6-tetramethyl-1-oxylpiperidine, 62.5 mg, 0.4 mmol,
2.0 equiv.) and K3PO4 (127 mg, 0.6 mmol, 3.0 equiv.) under a
nitrogen atmosphere at room temperature. The tube was
sealed and 4 mL of DCE was injected. Then the solvent was
degassed 3 times. The reaction mixture was stirred for 36 h at
room temperature and irradiated by 24 W blue LEDs. No
desired product was observed by TLC.
Fig. 1 Plausible reaction mechanism.
reduction of the bromine radical by radical anion species II
ðPC•ꢀ=PCÞ
25
ðE1=2
¼ ꢀ1:21 vs: SCEÞ
regenerates the photocatalyst
and furnishes the catalytic cycle.
Conclusions
Conflicts of interest
In summary, the photocatalytic synthesis of internal alkynes
via C(sp3)–C(sp) bond coupling of bromoalkynes and Hantzsch
esters was developed. All the primary, secondary and tertiary
alkyl radicals generated from the Hantzsch ester derivatives
worked well for the reaction. The reaction features good toler-
ance of many functional groups, including esters and ketones,
under metal-free conditions.
There are no conflicts of interest to declare.
Acknowledgements
Financial support from the National Natural Science
Foundation of China (no.: 21425207, 21521002, 21672216) is
gratefully acknowledged.
Experimental
Notes and references
Unless otherwise indicated, all reactions were carried out
with N2 protection with magnetic stirring. Anhydrous CH2Cl2
was distilled from CaH2. Column chromatography was per-
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