Transition-Metal-Free Coupling of Alkynes with α-Bromo Carbonyl Compounds: An Efficient Approach towards β,γ-Alkynoates and Allenoates

Article abstract of DOI:10.1002/chem.201600219

A direct transition-metal-free coupling between alkynes and α-bromo carbonyl compounds has been developed with ultraviolet (UV) light in aqueous media. This method represents a facile approach to synthetically useful β,γ-alkynyl esters and amides stereoselectively from two readily available starting materials. As an example of the synthetic application of the products, the alkynyl esters were readily converted into allenoates. Time for UV! A direct coupling between alkynes and α-bromo compounds has been developed with ultraviolet light in aqueous media (see scheme). This method represents a facile approach to synthetically useful β,γ-alkynyl esters and amides stereoselectively from two readily available starting materials.

Full text of DOI:10.1002/chem.201600219

DOI: 10.1002/chem.201600219
Communication
&
Photocatalysis
Transition-Metal-Free Coupling of Alkynes with a-Bromo Carbonyl
Compounds: An Efficient Approach towards b,g-Alkynoates and
Allenoates
Wenbo Liu, Zhengwang Chen, Lu Li, Haining Wang, and Chao-Jun Li*[a]
egy that can directly employ the commercially available com-
Abstract: A direct transition-metal-free coupling between
alkynes and a-bromo carbonyl compounds has been de-
veloped with ultraviolet (UV) light in aqueous media. This
method represents a facile approach to synthetically
useful b,g-alkynyl esters and amides stereoselectively from
two readily available starting materials. As an example of
the synthetic application of the products, the alkynyl
esters were readily converted into allenoates.
pounds, such as alkynes and a-halo carbonyl compounds,
would be more economical, convenient, and ideal.
Recently, we reported a light-promoted transition-metal-free
coupling reaction between aryl alkynes and non-activated alkyl
iodides in water.[8] Although the protocol[8a] allows several ad-
vantages over other methods, such as photo-driven, transition-
metal-free, and water as the only solvent, there are few key
limitations: A) only alkyl iodides can be successfully coupled,
whereas more common and cheaper alkyl bromides and alkyl
chlorides are not applicable; B) large amounts of alkyl iodides
(10 equiv) are required to ensure decent yields.[9] To overcome
a-Functionalization of carbonyl and carbonyl-like
groups (such as nitriles, sulfonates, phosphates, and
so forth) is crucial in organic synthesis.[1] Although
significant progresses have been made on the a-
functionalization of carbonyl groups with both
C(sp3)[2] and C(sp2)[3] coupling partners, scarce reports
are available for the C(sp) ones, presumably due to
the facile formation of diynes under traditional Sono-
gashira coupling conditions.[4] To our knowledge,
only three approaches to achieve such a transforma-
tion exist in the literature (Scheme 1): A) the coupling
of alkynylmetallic species (alkynylstannanes and alky-
nyltrifluoroborates) with a-halo carbonyl compounds
through the Pd-catalyzed Stille and Suzuki reac-
tions;[5] B) the reaction of gallium or indium acety-
lides with a-halo carbonyl compounds through
a tandem radical addition-fragmentation process;[6]
C) the Cu-catalyzed reaction between alkynes and di-
azocarbonyl compounds via a carbenoid intermedi-
ate.[7] However, besides the metal acetylides need to
be presynthesized in the first two approaches, han-
dling diazocarbonyl compounds in approach
C
(which also need to be presynthesized) is also opera-
tionally complicated. In addition, the usage of both
stoichiometric alkynylmetallic species and the diazo-
carbonyl compounds would increase cost and waste,
as well as impair the practicality. An alternative strat-
Scheme 1. Coupling a-carbon with another Csp center: Comparison between previous
strategies and the strategy reported herein.
these limitations, we hypothesized that the inapplicability of
the alkyl bromides and chlorides were likely due to their low
photo-reactivity, and the requirement of a large access of alkyl
iodides may be due to competing reactions resulting from
iodine radicals. We envisioned that the less reactive bromide
could become reactive by converting the bromides into io-
dides in the presence of iodide-based catalyst[10] in situ, and
the required large amount of alkyl iodides could be greatly re-
[a] W. Liu, Dr. Z. Chen, Dr. L. Li, Dr. H. Wang, Prof. Dr. C.-J. Li
Department of Chemistry and FQRNT Center
for Green Chemistry and Catalysis, McGill University
801 Sherbrooke Street West, Montreal, QC H3A 0B8 (Canada)
E-mail: cj.li@mcgill.ca
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600219.
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duced in presence of a mild reducing agent (e.g., Na2S2O3).
Herein, we report a novel direct coupling of alkynes with a-
bromo compounds, enabled by light in aqueous media,[11] to
produce highly synthetically useful b,g-alkynyl esters/amides/
thioesters, which can be further transformed into allenoates
(Scheme 1d).
butoxycarbonyl; Fmoc=fluorenylmethyloxycarbonyl) can be
tolerated well. Such broad functional group compatibility pro-
vides tremendous opportunities to further functionalize the
coupling products that will be valuable to synthesize more
complex compounds. Electron-donating (3e) and -withdrawing
groups (3g, 3h) can both deliver the coupling products in
good yields (60–69%). Mono- (3b, 3d), di- (3k), and trisubsti-
tuted (3j) aryl alkynes (including at ortho, meta, and para posi-
tions) all give the products smoothly (52–75%). Apart from the
aryl (heteroaryl) alkynes (3a, 3c), we gratefully found that trii-
sopropylsilyl (TIPS) acetylene (3i) can also be coupled in these
conditions in good yield (67%). Since TIPS can be readily de-
protected, further diversification of 3i using Sonogashira cou-
pling[13] and click chemistry[14] is thus feasible. Unfortunately,
neither the aliphatic alkyne (3v) nor the alkyne connected
with an electron-withdrawing group (3w) worked under our
present conditions (see the Supporting Information), which
may provide the opportunity to selectively functionalize the
aryl alkynes among aliphatic alkynes.
Initially, we selected phenylacetylene (1a) and (+/-)-methyl
2-bromobutanoate (2a)[12] as starting materials for our model
studies. Control experiments suggested that IÀ source, UV
light, and additive to trap the iodine radical were all indispen-
sable for the generation of the desired coupling product
(Table 1). After further extensively screening the reaction condi-
Table 1. Impact of different factors on the model reaction.[a]
Besides the scope of various alkynes, we also investigated
the scope of a-bromo carbonyl compounds (Scheme 3).
Beyond the regular a-bromo esters, including aliphatic (4b,
4n, 4p) and phenyl (4l) esters, which could deliver the cou-
pling products in good yields (70–75%), the lactone (4g) could
also form the product albeit with a lower yield (41%). Com-
pared to the secondary a-bromo carbonyl compounds, the
sterically encumbered tertiary a-bromo carbonyl compound
(4 f) is less effective, affording only 17% yield. Under our cur-
rent conditions, the primary a-bromo ester did not give any
coupling products (4r), which is complementary to previously
reported chemistry.[6b,c,7a] Besides the esters, we also tested the
scope of amides. Various amides, including the aryl (4a, 4c,
4e), primary aliphatic (4d, 4j, 4k), and secondary aliphatic
amides (4h, 4m), could be employed in our conditions, result-
ing in the products with modest to good yields (40–76%). To
our delight, when a propargyl alcohol was introduced into the
substrate (4p), the desired coupling product could still be iso-
lated in 75% yield, which confirmed the selective functionaliza-
tion between aryl alkynes and aliphatic alkynes. However,
when diallyamine amide (4i) was employed as the substrate,
less than 10% coupling product could be detected, probably
due to the facile radical intramolecular cyclization. In addition
to the esters and amides, we also examined the synthetically
valuable thioester[15] (4s), which gave the product in a 45%
yield. Inspired by the previous examples of stereoselectively
radical addition,[16] we also investigated the stereochemistry of
this coupling by using a chiral a-bromo ester (4n) and amide
(4o). When the (À)-menthol ester (4n) was used, a good dia-
stereoselectivity (d.r.=11:1) was obtained. As expected, a com-
paratively low d.r. (1.3:1) was detected when the chiral l-pro-
line methyl ester was installed (4o). In addition to a-bromo
carbonyl compounds, when the a-bromo sulfone substrate
(4q) was subjected to the conditions without any modification,
the desired coupling product could be obtained in a 60%
yield. This example highlights the potential of our current
method to other a-bromo compounds, such as sulfone, sulfox-
ide, phosphate, and nitriles.
Entry
Variation from standard conditions
Yield [%][b]
1
2
3
4
5
6
7
8
9
No change
No TBAI
TBAF instead of TBAI
NaI instead of TBAI
No hn
No Na2S2O3
No Na2CO3
In air
83 (78)[c]
0
0
30
0
0
55
45
0
O2
[a] All reactions were carried out with 1a (0.1 mmol), 2a (0.3 mmol), TBAI
(0.05 mmol), Na2CO3 (0.05 mmol), Na2S2O3 (0.3 mmol), PhCF3 (1.0 mL), H2O
(0.4 mL), and argon at 658C in a quartz tube. [b] 1H NMR yields by using
mesitylene as the internal standard. [c] Isolated yield. TBAI=tetrabutylam-
monium iodide; TBAF=tetrabutylammonium fluoride.
tions, including IÀ source (entries 2–4), the UV (entry 5), addi-
tives (entry 6), base (entry 7), atmosphere (entries 8 and 9), sol-
vents (see the Supporting Information), and the ratio of two
starting materials (see SI), we reached the optimized condi-
tions, referred as “standard conditions” (entry 1), to obtain
a 78% yield of the product (for full screening lists, see the Sup-
porting Information).
With the optimized conditions obtained, we examined the
scope of various alkynes (Scheme 2). Since our reaction condi-
tions are mild (658C, slightly basic solution, transition-metal
free), aryl alkynes with various functional groups, including
benzyl group (3b, 3d, 3j), heteroatom (3c), alcohol (OH; 3d),
phenyl ether (OMe; 3e), CF3 (3g), F (3h), Cl (3k), CN (3l), ester
(3n), and boronic ester groups (3s), can be tolerated very well.
However, the OH (phenol; 3 f), NH2 (3q), NMe2 (3r), aldehyde
(3u), and NO2 (3t) groups attached to the aryl rings (see the
Supporting Information) are not compatible with our current
conditions, probably due to their interference with UV irradia-
tion. Gratifyingly, the protected phenol (OMe; 3e) and aniline
(base-stable NHBoc 3o and acid-stable NHFmoc 3p; Boc=tert-
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Scheme 2. Scope of alkynes. [a] All reactions were carried out with 1a (0.1 mmol), 2a (0.3 mmol), TBAI (0.05 mmol), Na2CO3 (0.05 mmol), Na2S2O3 (0.3 mmol),
PhCF3 (1.0 mL), H2O (0.4 mL), and argon at 658C in a quartz tube; all the yields are referred to isolated ones unless otherwise indicated; TBAI=tetrabutylam-
monium iodide. [b] Reaction conditions for 3m: alkyne (0.1 mmol), 2a (0.6 mmol), TBAI (0.1 mmol), Na2S2O3 (0.6 mmol), PhCF3 (1.0 mL), and H2O (0.4 mL).
CÀC triple bonds and carbonyl groups, the two important
functional groups in our coupling products, are very useful
synthetic intermediates in organic synthesis. For example,
triple bonds can undergo reduction to alkenes or alkanes in
different conditions, whereas esters or amides could be re-
duced to aldehydes and alcohols, or amines, respectively, de-
pending on the reducing reagents. Remarkably, these alky-
noate coupling compounds could isomerize to allenoates
under mild conditions with high efficiency.
scribe herein that the alkynoates could isomerize into the alle-
noates very efficiently under mild conditions. Most of the alky-
noates (Scheme 2 and Scheme 3) obtained under the standard
conditions, when subjected to NEt3, could isomerize into alle-
noates with excellent yields (yields in Scheme 4 refer to the
overall yields from alkynes). Functional groups, such as unpro-
tected alcohol, CF3, F, ester, NHBoc, CN, Cl, and pyridine, can all
be tolerated, allowing for a rapid assembly of more complex
natural products through the resultant allenoates. By employ-
ing a chiral guanidine base, Tan and coworkers[17g] synthesized
1,3-disubstituted allenoates from racemic 3-alkynoates with
high enantioselectivity. Although Tan’s method suffers from
the scope limitation (only applicable to 1,3-disubstituted alle-
Allene, a type of versatile synthetic intermediate, has attract-
ed considerable attention recently.[17] Novel methods to syn-
thesize allenes from readily available starting materials are
always desirable. To illustrate the utility of our method, we de-
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Scheme 3. Scope of a-bromo compounds. [a] All the reactions were carried out with 1a (0.1 mmol), 2a (0.3 mmol), TBAI (0.05 mmol), Na2CO3 (0.05 mmol),
Na2S2O3 (0.3 mmol), PhCF3 (1.0 mL), H2O (0.4 mL), and argon at 658C in a quartz tube; the yields are referred to isolated ones unless otherwise indicated;
d.r.=diastereoisomer ratio. [b] 1H NMR yields by using mesitylene as the internal standard. [c] GC yields by using diphenylacetylene as the internal standard.
1
[d] The d.r. value was determined by H NMR analysis of the crude mixture. [e] The d.r. value was determined by 1H NMR and GC analysis.
noates), his work demonstrates that it is possible to get enan-
tioenriched allenoates from racemic alkynoates with a catalytic
amount of chiral base.
medium without using any transition metal. As a demonstra-
tion of the synthetic application of the products, the alky-
noates isomerized to allenoates efficiently under mild condi-
tions. Investigations on the stereochemistry of this coupling re-
action and expansion of the scope to other a-bromo com-
pounds are currently undergoing in our laboratory.
In summary, we have described a novel method to synthe-
size alkynoates by directly coupling alkynes with a-bromo car-
bonyl compounds. This reaction is driven by light in aqueous
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Keywords: allenoates · green chemistry · photochemistry ·
synthetic methods · water
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(0.1 mmol), 2a (0.3 mmol), TBAI (0.05 mmol), Na2CO3 (0.05 mmol), Na2S2O3
(0.3 mmol), PhCF3 (1.0 mL), H2O (0.4 mL), and argon at 658C; step 2: NEt3
(0.2 mmol), DCM (5 mL) at 658C. The yields are isolated ones based on the
alkynes of two steps unless otherwise indicated.
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Experimental Section
To a quartz tube (10 mL) were added Na2CO3 (5 mg, 0.05 mmol,
0.5 equiv), TBAI (19 mg, 0.05 mmol, 0.5 equiv), and Na2S2O3·5H2O
(75 mg, 0.03 mmol, 3 equiv). Next, PhCF3 (1 mL) and H2O (0.4 mL)
were introduced to the tube. After stirring for 5 min at room tem-
perature, a two-phase clear colorless mixture was obtained. The air
in the quartz tube was replaced with argon by using the frozen-
thaw cycle for three times. Then, phenylacetylene (11 mL, 1 equiv,
0.1 mmol) and (+/-)methyl 2-bromobutanoate (35 mL, 3 equiv,
0.3 mmol) were added through the rubber septum successively.
The quartz tube was put in the apparatus as shown in Figure S1
(right) in the Supporting Information. After irradiating the tube for
2.5 h, the reaction was terminated and water (2 mL) was added
into the mixture. The organic compounds were extracted by CHCl3
(3”2 mL). The combined organic layer was dried by anhydrous
Na2SO4, and the organic solvent was removed on a rotavap. The
residue was purified by flash column chromatography on silica gel
to get the desired coupling product 3a as a yellow oil (16 mg,
78% yield).
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We are grateful to the Canada Research Chair (Tier 1) founda-
tion, FQRNT (CCVC), CFI, and NSERC for their support for our
research.
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Received: January 16, 2016
Published online on March 15, 2016
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