AuIII-Catalyzed Formation of α-Halomethyl Ketones from Terminal Alkynes

Article abstract of DOI:10.1002/ejoc.201601416

A Au^III-catalyzed synthesis of α-halomethyl ketones from terminal alkynes was developed. This approach features excellent functional group compatibility and good yields for both aromatic and aliphatic terminal alkynes. The resulting α-halomethyl ketones were used to prepare heterocyclic indolizine structures. The plausible mechanism of the one-pot reaction is proposed.

Full text of DOI:10.1002/ejoc.201601416

A Journal of
Accepted Article
Title: Au (III)-Catalyzed Formation of α-Halomethyl Ketones from
Terminal Alkynes
Authors: Yalan Xing, Ming Zhang, Sarah Ciccarelli, John Lee, and
Bryant Catano
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601416
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601416
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European Journal of Organic Chemistry
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Au (III)-Catalyzed Formation of -Halomethyl Ketones from
Terminal Alkynes
Yalan Xing,a,* Ming Zhang,a Sarah Ciccarelli,a John Leea and Bryant Catanoa
Abstract: Au (III)-catalyzed synthesis of -halomethyl ketones from
terminal alkynes was developed. This approach features excellent
functional group compatibility and good yield for both aromatic and
aliphatic terminal alkynes. The resulting -halomethyl ketones were
used to prepare heterocyclic indolizine structures. The plausible
mechanism of the one-pot reaction was proposed.
α-Halogenated ketones are versatile intermediates in
organic synthesis due to their high reactivity for many SN2,
carbonyl, and Reformatsky reactions.3 Methyl ketones are
commonly used as starting materials to synthesize α-
Halogenated ketones.4 Despite the success achieved in the
preparation of α-halogenated ketone compounds, there
remained some challenges, such as nonregiospecific
halogenation and over-halogenation.5
We are interested in the preparation of substituted
carbonyl compounds from alkyne starting materials because the
alkyne functional group is relatively stable and easy to install.
Alkynes are used as carbonyl surrogates in total syntheses of
complex molecules to provide greater flexibility in synthetic
planning.6 In 2015, we reported an efficient synthesis of α,α-
dibromoketones from alkynes catalyzed by iron (III) chloride
(Scheme 1).7 As part of our effort to continue developing
transition metal-catalyzed reactions to prepare functionalized
ketones from alkynes, we explored the alkyne hydration reaction
to investigate selective synthesis of α-monohalogenated ketones
directly from alkyne starting materials.
Previously, hydration reactions of haloalkynes to generate
α-halomethyl ketones catalyzed by Au (I), Ag (I), and Cu (II)
were reported in literature (Scheme 1).8 These methods was
limited by the need to convert alkynes into haloalkynes before
being subjected to the hydration reaction. The Zhang group, on
the other hand, found that α-chloromethyl ketones and α-
bromomethyl ketones can be generated directly from terminal
alkynes catalyzed by a gold complex (Scheme 1).9 However,
stoichiometric amounts of the strong external oxidant, quinoline
N-oxide, were needed, and halogenated solvents were required
Introduction
Alkynes are readily available and useful building blocks for
organic synthesis because triple bonds can be functionalized
into a myriad of structures.1 The alkyne hydration reaction, when
alkynes are transformed into ketones, is a well-documented
reaction. It is also an excellent example of an atom-economical
and environmentally benign synthetic tool, because it affords
carbonyl compounds from alkynes without using redox
chemistry.2 However, direct conversion of alkynes into α-
functionalized ketones such as α-halogenated ketones in a
regioselective manner is much less explored and still
challenge.
a
as the halogen source.
In addition, Sheppard reported two
examples of direct conversion of terminal aromatic alkynes to α-
iodomethyl ketones catalyzed of Au (I) catalyst, but no systemic
investigation on substrate scopes and limitations was carried on
in their study.10 Herein, we report our one-pot synthesis of α-
halomethyl ketones directly from terminal alkynes, in the
presence of Au (III) catalyst under mild conditions, in good to
excellent yields.
Results and Discussion
Phenylacetylene 1 was chosen as the model substrate for
Scheme 1. Previous Work
catalyst screening. Since iron was known to promote alkyne
hydration reactions,11
5 mol% iron (III) salts FeCl3 and
FeCl3/AgNTf2 were used as the catalysts, and water was used
as the nucleophile in various solvents such as 1,4-dioxane,
dichloromethane, and acetonitrile (entry 1-4, Table 1).
Unfortunately, when NBS was added to the reaction mixture
after two hours of stirring the alkyne and nucleophile in the
presence of catalyst, no desired product was observed. Instead,
α,α-dibromoketone 3 was the major product isolated from these
reactions. We reasoned that iron (III) catalyst was not effective
for the alkyne hydration. Therefore, we turned our attention to
[a]
Y.Xing, M, Zhang, S. Ciccarelli, J. Lee and B. Catano
Department of Chemistry
William Paterson University of New Jersey
300 Pompton Rd, Wayne, NJ, 07470
E-mail: xingy@wpunj.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201601416
European Journal of Organic Chemistry
COMMUNICATION
gold catalysts due to their high catalytic efficiency in alkyne
hydration reactions.12 To our delight, 5 mol% AuCl3 in 1,4-
dioxane in the presence of H2O gave 25% of the desired α-
bromomethyl ketone product 2 and 35% of the hydration product
methyl ketone 5 (entry 5, table 1). When methanol was used as
the nucleophile,13 α-bromomethyl ketone was obtained in
excellent yield as the single product catalyzed by both AuCl3
(90%) and AuCl3/AgNTf2 (1:3)14 (92%) in 1, 4-dioxane (entries 7
and 8, Table 1). In addition, we did not observe any desired
product formation when AgNTf2 was used alone as the catalyst
(entry 6, Table 1). To our delight, when the catalyst loading of
AuCl3/AgNTf2 (1:3) pre-catalyst was decreased to 1 mol%
(AuCl3), the reaction underwent smoothly and gave good yield
(91%) (entry 10).
and obtained 80% yield. However, when silyl ethers such as
TBS, TBDPS, and TIPS ethers were present in the substrates,
the reaction did not proceed, and the starting materials
decomposed. Also, internal alkynes did not produce the desired
products under the optimal conditions (2v and 2w).
Table 1. Optimization of Reaction Conditions
Scheme 2. Au (III)-Catalyzed Formation of a-Halomethyl ketone from Terminal
Alkynes.
12p, 13
Based on our results and relevant literature,
we
proposed a plausible mechanism for this one-pot reaction
(Scheme 3). The alkyne is first hydrolyzed to the methyl ketone
by the Au (III) catalyst in the presence of methanol, and then the
resulting methyl ketone is converted to the α-bromomethyl
ketone upon the addition of NBS. A highly regioselective
bromination of methyl ketones usually requires catalysts such as
p-TsOH,5a NH4OAc,5b or other conditions.5c-e Our hypothesis,
however, is that this bromination is expedited by the presence of
the Au (III) catalyst, probably due to the Lewis acidity of AuCl3.
With the optimal conditions in hand (entry 9, Table 1), we
began our investigation of the substrate scope and limitations of
this reaction. As shown in Scheme 2, aromatic terminal alkynes
with electron-withdrawing and electron-donating groups on the
phenyl ring all delivered the desired product smoothly with
moderate to excellent yields. The heteroaromatic alkyne 2k also
underwent this reaction and generated the α-bromomethyl
ketone in excellent yield (87%). In addition, aliphatic alkynes
participated in this alkyne functionalization reaction and provided
the product in good yield and excellent regioselectively. In
general, aromatic alkynes provided better yields than aliphatic
alkynes. It is worth mentioning that in addition to NBS, NCS and
NIS can also be used as halogen sources to provide α-
chloromethyl ketones and α-iodomethyl ketones in good yields
(2n – 2u). Furthermore, many different functional groups can be
tolerated in these reaction conditions, such as esters, ethers,
and amides. To proof the robustness of this reaction, we
performed the reaction for the synthesis of 2a on a 1.5 g scale
Scheme 3. Proposed Reaction Mechanism.
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To elucidate the mechanism, we conducted three Conclusions
controlled experiments (Scheme 4). First, phenylacetylene 1
was treated with the standard condition without the additions of
NBS. The alkyne hydration product methyl ketone 5 was
generated as the single product with 99% GC conversion within
30 minutes, as confirmed by GC-MS and NMR. Then, we
treated methyl ketone 5 with NBS in the presence of the Au (III)
catalyst and methanol. The α-bromomethyl ketone was found to
be the single product in 99% GC conversion within 1 hour. Next,
we repeated our second controlled experiment without the gold
catalyst. The α-bromomethyl ketone was observed as the single
product with only 25% GC conversion for an extended reaction
time. These experiments confirmed the importance of the Au (III)
catalyst in both alkyne hydration and bromination.
In conclusion, we have developed an efficient and
convenient method for the synthesis of α-halomethyl ketones
from terminal alkynes using a Au (III) catalyst. This method
efficiently combines the alkyne hydration and methyl ketone
bromination, and allows for the expedient access of halogenated
ketones from alkyne starting materials in good yields. α-
Halomethyl ketones were generated in a highly regioselective
manner and with high functional group compatibility. Further
study of the synthetic applications of alkyne functionalization
reactions are underway in our research group.
Experimental Section
General procedure for product 2: To a 1 mL 1, 4-dioxane solution of
AuCl3 (0.002 mmol), AgNTf2 (0.006 mmol) was added at rt. The solution
was stirred for 30 min. Alkyne 1 (0.2 mmol) and methanol (0.3 mL) were
added to the solution. The reaction solution was stirred for 1 - 5 hr at 45
oC with TLC monitoring. When TLC showed full consumption of the
staring materials, NBS (0.2 mmol) was added. The reaction mixture
stirred for another 5 - 12 hr, and saturated NaCl solution was then added
to the reaction. The organic layer was extracted with EtOAc, dried with
Na2SO4, and filtered. The solvent was removed under reduced pressure,
and the residue was purified by flash column chromatography on silica
gel to give pure product.
Scheme 4. Controlled Experiments.
The products of this alkyne functionalization reaction, α-
halomethyl ketones, are useful synthetic intermediates for the
preparation of many heterocyclic structures.15 As shown in
Scheme 5, α-bromoketone 2a, 2e, and 2b underwent the
reported three-component reaction to generate indolizines 7a,
7e, and 7b in 82%, 78%, and 80% yield, respectively.16
Indolizines are important heterocyclic compounds which show a
variety of biological activities such as antibacterial, phosphatase
and aromatase inhibition, antioxidant, antidepressant, and
antitumor activity.16
Acknowledgements
This research was supported (in part) by a grant from the Center
for Research, College of Science and Health, William Paterson
University of New Jersey
Keywords: alkynes • hydration • Au (III) • -Halomethyl Ketones
• one-pot
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Key Topic*
Yalan Xing, * Ming Zhang, Sarah
Ciccarelli, John Lee and Bryant Catano
Page No. – Page No.
Au (III)-Catalyzed Formation of -
Halomethyl Ketones from Terminal
Alkynes
Text for Table of Contents



From alkynes to a-monohalogenated ketones
High yield, good functional group compatibility
High regioselectivity
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