Silver/NBS-Catalyzed Synthesis of α-Alkylated Aryl Ketones from Internal Alkynes and Benzyl Alcohols via Ether Intermediates

Article abstract of DOI:10.1021/acs.orglett.8b02252

The silver hexafluoroantimonate/N-bromosuccinimide (NBS)-catalyzed synthesis of α-alkylated aryl ketones with a tertiary carbon center from internal alkynes and benzyl alcohols is reported. This reaction proceeds via the etherification of benzyl alcohols with an in situ generated benzyl bromide, formed by the reaction of benzyl alcohol with a catalytic amount of NBS and AgSbF₆. Ag-catalyzed C-O cleavage of the ether leads to a tolyl radical, which undergoes addition to the alkyne, ultimately leading to the α-alkylated aryl ketone products.

Full text of DOI:10.1021/acs.orglett.8b02252

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Silver/NBS-Catalyzed Synthesis of α‑Alkylated Aryl Ketones from
Internal Alkynes and Benzyl Alcohols via Ether Intermediates
Supill Chun and Young Keun Chung*
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Korea
S
* Supporting Information
ABSTRACT: The silver hexafluoroantimonate/N-bromosuccinimide (NBS)-catalyzed synthesis of α-alkylated aryl ketones
with a tertiary carbon center from internal alkynes and benzyl alcohols is reported. This reaction proceeds via the etherification
of benzyl alcohols with an in situ generated benzyl bromide, formed by the reaction of benzyl alcohol with a catalytic amount of
NBS and AgSbF6. Ag-catalyzed C−O cleavage of the ether leads to a tolyl radical, which undergoes addition to the alkyne,
ultimately leading to the α-alkylated aryl ketone products.
α-Alkylated aryl ketones are a very important class of
compounds that have a wide range of pharmacological and
physiological activities.1 Their activities have attracted much
research interest in the synthesis of α-alkylated aryl ketones in
many groups. Although many methodologies have been
developed, there is still interest in exploring new reaction
systems.2 α-Alkylated aryl ketones are synthesized via α-
alkylation of nucleophilic enolates derived from ketones with
electrophilic alkylating agents in the presence of at least a
stoichiometric amount of a strong base (Scheme 1a).3
However, these procedures suffer from toxicity of the
alkylating agents and the generation of a large amount of
harmful waste salts. Thus, the α-alkylation of ketones with
alcohols (Scheme 1b) has attracted much attention4 because
alcohols can be used as an alkylating agent in the reaction with
α-functionalized carbonyl compounds via a hydrogen-borrow-
ing process5 in the presence of transition-metal catalysts.6
Recently, the α-alkylation of methylene ketones with alcohol
electrophiles has been also studied to prepare α-alkylated aryl
ketones.7 Several years ago, a strategy for the synthesis of α-
alkylated ketones via a catalytic hydration of terminal alkynes
and α-alkylation with primary alcohols was reported (Scheme
1c).8 However, no reaction occurred with internal alkynes such
as 5-decyne or diphenylacetylene.9 The use of in situ generated
α-substituted ketones from internal alkynes to form α-
branched alkylation products is less developed. Aryl ketones
may be synthesized by alkyne hydration;10 however, reactions
of internal alkynes often lead to a mixture of ketone
regioisomers.11 Thus, the regioselective functionalization of
unsymmetrically substituted alkynes is of fundamental
importance in organic synthesis.12 The coupling of internal
alkynes with aldehydes to afford α,β-unsaturated ketones has
been studied (Scheme 1d).13 However, in order to obtain α-
alkylated aryl ketones, they must be hydrogenated. Therefore, a
new synthetic strategy with a conceptually different reaction
pathway is required. We envisioned that the α-alkylation of
internal alkynes with alcohols could be a highly desirable
strategy for the synthesis of α-alkylated aryl ketones (Scheme
1e) if an alkylating agent could be catalytically generated from
primary alcohols and were regioselectively added to internal
alkynes.
Scheme 1. Various Synthesis Strategies for α-Alkylated Aryl
Ketone
Received: July 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02252
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Very recently, AgSbF6/NBS was found to be an excellent
catalytic system for the synthesis of α-alkylated aryl ketones
bearing a tertiary carbon center from internal alkynes and
benzyl alcohols. The reaction is regioselective and applicable to
a variety of internal alkynes and benzyl alcohols. A dibenzyl
ether was generated in situ as a key intermediate, and a radical
pathway, quite different from those proposed by previous
studies,8,13 was proposed. The present protocol provides a
green, concise, and benign method to access α-alkylated aryl
ketones. We communicate our preliminary results herein.
Organic halogenation compounds such as N-bromosuccini-
mide (NBS, 50%, entry 1), N-chlorosuccinimide (NCS, 46%,
entry 2), and N-iodosuccinimide (NIS, 50%, entry 3) were
screened as the catalyst (Table 1). As expected, without NBS
Scheme 2. Synthesis of α-Alkylated Aryl Ketones Using
Methyl Aryl Acetylenes with Various Alcohols
a
Table 1. Optimization of the Reaction Conditions for
Synthesis of α-Alkylated Aryl Ketone
a
cat. A (mol
%)
cat. B
(mol %)
yield
(%)
a
30 mol % of AgSbF6 was used unless otherwise noted, and all
products were isolated by column chromatography. 10 mol % of
AgSbF6 was used, and 1 mL of THF was used as solvent.
entry
solvent (1 mL)
b
1
2
3
4
5
6
NBS (20)
NIS (20)
NCS (20)
AgSbF6 (20) dioxane
AgSbF6 (20) dioxane
AgSbF6 (20) dioxane
AgSbF6 (20) dioxane
dioxane
AgNTf2(20) dioxane
AgSbF6 (30) dioxane
AgSbF6 (30) dioxane
AgSbF6 (30) THF
50
46
50
NR
NR
36
57
67
60
72
dependent on the identity of the halogen. The highest yield
(3a, 75%) was observed with a fluoro group and the lowest
(3d, 53%) with an iodo group. Interestingly, in the reaction
with 4-alkyl benzyl alcohols, the yields were rather insensitive
to the identity of the alkyl group (3e−g, 58−60%). When the
same reaction was carried out in THF for 18 h, the yields
dramatically improved (3e, 59 → 72%; 3f, 60 → 80%; 3g, 58
→ 74%) even with a sterically bulky substituent. Next, we
studied a reaction between prop-1-yn-1-yl-substituted ben-
zenes and 4-fluorobenzyl alcohol in the presence of NBS and
AgSbF6 (3h−k). The yield of the reaction was rather
insensitive to the position of a methyl group on the benzene
ring (ortho, 66%; meta, 60%; para, 63%). However, a rather
lower yield (3k, 41%) was observed with an acetyl group on
the benzene ring.
Other internal alkynes, including 1-phenyl-1-butyne, 1-
phenyl-1-pentyne, 1-phenyl-1-hexyne, and 1,2-diphenylethyne,
were also good substrates for reaction with 4-fluorobenzyl
alcohol in the presence of NBS and AgSbF6, affording the
corresponding α-alkylated aryl ketones in 60−72% yields (4a−
g, Scheme 3). In the reaction of 1,2-diphenylethyne,
lengthening the reaction time improved the yield from 45%
to 60% (4d). Notably, the reaction of benzyl alcohol having an
isopropyl substituent with internal alkynes in THF produced
relatively higher yields (4e,f; 68−71%, Scheme 3).
α-Alkylated aryl ketones are particularly useful due to the
possibility of a stereogenic center at the α-position to the
ketone group. The synthetic utility of our strategy could be
enhanced, provided racemic ketones could be transformed into
the optically active α-benzyl ketones. Fortunately, several years
ago, Tsunoda and co-workers reported14 the conversion of
racemic ketones bearing a stereogenic center α to the carbonyl
group into optically active ketones in the presence of
TADDOL-type host molecules in H2O/MeOH in suspension
in basic media. Thus, 3-(4-fluorophenyl)-2-methyl-1-phenyl-
propan-1-one (3a) was treated with base in aqueous MeOH in
NBS (20)
NBS (20)
NBS (20)
NBS (4)
NBS (4)
NBS (4)
b
7
b
8
b
9
b
10
AgSbF6 (30) dioxane/THF (0.3:0.7)
AgSbF6 (30) dioxane/THF (0.5:0.5)
b
11
NBS (4)
75
a
b
Isolated yields. 1a (0.7 mmol), 120 °C.
or AgSbF6, no reaction occurred, even at 130 °C (entries 4 and
5). When Bu4PF6, AgClO4, AgO2CCF3, NaSbF6, or [(4-
BrC6H4)3N]SbCl6 was used instead of AgSbF6, no reaction was
observed. When AgNTf2 was used for the reaction, a certain
amount of reaction proceeded (36%, entry 6), but the best
activity in terms of efficiency was observed when AgSbF6 was
used. The amounts of the alkyne and the alcohol used also had
an influence on the yield of the reaction (57%, entry 7). We
chose the ratio of alkyne to alcohol to be 0.7:0.5 mmol in 1.0
mL of 1,4-dioxane. The yields of the reaction were dependent
upon the amounts of NBS and AgSbF6 used. The amount of
NBS could be cut down to 4 mol %, but the amount of AgSbF6
was fixed at 30 mol % (67%, entry 8). The yield of the reaction
was also highly sensitive to the reaction medium (entries 9−
11). The best yield (75%, entry 11) was observed when the
reaction was carried out in a solvent mixture of THF and 1,4-
dioxane with a ratio of 1:1. Thus, we established the optimum
reaction conditions to obtain an α-alkylated aryl ketone from
1-phenyl-1-propyne and 4-fluorobenzyl alcohol.
With the optimum reaction conditions for the synthesis of α-
alkylated aryl ketones at hand, the substrate scope was
investigated (Scheme 2). We first tested a reaction between
1-phenyl-1-propyne with 4-substituted benzyl alcohols in the
presence of NBS and AgSbF6 (entries 3a−g). The correspond-
ing α-alkylated aryl ketones were isolated in 53−80% yields. In
the reaction with 4-halobenzyl alcohols, the yield was
B
DOI: 10.1021/acs.orglett.8b02252
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Organic Letters
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Scheme 3. Variation of the Acetylene Alkyl Group in the
Synthesis of α-Alkylated Aryl Ketones
Scheme 4. Control Experiments
a
a
30 mol % of AgSbF6 was used unless otherwise noted, and all
b
c
products were isolated by column chromatography. 24 h. 10 mol %
of AgSbF6 was used, and 1 mL of THF was used as solvent.
t h e p r e s e n c e o f ( − ) - ( 2 R , 3 R ) - t r a n s - 2 , 3 - b i s -
(hydroxyldiphenylmethyl)-1,4-dioxaspiro[5.4]decane (eq 1).
After workup, a highly optically pure ketone was isolated in
85% yield with 98% ee.
1-propyne to ethyl phenyl ketone did not occur during the
reaction. When 1-phenyl-1-propyne was reacted with 1,1′-
[oxybis(methylene)]bis[4-fluorobenzene] in the presence of
AgSbF6 in a solvent mixture of THF (0.5 mL) and 1,4-dioxane
(0.5 mL) at 120 °C for 18 h, 3a was isolated in 63% yield (eq
6), indicating that an ether was probably the reaction
intermediate. However, when 0.5 mmol of TEMPO was
added to the above solution, no reaction was not observed (eq
7). In the same way, no reaction was observed in the presence
of 2,6-di-tert-butyl-4-methylphenol. The observation of the
formation of toluene and the dimerized tolyl product may
provide some evidence that the reaction proceeds via a radical
pathway.
While we were studying the AgSbF6/NBS-mediated syn-
thesis of 3a from the reaction of 1-phenyl-1-propyne with 4-
fluorobenzyl alcohol, the formation of a symmetric ether, 1,1′-
[oxybis(methylene)]bis[4-fluorobenzene], was always ob-
served. Furthermore, formation of toluene was observed by
1H NMR. AgSbF6/NBS was also found to be a catalyst in the
etherification of benzyl alcohol (see the Supporting Informa-
tion (SI)). It seems that alcohols can be activated via
halogenation reactions to give more reactive organohalides,
and further serve as the alkylating reagents to afford symmetric
ethers.
To further validate the reaction mechanism, additional
experiments were performed (Scheme 4, eqs 2−7). When 4-
fluorobenzyl alcohol was treated with 4 mol % of NBS in a
solvent mixture of THF (0.5 mL) and 1,4-dioxane (0.5 mL) at
120 °C for 18 h, the formation of 4-fluorobenzyl bromide was
identified by GC analysis (eq 2). When 1-phenyl-1-propyne
was reacted with 4-fluorobenzyl bromide in the presence of
AgSbF6 (30 mol %) in a solvent mixture of THF (0.5 mL) and
1,4-dioxane (0.5 mL) at 120 °C for 18 h, 3a was isolated in
71% yield (eq 3). When 1-phenyl-1-propyne was reacted under
our reaction conditions, ethyl phenyl ketone was isolated in
31% yield (eq 4). However, when ethyl phenyl ketone was
treated with 4-fluorobenzyl alcohol in the presence of NBS (4
mol %) and AgSbF6 (30 mol %) in a solvent mixture of THF
(0.5 mL) and 1,4-dioxane (0.5 mL) at 120 °C for 18 h, no
desired product was observed (eq 5). Instead, formation of
1,1′-[oxybis(methylene)]bis[4-fluorobenzene] and 1,2-diphe-
nylethane (a tolyl dimerized compound) was observed. This
observation suggests that a direct transformation of 1-phenyl-
Based on our findings and previous studies,15 we propose a
possible mechanism as depicted in Figure 1. Two catalytic
cycles may operate: one is the generation of ether and oxonium
Figure 1. Proposed mechanism for synthesis of α-alkylated aryl
ketones using alkynes and alcohols.
C
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Organic Letters
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02252.
Experimental procedures and characterization data of
products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ykchung@snu.ac.kr.
ORCID
Young Keun Chung: 0000-0002-2837-5176
Notes
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The authors declare no competing financial interest.
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2015, 6, 7011.
ACKNOWLEDGMENTS
■
The authors thank Mr. Hawon Park (Department of
Chemistry, Seoul National University) for his initial study
using rhodium compounds as a catalyst. This work was
supported by a National Research Foundation of Korea (NRF)
grant funded by the Korean government (2014R1A5A1011165
and 2007-0093864). S.C. is a recipient of a BK21 Plus
Fellowship.
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