Fe(OTf)3-catalyzed α-benzylation of aryl methyl ketones with electrophilic secondary and aryl alcohols

Article abstract of DOI:10.1002/asia.201300956

Acid-catalyzed Friedel-Crafts alkylation of 1,3-dicarbonyl compounds with electrophilic alcohols, is known to be an effective C-C bond forming reaction. However, until now, this reaction has not been amenable for α-alkylation of aryl methyl ketones because of the notoriously low nucleophilicities of these compounds. Therefore, α-alkylation of aryl methyl ketone relies on precious metal catalysts and also, the use of primary alcohols is mandatory. In this study, we found that a system composed of a Fe(OTf)₃ catalyst and chlorobenzene solvent is sufficient to promote the title Friedel-Crafts reaction by using benzhydrols as electrophiles. 3,4-Dihydro-9-(2-hydroxy-4,4- dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-xanthen-1(2 H)-one was also applicable as an electrophile in this type of benzylation reaction. On the basis of this result, a three-component reaction of salicylaldehyde, dimedone, and aryl methyl ketone was also developed, and this provided an efficient way for the synthesis of densely substituted 4H-chromene derivatives. Copyright

Full text of DOI:10.1002/asia.201300956

FULL PAPER
DOI: 10.1002/asia.201300956
FeACHTUNGTRENNUNG(OTf)3-Catalyzed a-Benzylation of Aryl Methyl Ketones with Electrophilic
Secondary and Aryl Alcohols
Xiaojuan Pan,[a] Minghao Li,[a] and Yanlong Gu*[a, b]
Abstract:
Acid-catalyzed
Friedel–
mandatory. In this study, we found that
a system composed of a Fe(OTf)3 cata-
lyst and chlorobenzene solvent is suffi-
cient to promote the title Friedel–
Crafts reaction by using benzhydrols as
droxy-4,4-dimethyl-6-oxo-1-cyclohexen-
1-yl)-3,3-dimethyl-xanthen-1(2H)-one
Crafts alkylation of 1,3-dicarbonyl
compounds with electrophilic alcohols,
is known to be an effective C C bond
G
ACHTUNGTRENNUNG
was also applicable as an electrophile
in this type of benzylation reaction. On
the basis of this result, a three-compo-
nent reaction of salicylaldehyde, dime-
done, and aryl methyl ketone was also
developed, and this provided an effi-
cient way for the synthesis of densely
substituted 4H-chromene derivatives.
À
forming reaction. However, until now,
this reaction has not been amenable
for a-alkylation of aryl methyl ketones
because of the notoriously low nucleo-
philicities of these compounds. There-
fore, a-alkylation of aryl methyl ketone
relies on precious metal catalysts and
also, the use of primary alcohols is
electrophiles.
3,4-Dihydro-9-(2-hy-
Keywords: alkylation · aryl methyl
ketone · Friedel–Crafts reaction ·
iron catalysis
reaction
·
three-component
Introduction
pound could be ascribed to the presence of an equilibrium
between this compound and its enol form, which significant-
ly increases the electron density at the C2 position of the
molecule, thus activating this substrate.
The past decade has witnessed great strides in developing
active reagents and productive catalysts for Friedel–Crafts
alkylations, which have experienced a rekindled interest in
the synthetic community for the facile construction of the
carbon–carbon bond.[1] Recent enthusiasm of researchers in
this area was mostly inspired by the successful use of alco-
hols as electrophiles;[2] this avoids the generation of organic
or inorganic waste that results from alkyl halide reagents.
As for its nucleophile reaction partner, a breakthrough
comes from the use of 1,3-dicarbonyl compounds, with
which various useful molecules could be prepared by envi-
ronmentally benign methods (Scheme 1, the upper reaction
pathway).[3] The high reactivity of the 1,3-dicarbonyl com-
While the Friedel–Crafts alkylation of 1,3-dicarbonyl com-
pounds has been well investigated, far less attention has
been paid to the potential use of a simple ketone as nucleo-
phile in this type of reaction.[4] Obviously, an obstacle of this
chemistry stems from the inherent poor reactivity of
a simple ketone. Although some simple ketones can also be
transformed into their enol form, which should be more re-
active than the ketone form, unfortunately, the equilibrium
is thermodynamically unfavorable to afford the enolized
ketone. Futhermore, even if the enolized ketone was formed
under special reaction conditions, the reactivity is probably
still far from sufficient to ensure occurrence of the following
a-alkylation.
Aryl methyl ketone is an important ketone derivative,
which has often been used in organic transformations. Be-
cause of the possible existence of a conjugation effect, aryl
methyl ketone showed generally higher reactivity than that
of the other simple ketones. With the hope of using a simple
ketone as a nucleophile in the Friedel–Crafts a-alkylation,
we started, some time ago, a research program on the use of
aryl methyl ketones as substrates. Herein, we disclose the
successful outcome of this endeavor in which a Friedel–
Crafts-type a-alkylation of aryl methyl ketones was realized
by using either benzhydrol derivatives or 3,4-dihydro-9-(2-
hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-
[a] X. Pan, M. Li, Prof. Dr. Y. Gu
Hubei Key Laboratory of Material Chemistry and Service Failure
Key Laboratory for Large-Format Battery Materials and System
Ministry of Education, School of Chemistry
and Chemical Engineering
Huazhong University of Science and Technology (HUST)
1037 Luoyu road, Hongshan District, Wuhan 430074 (China)
Fax : (+86)027-87-54-37-45
E-mail: klgyl@hust.edu.cn
[b] Prof. Dr. Y. Gu
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences
Xanthen-1ACHTUGNTREN(NNUG 2H)-ones as electrophiles (Scheme 1, the bottom
Lanzhou, 730000 (P.R. China)
reaction pathway).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300956.
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Yanlong Gu et al.
However, 2a remains un-
changed at the end of the reac-
tion, and no triphenylbenzene
was detected.[6]
With the optimized condi-
tions in hand, we probed the
scope of the reaction with re-
spect to both the benzhydrol
and the aryl methyl ketone
components. As evidenced by
the results in Scheme 2, benzhy-
drols with different substituents
smoothly reacted with various
aryl methyl ketones, and pro-
duced the corresponding prod-
ucts in generally moderate to
good yields. In general, a me-
thoxy group is necessary in the
phenyl ring of the benzhydrol
Scheme 1. Schematic illustration of our study.
Results and Discussion
derivative to afford good yields. However, when this group
was introduced into one of the phenyl rings of benzhydrol,
an unexpected subtle influence of the substituent group in
another phenyl ring was observed. No reaction was observed
Our initial studies started by exploring a suitable catalyst for
the title reaction. In initial experiments, benzhydrol 1a and
acetophenone 2a were used as substrates in chlorobenzene,
and the mixture was heated at 1308C for 4 h in the presence
of a catalytic amount of p-toluenesulfonic acid (PTSA;
Table 1, entry 1). After the reaction reached completion,
a new product was obtained, and the following spectroscopic
analysis indicated that it was the expected product, 3a. In
the literature, the treatment of acetophenone under Friedel–
Crafts alkylation conditions mainly gave the m-alkylation
product.[5] Although the yield of the reaction was only 44%,
because only the a-alkylation product was obtained, the
product isolation was quite straightforward. This result en-
couraged us to investigate other catalysts with the hope of
increasing the reaction yield. As shown in Table 1, when the
reaction was carried out at 1308C in chlorobenzene, Brønst-
ed acids such as sulfuric acid and trifluoromethanesulfonic
acid were able to promote the model reaction (Table 1, en-
tries 2 and 3). Phosphomolybdic acid and phosphotungstic
acid were ineffective (Table 1, entries 4 and 5). A commonly
used Lewis acid, AlCl3, appeared to be less active, and pro-
duced only trace amounts of product after 4 h (Table 1,
Table 1. a-Benzylation of acetophenone with 1a under different condi-
tions.[a]
Entry
Catalyst
Solvent
T [8C]
Yield [%]
1
2
3
4
5
6
7
8
PTSA
H2SO4
CF3SO3H
H3PW12O40
H3PMoO40
AlCl3
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
CH3NO2
DBE[e]
DCE
1,4-dioxane
–
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
100
130
80
44
31
39
0
0
trace
39
27
26
20
30
32
51
27
60
0
54
31
17
36
42
59
59
32
FeCl3
ZnCl2
9
Cu
ACHTUNGERTN(NUNG OTf)2
10
11
12
13
14
15
16
17
18
19
20
21
22[b]
23[c]
24[d]
YACHTUNGTREN(NUGN OTf)3
ZrCl4
BiCl3
entry 6). FeCl3, ZnCl2, Cu
(OTf)3, and Sc(OTf)3 gave slightly better results, but Fe-
(OTf)3 showed the highest activity, and afforded 3a in 60%
ACHTUTGNERNNUG(OTf)2, YCAHTUNGTRENN(NGU OTf)3, ZrCl4, BiCl3, Bi-
G
ACHTUNGTRENNUNG
Bi
Sc
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
Fe
ACHTUNGTRENNUNG
yield (Table 1, entries 7–15). The effect of solvents on the
model reaction was also examined, and DBE and chloro-
benzene gave high yields (Table 1, entries 16–20). For safety
and economic reasons, we continued the reactions with
chlorobenzene. Further investigations revealed that the re-
action was also affected by other parameters including the
amount of catalyst, substrate ratio, temperature, and reac-
tion time, and the optimal reaction conditions should be
AHCTUNGTRENNUNG
T
AHCTUNGTRENNUNG
N
100
130
100
130
130
130
AHCTUNGTRENNUNG
T
PhCl
PhCl
PhCl
PhCl
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
5 mol% of FeACHTUNGTRENNUNG(OTf)3, 2a/1a is 3:1, at 1308C, and 4 h
(Table 1, entries 21–24). It should be noted that, under
[a] 1a (0.25 mmol), 2a (0.75 mmol), solvent (1 mL), catalyst (5 mol%),
yields reported are isolated product yields; [b] Fe(OTf)3 (10 mol%);
AHCTUNGTRENNUNG
acidic conditions, triple condensation of 2a is also possible.
[c] reaction time (6 h); [d] 2a/1a=1:1; [e] DBE=1,2-Dibromoethane.
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Yanlong Gu et al.
Scheme 2. Substrate scope of FeACTHNUTRGNENUG(OTf)3-catalyzed a-benzylation of aryl methyl ketones. [a] Yield of isolated product.
when an electron-withdrawing group, such as nitro, cyano,
and ester, was introduced into the second phenyl ring. This
can be ascribed to electronic effects. However, strong elec-
tron-donating groups, such as methoxy, methyl, and tert-
butyl, proved also to be detrimental for the reaction (see
Scheme S1 in the Supporting Information). On the contrary,
the benzhydrol derivatives with fluoro, chloro, and bromo
functionalities participated readily in the reaction. An unex-
pected product, 4,4’-dimethoxybenzophenone, was isolated
when 4,4’-dimethoxybenzhydrol
we expected, 4,4’-dimethoxybenzophenone could also be ob-
tained when 2a was replaced by cyclohexanone (Scheme 3).
In fact, this type of Meerwein–Ponndorf–Verley–Oppenauer
reaction has been observed when a Lewis acid or Brønsted
acid was used as the catalyst.[7] On the basis of these results,
we deduced that the title reaction is not only affected by the
electronic effect of the substituent groups, but also influ-
enced by the chemical stability of the alcohol substrate to-
wards oxidation with 2a. Electron-donating groups in both
was used as the substrate
(Scheme 3). In the absence of
FeACHTUNGTRENNUNG(OTf)3, no oxidation product
was obtained under identical
reaction conditions. As this
compound could also be
formed under an atmosphere of
nitrogen, we therefore speculat-
ed that, in this system, 2a is
playing a role of an oxidant. As Scheme 3. Oxidation of 4,4’-dimethoxybenzhydrol with ketones.
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Yanlong Gu et al.
phenyl rings of benzhydrol in-
creased not only the reactivity
of the alcohol substrate in the
SN1-type substitution reaction,
but also significantly increased
the reaction rate of the Oppe-
nauer oxidation. As a result,
Scheme 4. Mechanism of a-benzylation of 1a with 2a.
the a-benzylation of 2a was af-
fected.
It is well known that an electrophilic alkylation reaction
of benzaldehyde with an aromatic carbon-based nucleophile
generally involves formation of a secondary benzyl carboni-
um intermediate.[14] However, because the generated inter-
mediate will be preferentially trapped by the reactive aro-
matic carbon-based nucleophile, a less reactive nucleophile
almost has no chance to react with the carbonium ion inter-
mediate. Liu and co-workers[15] developed an elegant strat-
egy to avoid such problems by using an intramolecular reac-
tion of an aldehyde and nucleophile. However, the generali-
ty of this strategy is rather limited. We envisioned that an in-
termolecular variation of this strategy, if established, will be
a huge incentive for us. With the hope of extending our
method to perform a-benzylation of aryl methyl ketone, we
then examined a three-component reaction of salicylalde-
hyde, dimedone, and 2a. To our great delight, by using Fe-
It should be noted that although only moderate yields
were obtained in most cases, this system is very promising
because of the following considerations: (i) acid-catalyzed
Friedel–Crafts a-alkylation of aryl methyl ketone is notori-
ously difficult owing to the poor reactivity of the ketone;
and (ii) although the use of an alcohol as an alkylation re-
agent in the a-alkylation of aryl methyl ketone has been
achieved with the aid of precious metal catalysts, because
the catalysis is associated with a “hydrogen-borrowing”
mechanism, the use of a primary alcohol is mandatory;[8]
therefore, a-alkylation of aryl methyl ketone with a secon-
dary or tertiary alcohol remains to be a significant chal-
lenge.[9] Our present method thereby offers a complementary
system for implementing the title reaction.
The mechanism of the title reaction most likely involves
an acid-assisted nucleophilic substitution. However, because
AHCTUNGRTEGNUN(N OTf)3 as a catalyst, 6a was obtained in 56% yield under
Fe
G
the optimal reaction conditions (Scheme 5 and see Table S2
a hidden Brønsted acid (TfOH generated from FeACTHUNRGTNEUNG(OTf)3)
should be considered.[10] In fact, TfOH can indeed catalyze
our model reaction, although the yield obtained is inferior
as compared with that of FeACHTNUTRGNENG(U OTf)3 (Table 1, entry 3). We
have also meticulously investigated the performance of
TfOH catalyst in our reaction under different conditions,
and it was found that the maximum yield that can be ach-
ieved with TfOH is 39% (see Table S1 in the Supporting In-
formation). Interestingly, with TfOH catalyst, the triple con-
densation product of 2a, triphenylbenzene, in chlorobenzene
is formed.[11] However, this byproduct was not detected
Scheme 5. Reaction of salicylaldehyde, dimedone, and 2a.
when Fe
19F NMR spectroscopic analysis of the volatiles vacuum
transferred from preparative-scale Fe(OTf)3- and TfOH-
mediated a-benzylation of 2a reveals the presence of the
TfOH only in the latter reaction (Marksꢁs method to probe
the formation of TsOH from metal triflate).[12] All these re-
sults indicated that in the FeACHTNUTRGENNG(U OTf)3-mediated a-benzylation,
free TfOH is not formed in any significant quantities during
the catalytic cycle. Therefore, intervention of TfOH in the
catalytic cycle can be ruled out, and FeACTHNUTRGENUG(N OTf)3 can be consid-
ered as the real catalyst. The mechanism of the a-benzyla-
tion of acetophenone might be triggered by activation of
benzhydrol by the ironACTHNUTRGNE(NUG III) catalyst, and this resulted in for-
mation of a carbonium intermediate. This is followed by nu-
cleophilic attack of the enolized ketone, which leads to for-
mation of the desired product (Scheme 4).[13] If this mecha-
nism is operative, some other electrophiles that can generate
stable carbonium intermediates should be applicable in the
a-alkylation of aryl methyl ketones.
ACHTUNGTRENNUNG(OTf)3 was used as the catalyst. In addition,
in the Supporting Information). As shown in Scheme 6, aryl
methyl ketones with both electron-donating and electron-
withdrawing groups readily participated in the reaction.
Some other salicylaldehdyes and 1,3-cyclohexanediones can
also be employed in this type of three-component reaction,
and a random combination of the three starting materials
could give the final products with up to 73% yield. It should
be noted that salicylaldehdye containing an electron-with-
drawing group, such as 4-nitrosalicylaldehdye, cannot be
used in this type of reaction. Although the yield of the
model reaction is not very high under these conditions, con-
sidering the fact that synthesis of 6a-type 4H-chromenes has
been rarely described, our method thus offers a valuable
route to access these molecules.
AHCTUNGTRENNUNG
To shed light on the mechanism, compound 7a that was
synthesized by using salicylaldehyde and dimedone was
treated with 2a in the presence of FeACTHNUTRGNEUNG(OTf)3. In this case, 6a
was obtained in 43% yield (Scheme 7). It is known that, in
the presence of Lewis acid, the dimedone fragment in 7a is
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Yanlong Gu et al.
Fortunately, the dimedone frag-
ment in 7a is a leaving group in
the presence of a Lewis acid.
However, owing to the pres-
ence of an intramolecular hy-
drogen bond in 7a, the leaving
group ability of dimedone is di-
minished. 2a might play a key
role in the disengagement of
the intramolecular hydrogen
bond of 7a, thereby ensuring
regeneration of the intermedi-
ate (I). This reversible alkyla-
tion ensures trapping of (I)
with 2a to be feasible.
As phenylacetylene could be
converted into 2a in the pres-
ence of iron catalyst,[17] we then
investigated the feasibility of
replacing 2a with phenylacety-
lene in the three-component re-
action. As shown in Scheme 9,
in the FeACTHUNGTRENUNG(OTf)3/PhCl system,
salicylaldehyde and dimedone
are able to react smoothly with
phenylacetylene
thereby providing
derivatives,
6a-type
products in moderate to good
yields. It was also found that, at
the end of the synthetic reac-
tion of 6e, 2a was also obtained
in 34% yield (with respect to
phenylacetylene).
Therefore,
we suspected that the reactions
might proceed according to
Scheme 6. Substrate scope of FeACTHNUTRGENUG(N OTf)3-catalyzed reaction of salicylaldehyde, dimedone, and aryl methyl
ketone. [a] The reaction was conducted in DCE at 808C. [b] The molar ratio is 1:1:4. All yields reported are
isolated product yields.
a
hydration/Friedel–Crafts
tandem reaction pathway (see
Figure S1 in the Supporting In-
formation). It should be noted
that almost the same results were obtained with dried and
untreated (wet) chlorobenzene. This result implies that
a trace amount of water is sufficient enough to initiate the
hydration of alkyne under the present conditions. Because
some phenylacetylenes are now cheaper than the corre-
sponding acetophenones, these reactions provided alterna-
tive ways to access the target compounds with lower costs.
Reaction of benzhydrols and phenylacetylene was also ex-
amined, and the formed products retained the triple bond of
phenylacetylenes (see Scheme S2 in the Supporting Informa-
tion), which are in a good agreement with Jiao and co-work-
ers report.[18]
Scheme 7. a-Benzylation of 2a with 7a.
removed, thus generating a carbonium intermediate (I).[16]
On the basis of this result, we deduced that the initial event
in the three-component reaction is the formation of the car-
bonium intermediate (I) from salicylaldehyde and dime-
done, and this can be quickly trapped by dimedone to form
7a (Scheme 8). This can be verified by the fact that 7a
could be isolated in 13% yield at the end of the reaction.
Conclusions
In summary, we demonstrated that aryl methyl ketone can
be used as a nucleophile in Friedel–Crafts-type reactions al-
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Yanlong Gu et al.
by isolation with preparative TLC.
Tests for substrate scope were all per-
formed with an analogous procedure.
A typical procedure for reactions of
salicylaldehydes, dimedone, and aryl
methyl ketones
All reactions were conducted in
a 10 mL V-type flask equipped with
a
a
triangle magnetic stirring bar. In
typical reaction, salicylaldehyde
(61.1 mg, 0.5 mmol) was mixed with
dimedone (70.1 mg, 0.5 mmol) and
aryl methyl ketone (1.5 mmol) in
chlorobenzene (1.5 mL). The mixture
was then stirred at 1308C for 4 h.
After the reaction reached completion,
the mixture was cooled to room tem-
perature. The desired product was ob-
tained by isolation with preparative
TLC. Tests for substrate scope were all
performed with an analogous proce-
dure.
Scheme 8. Plausible mechanism of the three-component reaction.
Acknowledgements
The authors thank the National Natu-
ral Science Foundation of China for
the financial support (21173089). This
work was also supported by Special-
ized Research Fund for the Doctoral
Program
of
Higher
Education
(20090142120081). The authors are
also grateful to all the other staff
members in the Analytical and Testing
Center of HUST. The Program for
new Century Excellent Talents in the
University of China (NCET-10-0383),
the Cooperative Innovation Center of
Scheme 9. Reaction of salicylaldehyde, dimedone, and alkynes. [a] Chlorobenzene was purified and dried ac-
cording to a previously described procedure.[19]
Hubei Province and Chutian Scholar Program of the Hubei Provincial
Government are also acknowledged.
though its reactivity is notoriously poor. In the optimized
system, Fe(OTf)3/PhCl, aryl methyl ketone could react
ACHTUNGTRENNUNG
smoothly with benzhydrol, thus providing the corresponding
products in moderate to good yields. A new three-compo-
nent reaction of salicylaldehyde, dimedone, and aryl methyl
ketone was also developed, for the first time, and this pro-
vided an efficient way for the synthesis of densely substitut-
ed 4H-chromene derivatives. Although at the present stage,
the yields in these reactions are not very high, the transfor-
mation is interesting, and these results served already as
a starting point for further investigations, which are current-
ly ongoing in our laboratories.
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Experimental Section
A typical procedure for a-benzylation of aryl methyl ketones
All reactions were conducted in a 10 mL V-type flask equipped with a tri-
angle magnetic stirring bar. In a typical reaction, benzhydrol or xanthene
(0.25 mmol) was mixed with an aryl methyl ketone (0.75 mmol) and Fe-
ACHTUNGTRENNUNG(OTf)3 (6.3 mg, 5 mol%) in chlorobenzene (1.5 mL). The mixture was
then stirred at 1308C for 4 h. After the reaction reached completion, the
mixture was cooled to room temperature, and the product was obtained
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Yanlong Gu et al.
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Received: July 19, 2013
Revised: August 23, 2013
Published online: October 7, 2013
Chem. Asian J. 2014, 9, 268 – 274
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