Efficient metal-catalyzed direct benzylation and allylic alkylation of 2,4-pentanediones

Article abstract of DOI:10.1021/ol063048b

(Chemical Equation Presented) A highly effective metal-catalyzed benzylation and allylic alkylation of 2,4-pentanediones has been developed. This new bismuth-catalyzed direct carbon-carbon bond forming reaction provides the corresponding monoalkylated dicarbonyl compounds in high yields after short reaction times using the lowest amounts of catalyst (1 mol %) and the free alcohol. In addition, a new route to substituted indenes is presented.

Full text of DOI:10.1021/ol063048b

ORGANIC
LETTERS
2
007
Vol. 9, No. 5
25-828
Efficient Metal-Catalyzed Direct
Benzylation and Allylic Alkylation of
8
2,4-Pentanediones
Magnus Rueping,* Boris J. Nachtsheim, and Alexander Kuenkel
Degussa Endowed Professorship, Institute of Organic Chemistry & Chemical Biology,
Johann-Wolfgang Goethe UniVersity Frankfurt am Main, Max-Von-Laue-Str. 7,
D-60438 Frankfurt, Germany
m.rueping@chemie.uni-frankfurt.de
Received December 17, 2006
ABSTRACT
A highly effective metal-catalyzed benzylation and allylic alkylation of 2,4-pentanediones has been developed. This new bismuth-catalyzed
direct carbon carbon bond forming reaction provides the corresponding monoalkylated dicarbonyl compounds in high yields after short
reaction times using the lowest amounts of catalyst (1 mol %) and the free alcohol. In addition, a new route to substituted indenes is presented.
−
The functionalization of activated methylene units, such as
,3-dicarbonyl compounds, is one of the most utilized types
However, so far, C nucleophiles other than arenes have
not been investigated. Hence, we herein report the first direct
bismuth-catalyzed benzylation of 2,4-pentanediones using
1
of carbon-carbon bond forming reactions. Generally, these
transformations are performed using alkyl halides, and at least
equimolar amounts of base or Lewis acid are required,
resulting in large amounts of salt byproducts. Additionally,
the need of electrophile preformation and coproduction of
hydrogen halides may lead to undesired side reactions which
can be a significant drawback. Thus, in view of the demand
for efficient, economic, and ecologically valuable processes,
the development of direct catalytic carbon-carbon bond
forming reactions of prior unmodified substrates is an
important task. Recently, interesting examples of such
reactions have been reported, including the direct function-
alization of benzyl alcohols with the generation of water as
the single byproduct. In this context, considerable progress
has been made in the metal-catalyzed Friedel-Crafts-type
alkylations of arenes using benzyl alcohols as the electro-
philic component resulting in products containing a diaryl-
methane moiety commonly found in biologically active
4
benzyl alcohol and its derivatives. Furthermore, we de-
scribe an extension of this procedure to a new bismuth-
catalyzed allylic alkylation using the corresponding free
allylic alcohols.
Bismuth(III) salts have been used as a catalyst for various
transformations, including acylations, sulfonylations, phos-
phonylations, desilylations, Diels-Alder reactions, oxida-
5
tions, halogenations, and rearrangements. Among the bismuth-
(1) (a) ElGihani, M. T.; Heaney, H.; Shuhaibar, K. F. Synlett 1996, 871-
72. (b) Shimizu, I.; Khien, K. M.; Nagatomo, M.; Nakajima, T.; Yamamoto,
8
A. Chem. Lett. 1997, 851-852. (c) Tsuchimoto, T.; Tobita, K.; Hiyama,
T.; Fukuzawa, S. J. Org. Chem. 1997, 62, 6997-7005. (d) Shiina, I.; Suzuki,
M. Tetrahedron Lett. 2002, 43, 6391-6394. (e) Noji, M.; Ohno, T.; Fuji,
K.; Futaba, N.; Tajima, H.; Ishii, K. J. Org. Chem. 2003, 68, 9340-9347.
(f) Mertins, K.; Iovel, I.; Kischel, J.; Zapf, A.; Beller, M. Angew. Chem.,
Int. Ed. 2005, 44, 238-242. (g) Iovel, I.; Mertins, K.; Kischel, J.; Zapf,
A.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 3913. (h) Mertins, K.;
Iovel, I.; Kischel, J.; Zapf, A.; Beller, M. AdV. Synth. Catal. 2006, 348,
691-695.
1
(2) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. AdV. Synth. Catal.
compounds and pharmaceuticals. Recently, we were able
2
006, 348, 1033-1037.
to demonstrate that bismuth salts are highly efficient catalysts
for this transformation, and the use of 0.5-1 mol % of
(
3) For a metal-catalyzed hydroarylation of styrenes, see: Rueping, M.;
Nachtsheim, B. J.; Scheidt, T. Org. Lett. 2006, 8, 3717-3719.
4) During our investigations, Baba and co-workers described a similar
(
Bi(OTf)
3
was sufficient to catalyze the addition of benzyl
indium-catalyzed transformation: Yasuda, M.; Somyo, T.; Baba, A. Angew.
Chem., Int. Ed. 2006, 45, 793-796.
2
,3
alcohol and derivatives to arenes and heteroarenes.
1
0.1021/ol063048b CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/31/2007

(
III) derivatives, Bi(OTf)
used catalyst with Lewis acid properties comparable to other
metal triflates such as Sc(OTf) , Yb(OTf) , or Y(OTf)
3
belongs to the most reactive and
Table 3. Reaction of Various 1-Phenylethanol Derivatives
3
3
3
.
Attracted by the direct functionalization of alcohols and
therewith the prevention of electrophile preformation or
coproduction of hydrogen halides and the fact that certain
bismuth salts are compatible with air and moisture, we
investigated various bismuth salts and Brønsted acids in the
reaction of 1-phenylethanol with acetylacetone (Table 1).
Table 1. Evaluation of Bismuth(III) Salts and Brønsted Acids
entry
catalyst
BiCl3
mol %
time (h)
yield (%)a
1
2
3
4
5
6
7
8
9
5
5
5
5
1
0.1
3
10
-
3
3
3
3
3
6
3
4
4
87
90
68
93
91
83
0
BiBr3
Bi(NO3)3(H2O)5
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
TfOH
HCl
none
0
0
a
Isolated yield after column chromatography.
From these experiments, Bi(OTf)
3
, BiCl
, and BiBr
3 3
emerged as the best catalysts and the corresponding products
were obtained in 87-93% yield after column chromatogra-
6
phy (Table 1, entries 1-4). Brønsted acids, such as tri-
fluoromethanesulfonic acid or hydrochloric acid (Table 1,
entries 7 and 8), did not show catalytic activity. The catalyst
Table 2. Variation of the 1,3-Dicarbonyl Scaffold
a
b
Isolated yield after column chromatography. 10% of branched product
c
d
observed. Reaction performed at rt. Additionally, 16% of indene derivative
was obtained.
loading could be decreased to 1 mol % without loss of
reactivity, and even with 0.1 mol % of Bi(OTf)
3
catalyst the
product could be isolated in 83% yield (Table 1, entries 4-6).
(
5) For reviews see: (a) Leonard, N. M.; Wieland, L. C.; Mohan, R. S.
a
b
Isolated yield after column chromatography. dr: 1:1
Tetrahedron 2002, 58, 8373-8397. (b) Gaspard-Iloughmane, H.; Le Roux,
C. Eur. J. Org. Chem. 2004, 2517-2532.
826
Org. Lett., Vol. 9, No. 5, 2007

Further experiments concentrated on the evaluation of the
,3-dicarbonyl scaffold (Table 2). As expected, the use of
differently substituted benzyl alcohols could be applied, and
the products were isolated in good to excellent yields.
During our investigations of the bismuth-catalyzed alky-
lation with 1-trimethoxyphenylethanol as the electrophile
(Table 3, entry 7), we observed that product formation
proceeds already at room temperature with generation of a
second product (Scheme 1).
1
different 2,4-pentanediones resulted in the corresponding
products in good yields irrespective of whether a primary
or secondary benzyl alcohol was applied (Table 2).
However, the reaction with 1-phenylethanol proceeded
generally more readily, which is in agreement with a more
stabilized carbocation intermediate.
Hence, we applied various 1-phenyl ethanol derivatives
in the direct alkylation reaction of acetyl acetone using 1
mol % of Bi(OTf) as catalyst (Table 3). In general, a range
3
Scheme 1
of differently substituted benzyl alcohols with electron-
donating or -withdrawing groups are tolerated and the
corresponding products were isolated after short reaction
times (2-4 h) in good to excellent yields. Interestingly, if
1-phenylallyl alcohol was employed (Table 3, entry 6), the
linear styrene derivative was obtained as the main product,
together with the generation of 10% of the branched isomer.
In further experiments, we investigated the bismuth-
catalyzed alkylation of dibenzoylmethane by employing
various primary benzyl alcohol derivatives (Table 4). Again,
Table 4. Reaction with Various Benzyl Alcohol Derivatives
This byproduct was identified to be the indene derivative
2
b and is the result of the benzylation of acetyl acetone
followed by an intramolecular arylation. When performing
the reaction at higher temperature, we were able to shift the
product formation from the alkylated product 2a toward the
indene 2b, and at 100 °C only indene formation was
observed.
Following a successful bismuth-catalyzed direct benzyla-
tion of 2,4-pentanediones, we decided to examine cinnamyl
alcohols as the electrophile in this reaction (Table 5). The
allylic alkylation represents an important transformation, and
Table 5. Allylic Alkylation of Cinnamyl Alcohol Derivatives
a
a
Isolated yield after column chromatography.
Isolated yield after column chromatography.
Org. Lett., Vol. 9, No. 5, 2007
827

various metal-catalyzed processes, using predominantly
3
of 1 mol % of Bi(OTf) catalyst (Table 5, entries 1, 3, and
7
8
9
10
11
palladium but also copper, tungsten, nickel, ruthenium,
5). Again the products were obtained in good isolated yields
in short reaction times. Surprisingly, no significant improve-
ment on the reactivity was observed when cinnamyl acetate
was employed (Table 5, entries 2, 4, and 6).
Mechanistically, we believe that the alcohol is activated
by the oxophilic bismuth catalyst, resulting in a better leaving
group for the C nucleophile displacement.
In summary, we have developed a new and efficient
bismuth-catalyzed direct benzylation of 2,4-pentanediones
using various free benzyl alcohols and dicarbonyl com-
pounds. The corresponding products of this direct C-C bond
forming reaction have been isolated in good to excellent
yields (Tables 2-4). Furthermore, we were able to extend
this procedure to a direct allylic alkylation of 2,4-pentanedi-
ones resulting in the linear, unbranched products (Table 5).
Compared to previous alkylations with preformed or acti-
vated electrophiles and the use of stoichiometric amounts
of base and/or metal salts, this method requires remark-
ably small amounts of reactive, inexpensive, and nontoxic
1
2
13
14
15
molybdenum, iridium, indium, and iron complexes,
have been described.
Most of these reactions have been performed with
activated C nucleophiles or with acylated allyl alcohols
leading to the corresponding R-branched products. Here, we
present our investigations on the first bismuth-catalyzed
direct allylic alkylation using a free allylic alcohol as the
electrophile. Reactions were performed with different 1,3-
dicarbonyl compounds and cinnamyl alcohol in the presence
(6) In the case of benzyl alcohol as the electrophile and BiCl3 or BiBr3
as the catalyst, (1-((benzyloxy)methyl)benzene) was obtained as the major
product. For a BiBr3-promoted etherification using benzyl alcohols, see:
Boyer, B.; Keramane, E. M.; Roque, J. P.; Pavia, A. A. Tetrahedron Lett.
2
000, 41, 2891-2894.
(
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3
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3
Bi(OTf) catalyst (1 mol %) and the free benzylic or allylic
alcohol. Furthermore, the mild reaction conditions, opera-
tional simplicity, practicability, and applicability to various
substrates render this approach an interesting alternative to
previously applied procedures. Additionally, a first extension
of this procedure to highly functionalized indene derivatives
was accomplished.
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Acknowledgment. We gratefully acknowledge Degussa
AG for financial support and the Fonds der Chemischen
Industrie for a stipend to B.J.N.
Soc. 1995, 117, 7273-7274. (b) Chung, K.; Miyake, Y.; Uemura, S. J.
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Supporting Information Available: A general experi-
mental procedure and spectroscopic data of all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
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