Bronsted acid-catalyzed benzylation of 1,3-dicarbonyl derivatives

Article abstract of DOI:10.1021/ol070624a

The direct alkylation of 1,3-dicarbonyl compounds with benzylic alcohols is shown to be efficiently catalyzed by simple Bronsted acids such as triflic acid (TfOH) and p-toluenesulfonic acid (PTS) to give rise to monoalkylated dicarbonyl derivatives in high yields. In the absence of the nucleophile, substituted alkenes, generated through a formal dimerization reaction, are obtained. The reactions are carried out in air using undried solvents, with water being the only side product of the process.

Full text of DOI:10.1021/ol070624a

ORGANIC
LETTERS
2007
Vol. 9, No. 10
2027-2030
Brønsted Acid-Catalyzed Benzylation of
1,3-Dicarbonyl Derivatives
Roberto Sanz,*,† Delia Miguel,† Alberto Mart´ınez,† Julia M. A
Ä
lvarez-Gutie´rrez,† and
Fe´lix Rodr´ıguez‡
Departamento de Qu´ımica, AÄ rea de Qu´ımica Orga´nica, Facultad de Ciencias,
UniVersidad de Burgos, Pza. Misael Ban˜uelos s/n, 09001-Burgos, Spain, and Instituto
UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”, UniVersidad de OViedo,
C/Julia´n ClaVer´ıa, 8, 33006-OViedo, Spain
rsd@ubu.es
Received March 14, 2007
ABSTRACT
The direct alkylation of 1,3-dicarbonyl compounds with benzylic alcohols is shown to be efficiently catalyzed by simple Brønsted acids such
as triflic acid (TfOH) and p-toluenesulfonic acid (PTS) to give rise to monoalkylated dicarbonyl derivatives in high yields. In the absence of
the nucleophile, substituted alkenes, generated through a formal dimerization reaction, are obtained. The reactions are carried out in air using
undried solvents, with water being the only side product of the process.
As one of the most common strategies for the formation of
carbon-carbon bonds, the standard protocol for the alkyla-
tion of 1,3-dicarbonyl compounds usually requires the usage
of a stoichiometric amount of base and an organic halide.
Consequently, the development of alternative methods, via
acid-catalyzed addition of 1,3-dicarbonyl derivatives to
alkenes or alcohols, would provide a more environmen-
tally friendly and atom-economical process.1 In the last years
some metal-catalyzed intramolecular hydroalkylation of
alkenes by active methylene compounds have appeared.2 In
recent years, we3 and others4 have reported that simple
Brønsted acids, such as p-toluenesulfonic acid (PTS) or solid
acids based on montmorillonites are able to catalyze the
direct nucleophilic substitution of allylic and benzylic
alcohols with a variety of heteroatom- and carbon-centered
nucleophiles.5
The major issue with proton-catalyzed nucleophilic sub-
stitution reactions of alcohols is that the used nucleophile
must be less basic than the alcohol, to favor the formation
of carbenium ions in the presence of the nucleophile.6 In
this sense, the acid-catalyzed direct nucleophilic substitution
of alcohols by 1,3-dicarbonyl compounds would be a
favorable process.7
(4) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda,
K. Angew. Chem., Int. Ed. 2006, 45, 2605. Also, a surfactant-type Brønsted
acid has been described as a catalyst for nucleophilic substitution of alcohols
in water, see: Shirakawa, S.; Kobayashi, S. Org. Lett. 2007, 9, 311.
(5) An interesting direct substitution of allylic and benzylic alcohols by
nucleophiles catalyzed by InCl3 has recently appeared: Yasuda, M.; Somyo,
T.; Baba, A. Angew. Chem., Int. Ed. 2006, 45, 793. For an efficient bismuth-
catalyzed benzylation of arenes, see: Rueping, M.; Nachtsheium, B. J.;
Ieawsuwan, W. AdV. Synth. Catal. 2006, 348, 1033.
† Universidad de Burgos.
‡ Universidad de Oviedo.
(1) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
(2) Pd: (a) Han, X.; Wang, X.; Pei, T.; Widenhoefer, R. A. Chem.s
Eur. J. 2004, 10, 6333. Au: (b) Yao, X.; Li, C.-J. J. Am. Chem. Soc. 2004,
126, 6884. (c) Nguyen, R.-V.; Yao, X.-Q.; Bohle, D. S.; Li, C.-J. Org.
Lett. 2005, 7, 673.
(3) (a) Sanz, R.; Mart´ınez, A.; Miguel, D.; AÄ lvarez-Gutie´rrez, J. M.;
Rodr´ıguez, F. AdV. Synth. Catal. 2006, 348, 1841. (b) Sanz, R.; Mart´ınez,
A.; Miguel, D.; AÄ lvarez-Gutie´rrez, J. M.; Rodr´ıguez, F. Org. Lett. 2007, 9,
727.
(6) For other Brønsted acid-catalyzed reactions, see: (a) Sanz, R.;
Mart´ınez, A.; AÄ lvarez-Gutie´rrez, J. M.; Rodr´ıguez, F. Eur. J. Org. Chem.
2006, 1383. (b) Motokura, K.; Nakagiri, N.; Mori, K.; Mizugaki, T.; Ebitani,
K.; Jitsukawa, K.; Kaneda, K. Org. Lett. 2006, 8, 4617.
10.1021/ol070624a CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/21/2007

Herein, we report the use of TfOH as a powerful catalyst
for the direct substitution of secondary benzylic alcohols with
â-dicarbonyl compounds. While our work was in progress,
Rueping et al. reported a similar bismuth-catalyzed reaction.8
Surprisingly, these authors state in the paper that TfOH does
not show catalytic activity.
Table 1. Evaluation of Brønsted Acid Catalysts and Conditions
for the Nucleophilic Substitution of 1a with 2aa
The reaction of 1-phenylethanol 1a with acetylacetone 2a
under PTS-catalysis in CH2Cl2 afforded a mixture (ca. 4:1)
of the desired alkylated 1,3-diketone 3aa and 1,3-diphenyl-
but-1-ene 4a.3a The formation of the latter might be due to
a competitive elimination reaction that would afford styrene.
This compound could react with intermediate phenylethyl
cation to give, after subsequent elimination of a proton, the
alkene 4a (Scheme 1).9
temp
(°C)
time
(h)
3aa/4a
ratio
yield
(%)a
entry
catalyst
solvent
1
2
3
4
5
6
7
8
9
PTS
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
toluene
MeNO2
MeNO2
MeNO2
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
100
48
5
4
4/1
4/1
9/1
70
73
81
0b
80
88
58
76
94
0
DNBSA
TfOH
TfOH
TfOH
TfOH
PTS
DNBSA
TfOH
none
1
0.5
0.3
17
5
1
4
12/1
13/1
2.5/1
5/1
Scheme 1. Brønsted Acid-Catalyzed Reaction of
1-Phenylethanol 1a with Acetylacetone 2a
1/0
10
MeNO2
reflux
a Isolated yield of 3aa after column chromatography. b N-(1-phenylethy-
l)acetamide was generated through a Ritter-type reaction.
by using other catalysts in MeNO2 (entries 6-8), we
observed that the process could be carried out without
solvent, by using an excess of 2a. Under these conditions,
compound 4a was not detected and 3aa was isolated in 94%
yield (entry 9). Finally, as expected, no reaction took place
in the absence of catalyst (entry 10). Consequently, the
optimal conditions for the transformation of 1a and 2a into
3aa supposed the use of TfOH as catalyst (5 mol %) without
solvent or employing MeNO2.12
Owing to the great potential of Brønsted acids as easily
tunable, economical, and environmentally acceptable cata-
lysts,10 we investigated the model reaction of 1a with 2a by
using some Brønsted acids as catalysts under different
reaction conditions (Table 1).
Once the best reaction conditions were established, several
1,3-dicarbonyl compounds, including active methylene de-
rivatives 2a-c as well as active methine ones 2d,e, were
tested (Table 2, entries 1-5). Interestingly, ethyl acetoacetate
At the beginning we employed CH2Cl2 as solvent. As
shown in Table 1, similar results were obtained by using
2,4-dinitrobenzenesulfonic acid (DNBSA) or PTS as catalysts
(entries 1,2). However, the amount of the sideproduct 4a
could be reduced by using TfOH as catalyst (entry 3). The
evaluation of different solvents under TfOH-catalysis showed
that MeNO2 was superior, regarding both the yield and
selectivity, compared with CH2Cl2, MeCN, and toluene
(entries 3-6).11 Although no improvements were achieved
Table 2. 1,3-Dicarbonyl Compounds 2 Examineda
(7) For the Lewis acid-mediated direct reaction of alcohols with active
methylenes, see: (a) Bisaro, F.; Prestat, G.; Vitale, M.; Poli, G. Synlett
2002, 1823. (b) Liu, J.; Liang, F.; Liu, Q.; Li, B. Synlett 2007, 156.
(8) Rueping, M.; Nachtsheim, B. J.; Kuenkel, A. Org. Lett. 2007, 9, 825.
(9) This product has also been obtained as a byproduct in the metal
triflate-catalyzed secondary benzylation of benzylic alcohols with different
nucleophiles, see: Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.; Tajima, H.;
Ishii, K. J. Org. Chem. 2003, 68, 9340.
(10) For recent examples using Brønsted acids as catalysts, see: (a) Li,
Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He, C. Org. Lett.
2006, 8, 4175. (b) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya,
M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179. (c) Kampen, D.; List, B. Synlett
2006, 2589. (d) Kumar, R.; Kumar, D.; Chakraborti, A. K. Synthesis 2007,
299.
entry diketone
R1
R2
R3
product yield (%)a
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
Me Me
Ph
Ph
Me -(CH2)3-
Me Me
Me OEt
H
H
H
3aa
3ab
3ac
3ad
3ae
3af
88 (94)b
70
Ph
Me
80c
76c,d
71e
61c,f
Me
H
(11) It should be noted that Rueping et al. reported 0% yield of 3aa by
using similar conditions as those shown in entry 6 of Table 1 (see ref 8).
We performed the reaction as follows: TfOH (5 mol %) was added to a
mixture of 1a (3 mmol) and 2a (3 mmol) in MeNO2 (3 mL). The reaction
was stirred at reflux for 20 min (monitored by GC-MS). The solvent was
removed under reduced pressure, and the residue was purified by silica gel
chromatography (hexane/AcOEt, 15:1).
a Isolated yield after column chromatography. b In parenthesis yield
obtained in a gram-scale experiment (20 mmol) using 2a as solvent (3 equiv)
and TfOH (3 mol %). c Obtained as a ca. 1:1 mixture of diastereoisomers.
d Carried out in neat 2d (5 equiv). e A total of 10% of the alkene 4a was
also generated. f A total of 20% of the alkene 4a was also generated.
2028
Org. Lett., Vol. 9, No. 10, 2007

2f also undergoes Brønsted acid-catalyzed alkylation with
1a under solvent-free conditions, affording the corresponding
benzylated â-ketoester 3af (Table 2, entry 6).13
Scheme 2. Brønsted Acid-Catalyzed Reactions of Benzhydrol
5a
We then explored the generality of the reaction by varying
the substituents of the benzylic alcohols 1 (Table 3).
Table 3. Reactions of Secondary Benzylic Alcohols 1 with
Diketones 2a and 2ba
Different diarylcarbinols 5 were tested in their acid-
catalyzed substitution with 2a and 2f under solvent-free
conditions, and excellent yields of the corresponding alkyl-
ated â-dicarbonyl derivatives 8 were obtained in short
reaction times, even when strong electron-withdrawing
groups are present in the starting alcohol 5 (Table 4).
entry alcohol
Ar
R1
diketone product yield (%)b
1
2
3
4
5
1b
1c
1d
1e
1f
4-BrC6H4 Me
4-PhC6H4 Me
4-ClC6H4 Me
2-BrC6H4 Me
3-BrC6H4 Me
2-Nfd
Ph
4-ClC6H4 Bu
4-BrC6H4 Et
2-BrC6H4 Me
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
89
88
82
72c
70
6
7
8
1g
1h
1i
Me
Pr
90
70e
58f
57g
81c
53c
Table 4. Reactions of Benzhydryl Alcohols 5 with
â-Dicarbonyl Compounds 2a and 2fa
9
1j
3ja
3eb
3kbh
10
11
1e
1k
Ph
CHdCH2
a Reaction conditions: alcohol (3 mmol), diketone (15 mmol for 2a or
3 mmol for 2b), TfOH (0.15 mmol) in MeNO2 (3 mL for 2b) at 100 °C.
b Isolated yield after column chromatography. c Carried out in MeNO2.d 2-
Nf: 2-naphthyl. e 1-Phenyl-1-butene was obtained in 20% yield. f 1-(4-
Chlorophenyl)-1-pentene was obtained in 30% yield. g 1-(4-Bromophenyl)-
1-propene was obtained in 35% yield. h The linear styrene derivative which
corresponds to an SN2′-type process was obtained.
entry alcohol
Ar1
Ar2
R
product yield (%)b
1
2
3
4
5
6
5b
5c
5d
5e
5f
4-ClC6H4
4-NO2C6H4 Ph
4-BrC6H4
4-FC6H4
4-ClC6H4
Ph
Ph
Me
Me
Me
8b
8c
8d
8e
8f
91
88
87
96
95
84
Ph
4-FC6H4 Me
4-ClC6H4 Me
Functionalized 1-arylethanols 1b-g gave high yields of
3-alkylated-2,4-pentanediones 3ba-3ga in neat 2a (entries
1-6). Interestingly, benzylic alcohols 1h-j substituted with
ethyl, propyl, or butyl groups were appropriate starting
materials (entries 7-9). Moreover, dibenzoylmethane 2b also
yielded high yields of the alkylated products with different
benzylic alcohols by performing the reactions in MeNO2 as
solvent (entries 10-11).
5a
Ph
OEt
8g
a Reaction conditions: alcohol (3 mmol), 2a or 2f (15 mmol), PTS or
TfOH (0.15 mmol) at 100 °C. b Isolated yield after column chromatography.
Scheme 3 shows plausible mechanisms for the Brønsted
acid-catalyzed reaction of secondary benzylic alcohols 1 and
Interestingly, when we tried the reaction of 2a with
benzhydrol 5a under the standard conditions (TfOH as
catalyst in MeNO2), we isolated an equimolecular mixture
of diphenylmethane 6 and benzophenone 7 (Scheme 2).14
Surprisingly, the use of PTS instead of TfOH gave rise to
the alkylated diketone 8a in 83% yield. Moreover, the
reaction of 5a in neat 2a afforded 8a in 90-93% yield
irrespective of using PTS or TfOH-catalysis (Scheme 2).
Scheme 3. Plausible Pathways for the Catalyzed Reaction
(12) The use of other solvents like DMF and DMSO did not afford any
substitution products. In THF, only bis(1-phenyl-ethyl) ether was obtained.
(13) The TfOH-catalyzed reaction of 1a with 2d or 2f in MeNO2 gave
rise to low yields of 3ad or 3af, respectively.
(14) Some examples of disproportionation of benzhydrols in acidic media
are mentioned in the literature. See, for instance: (a) Bartlett, P. D.;
McCollum, J. D. J. Am. Chem. Soc. 1956, 78, 1441. (b) Harig, M.;
Neumann, B.; Stammler, H.-G.; Kuck, D. Eur. J. Org. Chem. 2004, 2381.
(c) L’Hermite, N.; Giraud, A.; Provot, O.; Peyrat, J.-F.; Alami, M.; Brion,
J.-D. Tetrahedron 2006, 62, 11994.
Org. Lett., Vol. 9, No. 10, 2007
2029

5 with 2a. One of them could be a direct alkylation of 2a
with a stabilized carbocation derived from the alcohol
(Scheme 3). Another probable pathway, at least for less bulky
carbocations, is a fast condensation of the starting alcohol
to the corresponding symmetric ether 9. Then, alkylation of
the dimeric ether by 2a takes place, affording the substitution
products 3 and 8 and releasing starting alcohol.15 Support
for this second mechanism was found in the reaction of 1a
with TfOH as catalyst in MeNO2 at room temperature. Under
these reaction conditions, dimerization to give bis(1-phenyl-
ethyl) ether 9a was observed. Moreover, reaction of isolated
9a in neat 2a at 100 °C in the presence of a catalytic amount
of the Brønsted acid led to the formation of the alkylated
1,3-diketone 3aa in almost quantitative yield (Scheme 3).
Finally, we turned our attention to the alkene derivative
4a, which was obtained as a side-product in low yield in the
reaction of 1a with 2a under Brønsted acid-catalysis (see
Scheme 1 and Table 1). As said before, this compound
formally comes from the dimerization of styrene, and this
process, that is, the dimerization of vinylarenes, is an
interesting reaction. As far as we know, this kind of reaction
has previously been carried out under palladium-catalysis.16
So, we envisaged that a metal-free alternative for the
dimerization of vinylarenes could be achieved by the reaction
of 1-arylethanol derivatives 1 under Brønsted acid-catalysis
in the asbsence of any external nucleophile. Gratifyingly,
1,3-diarylbut-1-ene derivatives 4 were easily obtained in
moderate yields17 when a solution of 1 in MeNO2 was
refluxed in the presence of a catalytic amount of TfOH (Table
5).
Table 5. Formation of 1,3-Diarylbut-1-ene Derivatives 4 from
1-Arylethanols 1 under Brønsted Acid Catalysisa
entry
alcohol
Ar
product
yield (%)a
1
2
3
4
5
1a
1b
1d
1e
1f
Ph
4a
4b
4d
4e
4f
43
55
67
45
52
4-BrC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
a Isolated yield after column chromatography.
and gives water as the only side product, represents a clean
and environmentally friendly alternative to the classical
halide-based strategies under basic conditions or to the
already established use of metallic catalysts. The results here
presented clearly demonstrate that Brønsted acids are ap-
propriate catalysts for the direct hydroxy substitution of
benzylic alcohols. So, the possibility of in situ formation of
a small amounts of Brønsted acids in related catalytic
reactions with metallic Lewis acids should be taken into
consideration.
Acknowledgment. We gratefully thank Junta de Castilla
y Leo´n (BU012A06) and Ministerio de Educacio´n y Ciencia
(MEC) and FEDER (CTQ2004-08077-C02-02/BQU) for
financial support. D.M. and A.M. thank MEC for FPU
predoctoral fellowships. J.M.A.-G. and F.R. are grateful to
MEC and the Fondo Social Europeo (“Ramo´n y Cajal”
contracts).
In summary, we have shown that simple Brønsted acids
such as TfOH and PTS are efficient catalysts for the direct
nucleophilic substitution of benzylic alcohols with active
methylene and methine 1,3-dicarbonyl compounds. This
metal-free method, which can be carried out without solvent
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds; copies of
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) This type of reaction course has also been proposed by different
authors, see ref 5 and 9.
(16) (a) Tsuchimoto, T.; Kamiyama, S.; Negoro, R.; Shirakawa, E.;
Kawakami, Y. Chem. Commun. 2003, 852. (b) Kabalka, G. W.; Dong, G.;
Venkataiah, B. Tetrahedron Lett. 2004, 45, 2775.
(17) Moderate yields are probably a reflection of the high tendency of
the final products to polymerize under the workup or purification conditions.
OL070624A
2030
Org. Lett., Vol. 9, No. 10, 2007