A simple and efficient FeCl3-catalyzed direct alkylation of active methylene compounds with benzylic and allylic alcohols under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2007.04.017

A highly efficient FeCl₃-catalyzed alkylation of various active methylene compounds with various benzylic or allylic alcohols under mild conditions has been developed. The reaction was carried out in the presence of a catalytic amount of anhydr

Full text of DOI:10.1016/j.tetlet.2007.04.017

Tetrahedron Letters 48 (2007) 4065–4069
A simple and efficient FeCl3-catalyzed direct alkylation of
active methylene compounds with benzylic and allylic alcohols
under mild conditions
Umasish Jana,* Srijit Biswas and Sukhendu Maiti
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
Received 15 February 2007; revised 26 March 2007; accepted 4 April 2007
Available online 11 April 2007
Abstract—A highly efficient FeCl3-catalyzed alkylation of various active methylene compounds with various benzylic or allylic alco-
hols under mild conditions has been developed. The reaction was carried out in the presence of a catalytic amount of anhydrous
FeCl3 (10 mol %) under reflux in methylene chloride. High to excellent yields were obtained.
Ó 2007 Elsevier Ltd. All rights reserved.
Alkylation of active methylene compounds, such as b-
diketones, b-diketoesters and malonic esters is a very
important transformation in organic synthesis which
has been investigated extensively.1 Generally, this trans-
formation is carried out using alkyl halides in the pres-
ence of a stoichiometric amount of base.2 Although
this method works well even on large scale, often it is
associated with significant drawbacks including non-
availability of halogenated substrate, toxicity of haloge-
nated substrates, the use of strong base and production
of large amounts of salts as by-products. Therefore, the
development of a practical and economical process for
carbon–carbon bond formation between active methyl-
ene compounds and unmodified substrates is an impor-
tant task. In this regard, carbon–carbon single bond
formation between an active methylene compound
(R1H) with an alcohol (R2OH) would be an attractive
salt-free and atom-economic3 process with water being
the only by-product (Scheme 1). However, little has been
explored on direct carbon–carbon bond formation using
alcohols.4–9
In principle, C–C bond formation by direct substitution
of an hydroxyl group is difficult because of its poor leav-
ing group ability. Therefore, a promoter would be
required for in situ activation of R2OH and R1H for
direct C–C bond formation.
A few methods have so far been reported for the reac-
tion of alcohols and active methylene compounds using
various transition-metal based reagents, such as palla-
dium4 in the presence of a base or acid, and equimolar
amounts of Cu(I)5 and Co-salts.6 Most of these methods
only worked well for allylic alcohols, but were not suit-
able for benzylic alcohols.4g,6b Recently, Lewis acid7,8
and protic acid9 catalyzed methods have been reported,
involving BF3ÆOEt2,7 InCl3,8 formic acid9a or H–Mont-
morillonite.9b However, the harsh conditions required,
long reaction times, high temperatures, and use of
expensive, toxic and moisture sensitive reagents in most
of the above methods limit their practical utility in
organic synthesis. Therefore, development of a more
practical and economical method for direct alkylation
of active methylene compounds using alcohols is highly
desirable. In recent years, iron(III) chloride10 has
emerged as a powerful Lewis acid catalyst and performs
many useful organic transformations under mild reac-
tion conditions. Moreover, iron-salts are inexpensive,
easy to handle and are environmentally friendly.
R1H + R2OH → R1-R2 + H2O
Scheme 1.
Keywords: Ferric chloride; Alkylation; Active methylene compounds;
Alcohols; Atom-economical.
Herein, we report FeCl3 as a catalyst for direct carbon–
carbon bond formation between active methylene com-
pounds and various benzylic or allylic alcohols in high
*
Corresponding author. Tel.: +91 33 2414 6223; fax: +91 33 2414
6584; e-mail: jumasish2004@yahoo.co.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.017

4066
U. Jana et al. / Tetrahedron Letters 48 (2007) 4065–4069
Table 1. Effect of solvent on the direct alkylation of acetylacetone with
benzhydrol in the presence of FeCl3
O
O
a
OH
3ab (%)
FeCl3 (10 mol %)
Entry
Solvent
Time (h)
O
O
+
1
2
3
4
5
Dichloromethane
Dichloroethane
Toluene
Tetrahydrofuran
Acetonitrile
3
3
9
15
10
98
95
90
<10
25
CH2Cl2, refulx
3 h, 98%
3a
2a
1a
Scheme 2.
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), FeCl3 (10 mol %),
solvent (3 mL), 45 °C.
b Pure isolated yield.
Table 2. Alkylation of different active methylene compounds with alcohols in the presence of FeCl3 (10 mol %)a
Entry
Nucleophile
Electrophile
Product
Time (h)
Yieldb (%)
Ref.
9a
OH
O
O
O
O
1
3
98
1a
2a
3a
O
O
OH
2
3
4
1a
4
5
6
98
12
9b
13
MeO
2b
3b
MeO
O
O
OH
1a
1a
93
2c
3c
O
O
OH
80c
Cl
2d
OH
Cl
3d
O
O
O
5
6
1a
1a
6
88
11
2e
3e
O
OH
12
82d
8
2f
3f
O
O
OH
7
8
1a
1a
5
6
65e
14
15
MeO
2g
3g
MeO
O
O
O
O
OH
68e
O
O
2h
3h

U. Jana et al. / Tetrahedron Letters 48 (2007) 4065–4069
4067
Table 2 (continued)
Entry
Nucleophile
Electrophile
Product
Time (h)
12
Yieldb (%)
Ref.
O
O
OH
9
1a
58f
16
2i
3i
O
O
OH
O
O
OEt
10
11
12
4
5
5
99
7
OEt
1b
2a
3j
O
O
OH
OEt
1b
98g
11
MeO
2b
MeO
3k
O
O
O
OH
OEt
1b
90g
13
2c
3l
O
OH
OEt
OEt
13
14
1b
6
80h
17
9a
2e
3m
O
O
OH
1b
12
72d
2f
3n
O
O
OH
O
O
EtO
OEt
15
4
97
18
EtO
OEt
1c
2a
3o
O
O
OH
EtO
OEt
16
1c
5
90
19
MeO
2b
MeO
O
3p
O
O
OH
O
OEt
17
OEt
5
95
11
2a
1d
3q
(continued on next page)

4068
U. Jana et al. / Tetrahedron Letters 48 (2007) 4065–4069
Table 2 (continued)
Entry
Nucleophile
Electrophile
Product
Time (h)
Yieldb (%)
Ref.
11
O
O
OH
OEt
18
1d
5
75i
MeO
2b
3r
MeO
a Reaction conditions: Nucleophile 1 (1 mmol), alcohol 2 (1 mmol), FeCl3 (0.1 mmol), CH2Cl2 (4 mL), reflux.
b The yields refer to pure isolated product characterized by spectral data.
c Dichloroethane was used as solvent under reflux.
d Toluene was used as solvent at room temperature.
e Product existed partly in the enol form.
f Compound 2i (4 mmol), regioisomers ꢀ 9:1 (GC).
g Mixture of diastereoisomers ꢀ 1:1 (1H NMR).
h Mixture of diastereoisomers ꢀ 2:1 (1H NMR).
i Mixture of diastereoisomers ꢀ 1:1.5 (1H NMR).
yields with complete selectivity under mild reaction
conditions.
and only ether formation was reported using H–Mont-
morillonite.9a Various functional groups that coordinate
to the Lewis acid, such as ether, ester, ketone, chloride
and dioxymethylene remained unaffected under the reac-
tion conditions. No side product was isolated in any of
the reactions. Acetophenone did not react using this
method. Moreover, both secondary and primary allylic
alcohols reacted smoothly to give the desired product
in high to moderate yields (Table 2, entries 6, 9 and
14). Although the primary allylic alcohol 2i (Table 2,
entry 9) initially reacted in a low yield, a higher loading
of 2i (4 mmol) improved the yield up to 58% (Table 2,
entry 9). Allylic alkylation is an important transforma-
tion, and various metal-complex catalyzed4–6,20 pro-
cesses have been reported so far. However, many of
these reactions have been performed with activated
nucleophiles or with acylated allyl alcohols.
For our initial studies we chose to explore the anhydrous
FeCl3-catalyzed alkylation of acetylacetone (1a) with
benzhydrol (2a) due to its high acidity (Scheme 2). The
reaction was carried out in the presence of a catalytic
amount of anhydrous FeCl3 (10 mol %) in dichlorometh-
ane under reflux. The alkylated product was obtained in
high yield with excellent regioselectivity under mild
conditions without exclusion of air or moisture.
The reaction yield depended on the solvent used (Table
1). Dichloromethane and dichloroethane were found to
be the most effective solvents in terms of time and yield.
The yield was lower with coordinating solvents such as
tetrahydrofuran and acetonitrile. Benzene and toluene
were also effective solvents, but the reactions were slug-
gish compared to dichloromethane and dichloroethane.
Thus, we decided to use low boiling dichloromethane as
the solvent for this transformation.
Thus, the present method has potential for direct alkyl-
ation of active methylene compounds with varieties of
benzylic and allylic alcohols with complete selectivity2
without the use of acids or base and toxic organohalides.
Compared to InCl3 (80 °C for 16 h) and H–Montmoril-
lonite (100–150 °C for 3 h) our method works under
mild conditions. Although the exact mechanism is not
known at this stage, presumably the reaction proceeds
due to complexation of both electrophile and nucleo-
phile simultaneously with FeCl3. Further investigation
on the elucidation of the mechanism and scope of this
reaction are currently underway in our laboratory.
Having established the reaction conditions, we further
explored the generality and efficiency of the FeCl3-cata-
lyzed direct alkylation of various active methylene
compounds such as a b-diketone, acyclic and cyclic b-
ketoesters and a b-diester with benzylic and allylic alco-
hols. In general, the reaction proceeded smoothly for all
cases in very good to excellent yields within a very short
period of time with complete selectivity. The results are
summarized in Table 2.
In conclusion, we have developed a new, efficient and
highly atom-economical method for direct benzylation
and allylation of active methylene compounds with var-
ious benzyl and allyl alcohols.
This procedure worked well with cyclic b-ketoester 1d
(Table 2, entries 17 and 18), a reaction which has not
previously been reported by other Lewis acid mediated
reactions.8,9 Both electron rich and electron poor benzyl
alcohols (Table 2, entries 2, 4, 11 and 15) underwent
smooth conversion to the desired products with excel-
lent yields. Alcohols sensitive to acid catalyzed dehydra-
tion also tolerated this method (Table 2, entries 3, 4, 5,
12 and 13). Surprisingly this method gave good yields
with primary benzylic alcohols (Table 2, entries 7, 8
Acknowledgements
We are pleased to acknowledge the financial support
from Jadavpur University and UGC-NET, New Delhi.
S.B. is also thankful to the UGC for his fellowship.
8
and 9). This reaction has not been reported using InCl3

U. Jana et al. / Tetrahedron Letters 48 (2007) 4065–4069
4069
Compound 3k (entry 11): Mixture of diastereoisomers: IR
References and notes
1
(neat) 1743, 1714, 1512, 1251 cmÀ1; H NMR (300 MHz,
CDCl3) d 0.98–1.06 (m, 3H), 2.09 (s, 3H), 3.74 (s, 3H),
3.94–4.03 (m, 2H), 4.47 (d, J = 12.2 Hz, 1H), 4.72 (d,
J = 12.2 Hz, 1H), 6.80 (d, J = 8.6 Hz, 2H), 7.12–7.22 (m,
7H); 13C NMR (75 MHz, CDCl3) d 13.84, 13.92, 30.02,
30.10, 50.20, 50.25, 55.24, 55.26, 61.53, 61.57, 65.45, 65.52,
114.06, 114.29, 126.82, 126.94, 127.66, 127.76, 127.95,
128.67, 128.80, 128.91, 133.40, 133.81, 141.70, 141.98,
158.44, 158.48, 167.82, 201.96, 202.11; HRMS: m/z calcd
for C20H22O4Na: 349.1416; found, 349.1404.
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Compound 3q (entry 17): IR (neat) 2979, 1749, 1718 cmÀ1
;
1H NMR (300 MHz, CDCl3) d 0.84 (t, J = 7.10 Hz, 2H),
1.45–1.49 (m, 1H), 1.66–1.89 (m, 2H), 2.20–2.30 (m, 2H),
3.03–3.07 (m, 1H), 3.84–4.01 (m, 2H), 5.25 (s, 1H), 7.07–
7.28 (m, 10H); 13C NMR (75 MHz, CDCl3) d 13.86, 20.14,
29.84, 38.91, 55.38, 62.06, 66.52, 126.89, 127.20, 128.69,
128.78, 128.44, 129.30, 130.56, 140.76, 141.68, 169.12,
214.36; HRMS: m/z calcd for C21H22O3Na: 345.1470;
found, 345.1467.
Compound 3r (entry 18): Mixture of diastereoisomers: IR
1
(neat) 2962, 1751, 1718, 1512 cmÀ1; H NMR (300 MHz,
CDCl3) d 0.81–0.92 (m, 3H), 1.47–1.54 (m, 1H), 1.70–1.90
(m, 2H), 2.21–2.31 (m, 2H), 3.00–3.10 (m, 1H), 3.74 (s,
1.8H), 3.77 (s, 1.2H), 3.85–4.00 (m, 2H), 5.19 (s, 0.4H),
5.21 (s, 0.6H), 6.72–6.82 (m, 2H), 6.98–7.10 (m, 2H), 7.17–
7.29 (m, 5H), 13C NMR (75 MHz, CDCl3) d 13.54, 13.68,
19.81, 19.87, 29.40, 29.42, 38.64, 38.65, 54.29, 55.20, 55.25,
54.35, 61.71, 61.75, 66.30, 66.40, 113.70, 113.77, 126.46,
128.33, 126.79, 128.44, 128.84, 130.04, 130.12, 131.24,
132.50, 133.32, 140.73, 141.65, 158.18, 158.36, 168.82,
168.84, 214.16, 214.30; HRMS: m/z calcd for
C22H24O4Na: 375.1570; found, 375.1572.
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11. Representative experimental procedure: To a stirred solu-
tion of benzhydrol 2a (184 mg, 1 mmol) and acetyl acetone
2a (100 mg, 1 mmol) in dry dichloromethane (4 mL) was
added anhydrous FeCl3 (16 mg, 0.1 mmol). The mixture
was refluxed for 3 h and concentrated under reduced
pressure and then the residue was purified by silica gel
column chromatography to afford 3-benzhydryl pentane
2,3-dione 3a as a white solid (261 mg, 0.98 mmol); mp
115 °C (lit. 115 °C);9a 1H NMR (300 MHz, CDCl3) d 2.00
(s, 6H), 4.71–4.83 (m, 2H), 7.16–7.20 (m, 2H), 7.26–7.30
(m, 8H).
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The spectral data for unknown compounds are given
below:
Compound 3e (entry 5): IR (neat) 2966, 1726, 1967 cmÀ1
;
1H NMR (300 MHz, CDCl3) d 0.69 (t, J = 7.3 Hz, 3H),
1.44–1.60 (m, 2H), 1.81 (s, 3H), 2.27 (s, 3H), 3.30–3.39 (m,
1H), 4.10 (d, J = 11.6 Hz, 1H), 7.13–7.31 (m, 5H); 13C
NMR (75 MHz, CDCl3) d 11.68, 27.64, 29.74, 29.94,
47.74, 76.26, 127.11, 128.35, 128.75, 140.60, 203.47,
203.75; HRMS: m/z calcd for C14H18O2Na: 241.1204;
found, 241.1218.