An efficient iron-catalyzed carbon-carbon single-bond cleavage via retro-claisen condensation: A mild and convenient approach to synthesize a variety of esters or ketones

Article abstract of DOI:10.1002/ejoc.201000128

An efficient iron-salt-catalyzed carbon-carbon bond cleavage occurring through a retro-Claisen condensation reaction has been developed. The reaction is useful for the synthesis of a variety of esters or ketones under mild conditions. This method works under solvent-free conditions without the need of an inert atmosphere. This protocol is also applicable for the one-pot syntheses of ketones through tandem carbon-carbon bond formation (substitution or Michael) followed by a retro-Claisen reaction. However, for Michael adducts, ring annulation takes place subsequently. Notably, this method is very simple, convenient, high yielding, and only a catalytic (5 to 1.0 mol-%) amount of Fe(OTf)₃ is needed.

Full text of DOI:10.1002/ejoc.201000128

FULL PAPER
DOI: 10.1002/ejoc.201000128
An Efficient Iron-Catalyzed Carbon–Carbon Single-Bond Cleavage via
Retro-Claisen Condensation: A Mild and Convenient Approach to Synthesize a
Variety of Esters or Ketones
Srijit Biswas,[a] Sukhendu Maiti,[a] and Umasish Jana*[a]
Keywords: Iron / Nucleophilic addition / Cleavage reactions / Esters / Ketones
An efficient iron-salt-catalyzed carbon–carbon bond cleav-
age occurring through a retro-Claisen condensation reaction
has been developed. The reaction is useful for the synthesis
of a variety of esters or ketones under mild conditions. This
method works under solvent-free conditions without the
need of an inert atmosphere. This protocol is also applicable
for the one-pot syntheses of ketones through tandem carbon–
carbon bond formation (substitution or Michael) followed by
a retro-Claisen reaction. However, for Michael adducts, ring
annulation takes place subsequently. Notably, this method is
very simple, convenient, high yielding, and only a catalytic
(5 to 10 mol-%) amount of Fe(OTf)3 is needed.
Therefore, considering these advantages and the diversity
of iron, the discovery of new iron-catalyzed reactions and
methodologies is still very much in demand in both acade-
mia and industrial research.
Introduction
Transition-metal-catalyzed reactions are among the most
powerful tools in modern organic synthesis. Extensive re-
search has been done in the development of palladium-,
ruthenium-, rhodium-, iridium-, and even nickel-catalyzed
reactions. However, due to the high cost and toxic nature
of many of these metal catalysts, there has been a recent
surge in the development of organic transformations cata-
lyzed by much cheaper and more environmentally friendly
metals. In this regard, iron has received a great deal of at-
tention as an effective and promising alternative transition
metal in the field of catalysis due to its high abundance, low
price, and environmentally friendly characteristics.[1] As a
consequence, a series of novel iron-catalyzed organic trans-
formations have been developed. Since the pioneering re-
search work of Tamura and Kochi,[2] a number of reactions
including iron-catalyzed oxidation,[3] hydrogenation,[4]
hydrosilylation,[5] rearrangement,[6] Michael addition,[7] car-
bon–carbon[8–10] and carbon–heteroatom bond-forming re-
actions,[11] and oxidative coupling of arynes[12] have been
extensively studied. In addition to that, various iron-cata-
lyzed cross-coupling reactions including Sonogashira,[13]
Heck,[14] Kumada,[15] Negishi,[16] and Suzuki[17] reactions
have also been developed. Moreover, iron salts have been
successfully employed for the synthesis of various heterocy-
clic compounds by us and other groups.[18] More recently,
we[19] and others[20] have also discovered novel iron-cata-
lyzed activation of alcohols towards various nucleophiles.
On the other hand, the catalytic cleavage of a carbon–
carbon single bond by transition-metal complexes is a po-
tentially useful organic transformation, for which, extensive
studies have been done.[21] However, in most of the reac-
tions, highly strained compounds such as three- or four-
membered carbocycles[22] and compounds with good leav-
ing groups[23] or chelating compounds[24] have been demon-
strated as substrates. Therefore, the development of new re-
actions and reagents for the catalytic cleavage of the car-
bon–carbon bond remains a challenging issue.
During our recent investigation of iron-salt-mediated
direct alkylation of active methylene compounds with
benzylic and allylic alcohols,[19d] we noticed that when an
aliphatic alcohol was treated with acetylacetone, an ester
was produced by direct carbon–carbon bond cleavage
through a retro-Claisen condensation type reaction.[25] This
observation encouraged us to study systematically the scope
of this reaction in organic synthesis. Herein, we wish to re-
port our discovery of an efficient, mild, and inexpensive
iron(III) trifluoromethanesulfonate mediated carbon–car-
bon bond cleavage reaction for the synthesis of esters or
ketones from acetylacetone and their derivatives by direct
[a] Department of Chemistry, Jadavpur University,
Kolkata 700032, West Bengal, India
Fax: +91-33-2414-6584
E-mail: jumasish2004@yahoo.co.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000128.
Scheme 1. Iron-salt-catalyzed retro-Claisen condensation reaction.
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2861
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S. Biswas, S. Maiti, U. Jana
FULL PAPER
carbon–carbon bond cleavage through a retro-Claisen con- Table 1. Reactions of acetylacetone (1a) with phenethyl alcohol
(2a) under various conditions in the presence of different cata-
densation reaction without the use of traditional organic
solvents (Scheme 1).
lysts.[a]
Results and Discussion
Entry Catalyst (mol-%)
Solvent
T [°C]
Yield [%][b]
1
2
3
4
5
6
7
8
9
FeCl3 (10)
FeCl3 (10)
FeCl3 (5)
FeCl3 (3)
FeBr3 (5)
1,2 DCE[c]
no solvent
no solvent
no solvent
no solvent
no solvent
no solvent
no solvent
no solvent
no solvent
no solvent
80
80
80
80
80
80
80
60
80
80
80
N.R.[d]
78
79
70
72
Synthesis of Esters
Ester formation is a fundamental reaction in organic syn-
thesis, as esters are very important in daily life and in vari-
ous fields of organic synthesis. Consequently, various meth-
ods have been developed,[26] and still it is highly desirable
to develop a new and cost-saving reaction for the prepara-
tion of esters under neutral mild conditions. The reaction
we wish to report here for the synthesis of esters is general,
convenient, and less expensive, and it works under neutral
conditions without any solvents in the presence of catalytic
iron salt.
Fe(OTf)3[e] (5)
Fe(OTf)3 (3)
Fe(OTf)3 (5)
Fe(acac)3[f] (5)
TfOH (15)
HCl (15)
98
92
22
N.R.[d]
36
10
11
27
[a] Reaction conditions: 1a (1 mmol), 2a (1 mmol), and catalyst
(0.05 mmol). [b] Pure, isolated yield after column chromatography.
[c] 1,2-DCE
[e] Fe(OTf)3 = iron(III) trifluoromethanesulfonate. [f] Fe(acac)3
iron(III) acetylacetonate.
= 1,2-dichloroethane. [d] N.R. = no reaction.
=
To optimize the reaction conditions, we initially studied
the reaction between phenethyl alcohol (2a) and acetyl-
acetone (1a) in different solvents, at different temperatures,
and with different amounts of the catalyst (Table 1). No efficiently with unsymmetrical 1,3-diketone such as acetyl-
reaction took place in 1,2-dichloroethane at 80 °C in the acetophenone (1b) chemoselectively, producing ester 3a in
presence of 10 mol-% of FeCl3 (Table 1, Entry 1); 78% yield 85% yield (Table 2, Entry 2); that is, the alcohol attacked
of the desired product was obtained when the reaction was only at the more reactive carbonyl carbon atom. Likewise,
carried out under neat conditions (Table 1, Entry 2). The benzoylacetophenone (1c) also reacted with phenethyl
product was obtained in almost the same yield with the use alcohol (2a) to give benzoyl ester 3c (Table 2, Entries 2 and
of 5 mol-% of FeCl3 (Table 1, Entry 3). Upon reduction of 3). However, due to the low reactivity of the carbonyl car-
the amount of catalyst to 3 mol-%, the yield of the product bon atom of compound 1c the reaction worked at higher
decreased (Table 1, Entry 4). Next, we examined different temperature (120 °C); under these conditions, desired prod-
iron salts (5 mol-%) at 80 °C without using any solvents to uct 3c was obtained in 87% yield. Moreover, cyclic 1,3-dike-
study their catalytic activities towards this reaction. FeBr3 tones such as 2-acetylcyclopentanone (1d) and 2-acetylcy-
also catalyzed the reaction and afforded the desired product clohexanone (1e) also underwent smooth carbon–carbon
in 72% yield (Table 1, Entry 5), whereas no reaction took bond cleavage with various alcohols in a highly regiospec-
place in the presence of Fe(acac)3 (Table 1, Entry 9). It was ific manner to yield exclusively the corresponding acyclic
observed that the reaction proceeded more efficiently when keto esters (Table 2, Entries 4–9, 11–14) in high yields. Sim-
Fe(OTf)3 (5 mol-%) was used as the catalyst to produce the ple aliphatic alcohols such as methanol (2i), ethanol (2b),
product in almost quantitative yield (Table 1, Entry 6). n-butanol (2c), and 3-methylbutanol (2d) were found to be
Decreasing the temperature as well as the amount of equally efficient nucleophiles. Furthermore, allyl (2e) and
Fe(OTf)3 led to a decrease in the yield of the desired prod- propargyl alcohols (2f) also reacted smoothly with 1d or 1e
uct (Table 1, Entries 7 and 8). The efficiency of Fe(OTf)3 to produce the corresponding long-chain keto esters with-
can be explained from the fact that metal triflates are more out disturbing the double and triple bonds (Table 2, En-
stable in protic media such as water and alcohols; moreover, tries 7, 8, 13, and 14). The secondary alcohol 2-propanol
iron(III) triflate is a stronger Lewis acid than FeCl3. The (2g) also reacted with 1d to produce corresponding keto
Brønsted acids TfOH and HCl were tested to catalyze this ester 3h in 82% yield (Table 2, Entry 9), whereas tert-butyl
reaction; however, the desired products were obtained in alcohol did not produce the desired ester with the reaction
very low yield even when the reaction was heated for a long of 2-acetylcyclopentanone (1d). Instead, carboxylic acid 3i
period of time (Table 1, Entries 10 and 11). From this ob- was produced (Table 2, Entry 10).[27] However, due to their
servation it may be concluded that the iron salt is directly low boiling points and volatility, all the alcohols except 2a
involved in the catalytic process. However, the generation were used in excess amounts (5 equiv.) with respect to the
and involvement of partly formed Brønsted acid cannot be diketones for their complete conversion to the desired prod-
completely over ruled in this transformation. The reaction uct. It is noteworthy that water also participated in this re-
did not proceed without any catalyst.
action as a nucleophile, as the reaction of water with cyclic
After optimizing the reaction conditions, we used dif- 1,3-diketones 1d and 1e produced the corresponding long-
ferent types of 1,3-diketones as well as alcohols; the results chain keto acids in 78 and 87% yield, respectively (Table 2,
are summarized in Table 2. Alcohol 2a was found to react Entries 15 and 16).
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Iron-Catalyzed Carbon–Carbon Single-Bond Cleavage
Table 2. Reactions of various 1,3-diketones with various alcohols tional simplicity in the presence of less-expensive catalysts
or water to produce esters or acids.[a]
is still highly desirable. After successful development of a
procedure for the synthesis of esters, we applied this retro-
Claisen condensation strategy to the synthesis of various
methyl ketones. In this strategy, simple aliphatic alcohols
such as methanol or butanol were used to cleave the car-
bon–carbon bond of substituted 1,3-diketones in the pres-
ence of a catalytic amount of Fe(OTf)3 so that volatile ester
components would be formed and could be removed during
workup. The results are summarized in Table 3. A wide
range of acetylacetone derivatives underwent the reaction
Table 3. Reactions of various substituted 1,3 diketones with
alcohols to produce methyl ketones.[a]
[a] Reaction conditions: 1,3-Diketone (1 mmol), alcohol or water
(5 mmol), Fe(OTf)3 (0.05 mmol), neat, 80 °C, 10 h. [b] Pure, iso-
lated yield after column chromatography. [c] 1 mmol of alcohol was
used. [d] Reaction was carried out at 120 °C.
Synthesis of Ketones
The derivatives of methyl ketone are important building
block in organic synthesis. Moreover, many methyl ketone
derivatives are present in flavor and aroma substances, and
some methyl ketones are natural products that are gener-
ated from decarboxylation of the corresponding fatty acids.
Consequently, a wide number of methods have been devel-
oped.[28] However, many of these methods suffer from a
[a] Reaction conditions: 1,3-Diketone (0.5 mmol), alcohol
(2.5 mmol), Fe(OTf)3 (0.025 mmol), neat, 90 °C, 12 h; then,
Fe(OTf)3 (0.025 mmol), 12 h. [b] Pure, isolated yield after column
chromatography. [c] Reaction was carried out at 120 °C. [d] 1,3-Di-
ketone (0.5 mmol), alcohol (2.5 mmol), Fe(OTf)3 (0.025 mmol),
neat, 120 °C, 10 h. [e] 1,3-Diketone (0.5 mmol), alcohol (2.5 mmol),
number of drawbacks such as the use of expensive and toxic
chemicals, unavailability of substrates, and cumbersome
procedures for product isolation. Therefore, the develop-
ment of new methods for the synthesis of methyl ketones in
terms of efficiency, mild reaction conditions, and opera- Fe(OTf)3 (0.025 mmol), neat, 90 °C, 10 h.
Eur. J. Org. Chem. 2010, 2861–2866
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S. Biswas, S. Maiti, U. Jana
FULL PAPER
smoothly with methanol (Table 3, Entries 1–5) to afford the annulations, leading to the one-pot synthesis of cyclohex-
desired methyl ketone derivatives in high yields, and in this enone derivatives 3x and 3y in good yields (Scheme 3).
reaction, volatile methyl acetate was formed as a byproduct.
When ethanol was used in place of methanol at 90 °C, a
lower yield of the desired product was observed. Probably,
at this temperature methanol is a better nucleophile com-
pared to its higher homolog due to steric reason. However,
with high boiling alcohols such as n-butanol the reaction
works efficiently at 120 °C, but the reaction was very slow
at 90 °C. So, the size of the alcohol and the effect of tem-
perature are very important for the efficient synthesis of
ketones. 1,3-Diketone 1k (Table 3, Entry 6) reacted ef-
ficiently with n-butanol to give a mixture of two unequal
amounts of ketones at 120 °C; the major product was ob-
tained by the reaction of the alcohol at the more reactive
carbonyl carbon atom. Similarly, with substituted cyclic
1,3-diketones such as 1l, 1m, and 1n (Table 3, Entries 7–9),
the alcohol reacted chemoselectively at the ring carbonyl
carbon atom and produced substituted methyl ketones in
good yields. Interestingly, the Michael adduct of acetyl-
acetone 1o (Table 3, Entry 10) also underwent smooth
retro-Claisen condensation; however, under the reaction
conditions ring annulations of the intermediate product in
the presence of the iron salt took place, leading to cyclohex-
enone derivative 3x in 78% yield.
On the basis of the experimental results, a possible
mechanism for the iron-salt-catalyzed retro-Claisen conden-
sation of 1,3-diketones is shown in Scheme 4. It is well
known that iron salts can coordinate to 1,3-diketones[7c] to
thus produce either B or C. This complexation increases the
nucleophilicity at the methylene carbon atom, so it can re-
act with a suitable electrophile such as a benzylic or allylic
carbocation, which can be generated from benzyl or allyl
alcohol.[19d] Moreover, it also simultaneously increases the
electrophilicity of the carbonyl carbon atom, so it can react
with suitable nucleophiles such as alcohols and water. Nu-
cleophilic addition of an alcohol affords intermediate D or
E, which then undergoes carbon–carbon bond cleavage
through a retro-Claisen condensation reaction and elimi-
nation of ester F and iron enolate G, which after proton-
ation regenerates the catalyst to produce ketone H. De-
pending on the nature of the alcohol or 1,3-diketone it
would be possible to synthesize either esters or ketones, as
the other component will be volatile and can be separated
during isolation of the product.
One-Pot Tandem C–C Bond Formations/Retro-Claisen
Condensations
To make this protocol more attractive, we investigated
the iron-salt-catalyzed tandem carbon–carbon bond forma-
tion through direct substitution of benzylic alcohols with
acetylacetone[19d] followed by carbon–carbon bond cleavage
to achieve ketones in one pot. To our delight, this one-pot
reaction also worked efficiently and gave desired products
3o and 3p in good yields: 69 and 65%, respectively
(Scheme 2). Similarly, we also demonstrated the iron-salt-
catalyzed tandem carbon–carbon bond formation through
Michael reaction of acetylacetone with α,β-unsaturated
Scheme 4. A possible mechanism for the iron-catalyzed carbon–
ketones[7c] followed by retro-Claisen condensation and ring carbon bond cleavage reaction.
Scheme 2. Fe(OTf)3-catalyzed tandem C–C bond formation and C–C bond cleavage.
Scheme 3. Fe(OTf)3-catalyzed tandem C–C bond formation, C–C bond cleavage, and ring annulation.
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Iron-Catalyzed Carbon–Carbon Single-Bond Cleavage
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Conclusions
In summary, we have demonstrated a novel and efficient
iron-salt-catalyzed carbon–carbon bond cleavage[29] of 1,3-
diektones, which occurs through a retro-Claisen condensa-
tion reaction. This protocol provides a simple and conve-
nient strategy for the efficient synthesis of structurally di-
verse esters or substituted methyl ketones. Moreover, tan-
dem carbon–carbon bond formation (through substitution
or Michael addition) followed by carbon–carbon bond
cleavage in one pot has also been demonstrated. Notably,
the use of less expensive and environmentally friendly iron
salts makes this protocol very attractive, and it can be useful
for large-scale applications.
[4]
[5]
Experimental Section
Representative Experimental Procedure for the Synthesis of Phen-
ethyl Acetate (3a): A 5-mL screw-cap vial was charged with acetyl-
acetone (100 mg, 1.0 mmol) and phenethyl alcohol (122 mg,
1.0 mmol). To this mixture was added Fe(OTf)3 (25 mg,
0.05 mmol), and the reaction mixture was stirred vigorously with a
small magnet at 80 °C for 10 h, keeping the cap of the vial tightly
closed. The progress of the reaction was followed by TLC. The
reaction mixture was allowed to attain room temperature and was
then taken up in ethyl acetate (50 mL). This mixture was washed
with water (20 mL) followed by brine solution (20 mL), and the
organic phase was dried with anhydrous Na2SO4. The solvent was
removed under reduced pressure, and the product was purified by
silica gel column chromatography (5% ethyl acetate in petroleum
spirit) to afford 3a (161 mg, 0.98 mmol, 98%) as a yellowish liquid.
[6]
[7]
[8]
1H NMR (300 MHz, CDCl3): δ = 2.04 (s, 3 H), 2.94 (t, J = 7.1 Hz, [9]
2 H), 4.29 (t, J = 7.1 Hz, 2 H), 7.21–7.34 (m, 5 H) ppm.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and spectroscopic data of all compounds.
Acknowledgments
We are pleased to acknowledge the financial and infrastructural
assistance from the UGC-CAS Programme of the Department of
Chemistry, Jadavpur University. S.B. and S.M. are also thankful to
the University Grants Commission (UGC), New Delhi, India and
Jadavpur University, respectively, for their fellowships.
[10]
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Received: January 30, 2010
Published Online: April 8, 2010
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Eur. J. Org. Chem. 2010, 2861–2866