A nucleophilic Fe catalyst for transesterifications under neutral conditions

Article abstract of DOI:10.1021/ol702580a

Carboxylic esters belong to the most important functional groups in organic chemistry. Strong efforts have been made in developing mild catalytic procedures for their preparation. Among the various methods developed to date, transesterifications have occupied an important space. In the present paper, a new catalytic method for this process based on the use of nucleophilic Fe(-II) complexes is presented. Evidence for the formation of an intermediate acyl Fe complex will be presented as well as investigations on scope and limitations.

Full text of DOI:10.1021/ol702580a

ORGANIC
LETTERS
2008
Vol. 10, No. 1
53-56
A Nucleophilic Fe Catalyst for
Transesterifications under
Neutral Conditions
Silja Magens, Melanie Ertelt, Anja Jatsch, and Bernd Plietker*
Institut fu¨r Organische Chemie, FB Chemie, UniVersita¨t Stuttgart, Pfaffenwaldring 55,
D-70569 Stuttgart, Germany
bernd.plietker@oc.uni-stuttgart.de
Received October 23, 2007
ABSTRACT
Carboxylic esters belong to the most important functional groups in organic chemistry. Strong efforts have been made in developing mild
catalytic procedures for their preparation. Among the various methods developed to date, transesterifications have occupied an important
space. In the present paper, a new catalytic method for this process based on the use of nucleophilic Fe(−II) complexes is presented. Evidence
for the formation of an intermediate acyl Fe complex will be presented as well as investigations on scope and limitations.
Within the past years, the use of less toxic and expensive
transition metals as environmentally benign catalysts has
gained increasing importance in organic chemistry. In
particular Fe-derived catalysts moved into the research focus
due to their ubiquitous availability and low toxicity.1
Recently, we initiated a research program aimed toward the
use of nucleophilic Fe complexes as novel catalysts for
organic syntheses. As a part of these investigations, we were
able to develop a protocol for allylic substitutions based on
the use of catalytic amounts of [Bu4N][Fe(CO)3(NO)]2 as a
nucleophilic Fe(-II) complex that allowed for a regioselec-
tive allylic substitution or amination.3 On the basis of recent
progress on the use of isoelectronic [Co(CO)4]- as catalyst
for transesterifications4 and with regard to the seminal
contribution of Coleman on the use of stoichiometric amounts
of acyl Fe complexes in various organic reactions,5 we
speculated that our nitrosyl Fe(-II) complex could act as a
potential acyl carrier in transesterification reactions. These
transformations are particularly challenging since they are
in equilibrium.6
Due to the importance of this reaction for organic
synthesis, a plethora of stoichiometric or catalytic methods
has been developed.7 The majority of methods, in which
(3) (a) Plietker, B. Angew. Chem. 2006, 118, 1497; Angew. Chem., Int.
Ed. 2006, 45, 1469. (b) Plietker, B. Angew. Chem. 2006, 118, 6200; Angew.
Chem., Int. Ed. 2006, 45, 6053. (c) Plietker, B.; Dieskau, A.; Mo¨ws, K.;
Jatsch, A. Angew. Chem. 2007, DOI: 10.1002/ange.200703874; Angew.
Chem., Int. Ed. 2007, DOI: 101002/anie.200703874.
(1) (a) Review on Fe catalysis: Bolm, C.; Legros, J.; Le Paih, J.; Zani,
L. Chem. ReV. 2004, 104, 6217. (b) Review on Fe-catalyzed cross-
couplings: Fu¨rstner, A.; Martin, R. Chem. Lett. 2005, 34, 624.
(2) (a) Hieber, W.; Kahlen, N.; Chem. Ber. 1958, 91, 2223. (b) Hieber,
W.; Kahlen, N. Chem. Ber. 1958, 91, 2234.
(4) (a) Wack, H.; Drury, W. J., III; Taggi, A. E.; Ferraris, D.; Lectka,
Th.; Org. Lett. 1999, 1, 1985. (b) Sun, H.; Zhang, J.; Liu, Q.; Yu, L.; Zhao,
J.; Angew. Chem. 2007, 119, 6180; Angew. Chem., Int. Ed. 2007, 46, 6068.
(5) Coleman, J. P. Acc. Chem. Res. 1975, 8, 342 and references cited
therein.
10.1021/ol702580a CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/04/2007

transition metal catalysts are used, employ either Lewis
acidic8 or alkoxide-based complexes,7,8 which limits their
scope due to their incompatibility with certain functional
groups. Among the metal-catalyzed protocols developed to
date, Otera’s tin-based catalysts proved to possess the
broadest applicability.6 Organocatalytic protocols are some-
what complementary. In general, a nucleophilic species, such
as a nitrogen base9 or carbene, is employed.10 These
procedures are much milder and allow for a selective
transesterification paired with a higher tolerance for func-
tional groups.
Table 1. Fe-Catalyzed Acylation of Alcohols
We started our investigation on the acylation of sterically
hindered L-menthol in the presence of vinyl acetate. We were
delighted to find that the reaction proceeds under the reaction
conditions known from the allylic substitution (Figure 1).
Figure 1. Solvent effects in Fe-catalyzed transesterification of
L-menthol.
Moreover, further solvent screening indicated that methyl
tert-butyl ether and n-hexane increase the reactivity signifi-
cantly.
Whereas the addition of ligands had no significant influ-
ence on the course of the reaction, the addition of 4 Å
molecular sieves (MS) proved beneficial. Under optimized
conditions, a decrease in the catalyst loading down to only
2.5 mol % and a reduction of the acyl donor down to only
1.5 equiv was possible. Having in hand the optimized
conditions, we were keen to explore the reaction scope (Table
a All reactions were performed on a 1 mmol scale in the presence of
vinyl acetate (1.5 mmol), 4 Å MS (100 mg), and Fe catalyst (0.025 mmol)
under a N2 atmosphere in n-hexane (1 mL). b Isolated yield. c Yield
according to GC integration (internal standard: n-dodecane).
1). As expected, the rate of this transformation is dependent
on steric congestions. Whereas primary and secondary
alcohols are esterified in good to excellent yields, tertiary
and sterically hindered secondary alcohols are almost unre-
active. The low reactivity, however, might be compensated
if the OH group is located in an allylic position.
(6) (a) Otera, J. Chem. ReV. 1993, 93, 1449. (b) Otera, J. Acc. Chem.
Res. 2004, 37, 288.
With regard to the applicability of this process to the
synthesis of more complex substrates, we subsequently
turned our attention to the identification of alternative
carboxyl donors. Although enol esters are available, the use
of simple and readily accessible carboxyl donors possesses
synthetic and practical advantages, among which the recy-
(7) For an excellent monography on this topic, see: Otera, J. Esterfi-
cation: Methods, Reactions and Applications; Wiley-VCH: Weinheim,
Germany, 2003.
(8) Stanton, M. G.; Gagne´, M. R. J. Org. Chem. 1997, 62, 8240.
(9) Taber, D. F.; Amedoi, J. C., Jr.; Patel, Y. K. J. Org. Chem. 1985,
50, 3618.
(10) For a recent review on transesterifications, see: Grassa, G. A.; Singh,
R.; Nolan, S. P. Synthesis 2004, 971.
54
Org. Lett., Vol. 10, No. 1, 2008

cling of the activating group is the most prominent one.
Hence some common acyl donor reagents were subjected to
the standard reaction conditions. Gratifyingly, we found
phenyl acetate to work equally well in the transesterification
process although at the cost of prolonged reaction times
(entry 2, Table 2). Alternative acyl donors, however, reacted
efficiently (Table 3). Whereas primary hydroxyl groups are
esterified in good yields, sterically more hindered secondary
and tertiary alcohols were unreactive.
The activating groups used so far increase the electrophi-
licity of the carbonyl carbon in order to facilitate the initial
addition of the Fe-based transesterification catalyst. The
strategy of using an electron-withdrawing activator in order
to increase the electrophilicity of otherwise less electrophilic
carbonyl groups is necessary for transesterifications using
electron-rich carboxylic moieties. The situation for the
reaction between an alcohol and a carboxylic acid that is
activated by an electron-withdrawing neighboring group is
somewhat different. The inherent higher electrophilicity of
the carbonyl group should allow for a transesterification
without the use of any activating group. In order to test this
hypothesis for our reaction, some activated methyl esters
were subjected to the reaction conditions (Table 4).
Table 2. Variation of the Acyl Donor
Table 4. Fe-Catalyzed Transesterification of Electron-Poor
Methyl Esters
a All reactions were performed on a 1 mmol scale in the presence of the
acyl donor (1.5 mmol), 4 Å MS (100 mg), and Fe catalyst (0.025 mmol)
under a N2 atmosphere in n-hexane (1 mL). b Conversion according to GC
integration. Conversion of the reaction in the absence of Fe catalyst is given
in parentheses.
in low conversions or even noncatalyzed in a sluggish way
(entries 3 and 4, Table 2).
In the process of these investigations, different phenyl
esters were prepared following standard procedures and were
subjected to the transesterification conditions (Table 3).
Under the standard reaction conditions, functionalized car-
boxylic acid esters possessing one or more π-bonds or
heterofunctionalities such as amide groups are esterified
a All reactions were performed on a 1.5 mmol scale in the presence of
alcohol 18 (1.0 mmol), 4 Å MS (100 mg), and Fe catalyst (0.025 mmol)
under a N2 atmosphere in n-hexane (1 mL). b Isolated yield. c 3 mmol of
alcohol 18 was used. The yield refers to the bis(2-phenyl ethyl) ester.
Table 3. Fe-Catalyzed Acylation of Alcohols
Fortunately, the activation by an electron-withdrawing
functional group allows for the mild transesterification of
different carboxylic acid methyl esters. Moreover, the
transesterification is applicable to sterically hindered car-
boxylic esters, as well. Hence, subjecting malonate 28 to
the standard reaction conditions led to the isolation of product
29 in moderate yield (Scheme 1). In sharp contrast to the
transesterification using dimethylmalonate 24, even in the
Scheme 1. Fe-Catalyzed Transesterification of Sterically
Hindered Malonate 28
a All reactions were performed on a 1.5 mmol scale in the presence of
alcohol 18 (1.0 mmol), 4 Å MS (100 mg), and Fe catalyst (0.025 mmol)
under a N2 atmosphere in n-hexane (1 mL). b Isolated yield.
Org. Lett., Vol. 10, No. 1, 2008
55

excess of alcohol 18, no double transesterification was
observed. This might be the result of the increase in steric
hindrance after the first transesterification event.
Although this result is of limited practical interest, it sheds
some light into the mechanism of this reaction. The suc-
cessful transesterification excludes the intermediate formation
of a ketene as it is observed under thermal conditions. In
analogy to the transesterifications catalyzed by tertiary N
bases, such as DMAP, we propose the reaction to proceed
via an intermediate carboxyl Fe complex iv, which is formed
upon nucleophilic displacement of the activating group in
the original acyl donor ii. The second nucleophilic attack of
alcohol iii leads to the formation of the desired product while
regenerating the catalytically active Fe catalyst. A mecha-
nistic rationale for this unprecedented reaction is shown in
Figure 2.
In the present communication, we summarized our initial
results on the use of nucleophilic Fe(-II) complexes as
catalyst for the mild transesterification of vinyl acetates,
phenyl carboxylates, and activated electron-poor esters using
primary, secondary, and tertiary (activated) alcohols. The
catalyst used in these studies allows for the reaction to be
performed under neutral conditions, which is in sharp contrast
to the alkoxide-based or Lewis acidic metal catalysts
employed in the majority of transesterification protocols.
Future work will concentrate on an extension of the
reaction scope and on mechanistic investigations aimed
toward the identification of catalytic intermediates. If our
mechanistic hypothesis holds true, the present reaction would
Figure 2. Mechanistic proposal.
be the first example of a catalytically active acyl Fe complex
and might open the door for an entire new field of Fe
catalysis in organic chemistry.
Acknowledgment. Financial support by the Fonds der
Chemischen Industrie, the Deutsche Forschungsgemeinschaft,
and the Deutsche Krebshilfe is gratefully acknowledged.
Supporting Information Available: Characterization
data for all new compounds and experimental procedures
are included. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL702580A
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Org. Lett., Vol. 10, No. 1, 2008