Acid-promoted olefination of ketones by an iron(III) porphyrin complex

Article abstract of DOI:10.1021/ol0347444

(Matrix presented) The acid-promoted olefination of unactivated ketones with diazo reagents in the presence of triphenylphosphine can be catalyzed by the commercially available iron(III) porphyrin complex Fe(TPP)Cl. The reactions were effectively carried out under mild conditions in a one-pot fashion with the use of a stoichiometric diazo reagents and substoichiometric benzoic acid. Examples include aromatic, aliphatic, cyclic, and unsaturated ketones with ethyl diazoacetate or tert-butyl diazoacetate.

Full text of DOI:10.1021/ol0347444

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2493-2496
Acid-Promoted Olefination of Ketones
by an Iron(III) Porphyrin Complex
Ying Chen, Lingyu Huang, and X. Peter Zhang*
Department of Chemistry, UniVersity of Tennessee, KnoxVille, Tennessee 37996-1600
pzhang@utk.edu
Received May 4, 2003
ABSTRACT
The acid-promoted olefination of unactivated ketones with diazo reagents in the presence of triphenylphosphine can be catalyzed by the
commercially available iron(III) porphyrin complex Fe(TPP)Cl. The reactions were effectively carried out under mild conditions in a one-pot
fashion with the use of a stoichiometric diazo reagents and substoichiometric benzoic acid. Examples include aromatic, aliphatic, cyclic, and
unsaturated ketones with ethyl diazoacetate or tert-butyl diazoacetate.
Transition metal complex-mediated olefination of carbonyl
compounds with diazo reagents in the presence of tertiary
phosphines has received increased attention in recent years.1
The new catalytic olefination approach promises to be
advantageous over the classic Wittig reaction, which cur-
rently remains the method of choice for constructing carbon-
carbon double bonds in organic synthesis for a variety of
applications.2 Specifically, the catalytic method can directly
use easily accessible diazo compounds3 for this important
and fundamental organic transformation under neutral condi-
tions, without the need for stepwise generation of phospho-
rane precursors under basic conditions. Furthermore, the
involvement of transition metal complexes in this process
could potentially allow the development of efficient asym-
metric olefination under catalytic conditions.4
Recently, we have developed general and efficient catalytic
systems, based on the commercially available Fe(TPP)Cl and
Ru(TPP)(CO) (Figure 1), for highly selective olefination of
a wide variety of aldehydes with ethyl diazoacetate (EDA)
in the presence of triphenylphosphine under mild conditions.5
Applying this methodology, we demonstrated that a series
of â-trifluormethyl-R,â-unsaturated esters can be efficiently
and stereoselectively synthesized form the corresponding
trifluormethyl ketones with EDA or tert-butyl diazoacetate
(t-BDA).6 When the method was applied to unactivated
ketones, however, no yields or very low yields of the desired
olefins were observed. After many failed attempts, we have
discovered that the addition of certain acids can dramatically
improve the olefination of unactivated ketones under condi-
tions similar to those for aldehydes. Herein, we report the
first examples of acid-promoted olefination of unactivated
(1) (a) Santos, A. M.; Roma˜o, C. C.; Ku¨hn, F. E. J. Am. Chem. Soc.
2003, 125, 2414. (b) Zhang, X.; Chen, P. Chem. Eur. J. 2003, 9, 1852. (c)
Cheng, G.; Mirafzal, G. A.; Woo, L. K. Organometallics 2003, 22, 1468.
(d) Mirafzal, G. A.; Cheng, G.; Woo, L. K. J. Am. Chem. Soc. 2002, 124,
176. (e) Grasa, G. A.; Moore, Z.; Martin, K. L.; Stevens, E. D.; Nolan, S.
P.; Paquet, V.; Lebel, H. J. Organomet. Chem. 2002, 658, 126. (f) Lebel,
H.; Paquet, V. Org. Lett. 2002, 4, 1671. (g) Lebel, H.; Paquet, V.; Proulx,
C. Angew. Chem., Int. Ed. 2001, 40, 2887. (h) Fujimura, O.; Honma, T.
Tetrahedron Lett. 1998, 39, 625. (i) Ledford, B. E.; Carreira, E. M.
Tetrahedron Lett. 1997, 38, 8125. (j) Herrmann, W. A.; Roesky, P. W.;
Wang, M.; Scherer, W. Organometallics 1994, 13, 4531. (k) Herrman, W.
A.; Wang, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1641. (l) Lu, X.;
Fang, H.; Ni, Z. J. Organomet. Chem. 1989, 373, 77.
(2) (a) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863. (b)
Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263. (c) Cristau, H.-J.
Chem. ReV. 1994, 94, 1299.
(3) (a) Ye, T.; McKervey, M. A. Chem. ReV. 1994, 94, 1091. (b) Doyle,
M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds: From Cyclopropanes to Ylides; John
Wiley & Sons: New York, 1998. (c) Doyle, M. P.; Forbes, D. C. Chem.
ReV. 1998, 98, 911.
(4) (a) Rein, T.; Reiser, O. Acta Chem. Scand. 1996, 50, 369. (b) Li,
A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. ReV. 1997, 97, 2341. (c) Rein,
T.; Pederson, T. M. Synthesis 2002, 5, 579.
(5) Chen, Y.; Huang, L.; Ranade, M. A.; Zhang, X. P. J. Org. Chem.
2003, 68, 3714.
(6) Chen, Y.; Huang, L.; Zhang, X. P. J. Org. Chem. In press.
10.1021/ol0347444 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/07/2003

Table 1. Olefination of Aldehydes and Activated and
Unactivated Ketones with EDA Catalyzed by Fe(TPP)Cla
Figure 1. Structures of Fe(TPP)Cl and Ru(TPP)(CO).
ketones with diazo reagents in the presence of triphenyl
phosphine catalyzed by the iron(III) porphyrin complex Fe-
(TPP)Cl.7,8 The catalytic reactions can be performed in a one-
pot fashion under mild conditions using substoichiometric
amounts of acid and can be applied to a variety of simple
ketones.
We first evaluated Fe(TPP)Cl-mediated olefination reac-
tions of different ketones under conditions that are similar
to those used for olefination of aldehydes5 and activated
trifluoromethyl ketones:6 the reactions were carried out in
toluene at 80 °C with 1.2 equiv of EDA using 1.5 mol %
Fe(TPP)Cl in the presence of 1.2 equiv of Ph3P per ketone
at a concentration of 0.25 M (0.50 mmol of ketone/2 mL of
toluene).9 Selected results are summarized in Table 1, along
with previous results for corresponding aldehydes5 and
trifluoromethyl ketones.6 As clearly shown in Table 1, it is
the electronic effect, not the steric effect, that is responsible
for the poor reactivities of simple ketones. For example, only
2% yield of desired olefin was observed for the reaction of
acetophenone under the aforementioned conditions after 51
h (Table 1, entry 3). As reported previously,5,6 the reactions
of benzaldehyde and trifluoroacetophenone under the same
conditions gave the corresponding olefins in 96 and 93%
yields, respectively, in much shorter reaction time (Table 1,
entries 1 and 2). Similar differences in reactivity were also
observed among R,â-unsaturated ketone trans-4-phenyl-3-
buten-2-one (18% yield in 50 h, Table 1, entry 6), trans-
cinnamaldehyde (99% yield in 1 h, Table 1, entry 4), and
trans-1,1,1-trifluoro-4-phenyl-3-buten-2-one (77% yield in
16 h, Table 1, entry 5). Low yields were also found for the
reactions of other ketones such as cyclic ketones (Table 1,
entries 7-9). Considering that the steric bulkiness of the
-CF3 group is at least the same as that for the -CH3 group,
the electron-withdrawing ability of the -CF3 group, which
enhances the electrophilicity of the carbonyl unit, is thus
probably related to the much higher olefination reactivity of
trifluoromethyl ketones than simple ketones.
a Reactions were carried out at 80 °C in toluene under N2 with 1.0 equiv
of ketone, 1.2 equiv of EDA, 1.2 equiv of Ph3P, and 1.5 mol % Fe(TPP)Cl.
Concentration: 0.5 mmol of ketone/2 mL of toluene. b Reaction times have
not been optimized. c Yields were determined by GC. d Results from ref 5.
e Results from ref 6.
Realization of the importance of carbonyl unit’s electro-
philicity in olefination reactions led us to search for potential
additives that could reduce the electron density of carbonyls
in simple ketones. Encouraged by previous reports on
hydrogen bonding- and Lewis acid-promoted reactivities of
unactivated ketones in different reactions,10 olefination
reactions of acetophenone in the presence of various additives
were systematically carried out. The results are summarized
in Table 2. Lewis acids had no effect on the reaction,
suggesting insufficient interaction between Lewis acid and
the carbonyl unit of acetophenone. For example, no formation
of desired olefin was observed when the reaction was
conducted in the presence of 0.3 equiv of BF3 for 19 h (Table
2, entry 1). Additives that could potentially form hydrogen
bonding with the carbonyl group were then examined. While
simple alcohols, even used as solvents, showed no activation
of the carbonyl group (Table 2, entry 2), addition of 1.0 equiv
of phenol resulted in formation of the desired olefin in 59%
isolated yield (Table 2, entry 4). No further improvement
was obtained with an increased amount of phenols (Table
(7) For catalytic olefination of fluorine-containing activated ketones, see
refs 6 and 1f.
(8) For a recent report on unsuccessful attempts to carry out catalytic
olefination of ketones under conditions similar to those used for aldehydes,
see ref 1c. With the use of large excesses of ketone and 2-4 days of reaction
time, the authors reported that acceptable yields of olefination products
(based on diazo reagent EDA) were obtained for a limited number of
ketones.
(10) (a) Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662.
(b) Jiang, S.; Turos, E. Tetrahedron Lett. 1991, 32, 4639. (c) Yasuda, M.;
Kitahara, N.; Fujibayashi, T.; Baba, A. Chem. Lett. 1998, 743.
(9) Caution: diazo compounds in general should always be presumed
to be potentially explosive, especially in large scale at high temperatures.
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Org. Lett., Vol. 5, No. 14, 2003

Table 2. Additive Effect on Olefination of Acetophenone with
Ethyl Diazoacetate (EDA) Catalyzed by Fe(TPP)Cla
Table 3. Acid-Promoted Olefination of Unactivated Ketones
with Ethyl Diazoacetate (EDA) Catalyzed by Fe(TPP)Cla
a Reactions were carried out in toluene under N2 with 1.0 equiv of ketone,
1.2 equiv of EDA, 1.2 equiv of Ph3P, and 1.5 mol % Fe(TPP)Cl in the
presence of acid. Concentration: 0.5 mmol of ketone/2 mL of toluene.
b Reaction times have not been optimized. c Yields were determined by GC.
d Ratio of E:Z isomers was determined by GC. e Yields represent isolated
1
yields of >95% purity as determined by GC and H NMR.
2, entry 5); dramatic yield reduction was observed when a
substoichiometric amount of phenol was used (Table 2, entry
3). A more remarkable effect, however, was noticed when
certain organic acids were used as additives. For example,
with addition of 0.5 equiv of benzoic acids, the olefination
of acetophenone with EDA at 80 °C in toluene changed from
a negative reaction (Table 1, entry 3) to a successful one
that afforded the desired olefin in 84% yield (Table 2, entry
8). This acid effect was observed even in the presence of
only 1.5-10 mol % benzoic acids (Table 2, entries 6 and
7), albeit to a lesser extent. It appeared that excess benzoic
acids could inhibit the reaction as observed in the reaction
with 2.5 equiv of the acids (Table 2, entry 9). Relatively
longer reaction times (∼50 h) and elevated temperatures
(∼80 °C) were needed for productive reactions, as lower
yields were obtained in either shorter reaction times (Table
2, entries 10 and 11) or at reduced reaction temperatures
(Table 2, entries 12 and 13). Higher reaction temperatures
did not improve the reaction further (Table 2, entry 14).
Several benzoic acid derivatives were also evaluated for
possible differences in promoting the reaction, including
those having an electron-withdrawing group (Table 2, entry
16), an electron-donating group (Table 2, entry 17), or an
ortho-substituted group (Table 2, entry 18).11 In all cases,
however, no noticeable differences in yields and (E)-
selectivity were found.
a Reactions were carried out at 80 °C in toluene under N2 with 1.0 equiv
of ketone, 1.2 equiv of EDA, 1.2 equiv of Ph3P, and 1.5 mol % Fe(TPP)Cl
in the presence of 0.5 equiv of benzoic acid. Concentration: 0.5 mmol of
ketone/2 mL of toluene. b Reaction times have not been optimized. c Yields
represent isolated yields of >95% purity as determined by GC and 1H NMR.
1
d Ratio of E:Z isomers was determined by GC or H NMR. e Yields were
determined by GC.
Using the above optimized reaction conditions (0.5 equiv
of benzoic acids at 80 °C in toluene) allowed the substrate
generality of the acid-promoted olefination to be investigated
using a variety of unactivated ketones (Table 3). Acetophe-
none having a para-chloro group could be olefinated in the
same yield as acetophenone, but in shorter reaction time and
better (E)-selectivity (Table 3, entries 1 and 2). When
4-nitroacetophenone was used, the desired olefin was ob-
tained in 93% yield and 69% (E)-selectivity (Table 3, entry
3). The 18% olefination yield of the R,â-unsaturated ketone
trans-4-phenyl-3-buten-2-one (Table 1, entry 6) was im-
proved to 92% with 72% (E)-selectivity by adding 0.5 equiv
of benzoic acid (Table 3, entry 5). The same acid-promoted
reaction could be performed in a much shorter time in a lower
(11) Use of strong organic acids such as trifluoroacetic acid and
toluenesulfonic acid gave only trace amounts of the desired product.
Org. Lett., Vol. 5, No. 14, 2003
2495

Scheme 1. Possible Mechanism for Acid-Promoted
Table 4. Acid-Promoted Olefination of Unactivated Ketones
with tert-Butyl Diazoacetate (t-BDA) Catalyzed by Fe(TPP)Cla
Olefination of Ketones by Fe(TPP)Cl
These reactions are assumed to proceed via a metallocar-
bene-phosphorane mechanism that was proposed previously
(Scheme 1).1,5,6 The Fe(III) porphyrin was presumably
reduced in situ by diazo reagents to the catalytically active
Fe(II) porphyrin.12 The activation of ketones by acids
operates possibly through protonation of the carbonyl oxygen,
which would render the carbonyl group a stronger electro-
phile toward reaction with phosphorane.
In summary, we have developed a general transition metal
complex-based catalytic system for olefination of unactivated
ketones with diazo reagents in the presence of tertiary
phosphine. The results above demonstrate a remarkable acid
enhancement effect on the catalytic reaction. We are currently
working to improve the stereoselectivity of the reactions by
using other possible acid additives under different reaction
conditions.
a Reactions were carried out at 80 °C in toluene under N2 with 1.0 equiv
of ketone, 1.4 equiv of t-BDA, 1.2 equiv of Ph3P, and 1.5 mol % Fe(TPP)Cl.
Concentration: 0.5 mmol of ketone/2 mL of toluene. Reaction times were
24 h. b Yields represent isolated yields of >95% purity as determined by
GC and 1H NMR. c Ratio of E:Z isomers was determined by GC or 1H
NMR. d Yields were determined by GC.
but acceptable yield (Table 3, entry 4). Aliphatic ketones
can also be olefinated as demonstrated with 2-nonanone (54%
yield, Table 3, entry 6). The olefination yields of cyclohex-
anone and its derivatives increased from 8-30% in the
absence of additives (Table 1, entries 7-9) to 83-89% in
the presence of 0.5 equiv of benzoic acid. (Table 3, entries
7-9). The benzoic acid-promoted olefination is also suitable
to five- and six-membered cyclic ketones such as cyclopen-
tanone and cycloheptanone, giving the corresponding olefins
in moderate yields (Table 3, entries 10 and 11).
In addition to the commonly used ethyl diazoacetate, the
acid-promoted catalytic olefination of unactivated ketones
can also be applied to the sterically hindered tert-butyl
diazoacetate. As shown in Table 4 for several different
ketones, the reaction yields with t-BDA are generally lower
than those with EDA, but with similar (E)-selectivities.
Acknowledgment. We are grateful for financial support
of this work from the Department of Chemistry of the
University of Tennessee. We wish to acknowledge Dr. Al
Tuinman of the University of Tennessee Mass Spectroscopy
Center for assistance with high-resolution mass spectroscopy.
Supporting Information Available: Analytical data for
all products. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0347444
(12) (a) Wolf, J. R.; Hamaker, C. G.; Djukic, J.-P.; Kodadek, T.; Woo,
L. K. J. Am. Chem. Soc. 1995, 117, 9194. (b) Salomon, R. G.; Kochi, J. K.
J. Am. Chem. Soc. 1973, 95, 3300.
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