Fe(0)-mediated synthesis of tri- and tetra-substituted olefins from carbonyls: An environmentally friendly alternative to Cr(II)

Article abstract of DOI:10.1021/jo061445u

Fe(0) was investigated as a cost-effective, environmentally friendly alternative to Cr(II) for the olefination of carbonyls by activated polyhalides. In many instances, Fe(0) was equivalent or superior to Cr(II). Notably, Fe(0), but not Cr(II), proved com

Full text of DOI:10.1021/jo061445u

Fe(0)-Mediated Synthesis of Tri- and Tetra-Substituted Olefins from
Carbonyls: An Environmentally Friendly Alternative to Cr(II)
J. R. Falck,*,† Romain Bejot,‡ Deb K. Barma,† Anish Bandyopadhyay,† Suju Joseph,† and
Charles Mioskowski*,‡
Department of Biochemistry, UniVersity of Texas Southwestern Medical Center, Dallas, Texas 75390, and
Laboratoire de Synthe`se Bio-Organique, UMR 7175-LC1, Faculte´ de Pharmacie, UniVersite´ Louis Pasteur,
74 Route du Rhin, BP 24, 67 401 Illkirch, France
j.falck@utsouthwestern.edu; mioskow@aspirine.u-strasbg.fr
ReceiVed July 11, 2006
Fe(0) was investigated as a cost-effective, environmentally friendly alternative to Cr(II) for the olefination
of carbonyls by activated polyhalides. In many instances, Fe(0) was equivalent or superior to Cr(II).
Notably, Fe(0), but not Cr(II), proved compatible with a wide range of functionality, inter alia, unprotected
phenol, aryl nitro, carboxylic acid, and alkyl nitrile. A surprising reversal of stereoselectivity for aldehydes
versus ketones was observed using both metals. The resultant R-halo-R,â-unsaturated or R,â-unsaturated
carboxylic acids, esters, and nitriles are common structural elements in numerous compounds of interest
as well as key intermediates in the preparation of other functionality.
Introduction
need for wide-ranging surveys of the reactivity and stereose-
lectivity of more benign metals and eco-friendly protocols.3
Since iron and its derivatives satisfy many of the desired criteria,
inter alia, minimal toxicity, ease of handling, good stability,
commercial availability in various forms, and relatively low
costs, it was singled out for further evaluation. While the utility
of polyvalent and complexed zerovalent iron for C-C coupling
has been cogently demonstrated,4,5 surprisingly few studies have
exploited iron in its elemental (solid) form. Herein, we describe
a comparative study of elemental Fe(0)- versus Cr(II)-driven
condensations of activated polyhalides (Scheme 1) and the
surprising reversal of stereoselectivity for aldehydes versus
ketones. The resultant R-halo-R,â-unsaturated or R,â-unsaturated
carboxylic acids, esters, and nitriles are common structural
elements in numerous compounds of interest as well as key
intermediates in the preparation of other functionality.6,7
Recent publications from these1 and other laboratories2 have
elucidated the rich mechanistic and synthetic versatility of
organochromium reagents. The efficacy of these transformations
and, in many cases, their unprecedented stereo- and/or chemose-
lectivities have accordingly attracted wide attention from the
chemical community. However, restrictions upon the use of toxic
heavy metals for organic synthesis have highlighted the urgent
† University of Texas Southwestern Medical Center. Tel: 214-648-2406.
Fax: 214-648-6455.
‡ Universite´ Louis Pasteur. Fax: (+33) 3-9024-4306.
(1) (a) Bejot, R.; Tisserand, S.; Reddy, L. M.; Barma, D. K.; Baati, R.;
Falck, J. R.; Mioskowski, C. Angew. Chem., Int. Ed. 2005, 44, 2008. (b)
Falck, J. R.; Bandyopadhyay, A.; Barma, D. K.; Shin, D. S.; Kundu, A.;
Kishore, R. V. K. Tetrahedron Lett. 2004, 45, 3039. (c) Barma, D. K.;
Kundu, A.; Bandyopadhyay, A.; Kundu, A.; Sangras, B.; Briot, A.;
Mioskowski, C.; Falck, J. R. Tetrahedron Lett. 2004, 45, 5917. (d) Barma,
D. K.; Kundu, A.; Zhang, H. M.; Mioskowski, C.; Falck, J. R. J. Am. Chem.
Soc. 2003, 125, 3218. (e) Baati, R.; Barma, D. K.; Falck, J. R.; Mioskowski,
C. Tetrahedron Lett. 2002, 43, 2183. (f) Baati, R.; Barma, D. K.; Falck, J.
R.; Mioskowski, C. Tetrahedron Lett. 2002, 43, 2179. (g) Falck, J. R.;
Barma, D. K.; Venkataraman, S. K.; Baati, R.; Mioskowski, C. Tetrahedron
Lett. 2002, 43, 963. (h) Baati, R.; Barma, D. K.; Krishna, U. M.;
Mioskowski, C.; Falck, J. R. Tetrahedron Lett. 2002, 43, 959.
(3) Bagchi, D.; Stohs, S. J.; Downs, B. W.; Bagchi, M.; Preuss, H. G.
Toxicology 2002, 180, 5.
(4) For recent examples of the application of iron derivatives in the
formation of C-C bonds, see: (a) Fu¨rstner, A.; Martin, R.; Majima, K. J.
Am. Chem. Soc. 2005, 127, 12236. (b) Fu¨rstner, A.; Martin, R. Chem. Lett.
2005, 34, 624. (c) Bolm, C.; Legros, J.; LePaih, J.; Zani, L. Chem. ReV.
2004, 104, 6217.
(5) For recent C-C couplings using Fe(0) complexes, see: (a) Terent’ev,
A. B.; Vasil’eva, T. T.; Kuz’mina, N. A.; Mysova, N. E.; Chakhovskaya,
O. V. Russ. J. Org. Chem. 2001, 37, 1273. (b) Terentiev, A. B.; Vasilieva,
T. T.; Kuz’mina, N. A.; Chakhovskaya, O. V.; Brodsky, E. S.; Belokon,
Y. N. Russ. Chem. Bull. 2000, 49, 722.
(2) Recent examples: (a) Nakagawa, M.; Saito, A.; Soga, A.; Yamamoto,
N.; Taguchi, T. Tetrahedron Lett. 2005, 46, 5257. (b) Concellon, J. M.;
Bernad, P. L.; Mejica, C. Tetrahedron Lett. 2005, 46, 569. (c) Takenaka, N.;
Xia, G. Y.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 13198. (d) Nam-
ba, K.; Kishi, Y. Org. Lett. 2004, 6, 5031. (e) Halterman, R. L.; Crow, L.
D. Tetrahedron Lett. 2003, 44, 2907. (f) Berkessel, A.; Menche, D.; Sklorz,
C. A.; Schroder, M.; Paterson, I. Angew. Chem., Int. Ed. 2003, 42, 1032.
10.1021/jo061445u CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/13/2006
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J. Org. Chem. 2006, 71, 8178-8182

Fe(0)-Mediated Synthesis of Olefins from Carbonyls
to impart chromium’s stereoselectivity,13 for instance, 16f17
(86%, Z/E > 99:1).
SCHEME 1
The range of suitable polyhalogenated substrates encompassed
ethyl dichlorofluoroacetate 20, methyl tribromoacetate 22,
tribromoacetic acid 24, ethyl dibromoacetate 26, trichloroaceto-
nitrile 28, and methyl 2,2-dichloro-2-methoxyacetate 31. These
provided access to (Z)-R-fluoroacrylate 21 (entry 10), (Z)-R-
bromoacrylate 23 (entry 11),14 (Z)-R-bromoacrylic acid 25 (entry
12), (E)-acrylate 27 (entry 13),15 R-chloro-R,â-unsaturated
nitriles 29/30 (entries 14 and 15), and (Z)-R-methoxyacrylate
32 (entry 16) in good to excellent yields. While the yields and
stereoselectivities were broadly similar, the superior functional
group compatibility of Fe(0) is patently evident in entries 12
and 15; only in entry 16 was the result with Fe(0) unsatisfactory.
Results and Discussion
It was anticipated that Cr(II) and Fe(0) would mediate many
of the same transformations since they have similar reduction
potentials (-0.41 and -0.45 V vs SHE, respectively).8 On the
other hand, the disparities (e.g., geometry, aggregation, and
Lewis acidity) manifested by organoiron reagents9 and compa-
rable organochromium species8 augured for useful variances in
stereoselectivity and/or functional group compatibility.
It was also gratifying to discover that a wide variety of
ketones were suitable condensation partners for trichloroacetates
(Table 2).16 Tetra-substituted olefins were generated in good
yields from aryl ketones 33 and 35 (entries 1 and 2), conjugated
ketones 37, 39, and 41 (entries 3, 4 and 5), and aliphatic methyl
ketones 43 and 45 (entries 6 and 7). Despite reports that benzyl
ethers are cleaved under some circumstances by iron and
chromium salts,17 we observed no evidence of this during the
reactions of 35.18 One should also note that while Cr(II)-
mediated condensations typically gave somewhat better yields,
for the sensitive cyclic ketone 41, Fe(0) was more efficacious
(entry 5). As might be anticipated, the E/Z ratio of the products
varied in accordance with the steric differential of the opposing
ketone appendages. The most noteworthy and unexpected result
was the moderate to high E-selectivity observed for all of the
Fe(0) reactions and all but one of the Cr(II) reactions. This is
in stark contrast to the Z-stereoselectivity characteristic of
aldehydes (Table 1).19,20 Furthermore, inspection of the data in
Table 2 reveals Fe(0) was consistently more stereoselective than
Cr(II).
The former prediction was confirmed during condensations
of benzaldehyde 1 and 4-dimethylaminobenzaldehyde 4 with
methyl trichloroacetate 2 in THF using Fe powder at 23-60
°C overnight or, as previously reported,1d using CrCl2 at room
temperature for 1-2 h. The yields and Z-stereoselectivities for
R-chloroacrylates 3 and 5 were outstanding and essentially
equivalent for both reagents (Table 1, entries 1 and 2,
respectively). As expected, Rieke iron exhibited higher reactivity
than commercial Fe(0) powder.10,11 All of the starting materials
were consumed after just 1 h at room temperature, but complex
product mixtures of R-chloroacrylate, dehalogenated acrylate,
dichlorohydrin, and uncharacterized compounds were obtained.
A determination of the scope of the condensation also
revealed some significant differences between the metal reduc-
tants. Under the influence of Fe(0) powder, phenol 6 and nitro
8 afforded 7 (entry 3) and 9 (entry 4), respectively, in good
yields and stereocontrol (Z/E > 99:1). The lack of competitive
aryl nitro reduction under these conditions is noteworthy.12 In
contrast, 6 and 8 did not react with CrCl2, even under forcing
conditions (refluxing THF, 12 h), and could be recovered
unchanged. Heterocyclic aldehydes were well tolerated as seen
in the smooth conversions of indole 10, furan 12, and thiophene
14 into the corresponding adducts 11 (entry 5),1d 13 (entry 6),
and 15 (entry 7). In this series, chromium displayed the superior
Z-stereoselectivity, whereas iron gave somewhat better yields,
except with indole 10. Conjugated and aliphatic aldehydes
behaved analogously, for example, 16f17 (entry 8) and 18f19
(entry 9), with CrCl2 providing nominally better yields and
conspicuously better Z/E ratios. Interestingly, the presence of
catalytic CrCl2 (20 mol %) under the usual Fe(0) reaction
conditions [Fe(0) (8 equiv), THF, 55 °C, 14 h] was sufficient
(13) CrCl3/Fe(0) redox systems have been described: Hu, C. M.; Chen,
J. J. Chem. Soc., Chem. Commun. 1993, 72.
(14) Control experiments indicate that 23 and 25 are stable under the
reaction conditions. We speculate the minor amounts of debrominated
byproducts arise via double metalation of the initial Reformatsky-type adduct
i to give ii. We and others have previously invoked the generation of gem-
dichromium intermediates: Baati, R.; Barma, D. K.; Falck, J. R.; Miosk-
owski, C. J. Am. Chem. Soc. 2001, 123, 9196. The greater reactivity of
bromides makes this process partially competitive with the pathway in Figure
1.
(6) (a) Mironiuk-Puchalska, E.; Kolaczkowska, E.; Sas, W. Tetrahedron
Lett. 2002, 43, 8351. (b) Dollt, H.; Zabel, V. Aust. J. Chem. 1999, 52, 259.
(c) Kakehi, A.; Ito, S. J. Org. Chem. 1974, 39, 1542. (d) Marvel, C. S.;
Weil, E. D.; Wakefield, L. B.; Fairbanks, C. W. J. Am. Chem. Soc. 1953,
75, 2326.
(7) Stille: (a) Tanaka, K.; Katsumura, S. Org. Lett. 2000, 2, 373.
Sonogashira: (b) Dai, W. M.; Wu, J. L.; Fong, K. C.; Lee, M. Y. H.; Lau,
C. W. J. Org. Chem. 1999, 64, 5062. Suzuki: (c) Zhou, S. M.; Yan, Y. L.;
Deng, M. Z. Synlett 1998, 198. (d) Rossi, R.; Bellina, F.; Bechini, C.;
Mannina, L.; Vergamini, P. Tetrahedron 1998, 54, 135. (e) Zhang, X. G.;
Qing, F. L.; Yu, Y. H. J. Org. Chem. 2000, 65, 7075. (f) Qing, F. L.; Zhang,
X. G. Tetrahedron Lett. 2001, 42, 5929.
(15) For a mechanistically related, stereoselective synthesis of (E)-R,â-
unsaturated esters using SmI2, see: Concellon, J. M.; Concellon, C.; Mejica,
C. J. Org. Chem. 2005, 70, 6111.
(16) In sharp contrast, reactions of methyl tribromoacetate with ketones
afforded complex product mixtures. This may reflect its greater steric profile
and/or the proclivity of the more reactive bromides toward undesired side
reactions.
(8) Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1.
(9) Rosenblum, M. Acc. Chem. Res. 1974, 7, 122.
(10) Rieke, R. D. Science 1989, 246, 1260.
(11) Fe(0) powder (<10 µm, 99.9%) was purchased from Aldrich and
Alfa Aeser and stored/handled under an inert atmosphere to minimize
formation of an oxide coating.
(12) Wang, L.; Li, P. H.; Wu, Z. T.; Yan, J. C.; Wang, M.; Ding, Y. B.
Synthesis 2003, 2001.
(17) (a) Rodebaugh, R.; Debenham, J. S.; Fraser-Reid, B. Tetrahedron
Lett. 1996, 37, 5477. (b) Park, M. H.; Takeda, R.; Nakanishi, K. Tetrahedron
Lett. 1987, 28, 3823.
(18) Considering standard reduction potentials of Fe(II)/Fe (-0.45 V),
Fe(III)/Fe (-0.04 V), and Fe(III)/Fe(II) (+0.77 V) compared to Cr(III)/
Cr(II) (-0.41 V), we postulate the formation of Fe(II) salts in the tandem
Reformatsky elimination reaction.
J. Org. Chem, Vol. 71, No. 21, 2006 8179

Falck et al.
TABLE 1. Fe(0)- versus Cr(II)-Mediated r-Halo-olefination of Aldehydes
a Fe powder (10 equiv), THF, 55-60 °C, 14 h. b CrCl2 (6 equiv), THF, 23 °C, 1-2 h. c Isolated yield after SiO2 chromatographic purification. Z/E ratio
determined by 1H NMR and/or GC. d 23 °C, 4 h. e Warmed to reflux. f 35% of 10 recovered. g Required 8 equiv of CrCl2 and 1.5 equiv of 2. h 23 °C. i 15%
dehalogenated adduct isolated. j 20% dehalogenated adduct isolated. k 90 °C. l Stereochemistry determined by nOe.
While the details have not been elucidated, it appears that
Fe(0)-mediated condensations of aldehydes follow the same
reaction pathway proposed for analogous chromium(II) olefin-
ations,1d,15 that is, initial one-electron transfer at the metal
interface resulting in rupture of a C-X bond,21 further reduction
of the nascent 2,2-dihaloacetate radical, and generation of a
metal-enolate complex. Whether the electron transfers are
innersphere or outersphere is not settled. Addition of the organo-
metallic species to the carbonyl is rapid and results in a Refor-
matsky-type adduct (Figure 1).22 Subsequent reductive, anti-
periplanar E2 elimination preferentially affords the Z-olefin. This
stereochemical outcome likely reflects the predominance of
conformer A versus the more sterically hindered conformer B.
For ketones, we propose an early and crucial change in
mechanism to explain the divergence in stereochemistry. Since
reduction of the carbon-halogen bond of the comparatively
more congested Reformatsky-type ketone adduct 47 is slower
(Figure 2), electron transfer occurs through the carbonyl to
generate metal enolate 48. It is likely that chelation plays an
important role in determining the conformation of 48. Subse-
quent elimination occurs preferentially via conformation C
which minimizes the steric interaction between the halide and
(19) The stereochemical assignments of adducts 34, 36, 38, 40, 44, and
46 were confirmed by LiAlH4 reduction (Et2O, 0 °C, 20 min) of the ester
and 2D nOe analysis of the resultant primary alcohols; comparable treatment
of 42 gave an unstable product, so its stereochemistry could not be
established.
(20) NB: The principal product of the CrCl2-mediated condensation of
33 and 2 was previously assigned structure (Z)-341d in accordance with
literature data (Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Bull. Chem.
Soc. Jpn. 1980, 53, 1698) but now must be revised as (E)-34 based upon
the above nOe experiments.
(22) (a) Rathke, M. W.; Weipert, P. In ComprehensiVe Organic Synthesis;
Heathcock, C. H., Ed.; Elsevier: Amsterdam, 1991; Vol. 2, p 277. (b)
Fu¨rstner, A. Synthesis 1989, 571.
(21) Nuzzo, R. G.; Dubois, L. H. J. Am. Chem. Soc. 1986, 108, 2881.
8180 J. Org. Chem., Vol. 71, No. 21, 2006

Fe(0)-Mediated Synthesis of Olefins from Carbonyls
TABLE 2. Fe(0)- versus Cr(II)-Mediated r-Chloro-olefination of Ketones
a Fe powder (10 equiv), THF, 55-60 °C, 14 h. b CrCl2 (6 equiv), THF, 23 °C, 1-2 h. c Isolated yield after SiO2 chromatographic purification. Z/E ratio
1
determined by H NMR and/or GC. d Required 8 equiv of CrCl2 and 1.5 equiv of 2. e Stereochemistry unassigned. f 40 °C, 12 h.
SCHEME 2
2-enoate (12-15%, Z/E ) 1:2) (Scheme 2). Exposure of the
former adduct to the chromium reaction conditions used in Table
2 led to methyl 2-chloro-3-methyl-5-phenylpent-2-enoate 46
(Z/E ) 1:3).
FIGURE 1. Reformatsky intermediate derived from aldehydes.
Conclusion
This contribution affords new insights into organoiron
chemistry. Fe(0) was found to be an effective reductant for
carbonyl-polyhalide condensations giving rise to tri- and tetra-
substituted olefins. Yields and stereoselectivities are good to
excellent and, in some cases, especially ketones, superior to
those achieved with CrCl2. Fe(0) displayed excellent compat-
ibility with a wide range of functionality, and we anticipate that
these Fe-mediated olefinations will find broad utility.
FIGURE 2. Reformatsky intermediate derived from ketones.
Experimental Section
the RL appendage as well as maximizes overlap of the electron-
rich sp3-hybridized oxygens (i.e., MeO- and XnMO-) with the
p-orbitals of the enolate CdC.
Fe(0) Condensations. Polyhalide (1.1 mmol) and aldehyde or
ketone (1 mmol) in anhydrous THF (2 mL) were added to a stirring,
room temperature suspension of Fe powder (10 mmol; Aldrich,
-325 mesh) in anhydrous THF (8 mL) under an argon atmosphere.
The mixture was warmed to 23-60 °C for 4-14 h, then cooled to
room temperature, quenched with water, filtered, and the filtrate
was extracted three times with ether. The combined ethereal extracts
were washed with brine, dried over anhydrous Na2SO4, and
evaporated to dryness under reduced pressure. Purification of the
residue via SiO2 column chromatography furnished the adduct in
the indicated yield (Tables 1 and 2).
In concert with this hypothesis, the E-stereoselectivity
observed with ketones is also realized using dichlorohydrins
obtained from ketones. For example, the addition of methyl
trichloroacetate 2 to benzylacetone 45 using only 2 equiv of
CrCl2 at 0 °C for 1.5 h or 4 equiv of Fe(0) at room temperature
gave methyl 2,2-dichloro-3-hydroxy-3-methyl-5-phenylpen-
tanoate (36-40%) and methyl 2-chloro-3-methyl-5-phenylpent-
J. Org. Chem, Vol. 71, No. 21, 2006 8181

Falck et al.
Fe(0)/Catalytic CrCl2 Condensations. Conducted as described
above using Fe powder (8 mmol; Aldrich, -325 mesh) and CrCl2
(0.20 mmol; Strem Chemicals).
Welch Foundation, and NIH (GM31278, DK38226) for financial
support of this work.
CrCl2 Condensations. Conducted as described above using
CrCl2 (6 mmol; Strem Chemicals) at 23 °C for 1-2 h.
Supporting Information Available: Experimental procedures
and full spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to the Ministe`re de´le´gue´
a` l’Enseignement supe´rieur et a` la Recherche, the Robert A.
JO061445U
8182 J. Org. Chem., Vol. 71, No. 21, 2006