Highly efficient alkene epoxidation and aziridination catalyzed by iron(II) salt + 4,4′,4″-trichloro-2,2′:6′,2″-terpyridine/ 4,4″-dichloro-4′-O-PEG-OCH3-2,2′:6′,2″- terpyridine

Article abstract of DOI:10.1021/ol801157m

(Chemical Equation Presented) "Iron(II) salt + 4,4′,4″- trichloro-2,2′:6′,2″-terpyridine" is an effective catalyst for epoxidation and aziridination of alkenes and intramolecular amidation of sulfamate esters. The epoxidation of allylic-substituted cycloalkenes achieved excellent diastereoselectivities up to 90%. ESI-MS results supported the formation of iron-oxo and -imido intermediates. Derivitization of Cl₃terpy to O-PEG-OCH₃-Cl₂terpy renders the terpyridine unit to be recyclable, and the "iron(II) salt + 4,4″-dichloro-4′-O-PEG-OCH3-2,2′:6′,2″- terpyridine" protocol can be reused without a significant loss of catalytic activity in the alkene epoxidation.

Full text of DOI:10.1021/ol801157m

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3275-3278
Highly Efficient Alkene Epoxidation and
Aziridination Catalyzed by Iron(II) Salt +
4,4′,4′′-Trichloro-2,2′:6′,2′′-terpyridine/
4,4′′-Dichloro-4′-O-PEG-OCH3-2,2′:6′,2′′-terpyridine
Peng Liu, Ella Lai-Ming Wong, Angella Wing-Hoi Yuen, and Chi-Ming Che*
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of
Molecular Technology for Drug DiscoVery and Synthesis, The UniVersity of Hong
Kong, Pokfulam Road, Hong Kong, China
cmche@hku.hk
Received May 21, 2008
ABSTRACT
“Iron(II) salt + 4,4′,4′′-trichloro-2,2′:6′,2′′-terpyridine” is an effective catalyst for epoxidation and aziridination of alkenes and intramolecular
amidation of sulfamate esters. The epoxidation of allylic-substituted cycloalkenes achieved excellent diastereoselectivities up to 90%. ESI-MS
results supported the formation of iron-oxo and -imido intermediates. Derivitization of Cl3terpy to O-PEG-OCH3-Cl2terpy renders the terpyridine
unit to be recyclable, and the “iron(II) salt + 4,4′′-dichloro-4′-O-PEG-OCH3-2,2′:6′,2′′-terpyridine” protocol can be reused without a significant
loss of catalytic activity in the alkene epoxidation.
The search for highly efficient and inexpensive metal
catalysts with potential practical applications is a challenge
in green chemistry. Compared with many catalysts containing
heavy transition metal ions, iron complexes are inexpensive
and biocompatible.1 However, practical applications of iron
complexes in organic synthesis are sparse.
Notably, iron pyridyl complexes have been shown to be
active catalysts for cis-dihydroxylation4 and epoxidation of
alkenes,5 as well as oxidation of alkanes6 and sulfides.7
Herein, we report the use of iron complex 1a or “Fe(II) salt
(4) (a) Costas, M.; Tipton, A. K.; Chen, K.; Jo, D.-H.; Que, L., Jr J. Am.
Chem. Soc. 2001, 123, 6722. (b) Chen, K.; Costas, M.; Kim, J.; Tipton,
A. K.; Que, L., Jr J. Am. Chem. Soc. 2002, 124, 3026. (c) Costas, M.; Que,
L., Jr Angew. Chem., Int. Ed. 2002, 41, 2179. (d) Fujita, M.; Costas, M.;
Que, L., Jr J. Am. Chem. Soc. 2003, 125, 9912.
Barton and co-workers2 and subsequently others3 had
reported the important use of pyridine as a ligand in the
development of iron-based catalysts for organic oxidations.
(5) (a) Nam, W.; Ho, R.; Valentine, J. S. J. Am. Chem. Soc. 1991, 113,
7052. (b) White, M. C.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc.
2001, 123, 7194. (c) Dubois, G.; Murphy, A.; Stack, T. D. P. Org. Lett.
2003, 5, 2469. (d) Kodera, M.; Itoh, M.; Kano, K.; Funabiki, T.; Reglier,
M. Angew. Chem., Int. Ed. 2005, 44, 7104. (e) Gelalcha, F. G.; Bitterlich,
B.; Anilkumar, G.; Tse, M. K.; Beller, M. Angew. Chem., Int. Ed. 2007,
46, 7293. (f) Anilkumar, G.; Bitterlich, B.; Gelalcha, F. G.; Tse, M. K.;
Beller, M. Chem. Commun. 2007, 289.
(1) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104,
6217.
(2) (a) Barton, D. H. R.; Doller, D. Acc. Chem. Res. 1992, 25, 504. (b)
Barton, D. H. R.; Beviere, S. D.; Chavasiri, W.; Doller, D.; Liu, W. G.;
Reibenspies, J. H. New J. Chem. 1992, 16, 1019. (c) Barton, D. H. R.
Tetrahedron 1998, 54, 5805.
(3) (a) Stavropoulos, P.; C¸ elenligil-C¸ etin, R.; Tapper, A. E. Acc. Chem.
Res. 2001, 34, 745. (b) Costas, M.; Mehn, M. P.; Jensen, M. P.; Que, L.,
Jr. Chem. ReV. 2004, 104, 939. (c) Groves, J. T. J. Inorg. Biochem. 2006,
100, 434.
(6) (a) Kim, C.; Chen, K.; Kim, J.; Que, L., Jr J. Am. Chem. Soc. 1997,
119, 5964. (b) van den Berg, T. A.; de Boer, J. W.; Browne, W. R.; Roelfes,
G.; Feringa, B. L. Chem. Commun. 2004, 2550. (c) Pavan, C.; Legros, J.;
Bolm, C. AdV. Synth. Catal. 2005, 347, 703.
10.1021/ol801157m CCC: $40.75
Published on Web 06/27/2008
2008 American Chemical Society

Table 1. Epoxidation of Alkenes by Oxone Catalyzed by 1aa
Figure 1. Structure of complex cations of 1a and 1b.
+ Cl3terpy” (Figure 1) as an efficient catalyst for the
epoxidation and aziridination of alkenes and intramolecular
amidation of saturated C-H bonds of sulfamate esters. Our
choice of the Cl3terpy ligand is due to its robustness under
oxidative conditions. Derivitization of Cl3terpy to O-PEG-
OCH3-Cl2terpy renders the terpy ligand to be recoverable
and can be easily separated from the reaction mixture.
Complex 1a was immediately formed by reacting
Fe(ClO4)2·6H2O with 4,4′,4′′-trichloro-2,2′:6′,2′′-terpyridine8
in MeCN at room temperature. The purple diamagnetic
compound formed was characterized by 1H NMR and
UV-vis spectroscopies, ESI-MS spectrometry, and X-ray
crystallography (see Supporting Information). The average
Fe-Npyridine bond distance of 1a is 1.94 Å, and this complex
shows a quasi-reversible Fe(III)/(II) couple at E1/2 ) 0.90 V
(vs Cp2Fe+/0) in 0.1 M nBu4NPF6 MeCN solution.
Table 1 depicts the activity of 1a toward catalytic
epoxidation of alkenes, ranging from electron-rich to electron-
deficient alkenes by Oxone. Treatment of different alkenes
with Oxone and NH4HCO3 catalyzed by 1a (5 mol %) at
room temperature for 2 h afforded the corresponding
epoxides. Unfunctionalized terminal alkene 2 was readily
epoxidized to 19 with 86% yield based on 70% substrate
conversion (Table 1, entry 1).
Alkene substrate conVersion of only 30% was found when
[Fe(terpy)2](ClO4)2 was used as the catalyst, and no epoxide
was obtained when Fe(ClO4)2·6H2O was used under the same
reaction conditions (see Supporting Information). Aryl
alkenes 3-6 were oxidized to corresponding epoxides 20-23
with product yields of 90%, 86%, 92%, and 42%, respec-
tively (Table 1, entries 2-5), while no diol product was
observed. Cis-stilbene 7 was oxidized to 24 in 96% yield
with a high stereoselectivity [cis:trans ratio of 27:1] (Table
1, entry 6). Epoxidation of cyclohexene 8 afforded 25 as
the only product in 96% yield with no alcohol or ketone
formed (Table 1, entry 7). The electron-deficient alkenes
9-13 (Table 1, entries 8-12) were effectively oxidized to
their corresponding epoxides with up to 96% yield and 100%
substrate conversion in 2 h. Steroid 14 was selectively
oxidized to epoxide 31 with an R:ꢀ ratio of 3:1 (Table 1,
entry 13). The unprotected hydroxyl group of the steroid
remained unchanged.
a Reaction conditions: substrate/1a/Oxone/NH4HCO3 molar ratio )
1/0.05/1.3/4, rt, 2 h. b Product yields based on conversions. c Determined
by GC analysis or 1H NMR spectroscopy of crude product. d Yield of
γ,δ-monoepoxide. e Yield of R,ꢀ:γ,δ-diepoxide. f Solvent for reaction:
CH3CN/H2O ) 2/1.
The epoxidation of R,ꢀ:γ,δ conjugated alkene 15 catalyzed
by 1a (Table 1, entry 14) afforded the γ,δ-monoepoxide 32a
in 71% yield and R,ꢀ:γ,δ-diepoxide 32b as the minor product
(23% yield). γ,δ-Monoepoxide 33 was obtained as the only
product in the 1a-catalyzed epoxidation of 16 (Table 1, entry
15). No R,ꢀ-monoepoxide was detected in both cases. The
selectivity of 1a-catalyzed epoxidation of R,ꢀ:γ,δ conjugated
alkene is different from those previously reported, in which
R,ꢀ-epoxide was obtained as the major product when
[RuIV(2,6-Cl2TPP)Cl2] (2,6-Cl2TPP ) 2,6-dichloropyridine
tetraphenyl porphyrin) was used as the catalyst and 2,6-
(7) (a) Legros, J.; Bolm, C. Angew. Chem., Int. Ed. 2004, 43, 4225. (b)
Legros, J.; Bolm, C. Chem.-Eur. J. 2005, 11, 1086.
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Mol. Catal. A-Chem. 2003, 203, 113.
3276
Org. Lett., Vol. 10, No. 15, 2008

dichloropyridine N-oxide was used as the terminal oxidant.9
Epoxidation of the allylic alkenes 17 and 18, catalyzed by
1a, afforded 34 and 35 in a cis:trans ratio of 1:7 and 1:10,
respectively (Table 1, entries 16 and 17). These values are
higher than that of 1:3 reported for the same reactions when
m-CPBA was used as the oxidant in the absence of metal
catalyst.10
Table 2. Intermoleculara and Intramolecularb Aziridination of
Alkenes and Sulfonamides and Intramolecular Amidationc d of
,
Sulfamate Esters Catalyzed by 1a
The catalytic activity of 1a toward aziridination of alkenes
and amidation of sulfamate esters was also evaluated (Table
2). Styrene 3 undergoing intermolecular aziridination with
PhINTs or PhINNs (Ts ) p-toluenesulfonyl; Ns ) p-
nitrobenzenesulfonyl) in the presence of 1a afforded aziridine
47 in 95% yield and 86% substrate conversion and aziridine
48 in 97% yield and 81% substrate conversion, respectively
(Table 2, entries 1 and 2). Cycloalkene 36 and aliphatic
terminal alkene 37 were converted to corresponding aziri-
dines 50 and 51 in 68% and 78% yield, respectively (Table
2, entries 4 and 5). Unsaturated sulfonamides 38-41 were
intramolecularly cyclized to give 52-55, respectively, in up
to 92% yield (Table 2, entries 6-9). Unsaturated sulfona-
mides 42 and 43 possessing allylic C-H bonds, which are
likely to undergo intramolecular amidation, underwent in-
tramolecular aziridination to give 56 and 57 as the only
products (Table 2, entries 10 and 11). The catalytic intra-
molecular amidation of sulfamate esters 44-46 catalyzed
by 1a (Table 2, entries 12-14) gave rise to 58-60 as single
products in 86%, 90%, and 84% yield, respectively.
Recently, there has been a surge of interest in nonheme
iron-oxo and -imido complexes.11 Reactive FedO and
FedNTs intermediates were, respectively, detected by
ESI-MS when an MeCN solution of 1a was treated with
Oxone or PhIdNTs (in a molar ratio of 1:4). Cluster peaks
at m/z 371.9 and 448.5 with peak separation of 0.5 Da were
observed, and the corresponding zoomed scan spectra (see
Supporting Information) match the simulated spectra for the
[Fe(Cl3terpy)2O]2+ and [Fe(Cl3terpy)2(NTs)]2+ ions, respec-
tively. The relative rates of epoxidation and aziridination of
para-substituted styrenes (para-substituent ) MeO, Me, H,
Cl, Br, CF3) were examined. An electron-rich substituent
accelerates the reaction, whereas an electron-deficient sub-
stituent retards the reaction. Plots of log kY/kH vs σp+ reveal
a linear relationship from which the slopes of the plots are
-0.55 and -0.72 (see Supporting Information) for epoxi-
dation and aziridination, respectiVely. The observed F+ value
(-0.55) for epoxidation is 2-3.6-fold smaller in magnitude
than those reported for styrene oxidation by peracids (F+ )
a Reaction conditions: substrate/1a molar ratio ) 1/0.05, 40 °C, 12 h.
b Substrate/1a/PhI(OAc)2 molar ratio ) 1/0.05/1.5, 40 °C, 12 h. c Substrate/1a/
PhI(OAc)2/MgO molar ratio ) 1/0.05/1.4/2.3, 80 °C, 12 h. d Substrate/1a/
PhI(OAc)2/MgO molar ratio ) 1/0.05/2.8/4.6, 80 °C, 12 h. e Product yields
based on conversions. f Determined by GC analysis or 1H NMR spectroscopy
of crude product.
-1.2),12 and (F20TPP)FeIVdO (F+ ) -1.1 to -2.0; TPP )
tetraphenyl porphyrin).13 This suggests that the reaction of
styrenes with the proposed [Fe(Cl3terpy)2O]2+ intermediate
is less sensitive to the para-substituent of styrene, and there
is less charge developed at the benzylic CR atom in the
reaction. This is consistent with the high stereoselectivity
observed in the 1a-catalyzed epoxidation of cis-stilbene to
cis-stilbene oxide. In contrast, the observed F+ value (-0.72)
for aziridination is comparable (1.5-fold smaller in magni-
(9) (a) Hummelen, J. C.; Wynberg, H. Tetrahedron Lett. 1978, 12, 1089.
(b) Zhang, J.-L.; Che, C.-M. Chem.-Eur. J. 2005, 11, 3899.
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Org. Lett. 2004, 6, 1597. (b) Chan, W.-K.; Wong, M.-K.; Che, C.-M. J.
Org. Chem. 2005, 70, 4226.
(11) (a) Chen, K.; Que, L., Jr Angew. Chem., Int. Ed. 1999, 38, 2227.
(b) Rohde, J.-U.; Bukowski, M. R.; Que, L., Jr Curr. Opin. Chem. Biol.
2003, 7, 674. (c) Rohde, J.-U.; In, J.-H.; Lim, M. H.; Brennessel, W. W.;
Bukowski, M. R.; Stubna, A.; Mu¨nck, E.; Nam, W.; Que, L., Jr Science
2003, 299, 1037. (d) He, C.; Mishina, Y. Curr. Opin. Chem. Biol. 2004, 8,
201. (e) Avenier, F.; Latour, J.-M. Chem. Commun. 2004, 1544. (f) Kryatov,
S. V.; Rybak-Akimova, E. V. Chem. ReV. 2005, 105, 2175. (g) Halfen,
J. A. Curr. Org. Chem. 2005, 9, 657. (h) Klinker, E. J.; Jackson, T. A.;
Jensen, M. P.; Stubna, A.; Juha´sz, G.; Bominaar, E. L.; Mu¨nck, E.; Que,
L., Jr Angew. Chem., Int. Ed. 2006, 45, 7394. (i) Wang, Z.; Zhang, Y.; Fu,
H.; Jiang, Y.; Zhao, Y. Org. Lett. 2008, 10, 1863.
(12) Ogata, Y.; Tabushi, I. J. Am. Chem. Soc. 1961, 83, 3440.
(13) Lee, K. A.; Nam, W. Bull. Korean Chem. Soc. 1996, 17, 669.
Org. Lett., Vol. 10, No. 15, 2008
3277

tude) to that of [RuVI(TPP)(NTs)2] (F+ ) -1.1).14 This
reveals that the C-N bond formation catalyzed by 1a is more
sensitive to the electronic effect of the para-substituent of
styrene.
Information); [Fe(O-PEG-OCH3-Cl2terpy)2]2+ 1b (charac-
terized by 1H NMR) was formed in situ by reacting
Fe(ClO4)2·6H2O (10 mmol) with 4,4′′-dichloro-4′-O-PEG-
OCH3-2,2′:6′,2′′-terpyridine (10 mmol) in MeCN (30 mL)
at room temperature. The reactivity of 1b toward catalytic
epoxidation and aziridination of alkenes was examined.
Complex 1b catalyzed the epoxidation of 9 to 26 in 96%
yield and the aziridination of 38 to 52 in 93% yield. The
substrate conversion was 100% in both cases.
The O-PEG-OCH3-Cl2terpy ligand can be separated from
the reaction products by diluting the reaction mixture with
H2O followed by Et2O extraction. The ligand left in the
aqueous layer can be reused to catalyze alkene epoxidation.
The catalyst loading for alkene epoxidation can be reduced
to 3 mol % without significantly affecting the product yield
and substrate conversion. As an example, using chalcone 9
(3 mol %) as substrate, epoxide 26 was obtained in 91%
yield and 86% substrate conversion under the same reaction
conditions over 2 h. Moreover, the catalysis described in this
work can be scaled up to gram level. As an example, epoxide
26 (9.1 g, 40.6 mmol) was obtained in 81% yield based on
91% substrate conversion by a one-pot reaction of chalcone
9 (10.5 g, 50.4 mmol) with Oxone (40.3 g, 65.5 mmol) and
NH4HCO3 (15.9 g, 201.6 mmol) in the presence of complex
1a (2.3 g, 2.5 mmol) for 2 h at room temperature. After the
one-pot reaction, the Cl3terpy ligand was recovered in 89%
(2.05 g, isolated yield).
The Cl3terpy ligand is oxidatively robust and can be reused
for catalysis simply by addition of a new batch of
Fe(ClO4)2·6H2O to the reaction mixture. A solution of MeCN:
H2O (3:2) containing 1a (5 mol %), Oxone:NH4HCO3 (1.3:
4; 0.2 mmol), and alkene substrate 9 (0.2 mmol) was stirred
at room temperature for 2 h. The substrate conversion of 9
was 100% as detected by 1H NMR spectroscopy. The
catalysis stopped, and presumably, 1a underwent demetala-
tion to give the free Cl3terpy ligand. Without isolation of
the Cl3terpy ligand, a new batch of Fe(ClO4)2·6H2O (5 mol
%), oxidant (1 equiv), and 9 (0.2 mmol) was added to the
reaction mixture, which was allowed to stir for another 2 h
at room temperature. The added Fe(ClO4)2·6H2O reacted with
the Cl3terpy to regenerate complex 1a in situ, as evidenced
by its absorption λmax at 561 and 321 nm. The in situ
generated 1a subsequently catalyzed the epoxidation of
alkene 9 to chalcone R,ꢀ-epoxide 26 (92% yield with 93%
substrate conversion) in the second run (see Supporting
Information).
As an example, an MeCN:H
2O (3:2) solution of 9 (0.2
mmol), catalyst 1b (5 mol %), and Oxone:NH4HCO3 (1.3:
4; 0.2 mmol) was stirred at room temperature for 2 h. The
epoxide product was obtained in 96% yield by an Et2O
extraction. The O-PEG-OCH3-Cl2terpy ligand left in the
aqueous phase was used to regenerate complex 1b in situ
by adding Fe(ClO4)2·6H2O, so as to restart the catalysis. This
process was repeated 5 times to afford the chalcone R,ꢀ-
epoxide 26 with 93% yield and 89% substrate conversion
after 5 runs (see Supporting Information).
In summary, we have developed an efficient and robust
protocol based on recyclable Cl3terpy or O-PEG-
OCH3-Cl2terpy ligand and Fe(II) salt to perform catalytic
oxidation and C-N bond formation reactions. Work is
ongoing to further expand the practical uses of these iron
complexes in organic synthesis.
Acknowledgment. We are thankful for the financial
support of The University of Hong Kong (University
Development Fund), Hong Kong Research Grants Council
(HKU 7012/05P) and (CityU 2/06C), and the Areas of
Excellence Scheme established under the University Grants
Committee of the Hong Kong Special Administrative Region,
China (AoE/P-10/01).
To simplify the recovery, the Cl3terpy ligand was deriv-
itized to O-PEG-OCH3-Cl2terpy, MW ) 9010 (details of
synthesis and characterization are given in the Supporting
Supporting Information Available: Experimental pro-
cedures and product characterizations. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Au, S.-M.; Huang, J.-S.; Yu, W.-Y.; Fung, W.-H.; Che, C.-M. J. Am.
Chem. Soc. 1999, 121, 9120.
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