Iron- or cobalt-catalyzed nazarov cyclization: Asymmetric reaction and tandem cyclization-fluorination reaction

Article abstract of DOI:10.1055/s-0029-1219782

We succeeded in demonstrating the iron- or cobalt-catalyzed asymmetric Nazarov cyclization of divinyl ketones using iron or cobalt catalysts, which were prepared from Co(ClO⁴)²6H²O, Fe(ClO ⁴)²6H²O, or Fe(OTf)² with a chiral pybox-type ligand. Furthermore, we found that Fe(OTf)² effectively catalyzed the tandem Nazarov cyclization-fluorination reaction of divinyl ketones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219782

LETTER
1243
Iron- or Cobalt-Catalyzed Nazarov Cyclization: Asymmetric Reaction and
Tandem Cyclization–Fluorination Reaction
I
ron- or Cobalt-Catalyz
o
ed
A
symme
t
tric
N
a
o
z
arovCycliz
i
a
tion Kawatsura,* Koji Kajita, Shuichi Hayase, Toshiyuki Itoh*
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
Fax +81(857)315259; E-mail: kawatsur@chem.tottori-u.ac.jp; E-mail: titoh@chem.tottori-u.ac.jp
Received 13 February 2010
reaction (entry 3). From these results obtained, we con-
Abstract: We succeeded in demonstrating the iron- or cobalt-cata-
cluded that L1 is a more appropriate ligand than L2 for the
Co(ClO4)2·6H2O-catalyzed enantioselective Nazarov cy-
clization reaction of 1a. We next examined the same reac-
lyzed asymmetric Nazarov cyclization of divinyl ketones using iron
or cobalt catalysts, which were prepared from Co(ClO4)2·6H2O,
Fe(ClO4)2·6H2O, or Fe(OTf)2 with a chiral pybox-type ligand. Fur-
thermore, we found that Fe(OTf)2 effectively catalyzed the tandem tion using an iron catalyst with chiral ligands L1 and L2
Nazarov cyclization–fluorination reaction of divinyl ketones.
(entries 4–6). For the Fe(ClO4)2·6H2O-catalyzed reaction,
the ligand L2 gave a better result than L1.8 The best enan-
tioselectivity (83% ee) was attained when CH2Cl2–hexane
(2:1) was used as the solvent (entry 6).
Key words: iron catalyst, cobalt catalyst, Nazarov cyclization,
fluorination
O
O
O
O
The Nazarov cyclization is one of the most versatile meth-
ods for the synthesis of five-membered carbocycles, and
it is known that several Lewis or Brønsted acids promote
this reaction.1,2 We also demonstrated the iron-catalyzed
Nazarov cyclization of thiophene and pyrrole deriva-
tives.3 However, there are only limited examples of the
catalytic asymmetric Nazarov cyclization: to the best of
our knowledge, effective transition-metal catalysts which
could promote the asymmetric induction are limited for
Cu, Sc, and Ni Lewis acids.4,5 We have been investigating
the possibility of iron- or cobalt-catalyzed asymmetric
reaction, and we recently developed the iron- or cobalt-
catalyzed enantioselective Michael addition of thiols to
a,b-unsaturated compound.6 Herein, we report the first
example of iron- or cobalt-catalyzed asymmetric Nazarov
cyclization reaction. Furthermore, we also succeeded in
demonstrating the tandem cyclization–fluorination reac-
tion by an iron catalyst.
Ph
Ph
Ph
Ph
[M/L*]
OEt
OEt
60 °C, 15 h
Ph
Ph
1a
2a
O
O
L1: R = i-Pr {(S,S )-ip-pybox}
L2: R = t-Bu {(S,S )-tb-pybox}
N
N
N
R
R
Scheme 1
Based on the results of the cobalt- or iron-catalyzed asym-
metric cyclization of 1a, we applied these catalyst systems
to the reaction of various types of divinyl ketones 1b–g
(Scheme 2). The chiral Co(ClO4)2·6H2O/L1 catalyst ex-
hibited a moderate enantioselectivity (63% ee) for 1b
when the reaction was conducted in CH2Cl2 (Table 2, en-
try 1), while the ee value was insufficient even when the
solvent was changed to CH2Cl2–hexane (2:1; entry 2).
The iron catalyst with L2 exhibited a good enantioselec-
tivity (74% ee), but the yield was very low (entry 4). The
reactivity of 1c, which had a 4-methoxyphenyl group at
the C1 position, was high and produced the cyclization
We initially tried the enantioselective Nazarov cyclization
reaction of divinyl ketone 1a.7 The screening of an effec-
tive cobalt or iron catalyst for the asymmetric reaction
was performed using various cobalt and iron salts, chiral
ligands, and solvent. We discovered that Co(ClO4)2·6H2O
and Fe(ClO4)2·6H2O with a chiral pybox-type ligand (L1
or L2) exhibited a moderate reactivity and enantioselec-
tivity for the reaction of 1a (Scheme 1). For example,
Co(ClO4)2·6H2O with (S,S)-ip-pybox (L1) gave the cy-
clization product 2a in 66% isolated yield with a 73% ee
(Table 1, entry 1). Switching the solvent from CH2Cl2 to
a mixture of CH2Cl2–hexane (2:1) increased both the yield
(76%) and enantioselectivity (78% ee, entry 2). We also
examined the reaction using a cobalt catalyst with (S,S)-
tb-pybox (L2), but the ligand was not effective for this
O
O
O
O
R
R
[Co/L] or [Fe/L]
OEt
OEt
60 °C, 16 h
Ph
Ar
Ph
Ar
1b–g
2b–g
1b R = Me, Ar = Ph
1c R = Ph, Ar = 4-MeOC6H4
1d R = Ph, Ar = 4-F3CC6H4
1e R = Ph, Ar = 4-O2NC6H4
1f R = Ph, Ar = 1-naphthyl
1g R = Ph, Ar = 2-naphthyl
SYNLETT 2010, No. 8, pp 1243–1246
x
x.
x
x.
2
0
1
0
Advanced online publication: 23.03.2010
DOI: 10.1055/s-0029-1219782; Art ID: U01310ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

1244
M. Kawatsura et al.
LETTER
Table 1 Asymmetric Nazarov Cyclization of 1a by Cobalt or Iron Salts with Pybox-Type Ligandsa
Entry
[M/L]
Solvent
Yield (%)b
ee (%)c
73
1
2
3
4
5
6
Co(ClO4)·6H2O/L1
Co(ClO4)·6H2O/L1
Co(ClO4)·6H2O/L2
Fe(ClO4)2·6H2O/L1
Fe(ClO4)2·6H2O/L2
Fe(ClO4)2·6H2O/L2
CH2Cl2
66
76
74
74
78
69
CH2Cl2–hexane (2:1)
CH2Cl2
78
68
CH2Cl2
55
CH2Cl2
73
CH2Cl2–hexane (2:1)
83
a Reaction conditions: Co(ClO4)·6H2O or Fe(ClO4)2·6H2O (0.05 mmol), L1 or L2 (0.05 mmol), 1a (0.10 mmol), solvent (1.5 mL), 60 °C, 15 h.
b Isolated yield by silica gel column chromatography.
c Values of ee were determined by chiral HPLC using Daicel CHIRALPAK AD-H (hexane–2-PrOH = 95:5).
product 2c in good yield, but both the cobalt and iron cat- yield with moderate enantiomeric excess. The highest
alysts are insufficient for the asymmetric induction (en- enantioselectivity (93% ee) was attained when the reac-
tries 5 and 6). On the other hand, the reaction of 1d, which tion was conducted in toluene even though the chemical
possesses a para-trifluoromethyl phenyl group at the C1 yield decreased (entry 14). We thus concluded that the
position, showed a moderate enantiomeric excess, but the iron/pybox catalyst produced a the higher enantioselectiv-
chemical yield decreased (entries 7 and 8). Therefore, we iy than the cobalt/pybox catalyst for most of the divinyl
reinvestigated to find more suitable chiral iron catalyst for ketones. Unfortunately, the chemical yield was not high
the asymmetric cyclization of divinyl ketone 1d and dis- enough, but we succeeded in obtaining the desired chiral
covered that the catalyst system of Fe(OTf)2 with L2 in cyclization product with up to a 93% ee using the iron cat-
toluene gave a very high enantioselectivity (89% ee, entry alyst.
9).9 We further examined the reaction of other divinyl ke-
tones using Fe(OTf)2/L2, and confirmed that the reaction
of 1g proceeded in providing the desired product in good
We next tried the iron-catalyzed tandem Nazarov cycliza-
tion–fluorination reaction. Recently, Ma et al. reported the
Table 2 Asymmetric Nazarov Cyclization of Divinyl Ketones (1b–e) by Cobalt or Iron Catalystsa
Entry
1
1
[M/L]
Solvent
Yield (%)b
ee (%)c
63
65
56
74
8
1b
1b
1b
1b
1c
1c
1d
1d
1d
1e
1e
1f
Co(ClO4)·6H2O/L1
Co(ClO4)·6H2O/L1
Fe(ClO4)2·6H2O/L2
Fe(ClO4)2·6H2O/L2
Co(ClO4)·6H2O/L1
Fe(ClO4)2·6H2O/L2
Co(ClO4)·6H2O/L1
Fe(ClO4)2·6H2O/L2
Fe(OTf)2/L2
CH2Cl2
53
26
30
13
70
81
36
23
53
23
13
85
84
40
2
CH2Cl2–hexane (2:1)
CH2Cl2
3
4
CH2Cl2–hexane (2:1)
CH2Cl2
5
6
CH2Cl2–hexane (2:1)
CH2Cl2
0
7
51
61
89
12
80
29
65
93
8
CH2Cl2–hexane (2:1)
Toluene
9
10
11
12
13
14
Co(ClO4)·6H2O/L1
Fe(OTf)2/L2
CH2Cl2
Toluene
Fe(OTf)2/L2
CH2Cl2
1g
1g
Fe(OTf)2/L2
CH2Cl2
Fe(OTf)2/L2
Toluene
a Reaction conditions: Co(ClO4)·6H2O or Fe(ClO4)2·6H2O (0.05 mmol), L1 or L2 (0.05 mmol), 1b–g (0.10 mmol), solvent (1.5 mL), 60 °C, 15
h.
b Isolated yield by silica gel column chromatography.
c Values of ee were determined by chiral HPLC: Daicel CHIRALPAK AD-H (hexane–2-PrOH = 95:5) for 2c–d and 2f–g. Daicel CHIRALCEL
OJ-H for 2b (hexane–2-PrOH = 95:5) and 2e (hexane–2-PrOH = 80:20).
Synlett 2010, No. 8, 1243–1246 © Thieme Stuttgart · New York

LETTER
Iron- or Cobalt-Catalyzed Asymmetric Nazarov Cyclization
1245
copper-catalyzed tandem Nazarov cyclization–electro-
philic fluorination reaction, and the aluminum-catalyzed
triple cascade Knoevenagel condensation–Nazarov cy-
clization–fluorination reaction.10 Based on their excellent
work, we also examined the iron-catalyzed tandem Naz-
arov cyclization–fluorination reaction. Initially, we found
that Fe(OTf)2 effectively catalyzed the reaction without
any ligand, and the reaction afforded the desired fluorinat-
ed product.11 Typically, the reaction was carried out as
follows: 10 mol% of Fe(OTf)2, divinyl ketone 1, and
NFSI (N-fluorobenzenesulfonimide) (2 equiv) were
mixed in toluene at room temperature for 15 hours
(Scheme 3). As shown in Table 3, most divinyl ketones
(1a–g) provided the desired product as a single stereoiso-
mer in moderate to good yields (up to 91% isolated yield).
We also examined the asymmetric tandem Nazarov cy-
clization–fluorination reaction by Fe(OTf)2 with several
chiral ligands, but unfortunately, we could not observe
any enantiomeric excess. Therefore, the asymmetric ver-
sion of this reaction will be the subject of future work.
References and Notes
(1) (a) Pellissier, H. Tetrahedron 2005, 61, 6479. (b) Frontier,
A. J.; Collison, C. Tetrahedron 2005, 61, 7577. (c) Tius, M.
A. Eur. J. Org. Chem. 2005, 2193. (d) Grant, T. N.; Rieder,
C. J.; West, F. G. Chem. Commun. 2009, 5676.
(2) (a) Jones, T. K.; Denmark, S. E. Helv. Chim. Acta 1983, 66,
2377. (b) Denmark, S. E.; Jones, T. K. J. Am. Chem. Soc.
1982, 104, 2642. (c) Denmark, S. E.; Klix, R. C.
Tetrahedron 1988, 44, 4043. (d) Kang, K.-T.; Kim, S. S.;
Lee, J. C.; U, J. S. Tetrahedron 1992, 33, 3495. (e) Wang,
Y.; Arif, A. M.; West, F. G. J. Am. Chem. Soc. 1999, 121,
876. (f) Clive, D. L. J.; Sannigrahi, M.; Hisaindee, S. J. Org.
Chem. 2001, 66, 954. (g) He, W.; Sun, X.; Frontier, A. J.
J. Am. Chem. Soc. 2003, 125, 14278. (h) Bee, C.; Leclerc,
E.; Tius, M. A. Org. Lett. 2003, 5, 4927. (i) Wang, Y.;
Schill, B. D.; Arif, A. A.; West, F. G. Org. Lett. 2003, 5,
2747. (j) Kerr, D. J.; Metje, C.; Flynn, B. L. Chem. Commun.
2003, 1380. (k) Janka, M.; He, W.; Frontier, A. J.;
Eisenberg, R. J. Am. Chem. Soc. 2004, 126, 6864. (l)Janka,
M.; He, W.; Haedicke, I. E.; Fronczek, F. R.; Frontier, A. J.;
Eisenberg, R. J. Am. Chem. Soc. 2006, 128, 5312.
(m) Malona, J. A.; Colbourne, J. M.; Frontier, A. J. Org.
Lett. 2006, 8, 5661. (n) Huang, J.; Frontier, A. J. J. Am.
Chem. Soc. 2007, 129, 8060. (o) Song, D.; Rostami, A.;
West, F. G. J. Am. Chem. Soc. 2007, 129, 12019.
(p) Shindo, M.; Yaji, K.; Kita, T.; Shishido, K. Synlett 2007,
1096. (q) He, W.; Huang, J.; Sun, X.; Frontier, A. J. J. Am.
Chem. Soc. 2007, 129, 498. (r) Walz, I.; Bertogg, A.; Togni,
A. Eur. J. Org. Chem. 2007, 2650. (s) He, W.; Herrick, I.
R.; Atesin, T. A.; Caruana, P. A.; Kellenberger, C. A.;
Frontier, A. J. J. Am. Chem. Soc. 2008, 130, 1003.
(t) Marcus, A. P.; Lee, A. S.; Davis, R. L.; Tantillo, D. J.;
Sarpong, R. Angew. Chem. Int. Ed. 2008, 47, 6379.
(u) Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem.
Soc. 2009, 131, 7504. (v) Malona, J. A.; Cariou, K.;
Frontier, A. J. J. Am. Chem. Soc. 2009, 131, 7560.
(w) Bachu, P.; Akiyama, T. Bioorg. Med. Chem. Lett. 2009,
19, 3764.
O
O
R
Fe(OTf)2 (10 mol%)
toluene, r.t., 15 h
OEt
1a–g
+
NFSI
F
(2 equiv)
Ph
Ar
3a–g
Scheme 3
Table 3 Catalytic Tandem Nazarov Cyclization–Fluorination Reac-
tion of 1a–ga
Entry
1
Yield (%)b
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
91
80
65
72
51
72
71
(3) (a) Kawatsura, M.; Higuchi, Y.; Hayase, S.; Nanjo, M.; Itoh,
T. Synlett 2008, 1009. (b) Fujiwara, M.; Kawatsura, M.;
Hayase, S.; Nanjo, M.; Itoh, T. Adv. Synth. Catal. 2009, 351,
123.
(4) (a) Aggarwal, V. K.; Belfield, A. J. Org. Lett. 2003, 5, 5075.
(b) Liang, G.; Gradl, S. N.; Trauner, D. Org. Lett. 2003, 5,
4931. (c) Liang, G.; Trauner, D. J. Am Chem. Soc. 2004,
126, 9544. (d) Walz, I.; Togni, A. Chem. Commun. 2008,
4315. (e) Yaji, K.; Shindo, M. Synlett 2009, 2524.
(5) For other asymmetric Nazarov cyclization, see: (a) Dhoro,
F.; Kristensen, T. E.; Stockmann, V.; Yap, G. P. A.; Tius,
M. A. J. Am. Chem. Soc. 2007, 129, 7256. (b) Rueping, M.;
Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J.
Angew. Chem. Int. Ed. 2007, 46, 2097. (c) Rueping, M.;
Ieawsuwan, W. Adv. Synth. Catal. 2009, 351, 78.
1g
a Reaction conditions: Fe(OTf)2 (0.01 mmol), 1a (0.10 mmol), NFSI
(0.20 mmol), toluene (0.2 mL), r.t., 15 h.
b Isolated yield by silica gel column chromatography.
(6) (a) Kawatsura, M.; Komatsu, Y.; Yamamoto, M.; Hayase,
S.; Itoh, T. Tetrahedron Lett. 2007, 48, 6480.
(b) Kawatsura, M.; Komatsu, Y.; Yamamoto, M.; Hayase,
S.; Itoh, T. Tetrahedron 2008, 64, 3488.
(7) Typical Procedure for the Asymmetric Nazarov
Cyclization of 1a
In conclusion, we succeeded in demonstrating the iron- or
cobalt-catalyzed asymmetric Nazarov cyclization of divi-
nyl ketones; some iron and cobalt catalysts, which were
prepared from Co(ClO4)2·6H2O, Fe(ClO4)2·6H2O or
Fe(OTf)2 with the chiral pybox-type ligand, exhibited
good to high enantioselectivities. Furthermore, we that
Fe(OTf)2 effectively catalyzed the tandem Nazarov
cyclization–fluorination reaction of divinyl ketones.
A solution of Fe(ClO4)·6H2O (18.1 mg, 0.050 mmol) and
(S,S)-tb-pybox (16.5 mg, 0.050 mmol) in anhyd CH2Cl2
(0.50 mL) was stirred at r.t. for 3 h, then 2-benzyliden-3-
oxo-4,5-diphenylpent-4-enoic acid ethyl ester (1a, 38.2 mg
0.10 mmol) in anhyd CH2Cl2 (0.50 mL) and hexane (0.50
mL) was added slowly, then stirred at 60 °C for 15 h. The
reaction mixture was quenched with H2O, and extracted with
EtOAc. The combined organic layers was washed with
Synlett 2010, No. 8, 1243–1246 © Thieme Stuttgart · New York

1246
M. Kawatsura et al.
LETTER
brine, dried over MgSO4, and evaporated. The residue was
chromatographed on silica gel (hexane–Et2O = 7:3) to give
26.4 mg (69%) of 2a.
(8) We also examined the reaction using other chiral pybox-type
ligands, such as (S,S)-phe-pybox and (S,S)-inda-pybox, but
enantioselectivities were 2% ee (92% yield) and 33% ee
(22% yield), respectively.
Analytical Data
[a]D24 +289 (c 1.0, CHCl3). The enantiomeric purity was
determined to be 83% ee by chiral HPLC analysis with a
Daicel CHIRALPAK AD-H [hexane–2-PrOH (95:5), flow:
0.5 mL/min, 35 °C, tmajor = 23 min, tminor = 33 min]. The
absolute configuration of the major enantiomer is (1R,5S) by
the comparison of the reported data. 1H NMR (400 MHz,
CDCl3): d = 1.31 (t, J = 6.8 Hz, 3 H), 3.64 (m, 1 H), 4.26 (m,
(9) Surprisingly, the reaction of 1a with Fe(OTf)2 in toluene did
not proceed.
(10) (a) Nie, J.; Zhu, H.-W.; Cui, H.-F.; Hua, M.-Q.; Ma, J.-A.
Org. Lett. 2007, 9, 3053. (b) Cui, H.-F.; Dong, K.-Y.;
Zhang, G.-W.; Wang, L.; Ma, J.-A. Chem. Commun. 2007,
2284.
(11) The relative stereochemistry of 3 was estimated by
comparison with the product from the reaction of 1 by
Cu(OTf)2, see ref. 10a.
2 H), 5.02 (d, J = 2.8 Hz, 1 H), 7.10–7.34 (m, 15 H). 13
C
NMR (125 MHz, CDCl3): d = 14.2, 50.9, 61.9, 62.5, 127.2,
127.7, 128.1, 128.2, 128.3, 128.9, 128.9, 129.6, 129.7,
131.2, 134.0, 138.7, 140.5, 168.3, 170.0, 199.4.
Synlett 2010, No. 8, 1243–1246 © Thieme Stuttgart · New York

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