Cationic iron-catalyzed intramolecular hydroalkoxylation of unactivated olefins

Article abstract of DOI:10.1016/j.tetlet.2007.03.004

Cationic iron complexes are effective catalysts for intramolecular hydroalkoxylation for unactivated olefins under mild conditions to form the corresponding cyclic ethers in excellent yield.

Full text of DOI:10.1016/j.tetlet.2007.03.004

Tetrahedron Letters 48 (2007) 3259–3261
Cationic iron-catalyzed intramolecular hydroalkoxylation of
unactivated olefins
Kimihiro Komeyama,* Takayuki Morimoto, Yuushou Nakayama and Ken Takaki*
Department of Chemistry and Chemical Engineering, Graduate School of Engineering, Hiroshima University, Kagamiyama,
Higashi-Hiroshima 739-8527, Japan
Received 14 February 2007; revised 24 February 2007; accepted 2 March 2007
Available online 4 March 2007
Abstract—Cationic iron complexes are effective catalysts for intramolecular hydroalkoxylation for unactivated olefins under mild
conditions to form the corresponding cyclic ethers in excellent yield.
Ó 2007 Elsevier Ltd. All rights reserved.
The importance of heterofunctionalization of unacti-
vated olefins has been widely recognized in the field of
synthesis of natural products and much effort has been
made towards the exploitation of this methodology.1
Of the recently developed processes, metal-catalyzed
heteroatom–carbon bond construction is a powerful
tool in this area; for instance, expensive Au, Ag, Pt,
Ir, and Ru catalysts, efficiently coordinate carbon–car-
bon multiple bonds like alkynes,2 diene,3 and allenes,4
to lead to the corresponding adducts in good yields.
However, their reactivity for the olefin moiety is low;
thus, high temperature and long reaction time are neces-
sary for the transformation to proceed.5 On the other
hand, we have recently demonstrated that iron salts
were good catalysts for intramolecular hydroamination
of unactivated olefins to provide N-heterocyclic com-
pounds in excellent yield under mild conditions.6 With
regard to the actual role of the iron in the reaction, there
was a possibility to generate Brønsted acid, particular
HCl, from the iron salt. Although, the reaction did
not proceed by means of the acid, the possibility has
not been completely ruled out so far. Therefore, the
present system was tried out for intramolecular hydro-
alkoxylation of unactivated olefins to elucidate this
point. Consequently, iron salts were found to exhibit a
catalyst activity that was superior to the activity of
Brønsted acids. We report herein these details.
nitrogen afforded 2-methyl-4,4-diphenyltetrahydrofuran
(2a) in 91% yield, whereas several dehydrated products7
were also given in the reaction (Table 1, entry 1). Similar
dehydration was observed using other iron (II) and (III)
chlorides (entries 2 and 3) and Brønsted acids (entries 11
and 12). In strong contrast, a cationic iron complex
Fe(OTf)3, which was conveniently prepared from the
treatment of FeCl3 and AgOTf with separating out
AgCl,8 could completely depress the formation of the
Table 1. Screening of catalysts for intramolecular hydroalkoxylation
of 1a
cat. (10 mol%)
OH
O
additive (x mol%)
Ph
Ph
DCE, 80 °C
Ph
Ph
2a
Time
Yielda (%)
1a
Entry
Catalyst
Additive (x)
1b
2b
3b
4
5
6
7
8
9
FeCl3Æ6H2O
FeCl3
FeCl2Æ4H2O
FeCl3
FeCl3
FeCl3
FeCl2Æ4H2O
FeCl2Æ4H2O
FeCl2Æ4H2O
AgOTfc
HCl
None
None
None
AgOTf (30)
AgClO4 (30)
AgBF4 (30)
AgOTf (20)
AgClO4 (20)
AgBF4 (20)
None
70 min
70 min
70 min
30 min
70 min
13 h
30 min
70 min
18 h
91
96
50
Quant
93
70
94
Quant
0
8
10
11b
12b
30 min
70 min
30 min
Treatment of c-hydroxyolefin 1a with 10 mol % of
FeCl3Æ6H2O in DCE (0.1 M) for 70 min at 80 °C under
None
None
56
90
TfOH
a Determined by 1H NMR.
b Small amounts (ca. 5%) of dehydrated byproducts were obtained.
c 30 mol % of catalyst was used.
*
Corresponding authors. E-mail: kkome@hiroshima-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.004

3260
K. Komeyama et al. / Tetrahedron Letters 48 (2007) 3259–3261
dehydrated products to give 2a in quantitative yield (en-
try 4). Moreover, the cationic complex was greatly supe-
rior to iron chloride in the reaction without the
formation of dehydrates. In this context, the reactivity
of the cationic iron complexes increased in the order:
ꢀBF4 < ꢀClO4 < ꢀOTf as counter anions. The same
trend was observed in the case of divalent iron species
(entries 7–9). AgOTf was of low activity in comparison
to the present catalyst system (entry 10).5b Favorable
solvents were non-polar ones like DCM, hexane, and
toluene, whereas polar solvents such as 2-propanol,
DMF, DMSO, and acetonitrile were disfavored in this
reaction.
To evaluate the actual role of the cationic iron species
for the heterofunctionalization, especially, whether the
iron participated in olefin activation or not, we com-
pared the present reaction with a Brønsted acid-cata-
lyzed reaction (Scheme 1). Reaction of 2,2,5-
triphenylpent-4-en-1-ol (1j) with 10 mol % of the cat-
ionic iron complex at 80 °C for 45 min gave only 6-
endo-trig cyclized product 3j in 76% yield.10 In strong
contrast, exposure of 1j to a solution of triflic acid
(10 mol %) in DCE effected the dehydrative isomeriza-
tion and the subsequent Friedel–Crafts cyclization to
produce bicyclic compound 4 in quantitative yield.11
These results could indicate that the reaction processes
of the present catalyst and that of Brønsted acid were
different. Thus, in the former case the iron metal center
might not only coordinate with the hydroxy group but
also the olefinic orbital, as shown in A. In contrast, in
the latter case proton should initially interact with only
the electron-rich hydroxy group, as depicted in B, to in-
duce the dehydration. On the other hand, the participa-
tion of a radical process in this media was tested using
AIBN (10 mol %) as radical initiator at 80 °C, but no
reaction was observed. In addition, the heterofunction-
alization of 1a could complete in the presence of 2,6-
di-tert-butyl-4-methylphenol (50 mol %), leading to 2a
in 91% yield within 70 min.
Next, the catalyst system could be extended to be the
synthesis of a diverse set of cyclic ethers (Table 2).9 In
the present system, it was easy for the hydroxy group
to take part in the heterofunctionalization of internal
olefins, leading to tetrahydrofuran derivatives as major
product in good yields (entries 3 and 4). Moreover, the
presence of useful functions: acetate, pivaloate, and ben-
zoate, was permitted in the reaction, but the addition led
to low stereoselectivity (entries 5–9).
Table 2. Intramolecular hydroalkoxylation of unactivated olefinsa
Based on these results described above, the reaction pro-
cess would be explained as depicted in Scheme 2. Coor-
dination of the cationic iron center with both the
hydroxy and the olefin moiety would yield a key inter-
mediate C. In this step, if the metal center was weakly
electron-deficient like FeCl3, dehydration might proceed
to provide by-products due to the inadequate coordina-
tion to the olefin. Then, the hydroxy group would attack
to iron-activated olefinic carbon to produce intermedi-
Entry Substrate
Time
Product
Yieldb
(%)
OH
O
Ph
Ph
Ph
Ph
1
2
30 min
97
Ph
Ph
Ph
2a
1a
OH
O
30 min
94
Ph
2b
1b
OH
Ph
Ph
OH
O
n
O
n
n
+
Ph
Ph
Ph
Ph
1j
Ph
Ph
Ph
3
4
n = 0 (1c)
n = 1 (1d)
45 min n = 0 (2c)
45 min n = 1 (2d)
94 [11:1]
95 [10:1]
FeCl3 (10 mol%)
AgOTf (30 mol%)
DCE, 80 ºC, 45 min
OH
O
TfOH (10 mol%)
DCE, 80 ºC, 45 min
5
30 min
95 (3:1)
Ph
Ph
1e
2e
O
Ph
OH
O
Ph
Ph
RO
Ph
RO
Ph
Ph
3j 76 %
4 quant
6
7
8
9
R = H (1f)
R = Ac (1g)
R = Piv (1h)
R = Bz (1i)
4 h
2 h
4 h
3 h
R = H (2f)
97 (1.2:1)
94 (1.4:1)
97 (1.1:1)
96 (1.2:1)
H
R = Ac (2g)
R = Piv (2 h)
R = Bz (2i)
H
[Fe]
Ph
OH
O
Ph
Ph
Ph
a Reaction conditions: hydroxyolefin (0.5 mmol), FeCl3 (10 mol %),
AgOTf (30 mol %), DCE (5 mL), 80 °C.
Ph
Ph
A
B
b Isolated yield. The value in parenthesis indicated [regioisomeric] and
(stereoisomeric) ratios, respectively.
Scheme 1.

K. Komeyama et al. / Tetrahedron Letters 48 (2007) 3259–3261
3261
2. (a) Messerle, B. A.; Vuong, K. Q. Pure Appl. Chem. 2006,
78, 385; (b) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree,
R. H. Org. Lett. 2005, 7, 5437; (c) Sheng, Y.; Musaev, D.
G.; Reddy, K. S.; McDonald, F. E.; Morokuma, K. J.
Am. Chem. Soc. 2002, 124, 4149; (d) Pale, P.; Chuche, J.
Tetrahedron Lett. 1987, 28, 6447; (e) Utimoto, K. Pure
Appl. Chem. 1983, 55, 1845; (f) Riediker, M.; Schreurs, J.
J. Am. Chem. Soc. 1982, 104, 5842.
O
R
O
R
E
E
2
3
[Fe]
3. (a) Utsunomiya, M.; Kawatsura, M.; Hartwig, J. F.
Angew. Chem., Int. Ed. 2003, 42, 5865; (b) Loh, T.-P.; Hu,
Q.-Y.; Ma, L.-T. S. J. Am. Chem. Soc. 2001, 123, 2450; (c)
Jolly, P. W.; Kokel, N. Synthesis 1990, 771.
4. (a) Hoffmann-Ro¨der, A.; Krause, N. Org. Lett. 2001, 3,
2537; (b) Arseniyadis, S.; Sartoretti, J. Tetrahedron Lett.
1985, 26, 729.
H
O
substrate 1
H
O
R
R
E
[Fe]
[Fe]
E
D
D'
H
O
[Fe]
R
E
5. (a) Yang, C.-G.; He, C. J. Am. Chem. Soc. 2005, 127,
6966; (b) Yang, C.-G.; Reich, N. W.; Shi, Z.; He, C. Org.
Lett. 2005, 7, 4553; (c) Han, H. Q. X.; Widenhoefer, R. A.
J. Am. Chem. Soc. 2004, 126, 9536.
C
Scheme 2. Plausible reaction mechanism.
6. Komeyama, K.; Morimoto, T.; Takaki, K. Angew. Chem.,
Int. Ed. 2006, 45, 2938.
7. The dehydrated products were not identified, but we firmly
confirmed them by GC–MS analysis and TLC monitoring
of the reaction mixture, wherein their Rf values were
judged as hydrocarbon.
ate D or D0 and the subsequent protonation could intra-
molecularly occur to afford cyclic ether 2 or 3.
In summary, we have demonstrated a catalytic activity
of the cationic iron complexes for intramolecular hydro-
alkoxylation of unactivated olefins under mild condi-
tions. The reaction system is compatible with many
functional groups, giving rise to various types of cyclic
ethers. The role of the cationic iron catalysts might be
a dual activation of both the hydroxy group and the ole-
fin moiety. The most striking feature is that the environ-
mentally friendly catalysis enables us to readily induce
hydroalkoxylation of unactivated olefins, that is hardly
attainable under mild conditions. Studies on improve-
ment of the selectivity of products and on details of
the reaction mechanism as well as on expansion of the
reaction scope are in progress.
8. All cationic iron complexes were preparated in situ from
the stirring of FeCl2 or 3 to AgX (X = OTf, ClO4, BF4; 2 or
3 equiv) in DCE for 2 h at room temperature. Similar
cationic iron complexes were synthesized in the following
report: Britovsek, G. J. P.; England, J.; Spintzmesser, S.
K.; White, A. J. P.; Williamson, D. A. Dalton Trans. 2005,
945.
9. General procedure for hydroalkoxylation 1. To cationic
iron complex, which was prepared in situ from iron
chloride (0.05 mmol) and AgOTf (0.15 mmol) in DCE
(2.5 mL) for 2 h at room temperature, was added the
solution of hydroxyolefins 1 (0.5 mol) in DCE (2.5 mL)
under N2 atmosphere. After heating during suitable time,
the reaction mixture was cooled, filtered through a short
silica-gel column using hexane/ethyl acetate as an eluent.
Separation by column chromatography (silica-gel 60 N,
63–200 lm) using hexane/ethyl acetate solvent afforded
products 2.
Acknowledgement
10. Similar 6-endo-trig cyclization was observed in our previ-
ous report; see Ref. 6.
This work is supported financially by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Science, Sports and Culture, Japan.
11. 4: Isolated as a white solid; mp: 120–121 °C; 1H NMR
(CDCl3) d 2.21–2.33 (2H, m), 2.39–2.49 (2H, m), 3.53 (1H,
dd, J = 16.7, 2.4 Hz), 3.68 (1H, d, J = 16.7 Hz), 3.97 (1H,
t, J = 2.4 Hz), 6.56 (1H, J = 7.7 Hz), 6.98–7.56 (12H, m);
13C NMR (CDCl3) d 30.5, 35.7, 44.9, 46.0, 47.6, 125.4,
126.0, 126.3, 126.4, 126.5, 126.8, 127.9, 128.1, 131.6, 125.5,
142.2, 143.6, 143.7, 147.9, aromatic two carbons were
overlapped; MS m/s 296 (M+, 88), 265 (18), 218 (19), 203
(40), 191 (100). Anal. Calcd for C23H20: C, 93.20; H, 6.80.
Found: C, 93.20; H, 6.68.
References and notes
1. Larock, R. C.; Leong, W. W. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 4, p 269.