induced cyclization of 6-alkynyl acetals formed iodoben-
zylidene cyclohexyl methyl ethers.12 SnCl4-initiated ring-
enlarging cyclopentene annulation was realized with silyl
ether alkynyl-aldehyde dimethyl acetals.13 Recently, iron salts
have emerged as alternative and promising catalysts for a
wide range of organic transformations due to their advantages
such as low cost, nontoxicity, good stability, and easy manner
to handle.14-18 FeX3 (X ) Cl, Br)-catalyzed Prins-type
cyclization between homopropargylic alcohol and aldehydes
formed 2-alkyl-4-halo-5,6-dihydro-2H-pyrans,19a and FeX3-
promoted coupling of alkynes and aldehydes afforded 1,5-
dihalo-1,4-dienes.19b Noniron Lewis acid-catalyzed cycliza-
tion of alkynes and aldehydes or alkynyl carbonyls have also
been documented.20 Intrigued by the versatile interactions
of Lewis acids with acetals, we envisioned that the reactions
of FeCl3 with acetals might generate active species which
can initiate new reactions. Herein, we report FeCl3- and
FeBr3-promoted cyclization/halogenation of alkynyl diethyl
acetals to form (E)-2-(l-halobenzylidene or alkylidene)-
substituted five-membered carbo- and heterocycles.
Table 1. Screening of the Reaction Conditionsa
entry
cat./equiv
FeCl3/0.10
solvent temp time (h) yield (%)b
1
CH2Cl2 rt
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
5
<19c
60
59
54
66
68
74
73
50
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
FeCl3/0.33
FeCl3/0.33
FeCl3/0.33
FeCl3/0.50
FeCl3/0.50
FeCl3/0.70
FeCl3/1.00
FeCl3/1.00
FeCl3/1.00
FeCl3/1.00
FeCl3/1.00
FeCl3/1.00
CH2Cl2 rt
CH2Cl2 reflux
CH2Cl2
0
CH2Cl2 rt
CH2Cl2
CH2Cl2
0
0
CH2Cl2 rt
CH2Cl2 reflux
CH2Cl2
toluene
THF
0
0
0
77
67
20
H2O
rt
0.5
<1c
CuCl2·2H2O/1.00 CH2Cl2 rt
12
12
0.2
0.5
In our initial studies, the reaction of alkynyl acetal 1a was
chosen to screen the reaction conditions (Table 1). Treatment
of 1a with 10 mol % FeCl3 in CH2Cl2 at ambient temperature
for 0.5 h afforded the desired product 2a in <19% yield
(entry 1) with a low conversion of 1a. Increasing the amount
of FeCl3 to 0.33 equiv (total chlorine ∼1.0 equiv), the same
reaction formed 2a with (E)-configuration in 60% isolated
yield with incomplete conversion of 1a within 30 min (entry
2), suggesting that the second and/or third chlorides in the
promoter took part in the reaction. A trace amount of
isomeric 2a (<5%), presumably the six-membered product
of Martín-type,19 was detected by GC-MS analysis (see
Supporting Information), but it was not successfully isolated.
Further increasing the amount of FeCl3 enhanced the
formation of 2a (entries 5-10). It was found that the 1:1
molar ratio reaction of 1a with FeCl3 proceeded more
efficiently at 0 °C than at other temperatures, reaching a 77%
FeCl2/1.00
TiCl4/1.00
SnCl4/1.00
CH2Cl2 reflux
CH2Cl2
CH2Cl2
0
0
6d
52
a Conditions: 1a, 0.5 mmol; solvent, 5 mL. b Isolated yields of 2a.
c Determined by GC analysis. d See eq 2.
yield for 2a. The reaction also worked well in toluene (entry
11) but less efficiently in THF and water (entries 12 and
13).
CuCl2·2H2O and FeCl2 did not initiate the reaction (entries
14 and 15). Unexpectedly, treatment of 1a with TiCl4 (1.0
equiv) afforded 2a (6%) and the dichloro product 3 (52%)
within 10 min (entry 16 and eq 2). However, the reaction of
1a with SnCl4 (1.0 equiv) exclusively gave 2a as the product
(52% yield, entry 17). Thus, the reaction conditions were
optimized to: 1a (0.5 mmol), FeCl3 (1.0 equiv), CH2Cl2 as
the solvent, 0 °C/0.5 h under a nitrogen atmosphere.
The reactions of FeCl3 and FeBr3 with other alkynyl acetals
were then carried out to define the protocol generality (Table
2). In all the cases, the (Z)-products were not isolated in a
measurable amount. With O-linked alkynyl acetals as the
substrates, the reactions produced the (E)-products 2a-i in
61-91% yields (entries 1-9). Substituents on the aryl group
of the alkynyl moiety did not obviously affect formation of
the desired products (entries 1-8), but an adjacent 2-sub-
stituent such as 2-methoxy lessened generation of the product
such as 2i (entry 9). Increasing the steric hindrance of the
linker chain dramatically decreased the reaction efficiency
(entry 10) or made the reaction complicated (entry 11).
Benzoyl alkynyl acetal (1l) also underwent a complicated
(12) Takami, K.; Yorimitsu, H.; Shinokubo, H.; Matsubara, S.; Oshima,
K. Synlett 2001, 2, 293.
(13) Johnson, T. O.; Overman, L. E. Tetrahedron Lett. 1991, 32, 7361.
(14) For recent reviews, see: (a) Correa, A.; Manchen˜o, O. G.; Bolm,
C. Chem. Soc. ReV. 2008, 37, 1108. (b) Enthaler, S.; Junge, K.; Beller, M.
Angew. Chem., Int. Ed. 2008, 47, 3317. (c) Fu¨rstner, A.; Martin, R.; Krause,
H.; Seidel, G.; Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008,
130, 8773. (d) Fu¨rstner, A.; Martin, R. Chem. Lett. 2005, 34, 624. (e) Bolm,
C.; Legros, J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104, 6217
.
(15) (a) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. J. Am.
Chem. Soc. 2008, 130, 5858. (b) Volla, C. M. R.; Vogel, P. Angew. Chem.,
Int. Ed. 2008, 47, 1305. (c) Lu, Z.; Chai, G. B.; Ma, S. M. J. Am. Chem.
Soc. 2007, 129, 14546
.
(16) (a) Carril, M.; Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2008,
47, 4862. (b) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008,
47, 2880. (c) Bistri, O.; Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2008,
47, 586
.
(17) (a) Wen, J.; Zhang, J.; Chen, S.-Y.; Li, J.; Yu, X.-Q. Angew. Chem.,
Int. Ed. 2008, 47, 8897. (b) Li, Z. P.; Yu, R.; Li, H. J. Angew. Chem., Int.
Ed. 2008, 47, 7497
.
(18) (a) Langlotz, B. K.; Wadepohl, H.; Gade, L. H. Angew. Chem.,
Int. Ed. 2008, 47, 4670. (b) Shaikh, N. S.; Enthaler, S.; Junge, K.; Beller,
M. Angew. Chem., Int. Ed. 2008, 47, 2497
.
(19) (a) Miranda, P. O.; D´ıaz, D. D.; Padro´n, J. I.; Bermejo, J.; Mart´ın,
V. S. Org. Lett. 2003, 5, 1979. (b) Miranda, P. O.; D´ıaz, D. D.; Padro´n,
J. I.; Ram´ırez, M. A.; Mart´ın, V. S. J. Org. Chem. 2005, 70, 57.
(20) (a) Saito, A.; Umakoshi, M.; Yagyu, N.; Hanzawa, Y. Org. Lett.
2008, 10, 1783. (b) Jin, T.; Yamamoto, Y. Org. Lett. 2008, 10, 3137.
2114
Org. Lett., Vol. 11, No. 10, 2009