Fe(III) halides as effective catalysts in carbon-carbon bond formation: Synthesis of 1,5-dihalo-1,4-dienes, αβ-unsaturated ketones, and cyclic ethers

Article abstract of DOI:10.1021/jo048410j

(Chemical Equation Presented). Iron(III) halides have proven to be excellent catalysts in the coupling of acetylenes and aldehydes. When terminal acetylenes were used the main products obtained were 1,5-dihalo-1,4-dienes with (E,Z)-stereochemistry contaminated in some cases with (E)-α,β- unsaturated ketones. The former carbonyl derivatives were the sole products isolated when nonterminal aromatic alkynes were used. When homopropargylic alcohols were used, a Prins-type cyclization occurred yielding 2-alkyl-4-halo-5,6-dihydro-2H-pyrans. In addition, anhydrous ferric halides are also shown to be excellent catalysts for the standard Prins cyclization with homoallylic alcohols. Isolation of an intermediate acetal, calculations, and alkyne hydration studies provide substantiation of a proposed mechanism.

Full text of DOI:10.1021/jo048410j

Fe(III) Halides as Effective Catalysts in Carbon-Carbon Bond
Formation: Synthesis of 1,5-Dihalo-1,4-dienes, r,â-Unsaturated
Ketones, and Cyclic Ethers
†
†
†,‡
†
Pedro O. Miranda, David D. D ´ı az, Juan I. Padr o´ n, Miguel A. Ram ´ı rez, and
V ´ı ctor S. Mart ´ı n*,
†
Instituto Universitario de Bio-Org a´ nica “Antonio Gonz a´ lez” and Departamento de F ´ı sica B a´ sica,
Universidad de La Laguna, C/Astrof ı´ sico Francisco S a´ nchez s/n, 38206 La Laguna,
Tenerife, Canary Islands, Spain
vmartin@ull.es
Received September 9, 2004
Iron(III) halides have proven to be excellent catalysts in the coupling of acetylenes and aldehydes.
When terminal acetylenes were used the main products obtained were 1,5-dihalo-1,4-dienes with
(
E,Z)-stereochemistry contaminated in some cases with (E)-R,â-unsaturated ketones. The former
carbonyl derivatives were the sole products isolated when nonterminal aromatic alkynes were used.
When homopropargylic alcohols were used, a Prins-type cyclization occurred yielding 2-alkyl-4-
halo-5,6-dihydro-2H-pyrans. In addition, anhydrous ferric halides are also shown to be excellent
catalysts for the standard Prins cyclization with homoallylic alcohols. Isolation of an intermediate
acetal, calculations, and alkyne hydration studies provide substantiation of a proposed mechanism.
4
Introduction
ethers as their main structural feature, we addressed
our attention to the use of dicobalt hexacarbonyl-
stabilized propargylic cations as an excellent synthetic
tool to control the carbon-oxygen bond in the propargylic
The formation of carbon-carbon bonds constitutes the
essence of synthetic organic chemistry. Coupling reac-
tions of alkynes and carbonyl compounds are important
transformations since they efficiently generate new
carbon-carbon bonds. From the existing methodology,
the synthesis of propargylic alcohols by basic C-H
activation in terminal acetylenes and further carbonyl
1
5
system. We were particularly interested in using such
nonbasic conditions since in the synthesis of compounds
isolated from the marine environment in the presence of
4
compounds having halides is quite common, in most
cases being noncompatible with the strong basic condi-
tions needed, for instance, for the synthesis of the
propargylic alcohols. Pondering the possibility of extend-
ing the use of acetylenes under nonbasic conditions to
control the cyclic ether formation and to form carbon-
carbon bonds, we decided to explore the direct coupling
of such units and carbonyl derivatives using Lewis acids
as catalysts.
addition is from the practical point of view one of the most
popular reactions.2 On the other hand, virtually all
transition metals react with alkynes, in most cases
evolving toward more elaborate complexes or organic
3
products.
As a result of our studies directed to the synthesis of
marine natural products characterized by having cyclic
*
Address correspondence to this author.
3
Within the Lewis acid catalog, FeX are inexpensive,
environmentally friendly, and stable Lewis acids, de-
scribed in the literature as effective agents for the
†
Instituto Universitario de Bio-Org a´ nica “Antonio Gonz a´ lez”.
Departamento de F ´ı sica B a´ sica.
‡
(1) Comprehensive Organic Synthesis; Trost, B. M., Fleming, T.,
Eds.; Pergamon: Oxford, UK, 1991; Vol. 3.
2) Brandsma, L. Preparative Acetylenic Chemistry; Elsevier Science
Publishers: Amsterdam, The Netherlands, 1988.
3) (a) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826-834.
(
(4) (a) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1-48 and preceding
issues. (b) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897-1909.
(5) (a) Betancort, J. M.; Mart ´ı n, T.; Palaz o´ n, J. M.; Mart ´ı n, V. S. J.
Org. Chem. 2003, 68, 3216-3224. (b) D ´ı az, D. D.; Mart ´ı n, V. S. Org.
Lett. 2000, 2, 335-337.
(
(
b) Schore, N. E. Chem. Rev. 1988, 88, 1081-1119. (c) Metal-Catalyzed
Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley: New
York, 1997.
1
0.1021/jo048410j CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/23/2004
J. Org. Chem. 2005, 70, 57-62
57

Miranda et al.
SCHEME 1. Reactions of FeX
3
with Different
TABLE 1. Synthesis of 2-Halovinyl and Methyl Ketone
Derivatives from Terminal Acetylenes
Unsaturated Substrates and Aldehydes
yield
(%)
entry
R1
R2
X
acid
3:4
1
2
3
4
5
6
7
8
9
n-C6H13
n-C6H13
n-C6H13
n-C6H13
n-C6H13
n-C6H13
n-C6H13
n-C6H13
n-C6H13
n-C6H13
Ph
H
H
H
H
H
H
H
H
H
H
H
H
Cl
-
-
100:0
100:0
100:0
100:0
100:0
54
51
88
80
82
75
80
85
70
Br
Cl HOAc
Cl TFA
Br BzOH
Cl aspartic acid 100:0
Cl CSA
Br CSA
Cl TsOH
Br MsOH
Cl HOAc
Cl CSA
Cl HOAc
Cl HOAc
38:62
10:90
100: 0
1
1
1
0
1
2
0:100
0:100
82
80
6
7
8
cleavage and formation of ethers, as oxidant agents,
in cross coupling of alkenyl or aryl derivatives and
Ph
13
14
Me
n-C3H7
n-C H
5
11
9
10
Grignard reagents, for carbometalation of olefins, in
n-C3H7
11
the synthesis of 2-aryl-tetrahydrofurans, for Nararov
to give the corresponding 2-halovinyl 316 derivatives
although with a moderate yield (entries 1 and 2).
Nevertheless, when we used stoichiometric amounts of
carboxylic acids, yields improved remarkably (entries
cyclizations, in the allylation of aldehydes,13 among
12
other applications.14 In this paper we would like to report
on the scope and limitations of the use of iron(III) halides
as effective catalysts in the coupling of acetylenes and
aldehydes to achieve a wide variety of useful synthetic
transformations in most cases depending on the structure
of the alkyne (basically, terminal or nonterminal) used
and/or the reaction conditions (Scheme 1). In addition,
iron(III) halides were also found to be excellent catalysts
for the Prins reaction with allylic alcohols.
3
-6). The use of sulfonic acid led to variable results.
Thus, while using camphorsulfonic acid, the methyl
ketone 417 was the major product (entries 7 and 8), tosyl
acid provided only the vinyl halide 3 (entry 9), and
methanesulfonic acid proved to be unsuitable for these
transformations (entry 10). The extension of these reac-
tions to aromatic alkynes such as phenylacetylene with
both carboxylic and sulfonic acids (entries 11 and 12)
produced only the ketone 4. Interestingly, when acetic
acid was used in addition to the methyl ketone 4, a tiny
amount (13%) of (Z)-4-chloro-4-phenylbut-3-en-2-one (5)
was obtained. Internal acetylenes were found to be
nonreactive under these conditions (entries 13 and 14).
Results and Discussion
Study of Reactivity between Alkynes and Iron-
III) Halides. Prior to carrying out the studies of
(
coupling between alkynes and aldehydes we decided to
explore the reactivity between acetylenes and iron(III)
halides in the absence of carbonyl species (Scheme 1,
route a). Table 1 summarizes the results obtained in this
study. We found that aliphatic terminal alkynes (1-
Of the different solvents screened (THF, CH
3
CN, EtOAc,
CHCl , CCl , CH NO , CH Cl , and 1,2-dichloroethane)
3
4
3
2
2
2
we found the best conditions using CH
dichloroethane.
2 2
Cl and 1,2-
15
3 3
octyne) react with iron(III) halides (FeCl and FeBr )
Coupling Reactions of Nonoxygenated Alkynes
and Aldehydes. After our initial studies between ter-
minal acetylenes and iron(III) halides we explored the
influence of such salts on coupling reactions of nonoxy-
genated alkynes and aldehydes (Scheme 1, routes b and
c). In this session we will discuss a new stereoselective
coupling of alkynes and aldehydes leading to (E,Z)-1,5-
dihalo-1,4-dienes 6 and/or (E)-R,â-unsaturated ketones
(
6) (a) Rodebaugh, R.; Debenham, J. S.; Fraser-Reid, B. Tetrahedron
Lett. 1996, 37, 5477-5478. (b) Padr o´ n, J. I.; V a´ zquez, J. T. Tetrahedron:
Asymmetry 1995, 6, 857-858. (c) Kartha, K. P. R.; Dasgupta, F.; Singh,
P. P.; Srivastava, H. C. J. Carbohydr. Chem. 1986, 5, 437-444.
(
7) Patney, H. K. Synlett 1992, 567-568.
(
8) (a) Takaki, K.; Yamamoto, J.; Matsushita, Y.; Morii, H.; Shishido,
T.; Takehira, K. Bull. Chem. Soc. Jpn. 2003, 76, 393-398. (b) Mart ´ı n,
S. E.; Garrone, A. Tetrahedron Lett. 2003, 44, 549-552.
(
9) (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am.
Chem. Soc. 2004, 126, 3686-3687. (b) F u¨ rstner, A.; Leitner, A.;
M e´ ndez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856-13863.
7
catalyzed by iron(III) trihalides (Table 2).
(
c) Neumann, S. M.; Kochi, J. K. J. Org. Chem. 1975, 40, 599-606. (d)
Recently, Kabalka et al. reported that the use of BX
3
generates 1,5-dihalo-1,4-pentadienes by coupling between
aryl aldehydes and aryl acetylenes, although the use of
Alvarez, E.; Cuvigny, T.; Herv e´ du Penhoat, C.; Julia, M. Tetrahedron
1
988, 44, 111-118.
10) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc.
000, 122, 978-979.
11) Sharma, G. V. M.; Kumar, K. R.; Sreenivas, P.; Krishna, P. R.;
(
2
aliphatic alkynes and aldehydes in this process gave only
(
18a
traces of the desired products.
Similar results were
Chorghade, M. S. Tetrahedron: Asymmetry 2002, 13, 687-690.
12) Kuroda, C.; Koshio, H.; Koito, A.; Sumiya, H.; Murase, A.;
Hirono, Y. Tetrahedron 2000, 56, 6441-6455.
(
obtained by the same authors with titanium(IV) halides,
utilizing both aromatic and aliphatic alkynes and
(
13) (a) Watahiki, T.; Akabane, Y.; Mori, S.; Oriyama, T. Org. Lett.
18b
aldehydes.
2
2
003, 5, 3045-3048. (b) Watahiki, T.; Oriyama, T. Tetrahedron Lett.
002, 43, 8959-8961.
(
14) Encyclopedia of Reagents for Organic Synthesis; Paquette, L.
(16) Cassagne, D.; Gillet, M.; Braun, J. Bull. Soc. Chim. Fr. 1979,
A., Ed.; Wiley: New York, 1995.
15) Anhydrous FeCl and FeBr
Company.
140-144.
(
3
3
were purchased from the Aldrich
(17) Damiano, J. P.; Postel, M. J. Organomet. Chem. 1996, 522, 303-
305.
58 J. Org. Chem., Vol. 70, No. 1, 2005

Fe(III) Halides as Effective Catalysts in C-C Bond Formation
TABLE 2. FeX3-Promoted Stereoselective Coupling of
Alkynes and Aldehydes
TABLE 3. FeX3-Promoted Coupling of Oxygenated
Terminal Alkynes and Aldehydes
yield
entry
R
time
yield (%)
R1
R2
R3
X
time
6:7
(%)
a
entry
1
2
3
4
5
CH2OH
10 m
10 m
15 m
12 h
12 h
-a
b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
n-C
4
4
H
9
H
i-C
i-C
i-C
i-C
4
4
4
4
H
H
H
H
9
9
9
9
Cl 10 m 73:27
Br 10 m 62:28
Cl 15 m 74:26
Br 20 m 75:25
96
88
97
96
91
97
70
44
a
b
b
b
CH2OTBS
(CH2)2OH
(CH2)3OH
(CH2)4OH
-
n-C
Ph
Ph
Ph
Ph
Bn
Bn
n-C
Ph
Ph
Ph
Ph
Ph
Bn
n-C
Ph
H
H
H
9
H
97
H
b
-
-
H
b
b
H
cyclohexylb Cl 30 m 75:25
H
cyclohexyl Br 40 m 64:26
a
Irresolvable mixture.
b
H
n-C
n-C
6
H
H
12
Cl 2 h
Br 5 h
Cl 12 h
100:0
100:0
b
H
6
12
b
4
9
H
Ph
c
0
1
2
3
4
5
6
7
CH
CH
CH
CH
CH
3
3
2
2
2
cyclohexyl Cl 5 m
0:100 65
0:100 80
0:100 33
0:100 52
to 1,5-dihalo-1,4-pentadienes small amounts were ob-
tained of (E)-R,â-unsaturated ketones (entries 1-6), as
determined by constant coupling measurements by means
of H NMR spectra. Such unsaturated carbonyl deriva-
tives were absent when benzyl alkynes (entries 7 and 8)
were used.
c
i-C
i-C
i-C
i-C
i-C
4
4
4
4
4
H
H
H
H
H
9
9
9
9
9
Cl 5 m
Cl 5 m
Cl 5 m
Cl 5 m
Cl 5 m
Cl 5 m
Cl 5 m
c
c
c
c
d
d
OH
OAc
CHdCH
1
17b
2
4 9
n-C H
c
5
11 CH
Ph
3
Ph
c
i-C
4
H
9
0:100 68
When nonterminal aromatic acetylenes were used we
found the trisubstituted (E)-R,â-unsaturated ketones 7
to be the exclusive compounds obtained. The procedure
is not valid for aliphatic (entries 15 and 16) and unsatur-
ated skipped (entry 14) alkynes since irresolvable mix-
tures were produced. The catalytic system is, however,
compatible with alcohols and their corresponding acetates
although limited yields were obtained (entries 12 and 13).
In such cases the system works well, even with 0.1 equiv
a
Yields are of products isolated by column chromatography
based on starting aldehyde. b The reaction was run with a 1:2
c
equiv ratio of aldehyde and acetylene. The reaction was run with
a 1:1 equiv ratio of aldehyde and acetylene.
Our first task was to investigate the coupling between
terminal alkynes and aldehydes (Table 2). We found that
both aliphatic and aromatic terminal alkynes (entries
-8) react with aliphatic aldehydes in the presence of
stoichiometric amounts of iron(III) trihalide (FeCl and
FeBr ) giving a mixture of (E,Z)-1,5-dihalo-1,4-dienes 6
and disubstituted (E)-R,â-unsaturated ketones 7, the
former being the major products in all cases. Trace
amounts of the (Z,Z)-isomers were not detected.
A variety of aldehydes and alkynes were examined for
this coupling. The reaction works with both aliphatic and
aromatic alkynes (entries 1-8), although the attempt to
carry out the reaction with aromatic aldehydes was
fruitless (entry 9). In addition, ketones were also unre-
active.
As shown in Table 2, the yields of 6 were close to 70%
entries 1-7) except that of entry 8, which was only 44%,
probably due to the greater bulkiness of the bromine.
This steric hindrance may also be related to the reaction
times. Thus, nonbulky aliphatic aldehydes (entries 1-4)
reacted in similar periods of time but when the bulkiness
increased, as occurred with cyclohexanal (entries 5 and
1
3
of FeCl as catalyst.
3
18
From the experimental point of view it must be
emphasized that when terminal alkynes are used the
acetylene:aldehyde ratio must be 2:1 equiv, leading to the
corresponding 1,5-dihalo-1,4-pentadienes as the major
products. However, when the trisubstituted-(E)-R,â-
unsaturated ketones are the desired products, the non-
terminal aromatic acetylenes must be used in a 1:1 ratio
relative to the aldehyde.
3
19
Coupling Reactions of Oxygenated Alkynes and
Aldehydes. To extend the synthetic use of the coupling
between aldehydes and terminal acetylenes (Scheme 1,
route d) we were interested in testing alkynes having
oxygenated functions in the linear chain (Table 3). We
found that only homopropargylic alcohols react properly
yielding as sole detected product the 2-substituted dihy-
dropyran 8 (entry 3). Propargylic alcohol and its TBS-
ether yielded irresolvable mixtures (entries 1 and 2).
Acetylenic alcohols having the hydroxyl group located at
a different distal position remained unaffected (entries
4 and 5).
(
6
), the reaction time became longer.
The coupling process is highly stereoselective as de-
termined (in all cases E,Z) by H and C NMR experi-
ments (the E,Z-diene displays two sets of signals for the
vinyl group).
despite varying the nature of the R and R groups,
thereby offering a new way to achieve the stereocon-
trolled C-C bond formation of such systems. In addition
1
13
This Prins-type20 cyclization provides a new method
1
8a
The stereochemistry did not change
21
for accessing 2-alkyl-4-halo-5,6-dihydro-2H-pyrans that
1
3
makes use of the direct coupling of homopropargylic
alcohol and aldehydes induced by a stoichiometric amount
of anhydrous ferric halides (FeCl
1
3
and FeBr
3
) (Scheme
is an
, route d).22 In addition, we found also that FeX
3
(
18) (a) Kabalka, G. W.; Wu, Z.; Ju, Y. Org. Lett. 2002, 4, 1491-
excellent catalyst in the Prins cyclization (Scheme 1,
route e), observing that the reaction between 3-buten-1-
ol and several aldehydes proceeded satisfactorily, afford-
ing the corresponding cis-4-halo-2-alkyl tetrahydropyrans
in good yields.22
1
3
493. (b) Kabalka, G. W.; Wu, Z.; Ju, Y. Org. Lett. 2002, 4, 3415-
417.
(
19) (a) Curini, M.; Epifano, F.; Maltese; Rosati, O. Synlett 2003,
5
1
1
52-553. (b) Viswanathan, G. S.; Li, C.-J. Tetrahedron Lett. 2002, 43,
613-1615. (c) Hayashi, A.; Yamaguchi, M.; Hirma, M. Synlett 1995,
95-196.
J. Org. Chem, Vol. 70, No. 1, 2005 59

Miranda et al.
Consideration on the Reaction Mechanism. In
accordance with our experimental results we can con-
clude that FeX have two major roles when acetylenes
3
and carbonyl compounds are used: as Lewis acids
activating the carbonyl functionality and forming alkyne-
iron complexes that may be an initial step in further
chemical events. The relative importance of both behav-
iors strongly depends on the nature of the components
used in terms of, for instance, the presence or absence of
oxygen or other functional groups, internal or external
acetylenes, steric hindrance, etc.
3
To rationalize the action modes of FeX in acetylenic
FIGURE 1. Molecular graphs corresponding to π-complex (a)
coupling we performed some calculations at the ab initio
level. In the first instance, and following a path parallel
to that of the experimental work, we focused our atten-
tion on the interaction between terminal acetylenic and
iron(III) halides.
3
and σ-complex (b) between propyne and FeCl . Small dots into
bond paths are the bonds critical points.
In accordance with Bader’s methodology, and for an
equilibrium structure, the existence of a bond path is both
a necessary and a sufficient condition for the existence
The theoretical study for the reaction between FeCl
and an alkyne compound is not trivial. One can reason-
ably assume that the FeCl , as an electrophilic species,
3
28
of a bond. The bond path between two atoms is the line
3
between two nuclei along which the electron density is
the local maximum and includes a saddle point, the bond
critical point, where the gradient of the electronic density
vanishes.
interacts with the nucleophilic triple bond to give a π-type
complex. This kind of interaction involves weak bonds
which require a relatively large basis set system with
diffuse functions to be described, and taking into account
the electron correlation also. Considering the above, we
performed some ab initio calculations for three alkyne
models (acetylene, propyne, and 2-butyne) using for
To start the Bader analysis we need to compute a good
electronic density but the pseudopotential basis sets
cannot be used to obtain it. We performed a single-point
energy calculation over previous optimized geometries,
using B3LYP/6-311+G*, for all of the atoms involved.
2
3
geometry optimizations the mixed functional B3LYP,
for alkyl substructure the 6-311+G*24 basis set, and for
iron and chlorine atoms the pseudopotential basis set
3
AIM analysis showed a propyne-FeCl complex as the
only stable structure (Figure 1a). The other two sym-
metric alkynes (acetylene and 2-butyne) gave conflicting
structures that were too unstable. This fact could justify
the absence of structures such as 3 or 4 when we use
nonterminal alkynes.
25
LANL2DZ. We found, for the three alkynes considered,
the three minima on the potential energy surface.
However this outcome is not by itself proof of the
existence of true structures: we need to evaluate the
correlation energy.26 A different and less expensive choice
is supplied if one uses the Atoms in Molecules (AIM)
method of Bader and co-workers.27 Such a method is
based on a careful analysis of electronic density topology
and permits drawing molecular graphs, representing a
network of bond paths linking together all pairs of atoms
that are believed to be bonded to one another. Such
graphs can be considered as the AIM definition of the
bond.
Figure 1a shows the most relevant structural features
of the π-complex. Metal is bonded only with the acetylenic
terminal carbon with an almost perpendicular approach
to the triple bond (CtC-Fe 87.3°). In addition, CtC and
tC-H bond lengths become longer.
Analysis of charge distribution can show the electro-
3
philic nature of FeCl in this association. However, it is
well-recognized that the concept of atomic charge in a
molecule is difficult to define because it is not related to
a true physical quantity and, therefore, is not rigorously
defined in quantum mechanics. The essence of the AIM
theory is the definition of an atom as it exists in the
molecule. We can then find atomic charges, without the
problems related to electronic distributions based on
orbital methods, by simple integration of electronic
density over the well-defined atomic basins. A charge
transfer corresponding to 0.3 electrons between propyne
and ferric chloride is in agreement with the electrophilic
character and rationalizes the π-complex by use of species
I and II.
(
20) For the synthesis of dihydropyrans using the Prins cyclization,
see: (a) Sun, Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126, 2425-
430. (b) Dobbs, A. P.; Guesn e´ , S. J. J.; Martinovi c´ , S.; Coles, S. J.;
2
Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880-7883. (c) Aubele, D.
L.; Lee, C. A.; Floreancig, P. E. Org. Lett. 2003, 5, 4521-4523. (d)
Dobbs, A. P.; Guesn e´ , S. J. J.; Hursthouse, M. B.; Coles, S. J. Synlett,
003, 1740-1742. (e) Dobbs, A. P.; Martinovi c´ , S. Tetrahedron Lett.
002, 43, 7055-7057. (f) Roush, W. R.; Dilley, G. J. Synlett 2001, 955-
59. (g) Viswanathan, G. S.; Yang, J.; Li, C.-J. Org. Lett. 1999, 1, 993-
95.
2
2
9
9
(
21) For precedents in the synthesis of halovinyl tetrahydropyrans,
see: (a) Melany, M. L.; Lock, G. A.; Thompson, D. W. J. Org. Chem.
1
3
985, 50, 3925-3927. (b) Chan, T. H.; Arya, P. Tetrahedron Lett. 1989,
0, 4065-4068. (c) Tsukayama, M.; Utsumi, H.; Kunugi, A.; Nozaki,
H. Heterocycles 1997, 45, 1131-1142.
Experimental evidence of methyl ketone 4 could be
explained by II, even though it must be pointed out that
(
22) For details about this process, see: Miranda, P. O.; D ´ı az, D.
D.; Padr o´ n, J. I.; Bermejo, J.; Mart ´ı n, V. S. Org. Lett. 2003, 5, 1979-
1
7
8
982.
(
23) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785-
(27) (a) Bader, R. F. W. In Atoms in Molecules: A Quantum Theory;
The International Series of Monographs of Chemistry; Halpen, J.,
Green, M. L. H., Eds.; Clarendon Press: Oxford, UK, 1990; pp 1-438.
(b) Bader, R. F. W. Chem. Rev. 1991, 91, 893-928. (c) Popelier, P. In
Atoms in Molecules: An Introduction; Prentice Hall: Harlow, New York,
2000; pp 1-164. (d) Gilespie, R. J.; Popelier, P. L. A. In Chemical
Bonding and Molecular Geometry: From Lewis to Electron Densities;
Oxford University Press: Oxford, UK, 2001; pp 134-268.
89. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
(
24) Frisch, M. J.; Pople, J. A.; Binkley, J. S. J. Chem. Phys. 1984,
0, 3265.
25) (a) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270-283.
b) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 284-298. (c) Hay,
P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299-310.
26) Muguet, F. F.; Robinson, G. W. J. Chem. Phys, 1995, 102, 3648-
654.
(
(
(
3
(28) Bader R. F. W. Acc. Chem. Res. 1985, 18, 9-15.
60 J. Org. Chem., Vol. 70, No. 1, 2005

Fe(III) Halides as Effective Catalysts in C-C Bond Formation
SCHEME 2. Plausible Mechanism for the
Coupling of Nonoxygenated Alkynes and
Aldehydes Catalyzed by Iron(III) Halides
the dipolar structure does not contribute significantly to
the ground-state structures as atomic charges over both
alkyne carbons on the propyne and its π-complex are
almost invariants. The lack of 0.3 electron when the
propyne is complexed is mainly distributed between
propargylic carbon and terminal hydrogen. In fact, only
when the external electrophile conditions are different
(
Table 1, entries 7 and 8) and/or additional stabilization
of the carbocation II is present (Table 1, entries 11 and
1
2) is a substantial amount of methyl ketone produced.
A π-complex can be transformed into a σ-complex after
initial complexation. Found energy for calculated equi-
librium geometry, using the previously cited basis-set,
shows a greater stabilization to the σ-complex vs the π
one at 3.11 kcal/mol. This geometry displays the metal
atom coordinated to the terminal alkyne carbon as shown
by the AIM molecular graph (Figure 1b). Such a complex
could be the origin of vinyl halides 3.
In light of these results, we postulate the overall
mechanism outlined in Scheme 2 that considers two
alternative pathways depending on the nature of the
acetylene derivative. 1,5-Dihalo-1,4-pentadienes 6 formed
3
only when a stoichiometric amount of FeX was used.
Region A outlines a proposal similar to that put forward
by Kabalka et al.1 in which the formation of 10 is
supported by both the above-described calculation and
the fact that the treatment of aliphatic terminal acety-
8b
3
SCHEME 3. Lewis Acid Role of FeX in the
Coupling of Homopropargylic Alcohol and
Aldehydes
3
lenes with FeCl led to 2-chloro-1-alkenes 3 or methyl
ketones 4. The formation of the (E)-trisubtituted R,â-
unsaturated ketones 7 occurs even with use of a minus-
cule amount of the iron halide (≈0.1 equiv). The catalytic
cycle outlined in region B invoked the formation of the
2
9
oxetene 11. Any attempt to control the final balance of
the obtained products under experimental conditions
(
temperature, addition order, solvent, etc.) proved fruit-
less. Thus the tendency to follow either the catalytic (B)
or the stoichiometric pathway (A) depends basically on
the substitution pattern of the used alkyne 1.
as the sole product even under catalytic conditions. The
reaction with homopropargylic alcohol permits access to
2-alkyl-4-halo-5,6-dihydro-2H-pyrans in good yields. In
When a hydroxy group is located in the â-position
3
addition, FeX efficiently catalyzes the Prins coupling
relative to a carbon-carbon unsaturation, FeX
essentially as a Lewis acid (Scheme 3). Thus, when
homopropargylic alcohol is used, the FeX -mediated
ionization of acetal 12 generates the oxonium ion 13 that
is intramolecularly trapped by the carbon-carbon un-
saturation with concomitant attack of the halide (Scheme
3
acts
between homoallylic alcohol and aldehydes to lead to cis-
4-halo-2-alkyl tetrahydropyrans. Experiments with ter-
minal acetylenes and ab inito calculations are the base
of a unified mechanism that rationalizes those reactions
in which the complex formation between the alkyne and
the iron(III) halides is the activating step. The Lewis acid
role of such halides appears to be the key behavior in
the coupling when homoallylic and homopropargylic
alcohols are used. Further synthetic applications of the
methodology described herein directed to the synthesis
of some natural products are currently under way.
3
3
). A similar mechanism may explain the Prins cycliza-
tion when homoallylic alcohols are used leading to
halotetrahydropyran.
Conclusions. In summary, iron(III) halides proved to
be excellent catalysts for the coupling of acetylenes and
aldehydes. Thus, when terminal nonoxygenated acety-
lenes are used, the main process is the stereoselective
reductive coupling leading to (E,Z)-1,5-dihalo-1,4-dienes
as the major product. However, nonterminal aromatic
alkynes led to trisubstituted (E)-R,â-unsaturated ketones
Experimental Section
1
Material and Methods. H NMR spectra were recorded
13
at 400 and 500 MHz, and C NMR spectra were recorded at
100 MHz, VTU 300.0 K. Chemical shifts were reported in parts
per million. The residual solvent peak was used as an internal
reference.
(
29) (a) Martino, P. C.; Shevlin, P. B. J. Am. Chem. Soc. 1980, 102,
For analytical and preparative thin-layer chromatography,
silica gel ready-foils and glass-backed plates (1 mm) were used,
5
3
429-5430. (b) Friedrich, L. E.; Lam, P. Y.-S. J. Org. Chem. 1981, 46,
06-311.
J. Org. Chem, Vol. 70, No. 1, 2005 61

Miranda et al.
respectively, being developed with 254 nm UV light and/or
sprayed with a solution of vainillin in EtOH:H SO :AcOH (15:
:1.3) and heated at 140 °C. Column chromatography was
the alkyne (ca. 5 min). Then water was added to the mixture
2
4
2 2
and extracted with CH Cl . The combined organic layers were
1
dried over magnesium sulfate and the solvent was removed
under reduced pressure. The crude was purified by flash
column chromatography (n-hexane/EtOAc solvent systems) to
performed with silica gel (0.015-0.04 mm) and n-hexane/
EtOAc solvent systems. All reagents were obtained from
commercial sources and used without further purification.
Solvents were dried and distilled before use. All reactions were
performed under a dry nitrogen atmosphere.
1
2
3
provide 6 (R ) Ph, R ) H, R ) C
4
H
9
-i, X ) Cl) (217 mg,
1
70%): H NMR (CDCl
3
) δ 0.76 (d, J ) 6.5 Hz, 3H), 0.88 (d, J
) 6.5 Hz, 3H), 1.40 (t, J ) 7.4 Hz, 2H), 1.59 (m, 1H), 3.72
(quint, J ) 8.6 Hz, 1H), 5.88 (d, J ) 10.4 Hz, 1H), 6.0 (d, J )
General Procedure for the Transformation of Non-
1
3
oxygenated Terminal Acetylenes into 2-Halo-1-alkenes.
8.2 Hz, 1H), 7.40 (m, 8H), 7.59 (dd, J ) 1.4, 7.7 Hz, 2H);
C
1
Preparation of 2-Chloro-1-octene (3, R ) C
6
H
13-n, X )
NMR (CDCl ) δ 22.3 (q), 22.8 (q), 35.6 (d), 39.2 (d), 44.7 (t),
3
Cl). To a stirred solution of 1-octyne (0.1 mL, 0.70 mmol) and
acetic acid (0.05 mL, 0.70 mmol) in dry CH Cl was added
anhydrous FeCl (110 mg, 0.70 mmol) in one portion at room
126.5 (d), 128.2 (d), 128.3 (d), 128.6 (d), 128.7 (d), 128.8 (d),
129.1 (d), 131.2 (d), 131.8 (s), 132.4 (s), 137.1 (s), 138.0 (s); IR
2
2
-
1
3
3
(CHCl ) (cm ) 3058.3, 2955.9, 1445.0, 759.1, 694.2; MS m/z
+
+
temperature. The mixture was stirred until the solution
became dark brown (ca. 2 min). Then water was added to the
mixture and extracted with CH Cl . The combined organic
2 2
(rel intensity) 344 (M - 1) (3), 287 (M - C
4
H
9
)
(100), 215
(56). Anal. Calcd for C21
73.07; H, 6.69.
H22Cl : C, 73.04; H, 6.42. Found: C,
2
layers were dried over magnesium sulfate and the solvent was
removed under reduced pressure. The crude was purified by
flash column chromatography (n-hexane/EtOAc, 99/1) to pro-
Typical Experimental Procedure for the Synthesis of
Aromatic r,â-Unsaturated Ketones. Preparation of (E)-
1
2
2,5-Dimethyl-1-phenylhex-2-en-1-one (7, R
) Ph, R )
1
1
3
vide 3 (R ) C
6
H
13-n, X ) Cl) (90 mg, 88%): H NMR (CDCl
3
)
3 4 9
CH , R ) C H -i). To a stirred solution of 1-phenyl-1-propyne
(0.1 mL, 0.80 mmol) and isovaleraldehyde (0.1 mL, 0.80 mmol)
in dry CH Cl was added anhydrous FeCl (130 mg, 0.8 mmol)
δ 0.90 (m, 3H), 1.30-1.55 (m, 10H), 2.34 (t, J ) 7.4 Hz, 2H),
5
2
.12 (d, J ) 7.0 Hz, 2H); 13C NMR (CDCl
7.3 (t), 28.3 (t), 31.4 (t), 39.1 (t), 111.6 (t), 143.2 (s); IR (CHCl
3
) δ 14.0 (q), 22.5 (t),
2
2
3
3
)
in one portion at room temperature. The mixture was stirred
until TLC showed complete conversion of the alkyne (ca. 5
min). Then water was added to the mixture and extracted with
CH Cl . The combined organic layers were dried over magne-
-
1
(
(
cm ) 2927.6, 1715.8; MS m/z (rel intensity) 303 (100), 147
+
8
M) (8), 55 (57); Anal. Calcd for C H15Cl: C, 65.52; H, 10.31.
Found: C, 65.61; H, 9.90.
2
2
General Procedure for the Transformation of Non-
sium sulfate and the solvent was removed under reduced
pressure. The crude was purified by flash column chromatog-
oxygenated Terminal Acetylenes into Methyl Ketones.
Preparation of Octan-2-one (4, R ) C
1
1
6
H13-n). To a stirred
raphy (n-hexane/EtOAc solvent systems) to provide 7 (R )
solution of 1-octyne (0.1 mL, 0.70 mmol) and camphorsulfonic
acid (158 mg, 0.7 mmol) in dry CH Cl was added anhydrous
FeBr (200 mg, 0.70 mmol) in one portion at room temperature.
The mixture was stirred until the solution became dark brown
ca. 2 min). Then water was added to the mixture and
extracted with CH Cl . The combined organic layers were dried
Ph, R
2
) H, R
3
1
3
) C H -i) (129 mg, 80%): H NMR (CDCl ) δ
4
9
2
2
0.92 (d, J ) 6.7 Hz, 6H), 1.74 (sep, J ) 6.7 Hz, 1H), 1.96 (s,
3
3H), 2.17 (t, J ) 7.0 Hz, 2H), 6.3 (t, J ) 7.4 Hz, 1H), 7.44 (m,
3H), 7.61 (d, J ) 8.1 Hz, 2H); 13C NMR (CDCl ) δ 12.6 (q),
3
(
22.5 (q), 28.4 (d), 38.2 (t), 128.0 (d), 129.2 (d), 131.3 (d), 137.0
(s), 138.8 (s), 145.7 (d), 199.0 (s); IR (CHCl ) (cm-1) 2957.4,
2
2
3
over magnesium sulfate and the solvent removed under
reduced pressure. The crude was purified by flash column
chromatography (n-hexane/EtOAc solvent systems) to provide
1649.5, 1285.1, 706.4; MS m/z (rel intensity) 202 (M) (33),
+
105 (100), 77 (76). Anal. Calcd. for C H O: C, 83.20; H, 8.97.
14
18
Found: C, 83.11; H, 9.02.
1
1
4
(R ) C
6 3
H13-n) (72 mg, 80%): H NMR (CDCl ) δ 0.81 (m,
3
H), 1.23 (m, 6 H), 1.50 (m, 2H), 2.08 (s, 3H), 2.37 (t, J ) 7.4
Acknowledgment. We thank the MCYT (PPQ2002-
04361-C04-02) of Spain and the Consejer ´ı a de Educa-
ci o´ n, Cultura y Deportes del Gobierno de Canarias, for
supporting this research. P.O.M. thanks the Spanish
MCYT for an FPI fellowship. D.D. thanks the Spanish
MCYT for a postdoctoral fellowship. J.I.P. thanks the
Spanish MCYT-F.S.E. for a Ram o´ n y Cajal contract.
1
3
Hz, 2H); C NMR (CDCl
3
) δ 14.0 (q), 22.5 (t), 23.7 (t), 28.9 (t),
-
1
2
1
9.7 (q), 31.5 (t), 43.7 (t), 209.1 (s); IR (CHCl
3
) (cm ) 2928.1,
716.3; MS m/z (rel intensity) 128 (M) (15), 71 (25), 58 (100).
+
Anal. Calcd for C
H, 12.20.
8
H16O: C, 74.94; H, 12.58. Found: C, 74.65;
Typical Experimental Procedure for the Synthesis of
(
E,Z)-1,5-Dihalo-1,4-dienes. Preparation of (1Z,4E)-1,5-
1
Dichloro-3-isobutyl-1,5-diphenylpenta-1,4-diene (6, R )
2
3
Ph, R ) H, R ) C
phenylacetylene (0.2 mL, 1.90 mmol) and isovaleraldehyde (0.1
mL, 0.90 mmol) in dry CH Cl was added anhydrous FeCl
153 mg, 0.9 mmol) in one portion at room temperature. The
mixture was stirred until TLC showed complete conversion of
4 9
H -i, X ) Cl). To a stirred solution of
Supporting Information Available: 1H NMR and 13
C
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
2
2
3
(
JO048410J
62 J. Org. Chem., Vol. 70, No. 1, 2005