Rhodium-catalyzed intramolecular [4 + 2] cycloadditions of alkynyl halides

Article abstract of DOI:10.1021/ol052412o

(Chemical Equation Presented) Cationic rhodium(I)-catalyzed intramolecular [4 + 2] cycloadditions of diene-tethered alkynyl halides were found to occur in good yields (70-87%). The halide moiety is compatible with the cycloaddition reactions, and no oxidative insertion to the alkynyl halide was observed. The halogen-containing cycloadducts could be transformed into a variety of products that are difficult or impossible to obtain via direct cycloaddition.

Full text of DOI:10.1021/ol052412o

ORGANIC
LETTERS
2005
Vol. 7, No. 26
5853-5856
Rhodium-Catalyzed Intramolecular
[4 2] Cycloadditions of Alkynyl
Halides
+
Woo-Jin Yoo, Anna Allen, Karine Villeneuve, and William Tam*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry,
Department of Chemistry, UniVersity of Guelph, Guelph, Ontario, Canada N1G 2W1
wtam@uoguelph.ca
Received October 5, 2005
ABSTRACT
Cationic rhodium(I)-catalyzed intramolecular [4
(70 87%). The halide moiety is compatible with the cycloaddition reactions, and no oxidative insertion to the alkynyl halide was observed. The
halogen-containing cycloadducts could be transformed into a variety of products that are difficult or impossible to obtain via direct cycloaddition.
+ 2] cycloadditions of diene-tethered alkynyl halides were found to occur in good yields
−
Alkynyl halides are useful building blocks in organic
synthesis. Traditionally, alkynyl halides were accessible
through the deprotonation of corresponding terminal alkynes
with a strong base, followed by trapping with a halogenating
agent.1 However, several mild and convenient methods have
been reported recently and thus have increased the attractive-
ness of this class of compounds in organic synthesis.2 The
alkynyl halide moiety can be conceived as a dual function-
alized molecule in transition metal-catalyzed reactions
(Scheme 1). In the presence of a low-valent transition metal,
alkynyl halide 1 can undergo oxidative insertion into the
metal to form the σ-acetylenic metal complex 2 (Type I).
On the other hand, a halovinylidene-metal complex 3 can
also be obtained from alkynyl halide 1 via a 1,2-migration
of the halogen (Type II). Finally, the π-system of the
acetylene can coordinate to the metal center in an η2 fashion
to form the acetylene π-complex 4 (Type III).
catalyzed cross-coupling reactions to form carbon-carbon
bonds via the oxidative insertion of the metal to the carbon-
halide bond (Type I). Useful building blocks such as
enynes,3 diynes,4 triynes,5 and ynamides6 have been synthe-
sized using this method. Formation of the halovinylidene-
metal complex 3 (Type II) is not common but has been
observed when an alkynyl iodide was treated with a tungsten
complex, W(CO)5(THF), to produce a iodovinylidene-
tungsten complex that underwent a 6π-electrocyclization.7
Formation of acetylene π-complex 4 (Type III) of alkynyl
halides are also rare, probably due to the potential problems
associated with the oxidative insertion of the metal into the
carbon-halide bond (Type I). Therefore, very few successful
Scheme 1. Potential Reactivity Pathways of Alkynyl Halides
in Transition Metal-Catalyzed Reactions
The most extensive studies and applications of alkynyl
halides in transition metal-catalyzed reactions are metal-
(1) (a) Vaughn, J. H. J. Am. Chem. Soc. 1933, 55, 3453. (b) Zweifel,
G.; Arzoumanian, H. J. Am. Chem. Soc. 1967, 89, 5086.
(2) (a) Hofmeister, H.; Annen, H.; Laurent, H.; Wiechert, R. Angew.
Chem., Int. Ed. Engl. 1984, 23, 727. (b) Ariamala, G.; Balasubramanian,
K. K. Tetrahedron 1989, 45, 309. (c) Brunel, Y.; Rousseau, G. Tetrahedron
Lett. 1995, 36, 2619. (d) Naskar, D.; Roy, S. J. Org. Chem. 1999, 64, 6896.
10.1021/ol052412o CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/22/2005

examples of any transition metal-catalyzed cycloadditions
with alkynyl halides, which rely on the formation of the
acetylene π-complex 4, have been reported in the literature.
In fact, to the best of our knowledge, there are only two
examples in the literature of transition metal-catalyzed
cycloadditions of alkynyl halides, a cobalt-catalyzed Pau-
son-Khand [2 + 2 + 1] cycloaddition and a ruthenium-
catalyzed [2 + 2] cycloaddition (Scheme 2).8,9 Balsells and
We have recently reported the ruthenium-catalyzed [2 + 2]
cycloadditions of alkynyl halides 9-11 with norbornadiene
6 and found that whereas the alkynyl chloride 9 and alkynyl
bromide 10 provided the cyclobutene cycloadducts as the
only products in good yields, alkynyl iodide 11 gave not
only the cyclobutene cycloadduct 12c (via an acetylene
π-complex 4, Scheme 1, Type III) but also an addition
product 13c (possibly via a σ-acetylenic metal complex 2,
Scheme 1, Type I).
Transition metal-catalyzed [4 + 2] cycloaddition is an
efficient and important method for the construction of six-
membered rings, especially between electronically similar
dienes and dienophiles, which usually require extreme
Scheme 2. Transition Metal-Catalyzed Cycloaddition
Reactions of Alkynyl Halides
conditions for the thermal cycloaddition to occur.10a
A
number of excellent metal catalysts have been discovered
and transition metal-catalyzed [4 + 2] cycloadditions are
emerging as synthetically useful processes.10-15 However,
to the best of our knowledge, the use of alkynyl halides as
the dienophile in both thermal and transition metal-catalyzed
[4 + 2] cycloadditions is unexplored. In this paper, we report
the first examples of thermal and rhodium-catalyzed in-
tramolecular [4 + 2] cycloadditions of alkynyl halides. To
initiate these studies, diene-tethered alkynyl bromide 14a and
15 were prepared from the corresponding terminal alkynes
using AgNO3 and NBS in acetone,16 and the results of the
thermal Diels-Alder cycloadditions are shown in Table 1.
No reaction was observed when diene-tethered alkynyl
bromide 14a was stirred at 25 °C for 24 h. However, at 50
°C, Diels-Alder started to occur slowly (entries 2-4), and
co-workers found that the cobalt-catalyzed Pauson-Khand
reaction between alkynyl chloride 9 and norbornadiene 6
gave the desired [2 + 2 + 1] cycloadduct 7 in only 45%
yield. The major product obtained was complex 8, which
formed through a homocoupling of the alkynyl chloride 5.8
(10) For reviews on transition metal-catalyzed cycloadditions, see: (a)
Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (b) Hegedus,
L. S. Coord. Chem. ReV. 1997, 161, 129. (c) Wender, P. A.; Love, J. A. In
AdVances in Cycloaddition; JAI Press: Greenwich, 1999; Vol. 5, pp 1-45.
(11) For Ni-catalyzed [4 + 2] cycloadditions, see: (a) Wender, P. A.;
Ihle, N. C. J. Am. Chem. Soc. 1986, 108, 4678. (b) Wender, P. A.; Jenkins,
T. E. J. Am. Chem. Soc. 1989, 111, 6432. (c) Wender, P. A.; Smith, T. E.
J. Org. Chem. 1995, 60, 2962. (d) Wender, P. A.; Smith, T. E. J. Org.
Chem. 1996, 61, 824. (e) Wender, P. A.; Smith, T. E. Tetrahedron 1998,
54, 1255.
(12) For Rh-catalyzed [4 + 2] cycloadditions, see: (a) Jolly, R. S.;
Luedtke, G.; Sheehan, D.; Livinghouse, T. J. Am. Chem. Soc. 1990, 112,
4965. (b) Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem. Soc. 1995,
117, 1843. (c) O’Mahony, D. J. R.; Belanger, D. B.; Livinghouse, T. Synlett
1998, 443. (d) Gilbertson, S. R.; Hoge, G. S. Tetrahedron Lett. 1998, 39,
2075. (e) Gilbertson, S. R.; Hoge, G. S.; Genov, D. G. J. Org. Chem. 1998,
63, 10077. (f) Murakami, M.; Ubukata, M.; Itami, K.; Ito, Y. Angew. Chem.,
Int. Ed. 1998, 37, 2248. (g) Paik, S.; Son, S. U.; Chung, Y. K. Org. Lett.
1999, 1, 2045. (h) Wang, B.; Cao, P.; Zhang, X. Tetrahedron Lett. 2000,
41, 8041. (i) Heath, H.; Wolfe, B.; Livinghouse, T.; Bae, S. K. Synthesis
2001, 2341. (j) O’Mahony, D. J. R.; Belanger, D. B.; Livinghouse, T. Org.
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U. Synlett 2003, 708. (l) Motoda, D.; Kinoshita, H.; Shinokubo, H.; Oshima,
K. Angew. Chem., Int. Ed. 2004, 43, 1860.
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F. Tetrahedron Lett. 2000, 41, 6757. (b) Hilt, G.; Korn, T. J. Tetrahedron
Lett. 2001, 42, 2783. (c) Hilt, G.; Smolko, K. I.; Lotsch, B. V. Synlett 2002,
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(14) For Ir-catalyzed [4 + 2] cycloadditions, see: Shibata, T.; Takasaku,
K.; Takesue, Y.; Hirata, N.; Takagi, K. Synlett 2002, 1681.
(15) For Pd-catalyzed [4 + 2] cycloadditions, see: (a) Murakami, M.;
Itami, K.; Ito, Y. J. Am. Chem. Soc. 1997, 119, 7163. (b) Murakami, M.;
Minamida, R.; Itami, K.; Sawamura, M.; Ito, Y. Chem. Commun. 2000,
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(b) Bouyssi, D.; Gore, J.; Balme, G. Tetrahedron Lett. 1992, 33, 2811. (c)
Beaudet, I.; Parrain, J.; Quintard, J. Tetrahedron Lett. 1995, 33, 3647. (d)
Tanaka, H.; Yamada, H.; Matsuda, A.; Takahashi, T. Synlett 1997, 381.
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(16) See Supporting Information for the details of preparation of all of
the diene-tethered alkynyl halides.
5854
Org. Lett., Vol. 7, No. 26, 2005

this catalyst is not commercially available, we attempted to
generate the active cationic Rh(I) species in situ using the
commercially available catalyst [RhCl(COD)]2 and a silver-
(I) salt. To our delight, this catalytic system was as effective
as the Chung system (entry 5).17
Table 1. Thermal Diels-Alder Reactions of Alknyl Halides
Optimization of the reaction conditions were carried out
using different Rh(I) catalysts (Table 3, entries 1-3),
alkynyl
entry bromide
temp time
conversion
n
R
(°C)
(h) cycloadduct
(%)a
Table 3. Optimization of Cationic Rh(I)-Catalyzed [4 + 2]
Cycloaddition
1
2
3
4
5
6
14a
14a
14a
14a
14a
15
1
1
1
1
1
2
Me
Me
Me
Me
Me
H
25
50
50
50
75
80
24
0.5
5
13
17
24
16a
16a
16a
16a
16a
17
0
0
22
36
98b
0
a Followed by 400 MHz 1H NMR. b 85% of cycloadduct 16a was isolated
after column chromatography.
entry
Rh(I)
AgX
solvent
CH2Cl2
CH2Cl2
CH2Cl2
dichloroethane
toluene
pentane
DMF
yield (%)
1
2
3
4
5
6
7
8
RhCl(PPh)3
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgOTf
AgSbF6
0
20
85
80
62
0
[RhCl(CO)2]2
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(COD)]2
when 14a was stirred at 75 °C for 17 h, 14a was almost
totally consumed and cycloadduct 16a was isolated in 85%.
This is apparently the first example of a thermal Diels-Alder
reaction of an alkynyl halide. Unfortunately, for the substrate
with a longer tether (entry 6), no thermal [4 + 2] cycload-
dition was observed even after prolonged heating. Attempts
to catalyzed the Diels-Alder reactions using Lewis acids
(e.g., AlCl3, FeCl3, BF3.OEt2, ZrCl4, etc.) were unsuccessful
and either no reaction was observed or the starting material
decomposed under the reaction conditions.
0
THF
83
87
71
87
9
10
11
acetone
acetone
acetone
In search of the most suitable set of conditions for the
intramolecular [4 + 2] cycloaddition of diene-tethered
alkynyl halides, several catalytic systems that are known to
catalyze intramolecular Diels-Alder reactions were tested.
Although the use of Ni,11 Co,13 and neutral Rh(I)12 catalysts
were all unsuccessful (Table 2, entries 1-3), in the presence
different solvents (entries 3-9), and different Ag(I) salts
(entries 9-11). The most efficient reaction conditions for
the intramolecular [4 + 2] cycloaddition of diene-tethered
alkynyl bromide 14a were found to be [RhCl(COD)]2
(2.5 mol %) and AgSbF6 (5 mol %)18 in acetone (0.2 M) at
25 °C.
To illustrate the general applicability of this catalytic
system in the intramolecular [4 + 2] cycloaddition with
diene-tethered alkynyl halides, a few different alkynyl halides
were chosen16 for further investigation, and the results are
shown in Table 4. In general, all cationic Rh(I)-catalyzed [4
+ 2] cycloadditions occurred smoothly at 25 °C in good
yields (70-87%), and in all cases single stereoisomers were
obtained (the R group and the H at the ring junction are anti
to each other, as determined by GOESY NMR experi-
ments).19,20 Regardless of the halide (Cl, Br, or I), the
cycloadditions occurred rapidly and without the formation
Table 2. Searching for Catalytic Systems
entry
catalytic system
yield (%)
1
2
3
4
5
Ni(COD)2, P(O-oBiPh)3, THF, 45 °C
CoBr2(dppe), Zn, ZnI2, CH2Cl2, 25 °C
[RhCl(COD)]2, P(O-oBiPh)3, THF, 45 °C
[(naphthalene)Rh(COD)]BF4, CH2Cl2, 25 °C
[RhCl(COD)]2, AgBF4, CH2Cl2, 25 °C
0a
0b
0a
85
85
(17) We also found that this commercially available, simple catalytic
system [RhCl(COD)]2/AgX (X ) BF4 or SbF6) is as active as the Chung
[(naphthalene)Rh(COD)]BF4 system to catalyze intermolecular [4 + 2]
cycloaddition between 2,3-dimethylbuta-1,3-diene with phenyl acetylene
(70%) or ethyl propiolate (99%).
(18) Both AgSbF6 and AgBF4 gave the same results, but AgSbF6 was
chosen due to lower cost.
a Only starting material was recovered. b Decomposition of starting
material was observed.
(19) GOESY is gradient enhanced nuclear Overhauser enhancement
spectroscopy, see: (a) Stonehouse, J.; Adell, P.; Keeler, J.; Shaka, A. J. J.
Am. Chem. Soc. 1994, 116, 6037. (b) Stott, K.; Stonehouse, J.; Keeler, J.;
Hwang, T.-L.; Shaka, A. J. J. Am. Chem. Soc. 1995, 117, 4199. (c) Dixon,
A. M.; Widmalm, G.; Bull, T. E. J. Magn. Reson. 2000, 147, 266.
(20) The stereochemistry of the cycloadducts are the same as those
previously reported in the Rh-catalyzed [4 + 2] cycloadditions for
nonhalogenated alkynes (e.g., X ) TMS and Me instead of a halide).
of the cationic Rh(I) catalyst [(naphthalene)Rh(COD)]BF4,
developed by Chung and co-workers,12g the [4 + 2] cycload-
dition of 14a occurred smoothly at room temperature, giving
the cycloadduct 16a in 85% isolated yield (entry 4). Since
Org. Lett., Vol. 7, No. 26, 2005
5855

Scheme 3. Synthetic Applications of Halogenated
Cycloadduct 16a
Table 4. Cationic Rh(I)-Catalyzed [4 + 2] Cycloadditions of
Various Diene-Tethered Alkynyl Halides
alkynyl
entry halide
time cyclo- yield
(h) adduct (%)a
X
Y
n
R
1
2
3
4
5
6
7
8
14b
14a
14c
15
18
19
Cl
Br
I
Br
Br NTs
Br NTs
O
O
O
O
1
1
1
2
1
2
1
2
Me 0.5
Me 0.5
Me 0.5
16b
16a
16c
17
22
23
82
87
75
86
77
70
78
85
H
2.5
Me 0.5
Me
H
H
3
0.5
3
20
21
Br C(COOEt)2
Br C(COOEt)2
24
25
cycloadditions of diene-tethered alkynyl halides. We found
the alkynyl halides moieties to be compatible with the Rh(I)-
catalyzed [4 + 2] cycloadditions and the cycloadditions
occurred smoothly at room temperature, giving the haloge-
nated cycloadducts as single stereoisomers in good yields.
The halide-containing cycloadducts can be converted to
products that are difficult to obtain via direct cycloaddition.
Further investigations on the intermolecular version of the
cycloaddition, and the use of the halogenated cycloadducts
for the synthesis of more complex polycyclic natural products
are currently in progress in our laboratory.
a Isolated yields after column chromatography.
of noticeable side products (by TLC and 1H NMR of crude
reaction mixtures), although the yield was slightly diminished
with alkynyl iodide 14c (Table 4, entries 1-3). For a longer
oxygen-tethered substrate 15, a longer reaction time was
required (compare entries 2 and 4). Similar trends were
observed with the nitrogen-tethered substrates (entries 5
and 6) and with the all-carbon tethered substrates (entries 7
and 8).
To illustrate the synthetic usefulness of the resulting
halogenated cycloadducts, cycloadduct 16a was converted
to various products that are difficult or impossible to obtain
via direct cycloaddition (Scheme 3). Aromatization of
bromide 16a was achieved using DDQ in benzene to provide
the halogenated aromatic compound 26 in 59%. Partial
hydrogenation of bromide 16a with H2/Pd/C afforded
compound 27 in 45%. These halogenated derivatives could
be further functionalzed by various metal-catalyzed coupling
reactions. For example, palladium-catalyzed Suzuki coupling
of vinyl bromide 27 gave compound 28 in 77%, and a
palladium-catalyzed Heck reaction of vinyl bromide 27
provided compound 29 in 86%.
Acknowledgment. This work was supported by NSERC
(Canada) and Boehringer Ingelheim (Canada) Ltd. W.T.
thanks Boehringer Ingelheim (Canada) Ltd. for a Young
Investigator Award. A.A. and K.V. thank NSERC for
postgraduate scholarships (CGS M and CGS D), and W.Y.
thanks the Ontario Government for a postgraduate scholar-
ship (OGSST).
Supporting Information Available: Experimental pro-
cedures and compound characterization data of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, we have demonstrated the first examples of
intramolecular thermal and cationic Rh(I)-catalyzed [4 + 2]
OL052412O
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Org. Lett., Vol. 7, No. 26, 2005