Ruthenium-catalyzed [2 + 2] cycloadditions between bicyclic alkenes and alkynyl halides

Article abstract of DOI:10.1021/ol048111g

(Chemical equation presented) Ru-catalyzed [2 + 2] cycloadditions between norbornadiene and alkynyl halides were found to occur in moderate to good yields (32-89%). The presence of the halide moiety greatly enhances the reactivity of the alkyne component in the cycloaddition and can be transformed into a variety of products that are difficult or impossible to obtain via direct cycloaddition.

Full text of DOI:10.1021/ol048111g

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4543-4546
Ruthenium-Catalyzed [2
Cycloadditions between Bicyclic
Alkenes and Alkynyl Halides
+ 2]
Karine Villeneuve, Nicole Riddell, Robert W. Jordan, Gavin C. Tsui, 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 September 16, 2004
ABSTRACT
Ru-catalyzed [2
+ 2] cycloadditions between norbornadiene and alkynyl halides were found to occur in moderate to good yields (32−89%).
The presence of the halide moiety greatly enhances the reactivity of the alkyne component in the cycloaddition and can be transformed into
a variety of products that are difficult or impossible to obtain via direct cycloaddition.
Transition metal-catalyzed cycloadditions have demonstrated
their usefulness as efficient methods in the formation of rings
and complex molecules.1 The use of transition metal catalysts
provides new opportunities for highly selective cycloaddition
reactions since complexation of the metal to an unactivated
alkene, alkyne, or diene significantly modifies the reactivity
of this moiety, opening the way for enhanced reactivity and
novel reactions. Recent developments in transition metal-
catalyzed [2 + 2 + 1],2 [4 + 2],3 [5 + 2],4 [4 + 4],5 and [6
+ 2]6 cycloaddition reactions have provided efficient meth-
ods for the construction of five- to eight-membered rings.
We and others have studied various aspects of transition
metal-catalyzed [2 + 2] cycloadditions between an alkene
and an alkyne for the synthesis of cyclobutene rings, in-
cluding development of novel catalysts, study of the in-
tramolecular variant of the reaction, and investigation on the
chemo- and regioselectivity of unsymmetrical substrates.7-10
More recently, we have demonstrated the first examples of
(3) (a) Wender, P. A.; Jenkins, T. E. J. Am. Chem. Soc. 1989, 111, 6432.
(b) Jolly, R. S.; Luedtke, G.; Sheehan, D.; Livinghouse, T. J. Am. Chem.
Soc. 1990, 112, 4965. (c) Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am.
Chem. Soc. 1995, 117, 1843. (d) O’Mahoney, D. J. R.; Belanger, D. B.;
Livinghouse, T. Synlett 1998, 443. (e) Murakami, M.; Ubukata, M.; Itami,
K.; Ito, Y. Angew. Chem., Int. Ed. 1998, 37, 2248. (f) Paik, S.-J.; Son, S.
U.; Chung, Y. K. Org. Lett. 1999, 1, 2045. (g) Hilt, G.; Smolko, K. I. Angew.
Chem., Int. Ed. 2003, 42, 2795. (h) Witulski, B.; Lumtscher, J.; Bergstra¨ber,
U. Synlett 2003, 708. (i) Hilt, G.; Lu¨ers, S.; Harms, K. J. Org. Chem. 2004,
69, 624.
(4) (a) Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem. Soc.
1995, 117, 4720. (b) Wender, P. A.; Rieck, H.; Fuji, M. J. Am. Chem. Soc.
1998, 120, 10976. (c) Trost, B. M.; Shen, H. Angew. Chem., Int. Ed. 2001,
40, 2313. (d) Wender, P. A.; Williams, T. J. Angew. Chem., Int. Ed. 2002,
41, 4550.
(5) (a) Wender, P. A.; Ihle, N. C. J. Am. Chem. Soc. 1986, 108, 4678.
(b) Wender, P. A.; Nuss, J. M.; Smith, D. B.; Suarez-Sobrino, A.; Vagberg,
J.; Decosta, D.; Bordner, J. J. Org. Chem. 1997, 62, 4908.
(6) Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J. Am. Chem. Soc.
2000, 122, 7815.
(7) Trost, B. M.; Yanai, M.; Hoogsteen, K. J. Am. Chem. Soc. 1993,
115, 5294.
(1) 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.
(2) For recent reviews on transition metal-catalyzed [2 + 2 + 1]
cycloadditions, see: (a) Pericas, M. A.; Balsells, J.; Castro, J.; Marchueta,
I.; Moyano, A.; Riera, A.; Vazquez, J.; Verdaguer, X. Pure Appl. Chem.
2002, 74, 167. (b) Sugihara, T.; Yamaguchi, M.; Nishizawa, M. Chem. Eur.
J. 2001, 7, 1589. (c) Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56,
3263. (d) Buchwald, S. L.; Hicks, F. A. In ComprehensiVe Asymmetric
Catalysis I-III, Jabosen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Berlin, 1999; Vol. 2, pp 491-510. (e) Keun Chung, Y. Coor. Chem.
ReV. 1999, 188, 297.
(8) Mitsudo, T.; Naruse, H.; Kondo, T.; Ozaki, Y.; Watanabe, Y. Angew.
Chem., Int. Ed. Engl. 1994, 33, 580.
(9) (a) Huang, D.-J.; Rayabarapu, D. K.; Li, L.-P.; Sambaiah, T.; Cheng,
C.-H. Chem. Eur. J. 2000, 6, 3706. (b) Chao, K. C.; Rayabarapu, D. K.;
Wang, C.-C.; Cheng, C.-H. J. Org. Chem. 2001, 66, 8804.
10.1021/ol048111g CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/02/2004

asymmetric induction studies in ruthenium-catalyzed [2 +
2] cycloadditions between symmetrical bicyclic alkenes and
alkynes bearing a chiral auxiliary, and excellent levels of
asymmetric induction (up to 98.8% ee, after removal of the
recoverable chiral auxiliary) in the cycloadditions were
achieved.10e Generally, excellent yields are obtained in the
Ru-catalyzed [2 + 2] cycloadditions between bicyclic alkenes
and electron-deficient alkynes (Table 1). However, limita-
successful examples of any transition metal-catalyzed cy-
cloadditions with alkynyl halides have been reported in the
literature. This is probably due to the potential problems
associated with a C-X oxidative addition at various stages
of reaction.11 For example, Balsells and co-workers inves-
tigated the cobalt-catalyzed Pauson-Khand reaction between
1-chloro-2-phenylethyne 4 and norbornadiene 1 (Scheme 1)
Scheme 1. Pauson-Khand Reaction of Norbornadiene 1 with
1-Chloro-2-phenylethyne 4
Table 1. Ruthenium-Catalyzed [2 + 2] Cycloaddition between
Norbornadiene and Alkynes Bearing Different Functional
Groups
entry
alkyne
X
temp (°C)
time (h)
yield (%)a
1
2
3
4
5
2b
2c
2d
2e
2a
COOEt
Me
SiMe3
Ph
60
95
95
100
80
48
90
90
120
16
90b
22c
0c
23d
44d,e
and found that the desired [2 + 2 + 1] cycloadduct 6 was
obtained in only 45% yield, and the major product obtained
was complex 7, which formed through a homocoupling of
the alkynyl chloride 4.12 Much to our delight, alkynyl halides
are compatible with the ruthenium-catalyzed [2 + 2] cy-
cloaddition reaction with bicyclic alkenes and no homocou-
pling products have been observed, vide infra.
H
a Yield of isolated cycloadducts 3. b See ref 10b. c See Supporting
Information. d See ref 8. e Homotrimerization of the terminal alkyne 2e was
also observed; see ref 8.
An initial investigation into various alkynyl bromides was
first undertaken to determine the scope of their utility (Table
2). The alkynyl bromides were easily prepared in high yields
through the treatment of their corresponding terminal alkynes
tions in the type of suitable alkynes are inevitable and low
yields were obtained when non-electron-deficient or bulky
alkynes were used (Table 1). This property of ruthenium-
catalyzed [2 + 2] cycloadditions has, to a certain extent,
limited the possible cycloadducts affordable through this
methodology.
Table 2. Ruthenium-Catalyzed [2 + 2] Cycloaddition between
Norbornadiene and Alkynyl Bromides
Alkynyl halides are an interesting class of alkynes to
explore since their electron-withdrawing ability could po-
tentially enhance the rate of the cycloaddition reaction. The
halide moiety could also be used for further functionalization,
thereby providing a complementary method for the prepara-
tion of those cycloadducts that are difficult or impossible to
obtain via direct cycloaddition. To the best of our knowledge,
all of the alkynes employed thus far in the ruthenium-
catalyzed [2 + 2] cycloadditions only contain carbon
substituents such as alkyl, aryl, ester, and ketone function-
alities, and no studies on the use of alkynes attached directly
to heteroatoms have been reported in the literature. In this
paper, we report the first examples of ruthenium-catalyzed
[2 + 2] cycloadditions of bicyclic alkenes with alkynyl
halides. This investigation is important because it provides
valuable information on the compatibility and reactivity of
alkynyl halides in ruthenium-catalyzed [2 + 2] cycloadditions
and also provides a method to obtain cycloadducts that are
impossible to obtain via direct cycloaddition. Very few
temp time
(°C) (h) cycloadduct
yielda
(%)
entry alkyne
R
1
2
8a
C6H5
60
25
65
25
65
25
65
40
25
65
25
60
25
41
44
72
72
72
72
72
168
72
72
72
72
168
69
96
1
9a
82
78
3
4
5
8b
8c
8d
p-MeO-C6H4
p-Me-C6H4
o-Me-C6H4
9b
9c
9d
63 (17)
75
20 (16)
28 (38)
42
21 (24)
8 (64)
75
40 (10)
38
32
72
52 (15)
85
48
6
7
8e
o-CF3-C6H4
9e
8
9
10
11
12
13
14
15
16
17
8f
m-F-C6H4
9f
8g
8h
n-Bu
9g
9h
CH2CH2OTBS 65
25
8i
8j
CO2Et
SO2Tol
25
65
9i
9j
(10) (a) Jordan, R. W.; Tam, W. Org. Lett. 2000, 2, 3031. (b) Jordan, R.
W.; Tam, W. Org. Lett. 2001, 3, 2367. (c) Jordan, R. W.; Tam, W.
Tetrahedron Lett. 2002, 43, 6051. (d) Villeneuve, K.; Jordan, R. W.; Tam,
W. Synlett 2003, 2123. (e) Villeneuve, K.; Tam, W. Angew. Chem., Int.
Ed. 2004, 43, 610.
65
a Yield of isolated cycloadducts 9. Yield of recovered alkyne in brackets.
4544
Org. Lett., Vol. 6, No. 24, 2004

with N-bromosuccinimide (NBS) in the presence of a
catalytic amount of silver nitrate.13 In the presence of 5 mol
% catalyst Cp*RuCl(COD) (Cp* ) 1,2,3,4,5-pentamethyl-
cyclopentadiene), [2 + 2] cycloadditions between alkynyl
bromide 8a (R ) Ph) and norbornadiene 1 occurred smoothly
at both 25 and 60 °C to provide the corresponding cycload-
duct 9a in 78 and 82% yields (Table 2, entries 1 and 2)). As
the electron-donating capacity of the substituent increased,
longer reaction times (R ) p-Me-C6H4, Table 2, entry 3)
and higher temperatures (R ) p-MeO-C6H4, Table 2, entry
4) were required. It was also observed that steric hindrance
associated with the alkyne affected the rate of reaction
(compare 8c vs 8d and 8e vs 8f). It should be noted that
less reactive alkynes did not allow a full recovery of the net
molar balance (i.e., the combined yields of the cycloadduct
and the recovered starting material did not add up to 100%).
Alkynyl bromides are not very stable in the reaction
conditions, and subsequently, when the reaction takes place
over a long reaction time at higher temperatures, decomposi-
tion occurs prior to completion of the cycloadddition reaction.
Control experiments showed that thermal decomposition of
the alkynyl bromides was observed upon heating in THF;
no decomposition was detected when the cycloadducts was
subjected to the same conditions.
chloride, bromide, and iodide occurred smoothly even at 25
°C in 1-2 h giving the corresponding cycloadducts in good
yields. For the phenyl series, although longer reaction times
were required (∼48 h), the cycloadditions of both alkynyl
chloride and bromide occurred smoothly at 25 and 60 °C,
respectively, providing the corresponding cycloadducts in
good yields (Table 3, entries 4-7). An uncharacteristic
difference in reactivity was observed for 1-iodo-2-phenyl-
ethyne 10d (Table 3, entries 8 and 9). Other than the
formation of the usual [2 + 2] cycloadduct 11d, a new
addition product (12, Figure 1) was also obtained in 26%
Figure 1. Side product obtained in the reaction between norbor-
nadiene 1 and 10b (12) and between norbornene and 10b (13).
yield. The structure and stereochemistry of this byproduct
The effect of the halogen group on the cycloaddition
reaction was also studied (Table 3).14 Two series of substrates
1
12 was determined using mass spectrometry and H, 13C
(JMOD), COSY, HSQC, and GOESY NMR experiments.15,16
We believe that the presence of this product can be explained
by a combination of two factors. Since iodide is less elec-
tronegative than bromide and chloride and the rate of the
reaction is increased by utilizing strong electron-withdrawing
groups, the cycloaddition occurs at a much slower rate. In
addition, because the C-I bond is weaker than both the
C-Br and C-Cl bonds, it is easier to oxidatively insert the
ruthenium metal into the C-I bond. To the best of our
knowledge, this is the first example of a ruthenium-cata-
lyzed haloalkynylation of alkynyl halide across a double
bond.
Table 3. Ruthenium-Catalyzed [2 + 2] Cycloaddition between
Norbornadiene and Different Alkynyl Halides
temp time
yielda
(%)
entry alkyne
R
X
(°C)
(h) cycloadduct
1
2
3
4
5
6
7
8
9
10a
8i
10b
10c
CO2Et Cl
25
25
25
60
25
60
25
65
25
1
1
2
48
49
48
49
43
168
11a
9i
11b
11c
74
85
89
82
80
82
78
41b
30 (30)b
To estimate the reactivity of alkynyl halides in the
ruthenium-catalyzed [2 + 2] cycloadditions, the relative rate
of the ruthenium-catalyzed [2 + 2] cycloadditions of several
alkynes with norbornadiene was measured by competition
experiments between alkyne 2a (R ) Ph, X ) COOEt) and
other alkynes (Table 4). A typical competition experiment
employed 4 equiv of equimolar amounts of alkyne 2a (a
stock solution of known concentration was prepared for 2a)
and alkyne 10c (R ) Ph, X ) Cl) with 1 equiv of
norbornadiene 1 in the presence of 5 mol % Cp*RuCl(COD)
Br
I
C6H5
Cl
Br
I
8a
9a
10d
11d
a Yield of isolated cycloadducts. Yield of recovered alkyne is in
parentheses. b Side product (12) was also obtained (see text and Figure 1).
(13) Kauffmann, T.; Abeln, R.; Wingbernu¨hle, D. Angew. Chem., Int.
Ed. 1984, 23, 729.
(14) (a) For a general procedure for the preparation of alkynyl cholrides,
see: Ariamala, G.; Balasubramanian, K. K. Tetrahedron 1989, 45, 309.
(b) For the preparation of 10a, see: Viehe, H. G. Chem. Ber. 1959, 92,
1950. (c) For a general procedure for the preparation of alkynyl iodides,
see ref 13.
(15) When 12 was reduced with lithium alminium hydride or treated
with tert-butyllithium followed by a quench with methanol, the loss of iodide
was observed.
(16) The exo stereochemistry of both groups was established by GOESY
NMR experiments of product 13, which was obtained through the same
conditions using norbornene instead of norbornadiene. Compound 13 could
also be prepared by hydrogenation of 12.
were investigated (R ) Ph and CO2Et). In the ester series
(Table 3, entries 1-3), the cycloadditions of all the alkynyl
(11) For selected examples of transition metal-catalyzed reaction involv-
ing alkynyl halides, see: (a) Beaudet, I.; Parrain, J.-L.; Quintard J.-P.
Tetrahedron Lett. 1992, 33, 3647. (b) Bouyssi, D.; Gore, J.; Balme, G.
Tetrahedron Lett. 1992, 33, 2811. (c) Weigelt, M.; Becher, D.; Poetsch,
E.; Bruhn, C.; Stro¨hl, D.; Steinborn D. J. Prakt. Chem. 1999, 341, 477. (d)
Abele, E.; Rubina, K.; Fleisher, M.; Popelis, J.; Arsenyan, P.; Lukecics, E.
Appl. Organomet. Chem. 2002, 16, 141.
(12) Balsells, J.; Moyano, A.; Riera, A.; Perica`s, M. Org. Lett. 1999, 1,
1981.
Org. Lett., Vol. 6, No. 24, 2004
4545

Scheme 2. Functionalization of 9a
Table 4. Relative Rate of Cycloaddition
entry
alkyne
X
cycloadduct
relative ratea
1
2
3
4
2b
2a
8a
Me
CO2Et
Br
3b
3a
9a
0.01
1
2
9
10c
Cl
11c
a Measured from competition experiments; see text. The number indicated
is the average number from 3 to 5 runs.
Table 1, these products are difficult or impossible to obtain
via direct cycloaddition.
in THF (large excesses of the alkynes were used in order to
approach pseudo-first-order conditions).17 The reactivity of
each alkyne was assessed by evaluation of the product ratio
by capillary gas chromatography. The results of these
reactivity studies are shown in Table 4. Alkyne 2a is one of
the most reactive alkyne studies so far in ruthenium-catalyzed
[2 + 2] cycloadditions and reacts ∼100 times faster than
unactivated alkynes such as 2b (R ) Ph, X )Me). When
comparing the reactivity of alkynyl halides 8a (X ) Br) and
10c (X ) Cl) with alkyne 2a (X ) CO2Et), cycloadditions
with these alkynyl halides appeared to occur even faster than
alkyne 2a. In fact, the rates of the cycloaddition of 8a and
10c with norbornadiene 1 were 2 and 9 times faster,
respectively, than 2a.
To illustrate the synthetic usefulness of the resulting
halogenated cycloadducts, cycloadduct 9a was treated under
a variety of reaction conditions to achieve further function-
alization. As shown in Scheme 2, lithium-halide exchange
followed by trapping with various electrophiles led to
products 3b,c,e in moderate to good yields. Suzuki coupling
between 9a and phenylboronic acid provided 3d in 75%
yield, and Sonogashira coupling between 9a and phenyl-
acetylene gave 14 in 64% yield. As previously shown in
In summary, we have demonstrated the first examples of
Ru-catalyzed [2 + 2] cycloadditions between alkynyl halides
and norbornadiene (yields up to 89%). The presence of the
halide moiety is compatible in the ruthenium-catalyzed [2
+ 2] cycloadditions and greatly enhances the reactivity of
the alkyne component in the cycloaddition. During this study,
we have also discovered a novel haloalkynylation reaction
between 1-iodo-2-phenylethyne and norbornadiene catalyzed
by the catalyst Cp*RuCl(COD). Further investigation of the
origin, reactivity, and application of this novel type of
ruthenium-catalyzed haloalkynylation is ongoing in our
laboratory.
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. NSERC and the Ontario Government
are thanked for providing postgraduate scholarships to K.V.,
N.R., and R.W.J..
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.
(17) Lautens, M.; Tam, W.; Edwards, L. E. J. Chem. Soc., Perkin Trans.
1 1994, 2143.
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Org. Lett., Vol. 6, No. 24, 2004