Study on the reactivity of the alkyne component in ruthenium-catalyzed [2 + 2] cycloadditions between an alkene and an alkyne

Article abstract of DOI:10.1021/jo060864o

The ruthenium-catalyzed [2 + 2] cycloadditions of norbornadiene with a variety of alkynes have been investigated. Electronic effect of the alkyne component has shown to play an important role on the rate of the cycloaddition, and the reactivity of the alkyne component increases dramatically as the alkyne becomes more electron deficient. Increase in the steric bulk of the alkyne component decreases the reactivity of the alkyne component. It was also found that chelation effect of propargylic alcohols greatly enhanced the reactivity of the alkyne component in the ruthenium-catalyzed [2 + 2] cycloadditions.

Full text of DOI:10.1021/jo060864o

and complex molecules.4 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],5 [4 + 2],6 [5 + 2],7 [4 + 4],8 and [6 + 2]9
cycloaddition reactions have provided efficient methods for the
construction of five- to eight-membered rings. We and others
have studied various aspects of transition-metal-catalyzed
[2 + 2] cycloadditions of an alkene and an alkyne for the
synthesis of cyclobutenes, including development of novel
catalysts, study of the intramolecular variant of the reaction,
investigation of the chemo- and regioselectivity of unsym-
metrical substrates, and asymmetric induction studies using
chiral auxiliaries on the alkyne component.3,10-12 To understand
the mechanism of the Ru-catalyzed [2 + 2] cycloadditions
thoroughly so that one can design more active catalysts for the
cycloadditions, studies on the reactivity of both the reaction
partners are essential. Very little is known whether electron-
rich or electron-deficient alkenes and alkynes react faster or
slower in the Ru-catalyzed [2 + 2] cycloadditions, and the steric
requirements of the cycloaddition have yet to be determined.
We have recently reported our studies on the reactivity of the
alkene component in ruthenium-catalyzed [2 + 2] cycloadditions
Study on the Reactivity of the Alkyne Component
in Ruthenium-Catalyzed [2 + 2] Cycloadditions
between an Alkene and an Alkyne
Robert W. Jordan, 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 April 25, 2006
The ruthenium-catalyzed [2 + 2] cycloadditions of norbor-
nadiene with a variety of alkynes have been investigated.
Electronic effect of the alkyne component has shown to play
an important role on the rate of the cycloaddition, and the
reactivity of the alkyne component increases dramatically
as the alkyne becomes more electron deficient. Increase in
the steric bulk of the alkyne component decreases the
reactivity of the alkyne component. It was also found that
chelation effect of propargylic alcohols greatly enhanced the
reactivity of the alkyne component in the ruthenium-
catalyzed [2 + 2] cycloadditions.
(4) 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, CT, 1999; Vol. 5, pp
1-45.
(5) 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.s
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. Coord.
Chem. ReV. 1999, 188, 297.
(6) (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.
(7) (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.
(8) (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.
(9) Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J. Am. Chem. Soc.
2000, 122, 7815.
(10) Trost, B. M.; Yanai, M.; Hoogsteen, K. J. Am. Chem. Soc. 1993,
115, 5294.
(11) (a) Mitsudo, T.; Kokuryo, K.; Takegami, Y. J. Chem. Soc., Chem.
Commun. 1976, 772. (b) Mitsudo, T.; Kokuryo, K.; Shinsugi, T.; Nakagawa,
Y.; Watanabe, Y.; Takegami, Y. J. Org. Chem. 1979, 44, 4492. (c) Mitsudo,
T.; Naruse, H.; Kondo, T.; Ozaki, Y.; Watanabe, Y. Angew. Chem., Int.
Ed. Engl. 1994, 33, 580.
(12) (a) Huang, D.-J.; Rayabarapu, D. K.; Li, L.-P.; Sambaiah, T.; Cheng,
C.-H. Chem.sEur. J. 2000, 6, 3706. (b) Chao, K. C.; Rayabarapu, D. K.;
Wang, C.-C.; Cheng, C.-H. J. Org. Chem. 2001, 66, 8804.
Cycloaddition reactions are among the most powerful and
most frequently used methods for the construction of rings.1
We have studied various types of cycloaddition reactions of
bicyclic alkenes and are especially interested in those catalyzed
by transition metals.2,3 Transition-metal-catalyzed cycloadditions
have demonstrated their usefulness in the formation of rings
(1) ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Paquette,
L. A., Eds.; Pergamon: Oxford, 1991; Vol. 5, Chapters 1-9. (b) AdVances
in Cycloaddition; JAI Press: Greenwich, CT, 1988-1999; Vols. 1-6.
(2) For our recent contributions on non-metal-catalyzed cycloaddition
reactions of bicyclic alkenes, see: (a) Yip, C.; Handerson, S.; Jordan, R.;
Tam, W. Org. Lett. 1999, 1, 791. (b) Tranmer, G. K.; Keech, P.; Tam, W.
Chem. Commun. 2000, 863. (c) Mayo, P.; Hecnar, T.; Tam, W. Tetrahedron
2001, 57, 5931. (d) Yip, C.; Handerson, S.; Tranmer, G. K.; Tam, W. J.
Org. Chem. 2001, 66, 276. (e) Tranmer, G. K.; Tam, W. J. Org. Chem.
2001, 66, 5113. (f) Tranmer, G. K.; Tam, W. Org. Lett. 2002, 4, 4101.
(3) For our recent contributions on metal-catalyzed cycloaddition reac-
tions of bicyclic alkenes, see: (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. (f) Jordan, R. W.; Khoury, P. K.;
Goddard, J. D.; Tam, W. J. Org. Chem. 2004, 69, 8467. (g) Villeneuve,
K.; Riddell, N.; Jordan, R. W.; Tsui, G. C.; Tam, W. Org. Lett. 2004, 6,
4543. (h) Riddell, N.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 3681.
(i) Villeneuve, K.; Tam, W. J. Am. Chem. Soc. 2006, 128, 3514. (j)
Villeneuve, K.; Tam, W. Organometallics 2006, 25, 843. (k) Riddell, N.;
Tam, W. J. Org. Chem. 2006, 71, 1934.
10.1021/jo060864o CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/29/2006
5830
J. Org. Chem. 2006, 71, 5830-5833

TABLE 2. Electronic Effect on the Relative Rate of Cycloaddition
SCHEME 1. Reactivity of the Alkene Component
relative
entry
alkyne
X
ratea
1
2
3
4
2g
2h
2i
2a-2f
Me
CH2OTBS
CH2OH
Cl, Br, SO2Ph, COOEt,
COMe, COOH
0.16
1
4
TABLE 1. Ru-Catalyzed [2 + 2] Cycloadditions of Norbornadiene
1 with a Variety of Alkynes
>100
a Measured from competition experiments; see text. The number indicated
is the average number from 3 to 5 runs.
norbornadiene 1 in the presence of the Ru catalyst (Cp*RuCl-
(COD)), giving the corresponding [2 + 2] cycloadducts in good
yields. On the other hand, alkynes without an electron-
withdrawing group are less reactive, and the reactions were
incomplete even after prolong heating at a higher temperature
(entries 7-9). Increase in the steric bulk of the substituent
attached to the alkyne also decreases the reactivity of the alkyne
in the ruthenium-catalyzed [2 + 2] cycloadditions (entries 10-
12). The primary alkyl-substituted alkyne 2j was completely
consumed within 70 h when reacted with norbornadiene in the
presence of the catalyst at 60 °C, whereas the secondary alkyl-
substituted alkyne 2k required a higher temperature (95 °C) and
a longer reaction time to go to completion (entries 10 and 11).
The most sterically hindered tertiary alkyl-substituted alkyne
2l was completely inactive in the ruthenium-catalyzed [2 + 2]
cycloaddition with norbornadiene (entry 12). Another interesting
observation was found when comparing alkyl-substituted alkynes
2j-2l with propargylic alcohols 2m-2o. The propargylic
alcohols seem to be more reactive than the alkyl-substituted
alkynes with similar steric environment. For example, the
cycloaddition of the primary propargylic alcohol 2m was
completed in 48 h, whereas the primary alkyl-substituted alkyne
2j required a longer reaction time. The tertiary alkyl-substituted
alkyne 2l was completely inactive, but the tertiary propargylic
alcohol 2o produced the cycloadduct in good yield in 48 h.
To confirm these qualitative observations and to estimate the
order of reactivity of different alkynes in the ruthenium-
catalyzed [2 + 2] cycloadditions, the relative rate of the
ruthenium-catalyzed [2 + 2] cycloadditions of different alkynes
with norbornadiene was measured by competition experiments
between different alkynes.14 A typical competition experiment
employed 4-5 equiv of equimolar amounts of two different
alkynes with 1 equiv of norbornadiene 1 in the presence of 5
mol % of Cp*RuCl(COD) in THF (large excesses of the alkynes
was used in order to approach pseudo-first-order conditions).14
The reactivity of each alkyne was assessed by evaluation of
the product ratio by capillary gas chromatography.15 The results
of these reactivity studies are shown in Tables 2-4.
temp
(°C)
time
(h)
yield
(%)a
entry
R1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R2
cycloadduct
1
2
3
4
5
6
7
8
COOH
COMe
COOEt
SO2Ph
Br
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
60
60
60
95
60
60
95
95
95
60
95
95
65
25
65
80
48
48
80
48
48
90
90
80
70
90
144
48
72
48
86
90
90
91
83
82
22b
34b
48b
89
88
0b
Cl
CH3
Ph
Ph
CH2OTBS
CH2OH
nBu
9
10
11
12
13
14
15
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
Cy
tBu
CH2OH
CHMeOH
CMe2OH
88
90
85
a Yield of isolated cycloadducts after column chromatography. b 45-
88% of the starting alkynes were recovered.
between an alkene and an alkyne.3f Our results indicated that
reactivity of the alkene component decreases dramatically as
the alkene becomes more electron deficient (Scheme 1). To the
best of our knowledge, no study on the reactivity of the alkyne
component has been reported in the literature. In this paper,
we report our results of the reactivity of the alkyne component
in ruthenium-catalyzed [2 + 2] cycloadditions between an alkene
and an alkyne.
The variety of alkynes employed thus far in the Ru-catalyzed
[2 + 2] cycloadditions is very limited, and only substituents
with primary alkyl groups, aryl groups, esters, and amides have
been used. To expand the scope of the cycloaddition, we
investigated the Ru-catalyzed [2 + 2] cycloadditions of nor-
bornadiene 1 with a variety of alkynes, which are shown in
Table 1.
To our delight, alkynes attached to various functional groups,
such as carboxylic acid (Table 1, entry 1), ketone (entry 2),
sulfone (entry 4), halides (entries 5 and 6), and propargylic
alcohols (entries 9, 13-15), are all compatible with the Ru
catalyst, giving the corresponding [2 + 2] cycloadducts as single
stereoisomers (exo cycloadducts) in moderate to good yields.13
It can be seen from Table 1 that alkynes attached to an electron-
withdrawing group are more reactive than those without an
electron-withdrawing group (compare entries 1-6 with entries
7-9). Complete consumption of the electron-deficient alkynes
(2a-2f) was observed within 48-80 h when reacted with
(14) For an example of estimating the reactivity of reaction partners in
metal-catalyzed cycloaddition reactions by competition experiments, see:
Lautens, M.; Tam, W.; Edwards, L. E. J. Chem. Soc., Perkin Trans. 1 1994,
2143. See also ref 3f.
(15) Since different cycloadducts may provide different response from
the detector of the GC, an equimolar amount of two different cycloadducts
may not provide exactly a 1:1 ratio of peak areas on the GC integration.
Thus, equimolar amount of each cycloadduct was injected into the GC,
and their integration areas were compared. These numbers were then used
to correct for the product ratios.
(13) For determination of exo and endo stereochemistry of [2 + 2]
cycloadducts, see our previous work in ref 3.
J. Org. Chem, Vol. 71, No. 15, 2006 5831

TABLE 3. Relative Rate of Cycloaddition with Electron-Deficient
Alkynes
and a secondary alkyl group (cyclohexyl, entry 3) reacts 7.2
times slower than a primary alkyl group (nBu, entry 2). Alkyne
with an aromatic group (Ph, entry 1) is more reactive than
aliphatic alkyl groups (entries 2-4). Similar trend is observed
with propargylic alcohols (entries 5-7). The primary propargylic
alcohol 2m reacts the fastest, then the secondary propargylic
alcohol 2n, and the tertiary propargylic alcohol 2o reacts the
slowest. It is interesting to compare the reactivity of the alkynes
containing alkyl groups with those containing propargylic
alcohol groups. For example, alkyne with a primary alkyl group
2j reacts 55 times slower than the corresponding primary
propargylic alcohol 2m (compare entry 2 with entry 5).
Similarly, alkyne with a secondary alkyl group 2k reacts 171
times slower than the corresponding secondary propargylic
alcohol 2n (compare entry 3 with entry 6). This rate enhance-
ment of propargylic alcohols is possibly due to the chelation of
the propargylic OH group with the Ru that stabilizes some of
the intermediates along the catalytic pathway.
relative
entry
alkyne
X
ratea
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
COOH
COMe
COOEt
SO2Ph
Br
1
1.6
1.8
2.2
3.6
16.2
Cl
a Measured from competition experiments; see text. The number indicated
is the average number from 3 to 5 runs.
TABLE 4. Steric and Chelation Effect
In conclusion, we have studied the reactivity of the alkyne
component in ruthenium-catalyzed [2 + 2] cycloadditions
between an alkene and an alkyne. We have greatly expanded
the variety of alkynes in the Ru-catalyzed [2 + 2] cycloadditions
and shown that alkynes attached to various functional groups,
such as carboxylic acid, ketone, sulfone, halides, and propargylic
alcohols, are all compatible with the Ru catalyst, giving the
corresponding [2 + 2] cycloadducts as single stereoisomers (exo
cycloadducts) in moderate to good yields. The results of our
study on the relative rate of various alkynes in Ru-catalyzed
[2 + 2] cycloadditions with norbornadiene indicated that
reactivity of the alkyne component increases dramatically as
the alkyne becomes more electron deficient. We have also
shown that increase in steric bulk of the alkyne decreases the
reactivity of the alkyne component in the Ru-catalyzed [2 + 2]
cycloaddition, and that addition of a propargylic alcohol group
greatly increases the reactivity of the alkyne component. Further
investigations on the use of the cycloadducts for the synthesis
of more complex polycyclic natural products are currently in
progress in our laboratory.
relative
entry
alkyne
R
ratea
1
2
3
4
5
6
7
2c
2j
2k
2l
2m
2n
2o
Ph
30.5
7.2
1
nBu
Cy
tBu
n/ab
397
171
6.2
CH2OH
CHMeOH
CMe2OH
a Measured from competition experiments; see text. The number indicated
is the average number from 3 to 5 runs. b No reaction was observed with
alkyne 2l.
Electron-deficient alkynes, such as those attached to halides,
a sulfone, an ester, a ketone, and a carboxylic acid (Table 2,
entry 4), are much more reactive than unactivated alkynes
(entries 1-3). Comparing the reactivity of alkynyl bromide 2e
with that of alkyne 2g (Br and Me have almost identical van
der Waal radii), it is clear that, under similar steric environment,
electron-deficient alkynes are much more reactive. It is also
interesting to note that propargylic alcohol 2i reacts 4 times
faster than the propargylic silyl ether 2h and reacts 25 times
faster than alkyne 2g. It is possibly due to the chelation of the
propargylic OH group with the Ru that stabilizes some of the
intermediates along the catalytic pathway (vide infra, see Table
4 for further investigation of this chelation effect).
The relative rate of cycloaddition with various electron-
deficient alkynes is shown in Table 3. Among all the electron-
deficient alkynes tested, alkyne 2a (X ) COOH) has the lowest
reactivity. The reactivity increases slightly with alkynyl ketone
2b, then with alkynyl ester 2c and alkynyl sulfone 2d. Alkynyl
halides were found to be the most reactive, with alkynyl bromide
2e reacting 3.6 times faster than alkyne 2a and alkynyl chloride
2f reacting 16.2 times faster than alkyne 2a.
Experimental Section16
General Procedure for the Ru-Catalyzed [2 + 2] Cyclo-
additions. A mixture of norbornadiene 1 (2.5-5 equiv), alkyne (1
equiv), and THF in an oven-dried vial was added via a cannula to
an oven-dried screw-cap vial containing Cp*RuCl(COD) (weighed
out from a drybox, 5-10 mol %) under nitrogen. The reaction
mixture was stirred in the dark at 25-95 °C for 48-90 h. The
crude product was purified by column chromatography (hexanes
or ethyl acetate/hexanes mixture) to give the cycloadduct.
4-Phenyltricyclo[4.2.1.02,5]nona-3,7-diene-3-carboxylic acid
(3a, Table 1, entry 1). Following the above general procedure,
with norbornadiene 1 (75.6 mg, 0.820 mmol), acetylene 2a (29.1
mg, 0.199 mmol), THF (0.35 mL), and Cp*RuCl(COD) (4.5 mg,
0.012 mmol). The reaction mixture was stirred in the dark at 60
°C for 80 h. The crude product was purified by column chroma-
tography (EtOAc:hexanes ) 1:4, 2:3) to provide cycloadduct 3a
(40.7 mg, 0.171 mmol, 86%) as a white solid: Rf 0.56 (EtOAc:
hexanes ) 2:3); mp 178.5-179.5 °C; GC (HP-1 column) retention
time ) 15.7 min; IR (neat) ν 2305-3100 (br s), 3058 (s), 2987
(s), 2941 (s), 1673 (s), 1610 (s), 1570 (w), 1491 (m), 1448 (w),
1423 (w), 1404 (m), 1317 (m), 1296 (m), 1266 (s) 1235 (m), 1046
(w) cm-1; 1H NMR (CDCl3, 400 MHz) δ 12.19 (w br s, 1H), 8.09
To investigate the steric effect of the alkyne component, the
relative rates of cycloaddition of alkynes 2c,2j-2l were
compared (Table 4, entries 1-4). In general, the greater the
steric hindrance around the alkyne component, the lower the
reactivity of the alkyne. For example, an alkyne with a tertiary
alkyl group (tBu, entry 4) was inactive in the cycloaddition,
(16) General methods were described in previous publications. See refs
2d and 3f.
5832 J. Org. Chem., Vol. 71, No. 15, 2006

(m, 2H), 7.44 (m, 3H), 6.25 (mABX, 2H), 2.82 (br s, 1H), 2.75 (br
Award. NSERC and the Ontario Government are thanked for
providing postgraduate scholarships to K.V. and R.W.J.
s, 1H), 2.74 (d, 1H, J ) 3.7 Hz), 2.65 (d, 1H, J ) 3.7 Hz), 1.40
2
(qAB, 2H, J ) 9.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 168.3,
160.7, 136.8, 135.4, 132.2, 130.5, 129.8, 129.2, 128.5, 43.4, 42.6,
39.8, 39.2, 38.9. Anal. Calcd for C16H14O2: C, 80.65; H, 5.92.
Found: C, 80.29; H, 6.12.
Supporting Information Available: Detailed experimental
procedures, compound characterization data, and 1H and 13C NMR
spectra of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by NSERC
(Canada) and Boehringer Ingelheim (Canada) Ltd. W.T. thanks
Boehringer Ingelheim (Canada) Ltd. for a Young Investigator
JO060864O
J. Org. Chem, Vol. 71, No. 15, 2006 5833