Ruthenium-catalyzed [2 + 2] cycloadditions of ynamides

Article abstract of DOI:10.1021/ol0512841

(Chemical Equation Presented) Ruthenium-catalyzed [2 + 2] cycloadditions between norbornene and ynamides were investigated. The ynamide moiety was found to be compatible with the ruthenium-catalyzed cycloaddition conditions, giving the corresponding cyclobutene cycloadducts in moderate to good yields (up to 97%).

Full text of DOI:10.1021/ol0512841

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3681-3684
Ruthenium-Catalyzed [2
Cycloadditions of Ynamides
+ 2]
Nicole Riddell, 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 June 1, 2005
ABSTRACT
Ruthenium-catalyzed [2
+ 2] cycloadditions between norbornene and ynamides were investigated. The ynamide moiety was found to be
compatible with the ruthenium-catalyzed cycloaddition conditions, giving the corresponding cyclobutene cycloadducts in moderate to good
yields (up to 97%).
Although ynamines and ynamides (electron-deficient
ynamines) have been shown to be useful building blocks in
organic synthesis,1 their inaccessibility has limited their
synthetic applications of these moieties. Recently, develop-
ments and improvements by Danheiser,2 Hsung,3 Cossy,4
Sato,5 and Witulski6 on the synthesis of ynamines and
ynamides have renewed the interest in these functional
groups in the synthetic community. The interest in the
applications of ynamides in organic synthesis has increased
enormously in recent years due to their higher stability than
ynamines. Recent studies on the synthetic versatility of
ynamides include Pauson-Khand [2 + 2 + 1] cycloaddi-
tions,7 thermal and transition metal-catalyzed [4 + 2]
cycloadditions,8 Lewis acid-catalyzed [2 + 2] cycloaddi-
tions,9 Rh-catalyzed [2 + 2 + 2] cycloadditions,10 ring-
closing metathesis (RCM),11 transition metal-catalyzed cou-
pling reactions,12 rearrangement reactions,13 hydrometalation
and hydrohalogenation reactions,14 and cyclization reac-
tions.15
We have studied various types of cycloaddition reactions
of bicyclic alkenes and are especially interested in those
catalyzed by transition metals.16,17 Transition metal-catalyzed
cycloadditions have demonstrated their usefulness as efficient
methods in the formation of rings and complex molecules.18
The use of transition metal catalysts provides new opportuni-
ties for highly selective cycloaddition reactions since com-
(8) Witulski, B.; Lumtscher, J.; Bergstra¨âer, U. Synlett 2003, 708.
(9) Hsung, R. P.; Zificsak, C. A.; Wei, L.-L.; Douglas, C. J.; Xiong, H.;
Mulder, J. A. Org. Lett. 1999, 1, 1237.
(1) For reviews of the chemistry of ynamines and ynamides, see: (a)
Ficini, J. Tetrahedron 1976, 32, 1448. (b) Collard-Motte, J.; Janousek, Z.
Top. Curr. Chem. 1986, 130, 89. (c) Zificsak, C. A.; Mulder, J. A.; Hsung,
R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575. (d)
Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379.
(2) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011.
(3) (a) Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas,
C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459. (b) Frederick, M. O.; Mulder,
J. A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. M. C.; Shen, L.;
Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368. (c) Zhang, Y.; Hsung,
R. P.; Tracey, M. R.; Kurtz, K. M. C.; Vera, E. L. Org. Lett. 2004, 6,
1151.
(4) Couty, S.; Barbazanges, M.; Meyer, C.; Cossy, J. Synlett 2005, 905.
(5) Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6, 727.
(6) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1998, 37, 489.
(7) (a) Rainier, J. D.; Imbriglio, J. E. Org. Lett. 1999, 1, 2037. (b)
Witulski, B.; Go¨âmann, M. J. Chem. Soc., Chem. Commun. 1999, 1879.
(c) Rainier, J. D.; Imbriglio, J. E. J Org. Chem. 2000, 65, 7272. (d) Witulski,
B.; Go¨âmann, M. Synlett 2000, 1793. (e) Shen, L. Hsung, R. P. Tetrahedron
Lett. 2003, 44, 9353.
(10) (a) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1999, 38, 2426.
(b) Witulski, B.; Alayrac, C. Angew. Chem., Int. Ed. 2002, 41, 3281.
(11) (a) Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, 803. (b) Huang,
J.; Xiong, H.; Hsung, R. P.; Rameshkumar, C.; Mulder, J. A.; Grebe, T. P.
Org. Lett. 2002, 4, 2417.
(12) (a) Tracey, M. R.; Zhang, Y.; Frederick, M. O.; Mulder, J. A.;
Hsung, R. P. Org. Lett. 2004, 6, 2209. (b) Couty, S.; Lie´gault, B.; Meyer,
C.; Cossy, J. Org. Lett. 2004, 6, 2511.
(13) (a) Mulder, J. A.; Hsung, R. P.; Frederick, M. O.; Tracey, M. R.;
Zificsak, C. A. Org. Lett. 2002, 4, 1383. (b) Frederick, M. O.; Hsung, R.
P.; Lembeth, R. H.; Mulder, J. A.; Tracey, M. R. Org. Lett. 2003, 5, 2663.
(14) (a) Witulski, B.; Buschmann, N.; Bergstra¨sser, U. Tetrahedron 2000,
56, 8473. (b) Minie`re, S.; Cintrat, J.-C. Synthesis 2001, 705. (c) Minie`re,
S.; Cintrat, J.-C. J. Org. Chem. 2001, 66, 7385. (d) Timbart, L.; Cintrat,
J.-C. Chem. Eur. J. 2002, 8, 1637. (e) Mulder, J. A.; Kurtz, K. C. M.;
Hsung, R. P.; Coverdale, H.; Frederick, M. O.; Shen, L.; Zificsak, C. A.
Org. Lett. 2003, 5, 1547.
(15) (a) Marion, F.; Coulomb, J.; Courillon, C.; Fensterbank, L.; Malacria,
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J.; Slafer, B. W.; Davis, A. Org. Lett. 2005, 7, 1047.
10.1021/ol0512841 CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/27/2005

Table 1. Synthesis of Acyclic Ynamides 3a-h,j-l
entry ynamide 3 alkyne 1 [equiv] amide 2 [equiv]
Cu [equiv]
base [equiv]
ligand [equiv] solvent/temp (°C) yield (%)a
1
2
3a
1a (2)
1a (2)
1a (2)
1a (2)
1a (1)
1a (1)
1a (3)
1a (2)
1a (1)
1a (2)
1a (1)
1a (2)
1b (2)
1c (2)
1d (2)
1e (1)
1f (1.4)
1g (1.2)
2a (1)
2a (1)
2a (1)
2a (1)
2a (1.1)
2b (1.2)
2b (1)
2c (1)
2c (1)
2c (1)
2d (1.7)
2e (1)
2e (1)
2e (1)
2e (1)
2e (1.4)
2e (1)
2e (1)
CuSO4 (0.1)
CuI (1.0)
CuI (0.06)
CuI (0.2)
CuI (0.06)
CuI (0.06)
CuI (0.08)
CuI (1.0)
K2CO3 (2.0)
Phen (0.2)
toluene/60
pyridine/25
toluene/90
toluene/90
toluene/90
toluene/60
toluene/90
pyridine/25
toluene/110
toluene/90
toluene/90
toluene/90
toluene/90
toluene/90
toluene/90
toluene/90
toluene/90
toluene/90
0
16
43
65
17
38
52
0
KHMDS (1.0)
KHMDS (1.2)
KHMDS (1.2)
KHMDS (1.1)
K2CO3 (2.0)
3b
Phen (0.14)
Phen (0.24)
DMED (0.1)
DMED (0.1)
Phen (0.12)
4b
5b
3b
3c
6
7b
KHMDS (1.2)
KHMDS (1.0)
8
9
CuCN (0.06) K3PO4 (2.0)
DMED (0.1)
Phen (0.26)
Phen (0.22)
Phen (0.24)
Phen (0.27)
Phen (0.26)
Phen (0.28)
Phen (0.46)
Phen (0.23)
Phen (0.36)
0
10b
11b
12b
13b
14b
15b
16b
17b
18b
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.4)
CuI (0.25)
CuI (0.3)
KHMDS (1.2)
KHMDS (1.0)
KHMDS (1.2)
KHMDS (1.2)
KHMDS (1.2)
KHMDS (1.1)
KHMDS (1.7)
KHMDS (1.0)
KHMDS (1.3)
61
68
65
48
39
54
59
26
90
3d
3e
3f
3g
3h
3j
3k
3l
plexation 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],19 [4 + 2],20 [5 + 2],21 [4 + 4],22 and [6 + 2]23
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 between an alkene and an
alkyne for the synthesis of cyclobutene rings, including
development of novel catalysts, study of the intramolecular
variant of the reaction, investigation of the chemo- and
regioselectivity of unsymmetrical substrates, and asymmetric
(19) 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.
(16) For our recent contibutions 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.
(17) For our recent contributions on Ru-catalyzed [2 + 2] cycloadditions,
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.
(20) (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.
(21) (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.
(18) 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.
(22) (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.
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2000, 122, 7815.
3682
Org. Lett., Vol. 7, No. 17, 2005

induction studies using a chiral auxiliary on the alkyne
component.17,24-26 However, to the best of our knowledge,
other than our recent studies of alkynyl halides in Ru-
catalyzed [2 + 2] cycloadditions,17g all the alkynes employed
thus far in transition metal-catalyzed [2 + 2] cycloadditions
only contain carbon substituents such as alkyl, aryl, ester,
and ketone functionalities, and the use of heteroatom-
substituted acetylenic substrates in transition metal-catalyzed
[2 + 2] cycloadditions is unexplored. In this paper, we report
the first examples of ruthenium-catalyzed [2 + 2] cycload-
ditions of bicyclic alkenes with ynamides.
Table 2. Ru-Catalyzed [2 + 2] Cycloaddition between
Norbornene and Acyclic Ynamides
entry ynamide
R1
EWG
R2
yield (%)a
55b
1
2
3a
3b
3c
3d
Ph
Ph
Ph
Ph
Ph
Ph
COOMe Cy
COOMe CH2CH2Ph 73
To begin this study, several acyclic ynamides were
prepared (Table 1). Screening of various methods for the
synthesis of ynamides found the methods by Danheiser2 and
Hsung3 to be the most reliable. However, fine-tuning of the
reaction conditions was required in order to optimize yields
for some of the desired ynamides. For example, using
Hsung’s catalytic CuSO4 method3c did not result in the
formation of ynamide 3a (entry 1), and only homocoupling
of alkynyl bromide 1a was observed. Similarly, Danheiser’s
stoichiometric CuI method2 only produced ynamide 3a in a
low yield of 16% (entry 2). Reexamination of Buchwald’s
amidation of aryl bromide27 suggested that the rate of
deprotonation of the amide has to match the rate of the
amidation reaction in order for the coupling reaction to be
successful. Buchwald suggested that the formation of excess
deprotonated amide deactivates the Cu catalyst by forming
an unreactive cuprate complex. With this insight, we modi-
fied Hsung’s catalytic CuI method3b by adding the base
(KHMDS) slowly to the reaction mixture over 3-4 h using
a syringe pump. To our delight, we were able to improve
the yield of ynamide 3a to 65% (entry 4). Similarly, for the
syntheses of ynamides 3b and 3c, several reaction conditions
were attempted, and it was found that our modified condi-
tions gave the best results. By using these modified reaction
conditions (0.2-0.3 equiv of CuI, 0.22-0.36 equiv of the
1,10-phen ligand, and adding 1.2 equiv of the base KHMDS
slowly over 3-4 h in toluene at 90 °C), we obtained
ynamides 3d-l in moderate to good yields (entries 11-18).
With these acyclic ynamides in hand, we studied their Ru-
catalyzed [2 + 2] cycloadditions with norbornene 4, and the
results are shown in Table 2.
3
COOMe CH2Ph
COOtBu CH2Ph
COOtBu CH2Ph
COOMe Ph
91
4
39 (5)
75 (9)c
97
5
6
3e
3f
7
p-Me-C6H5
o-Me-C6H5
m-F-C6H5
CH2OH
CH2OTBS
CH2CH2OTBS COOMe Ph
COOMe Ph
85b
8
3g
3h
3i
COOMe Ph
49 (32)b
58d
9
COOMe Ph
10
11
12
13
14
15
COOMe Ph
32d
3j
COOMe Ph
25d
3k
3l
78
iPr3Si
H
COOMe Ph
COOMe Ph
COOMe Ph
0 (93)
3m
3n
0d
COOEt
0 (34)d
a Yield of isolated cycloadducts after column chromatography. Yield of
recovered ynamide in brackets. b Reaction was stirred at 60 °C for 168 h.
c Reaction was stirred at 25 °C for 168 h. d Polymeric materials were also
obtained on the top of the column.
Hsung previously observed an unusual endo cycloaddition
of ynamides with bicyclic alkenes in the Co-catalyzed [2 +
2 + 1] Pauson-Khand cycloadditions.7e We did not observe
such an unusual change in stereochemistry with our Ru-
catalyzed [2 + 2] cycloadditions with ynamides.28
Several trends were observed in the Ru-catalyzed [2 + 2]
cycloadditions of acyclic ynamides (Table 2). With ynamides
3a-e (R1 ) Ph, entries 1-6), an increase in the steric bulk
of the substituents (R2 and EWG) on the nitrogen led to a
decrease in the yield (compare entries 1 and 2, R2 ) 2° alkyl
group vs 1° alkyl group; and compare entries 3 and 4, EWG
) COOMe vs COOtBu). For ynamides 3e-h (R2 ) Ph,
EWG ) COOMe, and R1 ) aromatic groups, entries 6-9),
both the electron-withdrawing aromatic group (m-F-C6H5,
entry 9) and sterically bulky aromatic group (o-Me-C6H5,
entry 8) led to a decrease in the yield in the cycloaddition.
Ynamides containing propargylic alcohol and propargylic
silyl ether groups (entries 10 and 11) gave low yields in the
cycloadditions, which may be explained by the observation
of polymeric materials. Also, ynamide with a very bulky
group on the alkyne (R1 ) SiiPr3, entry 13) and ynamide
containing an electron-withdrawing group (R1 ) COOEt,
entry 15) were both inert in the Ru-catalyzed [2 + 2]
cycloadditions. Terminal ynamide (R1 ) H, entry 14) gave
only polymeric materials under the cycloaddition conditions.
We have recently reported the first two examples of
asymmeteric induction studies of Ru-catalyzed [2 + 2]
cycloadditions between an alkene and an alkyne using a
chiral auxiliary attached to the alkyne component (Scheme
1).17d,e With the success of the Ru-catalyzed [2 + 2]
cycloadditions of acyclic ynamides, we were interested to
explore the reactivity and the degree of asymmeteric induc-
Unlike alkynes with electron-withdrawing groups attached
to the acetylenic carbon (e.g., COOEt17a or halides17g), which
undergo Ru-catalyzed [2 + 2] cycloadditions with bicyclic
alkenes at room temperature, these ynamides with a nitrogen
heteroatom attached to the acetylenic carbon were found to
be less reactive and usually required an elevated temperature
(60 °C) and a longer reaction time. Moderate to good yields
of the Ru-catalyzed [2 + 2] cycloadditions were obtained
with most of the ynamides. In all cases, single stereoisomers,
the exo cycloadducts 5, were formed.
(24) Trost, B. M.; Yanai, M.; Hoogsteen, K. J. Am. Chem. Soc. 1993,
115, 5294.
(25) Mitsudo, T.; Naruse, H.; Kondo, T.; Ozaki, Y.; Watanabe, Y. Angew.
Chem., Int. Ed. Engl. 1994, 33, 580.
(26) (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.
(27) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421.
(28) For determination of the exo and endo stereochemistry of [2 + 2]
cycloadducts, see our previous work in ref 17.
Org. Lett., Vol. 7, No. 17, 2005
3683

Scheme 1. Ru-Catalyzed [2 + 2] Cycloadditions between
Norbornene and Alkynes Containing a Chiral Auxiliary
Table 3. Ru-Catalyzed [2 + 2] Cycloaddition between
Norbornene and Chiral Cyclic Ynamides
tion in the Ru-catalyzed [2 + 2] cycloadditions of chiral
cyclic ynamides.
Several known (10a,d) and new chiral cyclic ynamides
(10b,c,e,f) were synthesized,29 and the results of the Ru-
catalyzed [2 + 2] cycloadditions of these chiral cyclic
ynamides are shown in Table 3. Good yields of the
cycloadditions were obtained with chiral cyclic ynamides
10a-d (entries 1-5); however, the diastereoselectivity was
only low to moderate. The diastereomeric ratios (dr) were
1
determined by 400 MHz H NMR, and the peaks were
compared to the 1:1 mixture of the diastereomers, which were
synthesized using Buchwald’s Cu-catalyzed amidation of
vinyl iodide 12 (Scheme 2).30
Scheme 2. Synthesis of 1:1 Diastereomers of 11a
a Yield of isolated cycloadducts after column chromatography. Yield of
recovered ynamide in brackets. b Diastereomeric ratios (drs) measured by
400 MHz 1H NMR. c Reaction was stirred for 168 h. d Reaction was stirred
at 25 °C for 216 h.
that the ynamide moiety is compatible with the Ru-catalyzed
[2 + 2] cycloadditions and that the reactivity of ynamide
functionality is generally lower than electron-deficient
alkynes. Moderate to good yields of the cycloadditions were
obtained with various acyclic and cyclic ynamides. However,
only low to moderate levels of asymmetric induction were
observed in the Ru-catalyzed [2 + 2] cycloadditions with
chiral cyclic ynamides. Further investigations on the mech-
anism of the cycloaddition, improvement of the asymmetric
induction using other chiral ynamides, and the use of the
cycloadducts for the synthesis of more complex polycyclic
natural products are currently in progress in our laboratory.
Decrease in the reaction temperature led to decrease in
the yield, and no improvement of the diastereoselectivity was
observed (entries 4 and 5). Ynamides 10e and 10f were too
bulky and found to be inert in the Ru-catalyzed [2 + 2]
cycloadditions (entries 6 and 7). It is worth noting that
ynamide 10f was unreactive in the Ru-catalyzed [2 + 2]
cycloaddition but that amide 6 (Scheme 1), with an extra
carbonyl group between the nitrogen atom and the acetylenic
carbon, gave an excellent yield and excellent diastereose-
lectivity in the cycloaddition.
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.
and N.R. Ms. Valerie Robertson is thanked for NMR
experiments and discussion of NMR data.
In summary, we have demonstrated the first examples of
Ru-catalyzed [2 + 2] cycloadditions of ynamides. We found
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.
(29) Known chiral ynamides 10a and 10d were prepared according to
Hsung’s method; see ref 3b. The new chiral ynamides 10e and 10f were
synthesized using Danheiser’s method; see Supporting Information for
details. The new chiral ynamide 10b was synthesized using the same method
as per the synthesis of acyclic ynamides 3a-l.
(30) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003,
5, 3667.
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