Ruthenium-catalyzed [2 + 2] cycloadditions of bicyclic alkenes and ynamides

Article abstract of DOI:10.1016/j.tet.2005.11.081

Ruthenium-catalyzed [2 + 2] cycloadditions between bicyclic alkenes 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%). Diastereoselective cycloaddition utilizing chiral cyclic ynamides were also examined and a low to moderate level of asymmetric induction was observed.

Full text of DOI:10.1016/j.tet.2005.11.081

Tetrahedron 62 (2006) 3823–3836
Ruthenium-catalyzed [2D2] cycloadditions
of bicyclic alkenes and ynamides
†
Karine Villeneuve, Nicole Riddell and William Tam
*
Department of Chemistry, Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry,
University of Guelph, Guelph, Ont., Canada N1G 2W1
Received 14 November 2005; accepted 26 November 2005
Available online 23 February 2006
Abstract—Ruthenium-catalyzed [2C2] cycloadditions between bicyclic alkenes 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%). Diastereoselective cycloaddition utilizing chiral cyclic ynamides were also examined and a low to
moderate level of asymmetric induction was observed.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
transition metal-catalyzed [2C2] 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 induction studies using chiral auxilliary on
the alkyne component.17,19–21 The alkynes employed in
transition metal-catalyzed [2C2] cycloadditions usually
contain carbon substituents such as alkyl, aryl, ester, and
ketone functionalities. However, we recently showed that
heteroatom substituted acetylenes such as alkynyl halides17g
and ynamides17h were also suitable substrates. We now
report a full account on the ruthenium-catalyzed [2C2]
cycloaddition reactions of bicyclic alkenes with ynamides.
Ynamines and ynamides (electron-deficient ynamines) have
been shown to be useful building blocks in organic
synthesis.1 However, their inaccessibility had limited their
synthetic usefulness until recent developments and
improvements in their synthesis were published by
Danheiser,2 Hsung,3 Cossy,4 Sato,5 and Witulski.6 Yn-
amides have been the main focus of research in this area due
to their greater stability over ynamines. Accordingly, the
interest in the application of ynamides in organic synthesis
has increased remarkably. Recent studies on the synthetic
value of ynamides include: Pauson–Khand [2C2C1]
cycloadditions,7 thermal and transition metal-catalyzed
[4C2] cycloadditions,8 Lewis acid catalyzed [2C2]
cycloadditions,9 Rh-catalyzed [2C2C2] cycloadditions,10
ring-closing metathesis (RCM),11 transition metal-catalyzed
coupling reactions,12 rearrangement reactions,13 hydrome-
talation and hydrohalogenation reactions,14 and cyclization
reactions.15
2. Results and discussion
2.1. Synthesis of ynamides
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 homo-coupling of alkynyl
bromide 1a was observed. Similarly, Danheiser’s stoichio-
metric CuI method2 only produced ynamide 3a in a low
yield of 16% (entry 2). Re-examination of Buchwald’s
amidation of aryl bromide22 suggested that the rate of
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 utility as
efficient methods in the formation of rings and complex
molecules.18 We and others have studied various aspects of
Keywords: Ynamines; Cycloaddition; Amidation.
*
Corresponding author. Tel.: C1 519 824 4120x52268; fax: C1 519 766
1499; e-mail: wtam@uoguelph.ca
† Current address: Wellington Laboratories, 345 Southgate Drive, Guelph,
Ontario, Canada N1G 3M5.
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.081

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K. Villeneuve et al. / Tetrahedron 62 (2006) 3823–3836
Table 1. Synthesis of acyclic ynamides 3a–h, 3j–l
Entry
Ynamide 3
Alkyne 1
(equiv)
Amide 2
(equiv)
Cu (equiv)
Base (equiv)
Ligand (equiv)
Solvent/
Temperature (8C)
Yield (%)a
1
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)
2b (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)
CuCN (0.06)
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)
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
2
KHMDS (0.1)
KHMDS (1.2)
KHMDS (1.2)
KHMDS (1.1)
K2CO3 (2.0)
KHMDS (1.2)
KHMDS (1.0)
K3PO4 (2.0)
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)
3b
Phen (0.14)
Phen (0.24)
DMED (0.1)
DMED (0.1)
Phen (0.12)
—
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)
4b
5b
3b
3c
6
7b
8
9
0
10b
11b
12b
13b
14b
15b
16b
17b
18b
61
68
65
48
39
54
59
26
90
3d
3e
3f
3g
3h
3j
3k
3l
a Yield of isolated cycloadducts after column chromatography.
b The base was added slowly to the reaction mixture at the indicated temperature through a syringe pump over 3–4 h. See text for details.
deprotonation of the amide had 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, Hsung’s
catalytic CuI method3b was modified by adding the base
(KHMDS) slowly to the reaction mixture over 3–4 h using a
syringe pump. To our delight, we could improve the yield of
ynamide 3a up to 65% (entry 4). Similarly, several reaction
conditions were attempted for the syntheses of ynamides 3b
and 3c and it was found that our modified conditions gave
the best results. By using the 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 8C), ynamides 3d–3l were
obtained in moderate to good yields (entries 11–18).
Scheme 1. Synthesis of (S)-4-hydroxymethyl-3-phenylethynyl-oxazolidin-
2-one (8). Reagents and conditions: (i) see Ref. 34; (ii) TBSCl, DMAP,
Et3N, CH2Cl2, 25 8C (80%); (iii) 1a, CuI, KHMDS, 1,10-phen, toluene,
90 8C (46%); (iv) TBAF, THF, K78 8C (40%).
Our attention was then directed towards the synthesis of
ynamides bearing an electron-withdrawing group at the
acetylenic position. To date, no method to couple amides or
sulfonamides with electron-deficient haloacetylenes has
been published. Indeed, all our attempts to couple 2e with
ethyl 3-bromopropynoate 10 utilizing different copper-
based coupling methodologies failed. Instead, 3n was
synthesized from 3l in two steps (Scheme 2).
This methodology was also effective for the synthesis of the
chiral ynamide 8 (Scheme 1). The synthesis first required
the preparation of 5 from (S)-4-hydroxymethyloxazolidin-2-
one 4 following a method developed by Sibi et al.23 Direct
coupling of 5 with bromophenylacetylene 1a did not
produce the desired product. However, when the alcohol
group was protected using TBSCl, the coupled product 7
was obtained in 46% yield. Deprotection of 7 afforded 8 in
a yield of 40%.
Electron-poor ynamide 3o was also prepared. Unlike all
previous cases, it was obtained through an unprecedented

K. Villeneuve et al. / Tetrahedron 62 (2006) 3823–3836
3825
Table 2. Ru-catalyzed [2C2] cycloaddition between norbornene and
acyclic ynamides
Entry Ynamide R1
EWG
R2
Yield
(%)a
55b
Scheme 2. Synthesis of N-ethoxycarbonylethynyl-N-phenylcarbamic acid
methyl ester 3n.
1
2
3
4
5
6
7
8
3a
3b
3c
3d
Ph
Ph
Ph
Ph
Ph
Ph
COOMe Cy
COOMe CH2CH2Ph 73
COOMe CH2Ph
COOtBu CH2Ph
COOtBu CH2Ph
COOMe Ph
COOMe Ph
COOMe Ph
COOMe Ph
COOMe Ph
COOMe Ph
91
39 (5)
75 (9)c
97
conjugate addition/elimination process. Sulfonamide 9 was
first deprotonated with butyllithium, and was then added to
the bromoester 10 in presence of aluminium chloride,
yielding to 3o in 61% (Scheme 3). Intrigued by this
expedient synthesis, we attempted to apply this method-
ology to the preparation of 3n from the amide 2e.
Unfortunately, this methodology is thus far only applicable
to sulfonamides.
3e
3f
3g
3h
3i
3j
3k
3l
p-Me–C6H5
o-Me–C6H5
m-F–C6H5
CH2OH
CH2OTBS
85b
49 (32)b
58d
9
10
11
12
13
14
15
16
32d
25d
78
CH2CH2OTBS COOMe Ph
iPr3Si
H
COOMe Ph
COOMe Ph
COOMe Ph
0 (93)
0d
3m
3n
3o
COOEt
COOEt
0 (34)d
0 (47)
SO2Tol
Bn
a Yield of isolated cycloadducts after column chromatography. Yield of
recovered ynamide in brackets.
b The reaction was stirred at 60 8C for 168 h.
c The reaction was stirred at 25 8C for 168 h.
d Polymeric materials were also obtained on the top of the column.
Scheme 3. Synthesis of 3o.
2.2. Ruthenium-catalyzed [2D2] cycloadditions
of ynamides
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 observance of polymeric materials. Terminal ynamide
3m (R1ZH, entry 14) gave only polymeric materials
under the cycloaddition conditions. Also, ynamide 3l, with
a very bulky group on the alkyne (R1ZSiiPr3, entry 13) and
ynamide 3n, containing an electron-withdrawing group
(R1ZCOOEt, entry 15), were both inert in the Ru-catalyzed
[2C2] cycloaddition. In the case of R1 being an electron-
withdrawing group, changing the electronics of the nitrogen
(EWGZSO2Tol, entry 16) did not improve the reactivity.
With these acyclic ynamides in hand, we studied their Ru-
catalyzed [2C2] cycloadditions with norbornene 4a and the
results are shown in Table 2. Unlike alkynes with electron-
withdrawing groups attached to the acetylenic carbon (e.g.,
COOEt17a or halides17g), which undergo Ru-catalyzed [2C
2] cycloadditions with bicyclic alkenes at room tempera-
ture, ynamides were found to be less reactive and usually
required an elevated temperature (60 8C) and a longer
reaction time in order for the reaction to go to completion.
Moderate to good yields of the Ru-catalyzed [2C2]
cycloadditions were obtained with most of the ynamides.
Interestingly, Hsung previously observed an unusual endo
cycloaddition of ynamides with bicyclic alkenes in the Co-
catalyzed [2C2C1] Pauson–Khand cycloadditions.7e We
did not observe such an unusual change in stereochemistry
with our Ru-catalyzed [2C2] cycloadditions with yn-
amides.24 In all cases single stereoisomers, the exo
cycloadducts 5 were formed.
The scope of the reaction of ynamide 3e with different
bicyclic alkenes was also investigated (Table 3). In general,
moderate to excellent yields were obtained (entries 1, 4–7),
with the exception of norbornadienes 4b and 4c (entries 2
and 3). This was surprising since previous examples using
these norbornadiene substrates suggested that the Ru-
catalyzed [2C2] cycloaddition reaction was feasible with
other alkynes.17a–g Furthermore, the presence of an extra
double bond of the norbornadienes usually enhances the rate
of the Ru-catalyzed [2C2] cycloaddition. In the present
cases, we believe that the alkyne moiety of the ynamide fails
to displace the alkene that chelates, in a bidentate fashion, to
the ruthenium catalyst. Therefore, the relatively stable
complex stays inert in the reaction conditions. As mentioned
previously, higher temperature and longer reaction time are
usually required with ynamides, which can be related to
their lower affinity to complex to the ruthenium catalyst.
Thus, utilizing 4d (entry 4) as the alkene partner, where
one of the double bonds is substituted by an aryl group,
Several trends were observed in the Ru-catalyzed [2C2]
cycloadditions of acyclic ynamides (Table 2). With
ynamides 3a–e (R1ZPh, 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,
R2Z28 alkyl group vs 18 alkyl group; and compare entries 3
and 4, EWGZCOOMe vs COOtBu). For ynamides 3e–h
(R2ZPh, EWGZCOOMe and R1Zaromatic 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

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K. Villeneuve et al. / Tetrahedron 62 (2006) 3823–3836
Table 3. Ruthenium-catalyzed [2C2] cycloaddition bicyclic alkenes and ynamide 3e
Entry
1
Alkene
Product
Yield (%)a
97
4a
5e
11
12
2
3
0 (97)
0 (98)
4b
4c
4
90
4d
4e
13
14
15
16
5
6
7
46
83
94
4f
4g
a Yield of isolated cycloadducts after column chromatography. Yield of recovered ynamide in brackets.
the reaction proceeded smoothly and a 90% yield of the
cycloadduct 13 was obtained. Similarly to 4d, alkenes 4e,
4f, and 4g containing a heteroatom-based group at the
bridgehead position, also underwent cycloaddition with
ynamide 3e (entries 5–7).
(Scheme 4) and good reactivity of acyclic ynamides in
the Ru-catalyzed [2C2] cycloadditions, we decided to
explore the chiral cyclic ynamides. Since the chiral
functional group would be closer to the reaction center, a
greater degree of asymmetric induction was anticipated.
On the other hand, this could also mean increased steric
congestion, which could potentially decrease the rate of
the reaction or even suppress the formation of the
cycloadduct since the acetylenic electron-withdrawing
carbonyl group is not present anymore.
2.3. Asymmetric ruthenium-catalyzed [2D2]
cycloadditions of chiral ynamides
We have recently reported the first two examples of
asymmetric induction studies of Ru-catalyzed [2C2]
cycloadditions between an alkene and an alkyne using a
Several known (22, 23) and new chiral cyclic ynamides
(7, 8, 24, 25) were synthesized and the results of the
Ru-catalyzed [2C2] cycloadditions of these chiral cyclic
ynamides are shown in Table 4. Good yields of the
cycloadditions were obtained with chiral cyclic ynamides
7, 8, 22 and 23 (entries 1–5), however, the diastereoselec-
tivity was only low to moderate. The diastereomeric ratios
chiral auxilliary attached to the alkyne component.17d,e
With the excellent level of asymmetric induction
obtained in the case of the chiral acetylenic acyl sultams
1
(dr) were 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 19 (Scheme 5).25
Scheme 4. Ru-catalyzed [2C2] cycloadditions between 4a and 17.

K. Villeneuve et al. / Tetrahedron 62 (2006) 3823–3836
3827
Table 4. Ru-catalyzed [2C2] cycloaddition between norbornene and chiral
cyclic ynamides
ynamide 25 was unreactive in the Ru-catalyzed [2C2]
cycloaddition, but that amide 17 (Scheme 4), with an extra
carbonyl group between the nitrogen atom and the
acetylenic carbon, gave excellent yield and excellent
diastereoselectivity in the cycloaddition.
3. Conclusion
Entry
Ynamide
Product
(% yield)a
dr (%)b
72:28
In summary, we have demonstrated that the ynamide moiety
is compatible with the Ru-catalyzed [2C2] cycloadditions
and that the reactivity of ynamide functionality is generally
lower than other electron-deficient alkynes. We also found
that diverse bicyclic alkenes could be utilized, with the
exception of norbornadienes. Moderate to good yields of the
cycloadditions were obtained with various acyclic and
cyclic ynamides. However, only low to moderate levels of
asymmetric induction was observed in the Ru-catalyzed
[2C2] cycloadditions with chiral cyclic ynamides. Futher
investigations on the mechanism of the cycloaddition,
improvement of the asymmetric induction using other
chiral ynamides, and the studies on regioselectivity of the
Ru-catalyzed [2C2] cycloadditions between unsymmetrical
bicyclic alkenes and ynamides are currently in progress in
our laboratory.
1
21 (83)
26 (72)
27 (81)d
22
2c
58:42
71:29
7
3c
8
4
28 (82)
74:26
75:25
5e
28 (60)d
4. Experimental
23
24
All reactions were carried out in an atmosphere of dry
nitrogen at ambient temperature unless otherwise stated.
Standard column chromatography was performed on 230–
400 mesh silica gel (obtained from Silicycle) using flash
column chromatography techniques.26 Analytical thin-layer
chromatography (TLC) was performed on Merck precoated
silica gel 60 F254 plates. All glassware was flame dried
under an inert atmosphere of dry nitrogen. Infrared spectra
were taken on a Bomem MB-100 FTIR spectrophotometer.
1H and 13C NMR spectra were recorded on Bruker Avance-
300, 400 or 600 spectrometer. Chemical shifts for 1H NMR
spectra are reported in parts per million (ppm) from
tetramethylsilane with the solvent resonance as the internal
standard (chloroform: d 7.26 ppm). Chemical shifts for 13C
NMR spectra are reported in parts per million (ppm) from
tetramethylsilane with the solvent as the internal standard
(deuterochloroform: d 77.0 ppm). High resolution mass
spectra were done by McMaster Regional Centre for Mass
Spectrometry at McMaster University, Hamilton, Ontario.
Elemental analyses were performed by Canadian Micro-
analytical Service Ltd, British Columbia or by Quantitative
Technologies Inc., New Jersey. Unless stated otherwise,
commercial reagents were used without purification.
Solvents were purified by distillation under dry nitrogen:
from CaH2 (pyridine); from sodium (toluene); and from
potassium/benzophenone (THF). Ynamides 22 and 23,27
and Cp*RuCl(COD)28 were prepared according to literature
procedures.
6c
29 (0)d
30 (0)d
NA
NA
7
25
a Yield of isolated cycloadducts after column chromatography. Yield of
recovered ynamide in brackets.
1
b Diastereomeric ratios (dr) measured by 400 MHz H NMR.
c The reaction was stirred for 168 h.
d 16–94% of starting material recovered.
e The reaction was stirred at 25 8C for 216 h.
A decrease in the reaction temperature led to a correspond-
ing decrease in the yield and no improvement of the
diastereoselectivity was observed (entries 4 and 5).
Ynamides attached to bicyclic frameworks were too bulky
and were found to be inert in the Ru-catalyzed [2C2]
cycloadditions (entries 6 and 7). It is worth noting that
Special note: for some of the acyclic ynamides as well as
their corresponding [2C2] cycloadducts, some of the 13C
NMR signals (especially those of acetylenic, olefinic and
carbonyl carbons, which are directly attached to the
nitrogen) are severely broadened and virtually lost
Scheme 5. Synthesis of 1:1 diastereomers of 23.

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K. Villeneuve et al. / Tetrahedron 62 (2006) 3823–3836
(or very hard to detect) in 1-D 13C NMR spectra. This is due
to the system undergoing chemical exchange near the
coalescence point, and in these cases, 2-D HMBC spectra
were obtained in which the ‘missing peaks’ can be
detected.29
The crude product was then purified by column chromato-
graphy (ethyl acetate/hexanes mixture) using silica.
4.1.1. N-Cyclohexyl-N-phenylethynylcarbamic acid
methyl ester (3a). Following the above general procedure
(A) with bromoethynylbenzene 1a30 (298.9 mg,
1.651 mmol) and N-cyclohexylcarbamic acid methyl ester
2a (127.4 mg, 0.8106 mmol), copper iodide (8.9 mg,
0.047 mmol), 1,10-phenanthroline (20.7 mg, 0.115 mmol),
and KHMDS (0.5 M in toluene, 2.0 mL, 1.0 mmol). The
crude product was purified by column chromatography
(EtOAc/hexanesZ1:49) to provide 3a (89.3 mg,
0.347 mmol, 43%) as a yellow oil. Rf 0.47 (EtOAc/
4.1. Synthesis of ynamides
General procedure (A) for the synthesis of the ynamides. A
mixture of the amide (1.0 equiv), alkynyl halide (2.0 equiv),
copper iodide (0.2 equiv), 1,10-phenanthroline (0.25 equiv),
and toluene (w0.6 M w.r.t. the amide) was prepared in an
oven-dried round-bottomed flask, equipped with a con-
denser, under nitrogen. The mixture was heated at 90 8C and
potassium bis(trimethylsilyl)amide (KHMDS, 1.2 equiv,
0.5 M in toluene) was added slowly via a syringe pump
over 3–4 h. The reaction mixture was stirred at 90 8C for
12 h under nitrogen. The reaction mixture was diluted with
diethyl ether and subsequently washed three times with 2:1
mixture of saturated sodium chloride solution and con-
centrated NH4OH. The aqueous layer was extracted three
times with diethyl ether and the combined organic layers
were washed with saturated sodium chloride, dried over
MgSO4, filtered, and concentrated using rotary evaporation.
The crude product was then purified by column chroma-
tography (hexanes or ethyl acetate/hexanes mixture) using
silica gel pre-treated with triethylamine.
1
hexanesZ1:4); H NMR (CDCl3, 400 MHz) d 7.40–7.43
(m, 2H), 7.24–7.35 (m, 3H), 3.99 (br t, 1H, JZ12.0 Hz),
3.84 (s, 3H), 1.82–1.89 (m, 4H), 1.58–1.68 (m, 3H),
1.33–1.43 (m, 2H), 1.11–1.19 (m, 1H); 13C NMR (APT,
CDCl3, 100 MHz) d 155.4, 131.1, 128.2, 127.4, 123.4, 80.6,
72.3, 56.5, 53.9, 30.5, 25.3, 25.1. This is a known compound
and the spectral data are identical to those reported in the
literature.31
4.1.2. N-Phenylethyl-N-phenylethynylcarbamic acid
methyl ester (3b). Following the above general procedure
(A) with bromoethynylbenzene 1a30 (662 mg, 3.657 mmol)
and N-phenylcarbamic acid methyl ester 2b (209.5 mg,
1.169 mmol), copper iodide (16.7 mg, 0.088 mmol), 1,10-
phenanthroline (24.7 mg, 0.137 mmol), and KHMDS
(2.8 mL, 1.4 mmol). The crude product was purified by
column chromatography (EtOAc/hexanesZ1:99) to pro-
vide 3b (171 mg, 0.6121 mmol, 52%) as an orange oil. Rf
0.43 (EtOAc/hexanesZ1:9); 1H NMR (CDCl3, 400 MHz) d
7.26–7.47 (m, 10H), 3.87 (t, 2H, JZ7.8 Hz), 3.84 (s, 3H),
3.09 (t, 2H, JZ7.8 Hz); 13C NMR (CDCl3, 100 MHz) d
155.5, 137.9, 131.3, 128.9, 128.5, 128.2, 127.6, 126.6,
123.1, 82.7, 71.0, 54.0, 51.3, 34.1. This is a known
compound and the spectral data are identical to those
reported in the literature.2
General procedure (B) for the synthesis of the ynamides. To
a cold solution (0 8C) of the amide (1.0 equiv) in pyridine
(0.4 M) was added dropwise potassium bis(trimethylsilyl)-
amide (KHMDS, 1 equiv, 0.5 M in toluene). The reaction
was stirred for 15 min then a solution of copper iodide
(1.0 equiv) in pyridine was added via a cannula. The
resulting mixture was allowed to warm up to 25 8C and
stirred for 2 h. A solution of alkynyl halide (2.0 equiv) in
THF was added via cannula over 30 min and the resulting
mixture was stirred at room temperature for 20 h. The
reaction mixture was diluted with diethyl ether and washed
three times with 2:1 mixture of saturated sodium chloride
solution and concentrated NH4OH. The aqueous layer was
extracted three times with diethyl ether and the combined
organic layers were washed with saturated sodium chloride,
dried over MgSO4, filtered, and concentrated using rotary
evaporation. The crude product was then purified by column
chromatography (hexanes or ethyl acetate/hexanes mixture)
using silica gel treated with triethylamine.
4.1.3. N-Benzyl-N-phenylethynylcarbamic acid methyl
ester (3c). Following the above general procedure (A) with
bromoethynylbenzene 1a30 (476 mg, 2.623 mmol) and
N-benzylcarbamic acid methyl ester 2c (208.7 mg,
1.263 mmol), copper iodide (47.6 mg, 0.250 mmol), 1,10-
phenanthroline (59.8 mg, 0.332 mmol), and KHMDS
(3.0 mL, 1.5 mmol). The crude product was purified by
column chromatography (EtOAc/hexanesZ1:49) to pro-
vide 3c (205.7 mg, 0.7753 mmol, 61%) as a yellow oil. Rf
0.31 (EtOAc/hexanesZ1:9); 1H NMR (CDCl3, 400 MHz) d
7.25–7.42 (m, 10H), 4.71 (s, 2H), 3.85 (s, 3H); 13C NMR
(CDCl3, 100 MHz) d 155.5, 135.8, 131.1, 128.5, 128.1,
128.0, 127.5, 123.0, 82.9, 71.1, 54.1. This is a known
compound and the spectral data are identical to those
reported in the literature.32
General procedure (C) for the synthesis of the ynamides. To
a cold solution (0 8C) of the sulfonamide (1.0 equiv) in THF
(w0.4 M w.r.t. the amide) prepared in an oven-dried round-
bottomed flask under nitrogen was added dropwise a
solution of butyllithium in THF (2.5 M, 1.01 equiv). The
mixture was stirred at 0 8C for 15 min and aluminium
chloride (0.1 equiv) was added. The reaction mixture was
then added via cannula to a cold solution (0 8C) of
bromoalkyne (1.1 equiv) in THF (w0.8 M w.r.t. the
bromoalkyne). The reaction mixture was stirred 30 min at
0 8C and then allowed to warm to room temperature until
completion. The reaction mixture was quenched with water
and diluted with diethyl ether, and the water was
subsequently removed using Na2SO4. The organic layer
was filtered, and concentrated using rotary evaporation.
4.1.4. N-Phenyl-N-phenylethynylcarbamic acid methyl
ester (3e). Following the above general procedure (A) with
bromoethynylbenzene 1a30 (478.1 mg, 2.641 mmol) and
N-phenylcarbamic acid methyl ester 2a (209.2 mg,
1.384 mmol), copper iodide (57.3 mg, 0.301 mmol), 1,10-
phenanthroline (60.9 mg, 0.338 mmol), and KHMDS
(3.2 mL, 1.6 mmol). The crude product was purified by
column chromatography (EtOAc/hexanesZ1:49) to

K. Villeneuve et al. / Tetrahedron 62 (2006) 3823–3836
3829
provide 3e (225.6 mg, 0.8978 mmol, 65%) as a yellow oil.
Rf 0.32 (EtOAc/hexanesZ1:9); 1H NMR (CDCl3,
400 MHz) d 7.26–7.56 (m, 10H), 3.92 (s, 3H); 13C NMR
(CDCl3, 100 MHz) d 154.8, 139.5, 131.4, 129.0, 128.2,
127.8, 127.0, 124.6, 122.8, 82.7, 70.1, 54.4. This is a known
compound and the spectral data are identical to those
reported in the literature.33
129.0, 127.1, 127.0 (d, JZ2.4 Hz), 124.7, 124.6, 117.9 (d,
JZ22.8 Hz), 114.9 (d, JZ21.2 Hz), 83.7, 69.1 (d, JZ
3.0 Hz), 54.4. HRMS calcd for C16H12NO2F: m/z 269.0852,
found m/z 269.0845. Anal. Calcd for C16H12NO2F: C,
71.37; H, 4.49. Found C, 71.48; H, 4.30.
4.1.8. N-(3-Hydroxy-1-propynyl)-N-phenylcarbamic
acid methyl ester (3i). A solution of 3j (79.4 mg,
0.249 mmol) in THF (0.5 mL) was cooled to K78 8C
under nitrogen in a dry round-bottom flask. A solution of
TBAF (1 M in THF, 0.46 mL, 0.46 mmol) was added
dropwise and the resulting mixture was stirred for 1 h. The
reaction was quenched with water at K20 8C and the
aqueous layer was extracted with ethyl acetate three times.
The organic layers were combined, dried over MgSO4,
filtered, and concentrated to dryness. The crude product was
purified using flash chromatography (EtOAc/hexanesZ2:3)
to provide 3i (33.4 mg, 0.163 mmol, 65%) as a white solid
(mp 81–84 8C). Rf 0.48 (EtOAc/hexanesZ2:3); IR (CH2Cl2,
NaCl) 3052 (w), 2987 (w), 2305 (w), 2253 (w), 1740 (m),
1487 (w), 1442 (w), 1266 (s), 1016 (w), 888 (w), 739 (s); 1H
NMR (CDCl3, 400 MHz) d 7.36–7.45 (m, 4H), 7.28 (m,
1H), 4.43 (s, 2H), 3.85 (s, 3H), 2.11 (br s, 1H); 13C NMR
(CDCl3, 100 MHz) d 155.0, 139.2, 129.0, 127.2, 124.8,
79.4, 68.6, 54.4, 51.1. HRMS calcd for C11H11NO3: m/z
205.0739, found m/z 207.0745.
4.1.5. N-Phenyl-N-p-tolylethynylcarbamic acid methyl
ester (3f). Following the above general procedure (A) with
1-bromoethynyl-4-methylbenzene
1b30
(596 mg,
3.040 mmol) and N-phenylcarbamic acid methyl ester 2e
(231 mg, 1.528 mmol), copper iodide (64.2 mg,
0.337 mmol), 1,10-phenanthroline (74.9 mg, 0.416 mmol),
and KHMDS (3.6 mL, 1.8 mmol). The crude product was
purified by column chromatography (EtOAc/hexanesZ
1:24) to provide 3f (196.1 mg, 0.7391 mmol, 48%) as an
orange solid (mp 59–63 8C). Rf 0.39 (EtOAc/hexanesZ
1:9); IR (CH2Cl2, NaCl) 3045 (w), 2955 (w), 2252 (m),
1738 (s), 1595 (w), 1492 (m), 1439 (m), 1362 (m), 1289 (s),
1124 (w), 1052 (w), 738 (s); 1H NMR (CDCl3, 400 MHz) d
7.61–7.63 (m, 2H), 7.40–7.47 (m, 4H), 7.32 (m, 1H),
7.15–7.17 (m, 2H), 3.93 (s, 3H), 2.37 (s, 3H); 13C NMR
(CDCl3, 100 MHz) d 154.6, 139.5, 137.7, 131.2, 128.9,
128.8, 126.7, 124.4, 119.5, 81.9, 70.0, 54.1, 21.2. HRMS
calcd for C17H15NO2: m/z 265.1103, found m/z 265.1113.
Anal. Calcd for C17H15NO2: C, 76.96; H, 5.70. Found C,
76.80; H, 5.86.
4.1.9. N-[3-(tert-Butyldimethylsilyloxy)-1-propynyl]-
N-phenylcarbamic acid methyl ester (3j). Following
the above general procedure (A) with (3-bromoprop-
2-ynyloxy)-tert-butyldimethylsilane 1e34 (146.4 mg,
0.5874 mmol) and N-phenylcarbamic acid methyl ester 2e
(120.6 mg, 0.7984 mmol), copper iodide (49.7 mg,
0.261 mmol), 1,10-phenanthroline (49.6 mg, 0.275 mmol),
and KHMDS (2.0 mL, 1.0 mmol). The crude product was
purified by column chromatography (Et2O/pentaneZ1:9) to
provide 3j (51.4 mg, 0.161 mmol, 35%) as an orange oil. Rf
0.48 (EtOAc/hexanesZ1:4); IR (CH2Cl2, NaCl) 3054 (w),
2987 (w), 2955 (w), 2859 (w), 2305 (w), 2253 (w), 1739
(m), 1596 (w), 1440 (w), 1266 (s), 1075 (w), 896 (w), 735
(s); 1H NMR (CDCl3, 400 MHz) d 7.44–7.46 (m, 2H),
7.35–7.41 (m, 2H), 7.26 (m, 1H), 4.49 (s, 2H), 3.86 (s, 3H),
0.91 (s, 9H), 0.12 (s, 6H); 13C NMR (CDCl3, 100 MHz) d
154.9, 139.3, 128.8, 127.0, 124.6, 78.4, 68.9, 54.1, 51.8,
25.8, 18.2, K5.2. HRMS calcd for C17H25NO3Si: m/z
319.1604, found m/z 319.1611.
4.1.6. N-Phenyl-N-o-tolylethynylcarbamic acid methyl
ester (3g). Following the above general procedure (A) with
1-bromoethynyl-2-methylbenzene 1c17g (321.4 mg,
1.648 mmol) and N-phenylcarbamic acid methyl ester 2e
(129.6 mg, 0.8579 mmol), copper iodide (36.4 mg,
0.191 mmol), 1,10-phenanthroline (40.9 mg, 0.227 mmol),
and KHMDS (2.0 mL, 1.0 mmol). The crude product was
purified by column chromatography (EtOAc/hexanesZ
1:24) to provide 3g (89.5 mg, 0.337 mmol, 39%) as an
orange oil. Rf 0.39 (EtOAc/hexanesZ1:9); IR (CH2Cl2,
NaCl) 3054 (w), 2987 (w), 2305 (w), 2250 (w), 1738 (m),
1491 (w), 1439 (w), 1360 (w), 1266 (s), 896 (w), 739 (s); 1H
NMR (CDCl3, 400 MHz) d 7.43–7.46 (m, 2H), 7.25–7.30
(m, 3H), 7.15 (m, 1H), 6.99–7.06 (m, 3H), 3.77 (s, 3H), 2.30
(s, 3H); 13C NMR (CDCl3, 100 MHz) d 154.7, 139.5, 139.5,
131.1, 129.3, 128.9, 127.6, 126.9, 125.4, 124.4, 122.6, 86.6,
69.3, 54.3, 20.6. HRMS calcd for C17H15NO2: m/z
265.1103, found m/z 265.1109.
4.1.10. N-[4-(tert-Butyldimethylsilyloxy)-1-butynyl]-N-
phenylcarbamic acid methyl ester (3k). Following the
above general procedure (A) with 1f17g (156.1 mg,
0.5930 mmol) and N-phenylcarbamic acid methyl ester 2e
(66.1 mg, 0.438 mmol), copper iodide (20.8 mg,
0.109 mmol), 1,10-phenanthroline (18.4 mg, 0.102 mmol),
and KHMDS (0.75 mL, 0.38 mmol). The crude product was
purified by column chromatography (EtOAc/hexanesZ
1:24) to provide 3k (37.8 mg, 0.113 mmol, 26%) as a
yellow oil. Rf 0.38 (EtOAc/hexanesZ1:9); IR (CH2Cl2,
NaCl) 3054 (w), 2956 (w), 2930 (w), 2857 (w), 1737 (m),
1492 (w), 1440 (m), 1298 (m), 1266 (s), 1104 (w), 838 (w),
4.1.7. N-(m-Fluorophenylethynyl)-N-phenylcarbamic
acid methyl ester (3h). Following the above general
procedure (A) with 1-bromoethynyl-3-fluorobenzene 1d17g
(335 mg, 1.683 mmol) and N-phenylcarbamic acid methyl
ester 2e (133.7 mg, 0.8851 mmol), copper iodide (37.5 mg,
0.197 mmol), 1,10-phenanthroline (44.8 mg, 0.249 mmol),
and KHMDS (2.0 mL, 1.0 mmol). The crude product was
purified by column chromatography (EtOAc/hexanesZ
1:19) to provide 3h (129.4 mg, 0.4805 mmol, 54%) as an
orange solid (mp 26–27 8C). Rf 0.37 (EtOAc/hexanesZ
1:9); IR (CH2Cl2, NaCl) 3065 (w), 2955 (w), 2252 (s), 1738
(s), 1579 (m), 1490 (m), 1439 (m), 1363 (m), 1290 (s), 1053
(w), 940 (w), 738 (s); 1H NMR (CDCl3, 400 MHz) d 6.80–
7.39 (m, 9H), 3.75 (s, 3H); 13C NMR (CDCl3, 100 MHz) d
162.3 (d, JZ246.2 Hz), 154.5, 139.2, 129.7 (d, JZ8.7 Hz),
1
740 (s); H NMR (CDCl3, 400 MHz) d 7.39 (m, 2H), 7.30
(m, 2H), 7.19 (m, 1H), 3.78 (s, 3H), 3.67 (t, 2H, JZ7.0 Hz),
2.48 (t, 2H, JZ7.0 Hz), 0.81 (s, 9H), K0.02 (s, 6H); 13C
NMR (CDCl3, 100 MHz) d 155.2, 139.8, 128.8, 126.7,

3830
K. Villeneuve et al. / Tetrahedron 62 (2006) 3823–3836
124.6, 74.6, 66.8, 62.0, 54.1, 25.8, 22.9, 18.3, K5.3. HRMS
calcd for C18H27NO3Si: m/z 333.1760, found m/z 333.1752.
(s); 1H NMR (CDCl3, 400 MHz) d 7.39–7.45 (m, 4H), 7.34
(m, 1H), 4.24 (q, 2H, JZ7.1 Hz), 3.93 (s, 3H), 1.30 (t, 3H,
JZ7.1 Hz); 13C NMR (CDCl3, 100 MHz) d 154.2, 154.0,
137.7, 129.3, 128.1, 125.0, 81.4, 65.8, 61.7, 55.0, 14.1.
HRMS calcd for C13H13NO4: m/z 247.0845, found m/z
247.0852.
4.1.11. N-Phenyl-N-triisopropylsilylethynylcarbamic
acid methyl ester (3l). Following the above general
procedure (A) with bromoethynyltriisopropylsilane 1g35
(2.9332 g, 11.226 mmol) and N-phenylcarbamic acid
methyl ester 2e (1.4324 g, 9.4823 mmol), copper iodide
(0.5808 g, 3.050 mmol), 1,10-phenanthroline (615.7 mg,
3.417 mmol), and KHMDS (24.0 mL, 12.0 mmol). The
crude product was purified by column chromatography
(EtOAc/hexanesZ1:24) to provide 3l (2.8186 g,
8.5017 mmol, 90%) as a yellow oil. Rf 0.53 (EtOAc/
hexanesZ1:9); IR (CH2Cl2, NaCl) 3052 (w), 2949 (m),
2865 (m), 2305 (w), 2178 (m), 1740 (m), 1596 (w), 1492
4.1.14. Ethyl [benzyl-(toluene-4-sulfonyl)-amino]-pro-
pynoate (3o). Following the above general procedure
(C) with sulfonamide 9 (204.1 mg, 0.781 mmol), THF
(2.0 mL), BuLi (0.37 mL, 0.93 mmol), AlCl3 (11.1 mg,
0.0832 mmol), alkynyl bromide 1036 (190.3 mg,
1.075 mmol) and THF (1.0 mL). The reaction mixture was
stirred at 25 8C for 1.5 h. The crude product was purified by
column chromatography (gradient EtOAc/hexanesZ1:19–
3:7) to provide ynamide 3o (171.0 mg, 0.4784 mmol, 61%)
as a colorless oil. Rf 0.26 (EtOAc/hexanesZ3:7); IR
(CH2Cl2, NaCl) 3090 (w), 3066 (w), 3034 (w), 2983 (m),
1
(w), 1440 (m), 1266 (s), 1055 (w), 881 (w), 740 (s); H
NMR (CDCl3, 400 MHz) d 7.56 (m, 2H), 7.41 (m, 2H), 7.29
(m, 1H), 3.90 (s, 3H), 1.14 (s, 21H); 13C NMR (CDCl3,
100 MHz) d 154.8, 139.2, 128.7, 126.5, 123.9, 96.2, 68.9,
54.0, 18.5, 11.3. HRMS calcd for C19H29NO2Si: m/z
331.1968, found m/z 331.1977. Anal. Calcd for
C19H29NO2Si: C, 68.83; H, 8.82. Found C, 68.72; H, 8.99.
2937 (m), 2219 (vs), 1704 (vs), 1374 (vs), 1165 (vs) cmK1
;
1H NMR (CDCl3, 400 MHz) d 7.73 (d, 2H, JZ8.4 Hz),
7.27–7.34 (m, 7H), 4.63 (s, 2H), 4.19 (q, 2H, JZ7.1 Hz),
2.45 (s, 3H), 1.29 (t, 3H, JZ7.1 Hz); 13C NMR (APT,
CDCl3, 100 MHz) d 153.9, 145.4, 134.2, 133.5, 129.8,
128.6, 127.7, 82.6, 68.0, 61.5, 55.4, 21.6, 14.1. HRMS (EI)
calcd for C19H19NO4S (MC): 357.1035; found: 357.1039.
4.1.12. N-Ethynyl-N-phenylcarbamic acid methyl ester
(3m). A solution of 3l (2.6024 g, 7.8497 mmol) in THF
(15 mL) was cooled to K78 8C under nitrogen in a dry
round-bottom flask. A solution of TBAF (1 M in THF,
15.0 mL, 15.0 mmol) was added dropwise and the resulting
mixture was stirred for 1 h. The reaction was quenched with
water at K20 8C and the aqueous layer was extracted with
ethyl acetate three times. The organic layers were
combined, dried over MgSO4, filtered, and concentrated to
dryness. The crude product was purified using flash
chromatography (EtOAc/hexanesZ1:24) to provide 3m
(1.0451 g, 5.9658 mmol, 76%) as a white solid (mp 48–
50 8C). Rf 0.38 (EtOAc/hexanesZ1:9); IR (CH2Cl2, NaCl)
3312 (w), 3055 (w), 2987 (w), 2306 (w), 2148 (w), 1742
(w), 1493 (w), 1440 (w), 1299 (w), 1266 (s), 896 (w), 738
4.1.15. (S)-4-(tert-Butyldimethylsilyloxymethyl)oxazo-
lidin-2-one (6). To a solution of (S)-4-hydroxymethyl-
oxazolidin-2-one 523 (1.16 g, 9.91 mmol) in CH2Cl2
(15 mL) were successively added triethylamine (1.50 mL,
10.8 mmol), 4-(N,N-dimethylamino)pyridine (DMAP,
70.3 mg, 0.575 mmol) and tert-butyl(chloro)dimethylsilane
(TBSCl, 2.04 g, 13.5 mmol). The reaction mixture was
stirred for 16 h at 25 8C under N2 then quenched with of
water (1 mL). Magnesium sulfate was added and the
mixture was filtered, and the filtrate was concentrated to
dryness. The crude product was purified by column
chromatography (EtOAc/hexanesZ3:2) to give the product
6 (1.84 g, 7.95 mmol, 80%) as a semi-solid. [a]2D3 C26 (c
0.59, CH2Cl2); Rf 0.55 (EtOAc); IR (neat) 3327 (s), 2956
1
(s), 705 (m); H NMR (CDCl3, 400 MHz) d 7.47 (m, 2H),
7.34 (m, 2H), 7.29 (m, 1H), 3.89 (s, 3H), 2.92 (s, 1H); 13C
NMR (CDCl3, 100 MHz) d 154.8, 138.8, 129.0, 127.2,
124.6, 76.2, 58.5, 54.4. HRMS calcd for C10H9NO2: m/z
175.0633, found m/z 175.0631.
1
(s), 2936 (s), 1748 (s), 1253 (s) cmK1; H NMR (CDCl3,
400 MHz) d 6.30 (br s, 1H), 4.42 (app t, 1H, JZ8.6 Hz),
4.18 (dd, 1H, JZ8.7, 4.8 Hz), 3.89–3.92 (m, 1H), 3.59 (d,
2H, JZ5.4 Hz), 0.87 (s, 9H), 0.05 (s, 6H); 13C NMR (APT,
CDCl3, 100 MHz) d 160.0, 67.1, 64.6, 53.6, 25.7, 18.1,
K5.6. HRMS (m/z) for C10H21NO3Si calcd 231.1291, found
231.1299.
4.1.13. N-Ethoxycarbonylethynyl-N-phenylcarbamic
acid methyl ester (3n). In a dry round-bottom flask, at
K78 8C and under a flow of nitrogen, LiHMDS (1 M in
THF, 1.85 mL, 1.85 mmol) was added dropwise to a
solution of 3m (186.4 mg, 1.064 mmol) in THF (8.5 mL).
The reaction mixture was allowed to warm slowly to
K40 8C and then stirred for 1 h. The reaction mixture was
then added to a solution of ethyl chloroformate (0.165 mL,
1.73 mmol) in THF (2.9 mL) at K40 8C via a cannula. The
reaction was quenched with a saturated NH4Cl solution and
the aqueous layer was extracted three times with ethyl
acetate. The organic layers were combined, dried over
MgSO4, filtered, and concentrated to dryness. The crude
product was purified using flash chromatography (EtOAc/
hexanesZ1:9) to provide 3n (29.1 mg, 0.118 mmol, 11%)
as a white solid (mp 82–84 8C). Rf 0.36 (EtOAc/hexanesZ
1:4); IR (CH2Cl2, NaCl) 3056 (w), 2981 (w), 2955 (w), 2237
(s), 1754 (s), 1705 (s), 1595 (w), 1492 (w), 1440 (m), 1288
(m), 1266 (s), 1197 (m), 1158 (m), 1025 (w), 896 (w), 740
4.1.16.
(S)-4-(tert-Butyldimethylsilyloxymethyl)-3-
phenylethnyloxazolidin-2-one (7). Following the above
general procedure (A) with alkynyl bromide 1a (1.095 g,
6.049 mmol) and 6 (900.3 mg, 3.891 mmol), copper iodide
(303.3 mg, 1.593 mmol), 1,10-phenanthroline (295.7 mg,
1.641 mmol), and KHMDS (0.5 M in toluene, 12.4 mL,
6.2 mmol). The crude product was purified by
column chromatography (EtOAc/hexanesZ1:4) to give
the ynamide 7 (592.6 mg, 1.788 mmol, 46%) as a semi-
solid. [a]2D3 K94 (c 0.30, CH2Cl2); Rf 0.56 (EtOAc/
hexanesZ2:3); IR (neat) 2961 (m), 2937 (m), 2251 (m),
1
1777 (s), 1414 (s) cmK1; H NMR (CDCl3, 400 MHz) d
7.43 (m, 2H), 7.30 (m, 3H), 4.48 (app t, 1H, JZ8.6 Hz),
4.43 (dd, 1H, JZ8.5, 5.2 Hz), 4.10–4.13 (m, 1H), 4.04
(dd, 1H, JZ11.3, 3.0 Hz), 3.72 (d, 1H, JZ11.3 Hz), 0.89

K. Villeneuve et al. / Tetrahedron 62 (2006) 3823–3836
3831
(s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (APT, CDCl3,
100 MHz) d 155.8, 131.6, 128.2, 128.1, 122.1, 77.8, 72.2,
65.4, 60.5, 58.6, 25.6, 18.0, K5.6. HRMS (m/z) for
C18H25NO3Si calcd 331.1604, found 331.1620.
(s, 3H); 13C NMR (APT, CDCl3, 100 MHz) d 131.7, 128.1,
127.8, 122.6, 76.7, 72.6, 67.2, 51.2, 49.8, 48.0, 44.4, 34.4,
31.6, 27.0, 20.2, 19.9. HRMS (m/z) for C18H21NO2S calcd
315.1293, found 315.1273. Anal. Calcd for C18H21NO2SZ
C, 68.54%; H, 6.71%; found C, 68.79%; H, 6.66%.
4.1.17. (S)-4-Hydroxymethyl-3-phenylethynyl-oxazoli-
din-2-one (8). To a cold solution (K78 8C) of 7
(500.1 mg, 1.508 mmol) in THF (3 mL) under N2 was
slowly added a solution of tetrabutylammonium fluoride
(1 M in THF, 3.0 mL, 3.0 mmol). After 30 min, the reaction
was quenched with saturated NH4Cl solution (3 mL) and
diluted with EtOAc. Layers were separated and aqueous
layer was extracted three times with EtOAc. Organics were
combined, dried over sodium sulfate and concentrated. The
crude product was purified by column chromatography
(EtOAc/hexanesZ2:3) to give ynamide 8 (142.3 mg,
0.6551 mmol, 48%) as a solid (mp 109–112 8C).
[a]2D3 K63 (c 0.40, CH2Cl2); Rf 0.13 (EtOAc/hexanesZ
2:3); IR (neat) 2942 (w), 2978 (w), 2253 (m), 1753 (s), 1414
(s) cmK1; 1H NMR (CDCl3, 400 MHz) d 7.42–7.26 (m, 2H),
7.29–7.33 (m, 3H), 4.46–4.56 (m, 2H), 4.16–4.22 (m, 1H),
4.11 (dd, 1H, JZ12.2, 3.5 Hz), 3.81 (d, 1H, JZ11.8 Hz),
2.06 (br s, 1H); 13C NMR (APT, CDCl3, 100 MHz) d 156.1,
131.5, 128.3, 121.9, 77.4, 72.5, 65.5, 60.1, 58.6. HRMS (m/z)
for C12H11NO3 calcd 217.0739, found 217.0729.
4.2. Ruthenium-catalyzed [2D2] cycloaddition
General procedure (D) for the Ru-catalyzed [2C2]
cycloaddition between bicyclic alkenes and ynamides. A
mixture of bicyclic alkene (2.5–5 equiv), ynamide (1 equiv)
and THF (0.2–0.5 M w.r.t. the ynamide) 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 dry box,
5–10 mol%) under nitrogen. The reaction mixture was
stirred in the dark at 25 or 65 8C for 68–168 h. The crude
product was purified by column chromatography to give the
cycloadduct.
4.2.1. Cycloadduct 5a. Following the above general
procedure (D) with norbornene 4a (15.8 mg, 0.168 mmol),
ynamide 3a (16.6 mg, 0.0645 mmol), THF (0.3 mL), and
Cp*RuCl(COD) (6.2 mg, 0.016 mmol). The reaction mix-
ture was stirred in the dark at 60 8C for 168 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ1:49) to provide cycloadduct 5a (12.4 mg,
0.0354 mmol, 55%) as a slightly yellow oil. Rf 0.48
(EtOAc/hexanesZ1:9); IR (CH2Cl2, NaCl) 3052 (m),
2987 (w), 2942 (w), 2305 (w), 1693 (m), 1442 (m), 1422
4.1.18. (D)-3-Phenylethynyl-3,3a,8,8a-tetrahydroin-
deno[1,2-d]oxazol-2-one (24). Following the above general
procedure (B) with bromoethynylbenzene 1a (631.2 mg,
1
(m), 1266 (s), 894 (w), 740 (s) cmK1; H NMR (CDCl3,
3.487 mmol) and (C)-2-azabicyclo[2.2.1]heptan-3-one37
(199.3 mg, 1.861 mmol), copper iodide (354.1 mg,
1.859 mmol), and KHMDS (0.5 M in toluene, 3.6 mL,
1.8 mmol). The crude mixture was the purified by column
chromatography (EtOAc/hexanesZ1:4) affording the yna-
mide 24 (181.9 mg, 0.8615 mmol, 46%) as a solid (mp 73–
77 8C). [a]2D3 C52 (c 0.37, CH2Cl2); Rf 0.45 (EtOAc/
hexanesZ3:7); IR (neat) 3052 (w), 2987 (w), 2246 (m),
400 MHz) d 7.28–7.29 (m, 4H), 7.20 (m, 1H), 3.93 (m, 1H),
3.59 (s, 3H), 2.74 (d, 1H, JZ3.5 Hz), 2.60 (d, 1H,
JZ3.5 Hz), 2.30 (br s, 1H), 2.09 (br s, 1H), 1.90 (m, 1H),
1.72–1.82 (m, 4H), 1.51–1.66 (m, 5H), 1.26–1.37 (m, 2H),
1.06–1.19 (m, 3H), 0.99 (m, 1H); 13C NMR (CDCl3,
150 MHz) d 154.7, 136.8, 133.7, 131.3, 128.1, 127.3, 126.4,
57.4, 52.7, 52.4, 43.9, 35.2, 34.2, 32.0, 31.1, 30.8, 28.6,
28.4, 26.0, 25.9, 25.5. HRMS calcd for C23H29NO2: m/z
351.2198, found m/z 351.2189.
1727 (s), 1397 (s), 1266 (vs) cmK1 1H NMR (CDCl3,
;
400 MHz) d 7.36–7.40 (m, 2H), 7.20–7.27 (m, 3H), 4.15 (br
s, 1H), 2.85 (m, 1H), 2.03 (dm, 1H, JZ9.9 Hz), 1.81–1.97
(m, 3H), 1.67–1.74 (m, 1H), 1.47 (dm, 1H, JZ9.9 Hz); 13C
NMR (APT, CDCl3, 100 MHz) d 177.7, 131.2, 128.1, 127.6,
122.7, 79.4, 72.2, 64.4, 44.1, 39.0, 27.6, 24.1. HRMS (m/z)
for C14H13NO calcd 211.0997, found 211.0991. Anal. Calcd
for C14H13NOZC, 79.59%; H, 6.20%; found C, 79.70%; H,
6.08%.
4.2.2. Cycloadduct 5b. Following the above general
procedure (D) with norbornene 4a (43.4 mg, 0.461 mmol),
ynamide 3b (26.9 mg, 0.0963 mmol), THF (0.3 mL), and
Cp*RuCl(COD) (4.5 mg, 0.012 mmol). The reaction mix-
ture was stirred in the dark at 60 8C for 72 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ1:49) to provide cycloadduct 5b (26.1 mg,
0.0698 mmol, 73%) as a yellow oil. Rf 0.34 (EtOAc/
hexanesZ1:9); IR (CH2Cl2, NaCl) 2950 (w), 2865 (w),
1711 (m), 1648 (w), 1493 (w), 1447 (m), 1390 (w), 1313
4.1.19. (L)-10,10-Dimethyl-4-phenylethynyl-3-thia-4-
aza-tricyclo[5.2.1.01,5]decane-3,3-dioxide (25). Following
the above general procedure (B) with bromoethynylbenzene
1a (69.4 mg, 0.383 mmol) and (1S)-(K)-2,10-camphor-
sultam (41.1 mg, 0.191 mmol), copper iodide (37.4 mg,
0.196 mmol), and KHMDS (0.5 M in toluene, 0.38 mL,
0.19 mmol). The crude mixture was the purified by column
chromatography (EtOAc/hexanesZ1:4) affording the yn-
amide 10f (41.5 mg, 0.132 mmol, 69%) as a pale yellow oil.
[a]2D3 K146 (c 0.52, CH2Cl2); Rf 0.41 (EtOAc/hexanesZ
3:7); IR (neat) 3058 (w), 3000 (m), 2962 (s), 2237 (s),
1
(w), 1203 (w), 765 (w), 694 (w) cmK1; H NMR (CDCl3,
400 MHz) d 7.13–7.34 (m, 10H), 3.80 (m, 1H), 3.68 (s, 3H),
3.60 (m, 1H), 2.83–2.99 (m, 2H), 2.74 (br s, 1H), 2.59 (d,
1H, JZ3.2 Hz), 2.32 (s, 1H), 2.14 (br s, 1H), 1.61–1.70 (m,
3H), 1.07–1.22 (m, 3H); 13C NMR (CDCl3, 150 MHz) d
155.1, 138.6, 134.1, 132.3, 130.7, 128.8, 128.4, 128.0,
126.9, 126.3, 52.6, 50.0, 48.6, 44.0, 35.4, 35.2, 34.5, 30.6,
28.4, 28.2. HRMS calcd for C25H27NO2: m/z 373.2042,
found m/z 373.2051.
1
1336 (s), 1146 (s) cmK1; H NMR (CDCl3, 400 MHz) d
7.40–7.44 (m, 2H), 7.27–7.29 (m, 3H), 3.68 (dd, 1H, JZ8.1,
4.1 Hz), 3.29 (s, 2H), 2.29 (dd, 1H, JZ13.4, 3.0 Hz), 1.98
(m, 1H), 1.89–1.93 (m, 2H), 1.82 (dd, 1H, JZ13.4, 8.2 Hz),
1.43–1.46 (m, 1H), 1.33–1.36 (m, 1H), 1.15 (s, 3H), 0.96
4.2.3. Cycloadduct 5c. Following the above general
procedure (D) with norbornene 4a (31.7 mg, 0.337 mmol),
ynamide 3c (31.9 mg, 0.120 mmol), THF (0.3 mL), and

3832
K. Villeneuve et al. / Tetrahedron 62 (2006) 3823–3836
Cp*RuCl(COD) (4.9 mg, 0.013 mmol). The reaction mix-
ture was stirred in the dark at 60 8C for 72 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ1:49) to provide cycloadduct 5c (39.4 mg,
0.110 mmol, 91%) as an orange solid (mp 55–60 8C). Rf
0.34 (EtOAc/hexanesZ1:9); IR (CH2Cl2, NaCl) 3054 (w),
2953 (m), 2871 (w), 2305 (w), 1710 (s), 1648 (m), 1494 (w),
mixture was stirred in the dark at 60 8C for 168 h. The
crude product was purified by column chromatography
(EtOAc/hexanesZ1:24) to provide cycloadduct 5f
(48.0 mg, 0.134 mmol, 85%) as a yellow solid (mp 69–
75 8C). Rf 0.36 (EtOAc/hexanesZ1:9); IR (CH2Cl2, NaCl)
3052 (m), 2954 (m), 2871 (m), 2350 (w), 2298 (w), 1714 (s),
1597 (m), 1492 (m), 1440 (m), 1266 (s), 1062 (m), 894 (w),
734 (s) cmK1; 1H NMR (CDCl3, 400 MHz) d 7.24–7.31 (m,
4H), 7.18 (m, 1H), 6.99–7.06 (m, 4H), 3.65 (s, 3H), 2.59 (d,
1H, JZ3.5 Hz), 2.54 (d, 1H, JZ3.6 Hz), 2.26 (s, 3H), 2.25
(br s, 1H), 1.84 (d, 1H, JZ3.6 Hz), 1.43–1.65 (m, 3H),
0.94–1.13 (m, 3H); 13C NMR (CDCl3, 150 MHz) d 154.4,
139.8, 136.9, 132.0, 130.8, 130.6, 128.9, 128.7, 126.7,
126.5, 53.0, 49.7, 43.8, 35.4, 34.3, 30.8, 28.5, 28.2, 21.3.
HRMS calcd for C24H25NO2: m/z 359.1885, found m/z
359.1896.
1
1447 (m), 1265 (s), 974 (w), 896 (w), 738 (s) cmK1; H
NMR (CDCl3, 400 MHz) d 7.21–7.33 (m, 10H), 4.83 (d, 1H,
JZ15.3 Hz), 4.62 (d, 1H, JZ15.4 Hz), 3.70 (s, 3H), 2.71 (br
s, 1H), 2.54 (d, 1H, JZ3.4 Hz), 2.26 (s, 1H), 2.00 (br s, 1H),
1.53–1.64 (m, 2H), 1.40 (m, 1H), 1.06–1.17 (m, 2H), 0.91
(m, 1H); 13C NMR (CDCl3, 150 MHz) d 155.6, 138.1,
134.3, 132.2, 130.5, 128.3, 128.0, 127.4, 127.2, 126.9, 52.9,
50.1, 50.0, 44.1, 35.2, 34.4, 30.4, 28.4, 28.1. HRMS calcd
for C24H25NO2: m/z 359.1885, found m/z 359.1892.
4.2.4. Cycloadduct 5d. Following the above general
procedure (D) with norbornene 4a (72.6 mg, 0.771 mmol),
ynamide 3c (32.5 mg, 0.106 mmol), THF (0.3 mL), and
Cp*RuCl(COD) (4.3 mg, 0.011 mmol). The reaction mix-
ture was stirred in the dark at 25 8C for 168 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ1:49) to provide cycloadduct 5d (31.8 mg,
0.0792 mmol, 75%) as a colorless oil. Rf 0.63 (EtOAc/
hexanesZ1:4); IR (CH2Cl2, NaCl) 2949 (m), 2865 (w),
1698 (s), 1383 (m), 1364 (m), 1313 (m), 1248 (w), 1161 (m),
4.2.7. Cycloadduct 5g. Following the above general
procedure (D) with norbornene 4a (38.7 mg, 0.411 mmol),
ynamide 3g (38.6 mg, 0.146 mmol), THF (0.3 mL), and
Cp*RuCl(COD) (6.3 mg, 0.017 mmol). The reaction mix-
ture was stirred in the dark at 60 8C for 168 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ1:9) to provide cycloadduct 5g (26.7 mg,
0.0742 mmol, 51%) as pale yellow oil. Rf 0.53 (EtOAc/
hexanesZ1:4); IR (CH2Cl2, NaCl) 3054 (m), 2954 (m),
1718 (m), 1597 (w), 1491 (w), 1440 (m), 1348 (m), 1266 (s),
896 (w), 740 (s) cmK1; 1H NMR (CDCl3, 400 MHz) d 7.21–
7.25 (m, 2H), 7.13–7.18 (m, 3H), 6.99–7.04 (m, 4H), 3.48
(s, 3H), 2.70 (d, 1H, JZ3.0 Hz), 2.60 (d, 1H, JZ3.4 Hz),
2.25 (s, 3H), 2.17 (br s, 1H), 1.85 (br s, 1H), 1.74 (d, 1H, JZ
10.1 Hz), 1.48–1.56 (m, 2H), 1.00–1.07 (m, 3H); 13C NMR
(CDCl3, 150 MHz) d 154.4, 139.0, 136.0, 135.4, 132.9,
129.6, 128.6, 127.7, 127.6, 127.0, 126.5, 124.8, 52.7, 49.7,
46.9, 35.6, 34.9, 30.6, 28.2, 28.1, 20.5. HRMS calcd for
C24H25NO2: m/z 359.1885, found m/z 359.1880.
1
688 (w) cmK1; H NMR (CDCl3, 400 MHz) d 7.13–7.25
(m, 10H), 4.79 (d, 1H, JZ15.0 Hz), 4.46 (d, 1H, JZ
15.4 Hz), 2.68 (br s, 1H), 2.43 (br s, 1H), 2.23 (br s, 1H),
1.93 (br s, 1H), 1.50–1.54 (m, 2H), 1.36 (d, 1H, JZ
10.1 Hz), 1.28 (s, 9H), 1.02–1.08 (m, 2H), 0.84 (d, 1H, JZ
10.1 Hz); 13C NMR (CDCl3, 150 MHz) d 153.8, 138.7,
135.0, 132.6, 129.6, 128.3, 127.8, 127.3, 127.0, 126.6, 80.9,
50.2, 49.4, 44.3, 35.6, 34.3, 30.4, 28.5, 28.2, 28.1. HRMS
calcd for C27H31NO2: m/z 401.2355, found m/z 401.2330.
Anal. Calcd for C27H31NO2: C, 80.76; H, 7.78. Found C,
80.65; H, 7.89.
4.2.8. Cycloadduct 5h. Following the above general
procedure (D) with norbornene 4a (35.0 mg, 0.372 mmol),
ynamide 3h (31.0 mg, 0.115 mmol), THF (0.3 mL), and
Cp*RuCl(COD) (5.6 mg, 0.015 mmol). The reaction mix-
ture was stirred in the dark at 60 8C for 168 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ1:19) to provide cycloadduct 5h (24.3 mg,
0.0668 mmol, 58%) as a yellow oil. Rf 0.38 (EtOAc/
hexanesZ1:9); IR (CH2Cl2, NaCl) 3054 (m), 2954 (m),
2872 (w), 2298 (w), 1718 (m), 1610 (w), 1596 (w), 1581
(w), 1494 (w), 1440 (m), 1348 (m), 1266 (s), 1062 (w), 851
(w), 739 (s) cmK1; 1H NMR (CDCl3, 400 MHz) d 7.24–7.28
(m, 2H), 7.14–7.20 (m, 3H), 7.07 (m, 1H), 6.66–6.82 (m,
3H), 3.64 (s, 3H), 2.63 (d, 1H, JZ3.6 Hz), 2.50 (d, 1H, JZ
3.6 Hz), 2.22 (d, 1H, JZ3.5 Hz), 1.86 (d, 1H, JZ3.4 Hz),
1.47–1.59 (m, 3H), 0.96–1.10 (m, 3H); 13C NMR (CDCl3,
150 MHz) d 162.5 (d, JZ244.8 Hz), 154.1, 139.4, 135.8 (d,
JZ7.2 Hz), 133.1, 129.2 (d, JZ7.4 Hz), 129.0, 128.8,
127.0, 126.9, 122.4, 113.6 (d, JZ21.4 Hz), 113.4 (d, JZ
21.7 Hz), 53.1, 50.0, 44.2, 35.5, 34.3, 30.7, 28.4, 28.2.
HRMS calcd for C23H22NO2F: m/z 363.1635, found m/z
363.1643.
4.2.5. Cycloadduct 5e. Following the above general
procedure (D) with norbornene 4a (36.6 mg, 0.389 mmol),
ynamide 3e (32.5 mg, 0.129 mmol), THF (0.3 mL), and
Cp*RuCl(COD) (5.2 mg, 0.014 mmol). The reaction mix-
ture was stirred in the dark at 60 8C for 72 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ1:49) to provide cycloadduct 5e (43.3 mg,
0.125 mmol, 97%) as a pale yellow solid (mp 66–69 8C).
Rf 0.36 (EtOAc/hexanesZ1:9); IR (CH2Cl2, NaCl) 3054
(w), 2955 (w), 2865 (w), 2363 (w), 2305 (w), 1715 (m),
1596 (w), 1493 (w), 1442 (w), 1266 (s), 894 (w), 741
1
(s) cmK1; H NMR (CDCl3, 400 MHz) d 7.18–7.38 (m,
10H), 3.73 (s, 3H), 2.70 (d, 1H, JZ3.4 Hz), 2.64 (d, 1H, JZ
3.5 Hz), 2.35 (d, 1H, JZ3.6 Hz), 1.95 (d, 1H, JZ3.5 Hz),
1.55–1.73 (m, 2H), 0.92–1.30 (m, 4H); 13C NMR (CDCl3,
150 MHz) d 158.0, 154.4, 139.6, 133.6, 131.7, 128.9, 127.9,
127.0, 126.8, 126.7, 126.6, 53.0, 49.8, 44.0, 35.5, 34.3, 30.8,
28.4, 28.2. HRMS calcd for C23H23NO2: m/z 345.1729,
found m/z 345.1722.
4.2.6. Cycloadduct 5f. Following the above general
procedure (D) with norbornene 4a (60.2 mg, 0.639 mmol),
ynamide 3f (41.5 mg, 0.156 mmol), THF (0.3 mL), and
Cp*RuCl(COD) (8.7 mg, 0.023 mmol). The reaction
4.2.9. Cycloadduct 5i. Following the above general
procedure (D) with norbornene 4a (44.6 mg, 0.474 mmol),
ynamide 3i (24.5 mg, 0.119 mmol), THF (0.3 mL), and

K. Villeneuve et al. / Tetrahedron 62 (2006) 3823–3836
3833
Cp*RuCl(COD) (7.3 mg, 0.019 mmol). The reaction mix-
ture was stirred in the dark at 60 8C for 72 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ1:4) to provide cycloadduct 5i (11.6 mg,
0.0387 mmol, 32%) as a yellow oil. Rf 0.35 (EtOAc/
hexanesZ2:3); IR (CH2Cl2, NaCl) 3052 (m), 2955 (m),
2871 (w), 1712 (m), 1596 (w), 1493 (w), 1442 (m), 1313
product was purified by column chromatography (EtOAc/
hexanesZ1:4) to provide cycloadduct 13 (54.6 mg,
0.107 mmol, 90%) as a white solid (mp 112–114 8C). Rf
0.13 (EtOAc/hexanesZ1:4); IR (CH2Cl2, NaCl) 3054 (w),
3027 (w), 2985 (w), 2954 (w), 1760 (vs), 1722 (vs), 1204
(vs), 1155 (vs) cmK1; 1H NMR (CDCl3, 300 MHz) d 7.19–
7.40 (m, 10H), 6.80 (ABq, 2H, JZ9.0, 2.4 Hz), 3.76 (s, 3H),
3.27 (br s, 1H), 2.94–2.96 (m, 2H), 2.87 (br s, 1H), 2.38 (s,
3H), 2.28 (s, 3H), 2.13 (d, 1H, JZ9.8 Hz), 1.78 (d, 1H, JZ
9.7 Hz); 13C NMR (APT, CDCl3, 75 MHz) d 169.1, 169.0,
154.1, 142.34, 142.29, 141.0, 140.7, 139.4, 132.9, 132.6,
129.6, 129.0, 127.9, 127.3, 127.05, 127.02, 126.8, 120.10,
120.06, 53.1, 47.2, 41.5, 40.8, 39.1, 20.9, 20.7. HRMS (CI)
calcd for C31H27NO6 ((MCH)C): 510.1917; found:
510.1923. Anal. Calcd for C31H27NO6ZC, 73.07%; H,
5.34%; foundZC, 73.40%; H, 5.21%.
1
(m), 1266 (s), 1055 (w), 894 (w), 740 (s) cmK1; H NMR
(CDCl3, 400 MHz) d 7.32–7.42 (m, 3H), 7.20–7.22 (m, 2H),
3.74 (m, 1H), 3.70 (s, 3H), 3.66 (m, 1H), 2.50 (br s, 1H),
2.27 (d, 1H, JZ3.3 Hz), 2.08 (d, 1H, JZ3.3 Hz), 1.77 (br s,
1H), 1.43–1.52 (m, 3H), 0.07–1.04 (m, 3H); 13C NMR
(CDCl3, 150 MHz) d 154.6, 139.2, 132.9, 129.2, 128.0,
127.9, 125.4, 57.6, 53.3, 49.3, 44.2, 35.0, 34.1, 30.3, 28.1,
27.9. HRMS calcd for C18H21NO3: m/z 299.1521, found m/z
299.1530.
4.2.10. Cycloadduct 5j. Following the above general
procedure (D) with norbornene 4a (24.8 mg, 0.263 mmol),
ynamide 3j (21.0 mg, 0.0657 mmol), THF (0.3 mL), and
Cp*RuCl(COD) (5.9 mg, 0.016 mmol). The reaction mix-
ture was stirred in the dark at 60 8C for 72 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ1:9) to provide cycloadduct 5j (6.8 mg,
0.016 mmol, 25%) as a yellow oil. Rf 0.58 (EtOAc/
hexanesZ1:4); IR (CH2Cl2, NaCl) 3052 (w), 2981 (w),
2949 (w), 2305 (w), 1719 (w), 1442 (w), 1422 (w), 1266 (s),
4.2.13. Cycloadduct 14. Following the above general
procedure (D) with alkene 4e (32.9 mg, 0.135 mmol),
ynamide 3e (22.7 mg, 0.0903 mmol), THF (0.3 mL), and
Cp*RuCl(COD) (4.1 mg, 0.011 mmol). The reaction mix-
ture was stirred in the dark at 60 8C for 72 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ3:7) to provide cycloadduct 14 (20.4 mg,
0.0412 mmol, 46%) as a white solid (mp 152–153 8C). Rf
0.42 (EtOAc/hexanesZ3:7); IR (CH2Cl2, NaCl) 3060 (w),
2968 (w), 1729 (s), 1691 (s) cmK1 1H NMR (CDCl3,
;
1036 (w), 894 (w), 740 (s) cmK1
;
1H NMR (CDCl3,
300 MHz) d 7.05–7.41 (m, 12H), 6.66–6.93 (m, 2H), 5.11
(m, 2H), 3.77 (s, 3H), 3.19 (br d, 1H, JZ3.5 Hz), 2.74 (br s,
1H), 1.36 (s, 3H), 1.25 (s, 6H). HRMS (CI) calcd for
C31H30N2O4 ((MCH)C): 495.2284; found: 495.2280. Anal.
Calcd for C31H30N2O4ZC, 75.28%; H, 6.11%; foundZC,
75.55%; H, 6.01%.
400 MHz) d 7.37–7.40 (m, 2H), 7.33 (m, 1H), 7.20–7.22
(m, 2H), 3.70 (s, 3H), 3.48 (d, 1H, JZ13.6 Hz), 3.38 (d, 1H,
JZ13.6 Hz), 2.73 (br s, 1H), 2.29 (d, 1H, JZ3.1 Hz), 2.07
(br s, 1H), 2.02 (br s, 1H), 1.51–1.53 (m, 3H), 0.96–1.04 (m,
3H), 0.81 (s, 9H), K0.07 (s, 3H), K0.09 (s, 3H); 13C NMR
(CDCl3, 150 MHz) d 154.1, 139.8, 132.3, 130.5, 129.2,
128.1, 127.6, 57.4, 52.9, 49.7, 44.2, 35.3, 34.4, 30.4, 28.1,
28.1, 25.9, 18.3, K5.4. HRMS calcd for C24H35NO3Si: m/z
413.2386, found m/z 413.2391.
4.2.14. Cycloadduct 15. Following the above general
procedure (D) with alkene 4f (47.0 mg, 0.326 mmol),
ynamide 3e (26.5 mg, 0.105 mmol), THF (0.3 mL), and
Cp*RuCl(COD) (4.6 mg, 0.012 mmol). The reaction mix-
ture was stirred in the dark at 60 8C for 72 h. The crude
product was purified by column chromatography (gradient
EtOAc/hexanesZ1:19–1:4) to provide cycloadduct 15
(37.2 mg, 0.0872 mmol, 83%) as a white solid (mp 164–
166 8C). Rf 0.22 (EtOAc/hexanesZ1:9); IR (CH2Cl2, NaCl)
4.2.11. Cycloadduct 5k. Following the above general
procedure (D) with norbornene 4a (36.0 mg, 0.382 mmol),
ynamide 3k (37.8 mg, 0.113 mmol), THF (0.3 mL), and
Cp*RuCl(COD) (4.9 mg, 0.013 mmol). The reaction mix-
ture was stirred in the dark at 60 8C for 72 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ1:24) to provide cycloadduct 5k (37.7 mg,
0.0881 mmol, 78%) as a yellow oil. Rf 0.48 (EtOAc/
hexanesZ1:9); IR (CH2Cl2, NaCl) 3052 (w), 2954 (m),
2871 (w), 1716 (m), 1442 (m), 1351 (w), 1266 (s), 1087 (w),
3055 (m), 3026 (m), 2993 (m), 2952 (m), 1727 (vs) cmK1
;
1H NMR (CDCl3, 300 MHz) d 7.54 (d, 2H, JZ7.8 Hz),
7.06–7.46 (m, 12H), 5.30 (s, 1H), 5.17 (s, 1H), 3.91 (s, 3H),
3.39 (d, 1H, JZ3.6 Hz), 3.01 (d, 1H, JZ3.7 Hz); 13C NMR
(CDCl3, 75 MHz) d 154.2, 145.3, 139.5, 133.4, 132.4,
128.8, 127.8, 127.5 (br), 127.1, 126.7, 126.63, 126.57,
126.5, 119.9, 119.6, 77.2, 76.1, 53.4, 45.9, 43.3. HRMS (CI)
calcd for C26H21NO3 ((MCH)C): 396.1600; found:
396.1609. Anal. Calcd for C26H21NO3ZC, 79.97%; H,
5.35%; foundZC, 79.11%; H, 5.30%.
1055 (w), 836 (w), 740 (s) cmK1 1H NMR (CDCl3,
;
400 MHz) d 7.36–7.39 (m, 2H), 7.29 (m, 1H), 7.21–7.22
(m, 2H), 3.70 (s, 3H), 3.43 (t, 2H, JZ7.2 Hz), 2.75 (br s,
1H), 2.18 (d, 1H, JZ3.1 Hz), 2.00 (br s, 1H), 1.98 (br s, 1H),
1.48–1.73 (m, 5H), 0.95–1.05 (m, 3H), 0.84 (s, 9H), K0.03
(s, 6H); 13C NMR (CDCl3, 150 MHz) d 154.2, 140.0, 133.4,
129.0, 128.0, 127.3, 125.1, 61.1, 52.8, 50.2, 45.4, 35.1, 34.1,
30.4, 30.4, 28.2, 28.0, 25.9, 18.2, K5.3. HRMS calcd for
C25H37NO3Si: m/z 427.2543, found m/z 427.2548.
4.2.15. Cycloadduct 16. Following the above general
procedure (D) with alkene 4g (47.2 mg, 0.256 mmol),
ynamide 3e (27.1 mg, 0.108 mmol), THF (0.3 mL), and
Cp*RuCl(COD) (4.9 mg, 0.013 mmol). The reaction mixture
was stirred in the dark at 60 8C for 72 h. The crude product
was purified by column chromatography (gradient EtOAc/
hexanesZ1:19–2:3) to provide cycloadduct 16 (47.0 mg,
0.102 mmol, 94%) as a white solid (mp 130–133 8C). Rf 0.30
(EtOAc/hexanesZ2:3); IR (CH2Cl2, NaCl) 3061 (w), 2981
4.2.12. Cycloadduct 13. Following the above general
procedure (D) with alkene 4d (73.6 mg, 0.285 mmol),
ynamide 3e (29.9 mg, 0.119 mmol), THF (0.3 mL), and
Cp*RuCl(COD) (4.1 mg, 0.011 mmol). The reaction mix-
ture was stirred in the dark at 60 8C for 72 h. The crude

3834
K. Villeneuve et al. / Tetrahedron 62 (2006) 3823–3836
1
(m), 2928 (m), 2892 (m), 2875 (m), 2811 (w), 1722 (vs), 1302
0.0611 mmol, 72%, drZ58:42 measured by 400 MHz H
1
(vs) cmK1; H NMR (CDCl3, 300 MHz) d 7.43 (d, 2H, JZ
NMR) as pale yellow oil. Rf 0.49 (EtOAc/hexanesZ1:4); IR
(neat) 3055 (w), 3026 (w), 2952 (s), 2868 (m), 1760 (vs),
7.8 Hz), 7.21–7.27 (m, 2H), 7.02–7.13 (m, 4H), 6.85–6.94 (m,
2H), 4.40(s, 1H), 4.21(s, 1H), 3.79(s, 3H), 3.34–3.48(m, 5H),
3.36 (s, 3H), 3.34 (s, 3H), 2.94 (d, 1H, JZ3.7 Hz), 2.10–2.20
(m, 2H); 13C NMR (CDCl3, 75 MHz) d 154.4, 139.7, 132.3,
131.7, 128.9, 128.7, 127.7, 126.9, 126.1, 125.9, 77.3, 75.7,
71.00, 70.97, 58.85, 58.75, 53.3, 50.8, 45.4, 44.8, 44.2. HRMS
(CI) calcd for C26H29NO5 ((MCH)C): 436.2124; found:
436.2130. Anal. Calcd for C26H29NO5ZC, 71.70%; H,
6.71%; foundZC, 71.44%; H, 6.98%.
1650 (m), 1404 (vs) cmK1; H NMR (CDCl3, 400 MHz) d
1
7.29–7.34 (m, 2H), 7.21–7.24 (m, 3H), 4.43 (d, 0.42H, JZ
8.6 Hz), 4.41 (d, 0.58H, JZ8.6 Hz), 4.33 (dd, 0.42H, JZ
8.4, 3.6 Hz), 4.28 (dd, 0.58H, JZ8.6, 4.4 Hz), 4.17–4.21
(m, 1H), 3.50 (dd, 0.42H, JZ10.4, 5.2 Hz), 3.46 (dd, 0.58H,
JZ10.6, 4.7 Hz), 3.40 (dd, 0.58H, JZ10.4, 3.0 Hz), 3.29
(dd, 0.42H, JZ10.6, 2.4 Hz), 3.02 (br d, 0.58H, JZ3.5 Hz),
2.79 (br d, 0.42H, JZ3.5 Hz), 2.72 (br d, 0.42H, JZ
3.4 Hz), 2.59 (d, 0.58H, JZ3.6 Hz), 2.48 (br s, 0.42H), 2.41
(br s, 0.58H), 2.19 (br s, 0.58H), 2.02 (br s, 0.42H), 1.53–
1.64 (m, 3H), 1.12–1.18 (m, 2H), 1.06 (d, 0.58H, JZ
10.3 Hz), 1.02 (d, 0.42H, JZ10.2 Hz), 0.83 (s, 3.78H), 0.81
(s, 5.22H), K0.06 (s, 1.26H), K0.08 (s, 1.74H), K0.09 (s,
1.26H), K0.10 (s, 1.74H); 13C NMR (APT, CDCl3,
100 MHz) major diastereomer: d 155.0, 134.8, 128.1,
128.0, 127.2, 126.99, 126.3, 65.1, 55.5, 48.8, 46.4, 45.2,
36.3, 34.3, 30.6, 28.26, 28.1, 25.6, K5.6; minor diaster-
eomer: d 155.1, 133.8, 128.7, 128.2, 127.5, 127.1, 125.2,
65.1, 60.9, 55.9, 48.5, 45.2, 35.5, 34.5, 30.5, 28.35, 27.8,
25.6, K5.8. HRMS (m/z) for C25H35NO3Si calcd 425.2386,
found 425.2367. Anal. Calcd for C25H35NO3SiZC,
70.55%; H, 8.29%; found C, 70.40%; H, 8.44%.
4.2.16. Cycloadduct 21. Following the above general
procedure (D) with norbornene 4a (54.1 mg, 0.575 mmol),
ynamide 22 (54.6 mg, 0.207 mmol), THF (0.60 mL), and
Cp*RuCl(COD) (5.0 mg, 0.013 mmol). The reaction mix-
ture was stirred in the dark at 65 8C for 68 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ3:7) to give the cycloadducts 21 as an inseparable
mixture of diastereoisomers (60.4 mg, 0.169 mmol, 83%,
drZ72:28 measured by 400 MHz 1H NMR) as pale yellow
oil. Rf 0.37 (EtOAc/hexanesZ3:7); IR (neat) 3065 (w),
3032 (w), 2949 (m), 2872 (w), 1762 (s), 1648 (w), 1395
(s) cmK1; 1H NMR (CDCl3, 400 MHz) 7.18–7.36 (m, 8H),
7.08–7.17 (m, 0.56H), 6.93–6.97 (m, 1.44H), 5.11–5.15 (m,
1H), 4.74 (app t, 0.28H, JZ8.8 Hz), 4.73 (app t, 0.72H, JZ
8.8 Hz), 4.22 (dd, 0.72H, JZ8.8, 5.8 Hz), 4.18 (dd, 0.28H,
JZ8.8, 5.8 Hz), 2.86 (br d, 0.72H, JZ3.6 Hz), 2.57 (br d,
0.56H), 2.50 (br d, 0.72H, JZ3.6 Hz), 2.18 (br s, 0.72H),
2.06 (br s, 0.72H), 2.02 (br s, 0.56H), 1.46–1.58 (m, 2H),
1.27 (d, 0.28H, JZ10.4 Hz), 1.14–1.23 (m, 2H), 0.85 (d,
0.72H, JZ10.4 Hz), 0.79 (d, 0.28H, JZ10.4 Hz), 0.74 (d,
0.72H, JZ10.4 Hz); 13C NMR (APT, CDCl3, 75 MHz) d
154.94, 154.91, 138.6, 134.9, 133.5, 130.3, 129.3, 128.8,
128.7, 128.6, 128.04, 127.97, 127.94, 127.89, 127.84,
127.76, 127.43, 127.35, 127.1, 126.9, 126.5, 126.2, 70.4,
70.2, 59.6, 58.7, 55.9, 48.6, 48.5, 46.3, 44.8, 35.4, 35.0,
34.1, 34.0, 30.3, 29.8, 28.10, 28.07, 28.03, 28.0. HRMS
(m/z) for C24H23NO2 calcd 357.1729, found 357.1720.
Anal. Calcd for C24H23NO2ZC, 80.64%; H, 6.49%; found
C, 80.78%; H, 6.30%.
4.2.18. Cycloadduct 27. Following the above general
procedure (D) with norbornene 4a (62.6 mg, 0.665 mmol),
ynamide 8 (46.8 mg, 0.215 mmol), THF (0.50 mL), and
Cp*RuCl(COD) (7.3 mg, 0.019 mmol). The reaction mix-
ture was stirred in the dark at 65 8C for 68 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ3:2) to give the cycloadducts 27 as an inseparable
mixture of diastereoisomers (54.6 mg, 0.174 mmol, 81%,
drZ71:29 measured by 400 MHz 1H NMR) as a pale yellow
oil. Rf 0.47 (EtOAc/hexanesZ3:2); IR (neat) 3058 (w),
2953 (m), 2870 (m), 1739 (s), 1649 (m), 1409 (s) cmK1; 1H
NMR (CDCl3, 300 MHz) d 7.24–7.31 (m, 5H), 4.43–4.47
(m, 2H), 4.20–4.23 (m, 1H), 3.50–3.63 (m, 1H), 3.38–3.48
(m, 1H), 2.99 (br s, 0.71H), 2.77 (br s, 0.29H), 2.73 (br s,
0.29H), 2.62 (br s, 0.71H), 2.40 (br s, 1H), 2.16 (br s,
0.71H), 2.08 (br s, 0.29H), 1.99 (br s, 0.29H), 1.89 (br s,
0.71H), 1.52–1.69 (m, 3H), 1.02–1.25 (m, 3H); 13C NMR
(APT, CDCl3, 75 MHz) major diastereomer: d 155.1, 134.3,
128.5, 128.2, 127.42, 127.38, 127.1, 64.9, 60.9, 55.6, 48.8,
46.0, 36.0, 34.1, 30.4, 28.2, 28.1; minor diastereomer: d
155.2, 133.4, 128.3, 128.06, 128.01, 127.34, 127.24, 65.1,
60.8, 56.1, 48.8, 45.1, 35.3, 34.4, 30.5, 28.3, 27.9. HRMS
(m/z) for C19H21NO3 calcd 311.1521, found 311.1530.
Anal. Calcd for C19H21NO3ZC, 73.29%; H, 6.80%; found
C, 73.44%; H, 6.71%.
The 1:1 diastereomeric mixture of 21 was prepared as
follow: to a flask under nitrogen containing K3PO4
(52.4 mg, 0.247 mmol), CuI (3.3 mg, 0.017 mmol) and
(R)-(K)-4-phenyl-2-oxazolidinone (23.4 mg, 0.129 mmol)
was added a solution of 2017g (32.5 mg, 0.101 mmol) in
toluene (0.4 mL) via cannula. N,N0-dimethylethylenedia-
mine (15 mL, 0.14 mmol), prior to heat the reaction mixture
at 90 8C for 20 h. The crude mixture was then cooled to
room temperature and purified by column chromatography
to give 21 as an inseparable mixture of diastereoisomers
(25.1 mg, 0.0702 mmol, 70%, drZ53:47 measured by
400 MHz 1H NMR).
4.2.19. Cycloadduct 28. Following the above general
procedure (D) with norbornene 4a (74.3 mg, 0.789 mmol),
ynamide 23 (65.2 mg, 0.237 mmol), THF (0.40 mL), and
Cp*RuCl(COD) (5.4 mg, 0.014 mmol). The reaction mix-
ture was stirred in the dark at 65 8C for 68 h. The crude
product was purified by column chromatography (EtOAc/
hexanesZ3:7) to give an inseparable mixture cycloadducts
28 as an inseparable mixture of diastereoisomers (72.0 mg,
4.2.17. Cycloadduct 26. Following the above general
procedure (D) with norbornene 4a (29.7 mg, 0.315 mmol),
ynamide 7 (28.1 mg, 0.0848 mmol), THF (0.40 mL), and
Cp*RuCl(COD) (3.4 mg, 0.0089 mmol). The reaction
mixture was stirred in the dark at 65 8C for 68 h. The
crude product was purified by column chromatography
(EtOAc/hexanesZ1:4) to give the cycloadducts 26 as an
inseparable mixture of diastereoisomers (26.1 mg,
1
0.195 mmol, 82%, drZ74:26 measured by 400 MHz H
NMR) as a pale yellow oil. Rf 0.51 (EtOAc/hexanesZ3:7);
IR (neat) 3065 (m), 2953 (s), 2871 (m), 1751 (s), 1651 (s),

K. Villeneuve et al. / Tetrahedron 62 (2006) 3823–3836
3835
1385 (s), 1266 (m) cmK1 1H NMR (CDCl3, 400 MHz)
;
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.
7.38–7.39 (m, 1H), 7.24–7.33 (m, 5H), 7.18–7.22 (m, 1H),
7.10–7.14 (m, 1H), 7.04–7.06 (m, 1H), 5.58 (d, 0.26H, JZ
6.5 Hz), 5.57 (d, 0.74H, JZ7.3 Hz), 5.35–5.41 (m, 1H),
3.33–3.41 (m, 2H), 3.12 (br d, 0.74H, JZ3.6 Hz), 2.86 (br d,
0.26H, JZ3.6 Hz), 2.73 (br d, 0.26H, JZ3.5 Hz), 2.68 (br
d, 0.74H, JZ3.6 Hz), 2.60 (br s, 0.26H), 2.48 (br d, 0.74H,
JZ3.1 Hz), 2.13 (br d, 0.74H, JZ2.9 Hz), 2.11 (br s,
0.26H), 1.57–1.70 (m, 3H), 1.14–1.23 (m, 2H), 1.08 (d,
0.26H, JZ10.3 Hz), 1.00 (d, 0.74H, JZ10.4 Hz); 13C NMR
(APT, CDCl3, 75 MHz) d 154.1, 154.0, 140.04, 139.93,
139.0, 138.6, 134.6, 133.5, 129.5, 129.4, 128.5, 128.2,
127.9, 127.7, 127.63, 127.55, 127.4, 127.3, 127.2, 127.1,
127.0, 126.6, 125.6, 125.33, 125.26, 78.1, 77.8, 63.3, 63.2,
49.1, 49.0, 46.2, 44.9, 38.6, 38.1, 36.2, 35.6, 34.3, 34.1,
30.6, 30.3, 28.3, 28.2, 28.0, 27.8. HRMS (m/z) for
C25H23NO2 calcd 369.1729, found 369.1717. Anal. Calcd
for C25H23NO2ZC, 81.27%; H, 6.27%; found C, 81.36%;
H, 6.14%.
12. (a) Tracey, M. R.; Zhang, Y.; Frederick, M. O.; Mulder, J. A.;
´
Hsung, R. P. Org. Lett. 2004, 6, 2209. (b) Couty, S.; Liegault,
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.; Bergstrasser, U. Tetrahedron
`
2000, 56, 8473. (b) Miniere, S.; Cintrat, J.-C. Synthesis 2001,
`
705. (c) Miniere, S.; Cintrat, J.-C. J. Org. Chem. 2001, 66,
7385. (d) Timbart, L.; Cintrat, J.-C. J. 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, M. Org. Lett. 2004, 6, 1509. (b) Zhang, Y.; Hsung,
R. P.; Zhang, X.; Huang, J.; Slafer, B. W.; Davis, A. Org. Lett.
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16. For our recent contributions on non metal-catalyzed cyclo-
addition 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.
Acknowledgements
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.
17. For our recent contributions on Ru-catalyzed [2C2] cyclo-
additions, 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.
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