Ruthenium-catalyzed [2 + 2] cycloadditions between norbornene and propargylic alcohols or their derivatives

Article abstract of DOI:10.1021/om500563h

Diastereoselective ruthenium-catalyzed [2 + 2] cycloadditions of norbornene and propargylic alcohols or their derivatives were investigated. The cycloadditions were found to be highly stereoselective, giving exo cycloadducts in moderate to excellent yields with diastereoselectivities up to 92:8. When a chiral propargylic alcohol was used in the cycloaddition, up to 80% ee of the [2 + 2] cycloadducts was observed after oxidation of the alcohol.

Full text of DOI:10.1021/om500563h

Article
pubs.acs.org/Organometallics
Ruthenium-Catalyzed [2 + 2] Cycloadditions between Norbornene
and Propargylic Alcohols or Their Derivatives
Gavin C. Tsui, Karine Villeneuve, Emily Carlson, and William Tam*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry, University of Guelph,
Guelph, Ontario, Canada N1G 2W1
S
* Supporting Information
ABSTRACT: Diastereoselective ruthenium-catalyzed [2 + 2]
cycloadditions of norbornene and propargylic alcohols or their
derivatives were investigated. The cycloadditions were found
to be highly stereoselective, giving exo cycloadducts in
moderate to excellent yields with diastereoselectivities up to
92:8. When a chiral propargylic alcohol was used in the cycloaddition, up to 80% ee of the [2 + 2] cycloadducts was observed
after oxidation of the alcohol.
enantioselective [2 + 2] cycloadditions of alkynyl esters and
norbornene derivatives have been reported, demonstrating
excellent enantioselectivity using a chiral rhodium catalyst (eq
2).36
INTRODUCTION
■
The development of ruthenium-catalyzed chemical processes has
become an emerging field over the past decade.1−4 With their
wide range of oxidation states (from −2 to +8) and several
coordination geometries, ruthenium catalysts can form a variety
of intermediates such as (π-allyl)ruthenium,5 ruthenium−
carbene,6 and ruthenacycle species.7 Among various ruthenium
complexes, CpRu(COD)Cl and Cp*Ru(COD)Cl have been
found to be the catalysts of choice in many reactions such as [2 +
2 + 2] cycloadditions,8−10 conjugate additions,11 bis-Diels−
Alder cycloadditions,12 Alder-ene reactions,13,14 cross-benzan-
nulations,15 and many others.1,2 We and other groups have been
largely involved in the preparation of cyclobutene rings via
ruthenium-catalyzed [2 + 2] cycloadditions.16−28
In our preliminary communication19 we reported a diaster-
eoselective ruthenium-catalyzed [2 + 2] cycloaddition between
bicyclic alkenes and chiral alkynes 2a−f (Table 1). In this full
paper, we have identified the previously undetermined structures
of the major diastereomers, and have expanded our investigation
to the effects of propargylic and acetylenic substituents on the
diastereoselectivity of cycloaddition (Tables 2 and 3). The use of
homopropargylic alcohols as the alkyne partner in the Ru-
catalyzed cycloaddition has also been demonstrated (Table 4).
RESULTS AND DISCUSSION
Although asymmetric versions of transition-metal-catalyzed
cycloaddition reactions such as [4 + 2],29 [2 + 2 + 1],30,31 [2 + 2 +
2],32,33 and [4 + 2 + 2]34 have been recognized, to the best of our
knowledge, very few studies on the asymmetric transition-metal-
catalyzed [2 + 2] cycloadditions between an alkene and an alkyne
have been reported in the literature. We have demonstrated the
first examples of asymmetric induction studies in ruthenium-
catalyzed [2 + 2] cycloadditions between symmetrical bicyclic
alkenes and alkynes bearing a chiral sultam auxiliary, achieving
excellent levels of asymmetric induction after recovery of the
chiral auxiliary (eq 1).35 More recently, rhodium-catalyzed
■
Our initial trials of Ru-catalyzed [2 + 2] cycloaddition between
norbornene 1 and chiral propargylic alcohol 2f or its derivatives
2a−e are summarized in Table 1. The chiral alkynes 2a−f were
synthesized from the common precursor (S)-(−)-3-butyn-2-ol
((S)-3), which was commercially available in an optically pure
form (Scheme 1).
All cycloadditions were highly stereoselective, providing only
exo cycloadducts 4/5 with yields from 33% to 71%. However,
while in our preliminary communication we assumed that chiral
alkynes 2a−f all gave the same major diastereomers upon
cycloaddition,19 further investigation has shown that this is in fact
not the case. In order to identify the structure of each major
diastereomer unambiguously by X-ray diffraction analysis, we
needed to find a pair of diastereomeric cycloadducts that were
separable and crystalline. After numerous trials, we found that,
when benzonorbornene 6 was reacted with the chiral propargylic
alcohol 2f under the cycloaddition conditions (Scheme 2), the
diastereomeric cycloadducts 7 and 8 could be subsequently
esterified with p-nitrobenzoyl chloride in pyridine to yield a
Received: May 26, 2014
Published: July 16, 2014
© 2014 American Chemical Society
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Assuming that norbornene 1 and benzonorbornene 6 give
similar major diastereomers in the Ru-catalyzed cycloaddition,
the major diastereomer resulting from cycloaddition between
norbornene 1 with chiral propargylic alcohol (S)-2f would be
cycloadduct 4f (Table 1, entry 6; 4f:5f = 81:19). While the
structure of the major diastereomer obtained from propargylic
alcohol 2f had been determined, NMR studies of the major
diastereomers obtained from alkynes 2a−e provided surprising
results. A comparison of the 1H NMR spectrum of the
diastereomeric cycloadducts 4b/5b (entry 2) with that of the
same products obtained through a different route of cyclo-
addition with 2f followed by acetylation demonstrates this
(Scheme 3).
On the basis of the structures of the major diastereomer 9
(Scheme 2) and 4f (Table 1, entry 6), the quartet between 5.7
and 5.8 ppm can be assigned to Hb while the quartet between 5.8
and 5.9 ppm is assigned to Ha. From the reversal in relative
integration of these quartets, it is clear that the major
diastereomer from the cycloaddition with alkyne 2b is the
opposite of that obtained from the cycloaddition with alkyne 2f.
Similar results were observed when the 81:19 mixture of
diastereomeric cycloadducts 4f and 5f (Table 1, entry 6) was
converted to 4a/5a, 4c/5c, 4d/5d, or 4e/5e and their NMR
spectra were compared. Cycloaddition with alkynes 2a−e in all
cases gave the major diastereomer opposite of that formed via
cycloaddition with alkyne 2f. This suggests that a different mode
of asymmetric induction is at play with propargylic alcohols. A
plausible explanation for the difference in observed diaster-
eoselectivity could invoke intramolecular hydrogen bonding
(Figure 1). It has been reported that the chloride of M−Cl (M =
metal) can act as a good hydrogen acceptor.38 Recent
computational studies have also suggested that such interactions
are indeed present at every stage of Ru-catalyzed [2 + 2]
cycloaddition of propargylic alcohols.39 Therefore, the diaster-
eoselectivity is thought to arise from a rigid ruthenium complex
in which the metal interacts with the hydroxyl group of the alkyne
via intramolecular hydrogen bonding.
Table 1. Ru-Catalyzed [2 + 2] Cycloadditions between
Norbornene 1 and Chiral Alkynes 2a−f
a
b
entry
alkyne
OR
time (h)
yield (%)
dr (4:5)
1
2
3
4
5
6
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(S)-2e
(S)-2f
OC(O)OEt
OAc
48
62
35
33
45
47
65
71
40:60
40:60
42:58
29:71
32:68
81:19
OMEM
OBn
72
150
43
OTBS
OH
72
a
b
Isolated yields after column chromatography. Diastereomeric ratios
1
(dr) were determined by GC and/or H NMR (400 MHz).
Scheme 1. Synthesis of Chiral Alkynes 2a−f
To prove that the diastereoselectivities arise from the
asymmetric induction of the chiral propargylic alcohol in the
cycloadditions (and are not due to racemization of the chiral
alcohol by the metal catalyst), the diastereomeric cycloadducts
4f/5f were oxidized and the enantiomeric excess (ee) of the
products was measured and compared to the diastereomeric ratio
separable mixture of diastereomeric products 9 and 10.
Fractional recrystallization in Et2O/hexanes provided the
major diastereomer 9. Suitable crystals were then grown from
Et2O/hexanes, and the structure of 9 was confirmed.37
Scheme 2. Structural Determination of the Major Diastereomer
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Scheme 3. Partial 1H NMR Spectra of the Diastereomeric Cycloadducts 4b/5b
Scheme 5. Cycloaddition between Norbornene and a Racemic
Alkyne
Figure 1. Possible intramolecular hydrogen bonding.
(dr) of the cycloadducts (Scheme 4). The diastereomeric ratio
for the cycloadducts 4f/5f was found to be identical with the
enantiomeric ratio of products 11f/12f; therefore, the
diastereoselectivities must arise from asymmetric induction of
the chiral propargylic alcohol in the cycloadditions.
It should be noted, however, that although only chiral alkynes
were used in the above studies, identical diastereomeric ratios are
to be expected from the use of racemic alkynes. For instance,
while pure (S)-13 affords compounds (S)-14 and (S)-15, its
enantiomer (R)-13 would simply furnish the respective cyclo-
adducts of opposite absolute stereochemistry, (R)-14 and (R)-15
(Scheme 5). Thus, although the chiral substituent helps to define
the stereochemistry of the cycloadduct, the absolute stereo-
chemistry of the alkyne does not affect the overall diastereomeric
ratio. As such, subsequent studies were performed on racemic
alkynes.
(17) followed by deprotonation with n-BuLi and trapping with
paraformaldehyde, acetone, or di-tert-butyl dicarbonate and
subsequent removal of the protecting group furnished various
acetylenic substituent groups, including CH2OH (16a), C-
(CH3)2OH (16b), and tert-butyl ester (16c). Bromination of 17
with NBS and AgNO3 in acetone afforded propargylic alcohol
16d with an acetylenic Br group, and deprotonation of terminal
alkynes 1-hexyne (18e), 1-octyne (18f), and phenylacetylene
(18g) afforded the corresponding propargylic alcohols with R1
groups n-butyl (16e), n-hexyl (16f), and phenyl (16g). R2
functionalized alcohols 16h−j were similarly prepared by
trapping the deprotonated ethyl propiolate (19) with the
corresponding aldehyde. The effect of R1 substituent on
In order to investigate the effects of various propargylic
substituents on the diastereoselectivity of cycloaddition, alkynes
16a−j were prepared (Scheme 6). Protection of 3-butyn-2-ol
Scheme 4. Comparison of dr Values of the Cycloadducts and er Values of the Oxidized Cycloadducts
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Scheme 6. Synthesis of Propargylic Alcohols 16a−j
diastereoselectivity was then assessed by reacting propargylic
alcohols 16a−g with norbornene 1 (Table 2).
The effect of R2 substituent on cycloaddition was then assessed
(Table 3). Much to our delight, a significant improvement in
Table 3. Effect of Varying R2 Substituent on Ru-Catalyzed [2 +
2] Cycloadditions between Norbornene and Various
Propargylic Alcohols
Table 2. Effect of R1 Substituent on Ru-Catalyzed [2 + 2]
Cycloadditions between Norbornene and Propargylic
Alcohols
a
b
entry
alcohol
R2
yield (%)
dr
a
b
entry
alcohol
R1
yield (%)
dr
1
2
3
4
2f
Me
Ph
71
74
75
81:19
90:10
92:8
1
2
3
4
5
6
7
8
2f
COOEt
COO-t-Bu
Ph
71
74
57
88
44
61
56
81:19
78:22
64:36
82:18
77:23
55:45
50:50
N.A.
16h
16i
16j
16c
16g
16e
16f
16a
16b
16d
t-Bu
Cy
98
b
88:12
n-Bu
a
Isolated yields after column chromatography. Diastereomeric ratios
(dr) were determined by GC and/or H NMR (400 MHz).
n-Hex
1
c
c
CH2OH
C(CH3)2OH
Br
diastereoselectivity was observed when a bulkier R2 substituent
was present on the alkyne, relative to propargylic alcohol 2f.
While diastereomeric ratios were similar for all R2 derivatized
cycloadducts, the t-Bu derivative gave the highest diastereose-
lectivity of 92:8 for 19:20 (entry 3). Moreover, cycloadducts
20h−j were obtained in good to excellent yields, with the
cyclohexyl adduct 20j obtained in 98% isolated yield, the highest
achieved in our studies thus far.
Next an asymmetric version of the cycloaddition was
performed using the chiral propargylic alcohol (R)-21, prepared
from its enantiomerically pure commercial precursor (R)-1-
phenyl-2-propyn-1-ol (22) in three steps (Scheme 7). Upon
reaction of norbornene 1 and the chiral propargylic alcohol (R)-
21 the diastereomeric cycloadducts 23/24 obtained were
oxidized to the pair of enantiomers 25/26. The enantiomeric
excess of 25/26 was determined by chiral HPLC to be 80%,
which was appreciably higher than the 62% obtained by 2f in our
initial studies.
d
0
b
a
Isolated yields after column chromatography. Determined by GC
c
and/or 1H NMR (400 MHz). Determined by GC from the acetylated
d
products. Full consumption of starting material determined by TLC;
inseparable mixture of products.
Relative to alcohol 2f (Table 2, entry 1), the diastereose-
lectivity was generally lower for the R1 derivatized species. A
small decrease in the diastereomeric ratio was observed when a
bulky tert-butyl ester was present at the acetylenic position of
alcohol 16c (entry 2). The presence of a phenyl group in alcohol
16g caused a sharp decrease in both diastereomeric ratio and
yield (entry 3). Of the alcohols 16e,f containing linear acetylenic
alkyl groups, both a higher yield and diastereomeric ratio were
observed for the n-butyl derivative (entries 4 and 5). Primary and
tertiary alcohols of the diols 16a,b had essentially no effect on
diastereoselectivity, and the yields were moderate (entries 6 and
7). Finally, although thin-layer chromatography (TLC) indicated
full consumption of starting material for bromide 16d, the
corresponding cycloadduct could not be isolated since an
inseparable complicated mixture of products resulted (entry 8).
Finally, the cycloaddition chemistry was applied to homo-
propargylic alcohols 27a−c. Racemic homopropargylic alcohols
27a,b were synthesized via deprotonation of ethyl propiolate
(19) followed by trapping with an epoxide (Scheme 8), while
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Scheme 7. Preparation and Use of a Chiral Propargylic Alcohol in Asymmetric Cycloaddition
Scheme 8. Synthesis of Homopropargylic Alcohols 27a−c
alcohol 27c was prepared from the benzylic alcohol 28 via a
Barbier-type reaction. The results of cycloaddition between 1
and 27a−c are summarized in Table 4. Excellent yields of
current study. It is possible that this reduced diastereoselectivity
is a result of the increased distance between the stereocenter and
the reaction site, which exerts less steric control over the
preferential formation of one diastereomer. However, it is also
conceivable that a geometric requirement must be met in order
to achieve high diastereoselectivity, which is not possible with the
homopropargylic alcohols.
Table 4. Ru-Catalyzed [2 + 2] Cycloadditions between
Norbornene 1 and Homopropargylic Alcohols 27a−c
As mentioned, the reaction mechanism is predicted to involve
hydrogen bonding of the alcohol hydrogen with the chloride
ligand, which stabilizes the transition state. On the basis of
calculations performed on the interactions of norbornadiene
with a model propargylic alcohol (R1 = COOEt, R2 = H), we have
learned that, over the course of the reaction, the most stable
conformation between bicycloalkene and alkyne involves a
geometrically restricted six-membered ring consisting of the
atoms Cl−Ru−Ca−Cb−O−H in structures 31a−d (Figure 2).39
As the size of the R2 substituent is increased, a greater distortion
in the cyclic arrangement is expected, since Cb bearing the R2
group will rotate to relieve steric strain. As a result, we suggest
that the cycloaddition of norbornene with propargylic alcohols is
highly dependent on the size of the R2 substituent, which causes
the reaction to become biased toward the formation of one
diastereomer over the other. This is consistent with our
experimental findings of R2 substituents providing higher
diastereoselectivity than R1 substituents, which do not participate
in the six-membered interaction. With homopropargylic R3
substituents, a similar argument can be made in that this
a
b
entry
alcohol
R3
yield (%)
dr
1
2
3
27a
27b
27c
Et
91
92
63:37
56:44
72:28
CH2OTBDMS
Ph
89
a
b
Isolated yields after column chromatography. Diastereomeric ratios
(dr) were determined by GC and/or H NMR (400 MHz).
1
cycloadducts 29/30 were obtained for all three trials involving
the homopropargylic alcohols. To the best of our knowledge,
these are the first examples of Ru-catalyzed [2 + 2] cyclo-
additions between a bicyclic alkene and a homopropargylic
alcohol. In comparison to the propargylic alcohols (Tables 2 and
3), the effects of the R3 substituent on diastereoselectivity were
not as pronounced. As the propargylic data were more desirable,
we chose not to pursue homopropargylic species further for the
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Figure 2. Predicted intramolecular hydrogen-bonding structures in the ruthenium-catalyzed [2 + 2] cycloaddition of norbornadiene with
homopropargylic alcohol (R1 = COOEt, R2 = H): 31a, prereaction π complex; 31b, oxidative coupling transition state; 31c, ruthenacyclopentene; 31d,
reductive elimination transition state (see Scheme 9 for details using the analogous structures 34a−d).
Scheme 9. Proposed Catalytic Cycle for Cp*RuCl(COD)-Catalyzed [2 + 2] Cycloaddition between Norbornene 1 and Propargylic
Alcohols 16
stereoselective arrangement is not permitted with the added
carbon atom.
CONCLUSION
■
In summary, we have investigated the scope of diastereoselective
ruthenium-catalyzed [2 + 2] cycloadditions between norbornene
and propargylic alcohols or their derivatives. We have reassessed
and confirmed the previously undetermined structures of the
major diastereomers from our preliminary work by X-ray
diffraction analysis and have performed cycloadditions between
norbornene and propargylic, acetylenic, or homopropargylic
alcohols to investigate the effects of substituents on diaster-
eoselectivity. High stereoselectivity was observed in all cases,
providing exo cycloadducts with diastereoselectivity as high as
92:8 for the bulky t-Bu acetylenic alcohol. Furthermore, using a
chiral propargylic alcohol, enantioselectivity up to 80% ee of the
cycloadducts was attained upon oxidation of the alcohol. The
first examples of [2 + 2] cycloaddition between norbornene and
Scheme 9 depicts our proposed mechanism for the Ru-
catalyzed [2 + 2] cycloaddition between norbornene and
propargylic alcohols. Initially, dissociation of a COD ligand
from Cp*RuCl(COD) 32 yields the active catalytic species,
Cp*RuCl 33 (step 1). The unsaturated ruthenium coordinates
with the alkene of 1 and alkyne of 16 (step 2) to form π complex
34a. Oxidative coupling via the rate-determining transition state
34b affords ruthenacyclopentene 34c (step 3). Successive
reductive elimination through 34d provides representative exo
cycloadduct 35 and regenerates the active catalyst 33 (step 4).
The exo product is favored due to the higher π-electron density
and steric accessibility of the exo face of 1 over its endo face,
which in effect promotes the coordination of ruthenium
preferentially to this face.33
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5.74 (q, 0.4H, J = 6.7 Hz), 4.13−4.19 (m, 2H), 2.53 (m, 1.6H), 2.42 (m,
0.4H), 2.18 (br s, 1H), 2.13 (br s, 0.4H), 2.07 (s, 1.2H), 2.05 (s, 1.8H),
1.98 (br s, 0.6H), 1.54−1.58 (m, 2H), 1.39 (d, 1.2H, J = 6.8 Hz), 1.36 (d,
1.8H, J = 6.8 Hz), 1.34 (m, 1H, J = 12.6 Hz), 1.28 (t, 3H, J = 7.1 Hz),
1.06−0.99 m, 3H, J = 7.4 Hz); 13C NMR (APT, CDCl3, 100 MHz)
major diastereomer δ 170.1, 162.2, 158.9, 130.6, 67.1, 60.0, 46.3, 46.0,
34.3, 33.8, 30.4, 28.1, 28.0, 21.0, 18.8, 14.3, minor diastereomer δ 170.1,
162.2, 159.3, 130.4, 68.0, 60.0, 47.1, 45.6, 34.09, 34.04, 30.6, 28.2, 27.8,
21.0, 19.0, 14.3; HRMS (EI) calcd for C16H22O4 [M]+ 278.1518, found
278.1527.
Cycloadducts (S)-4c and (S)-5c (Table 1, Entry 3). Following the
above general procedure with norbornene 1 (36.8 mg, 0.392 mmol),
acetylene 2c (28.4 mg, 0.123 mmol), THF (0.1 mL), and Cp*Ru-
(COD)Cl (3.8 mg, 0.012 mmol), the reaction mixture was stirred for 72
h. The crude product was purified by column chromatography (EtOAc/
hexanes 1/17) to give an inseparable mixture of cycloadducts 4c and 5c
(18 mg, 0.055 mmol, 45%, dr = 42:58 measured by 1H NMR and GC) as
a colorless oil: Rf = 0.29 (EtOAc/hexanes 3/7); GC (HP-1 column)
retention time for major isomer 24.94 min, retention time for minor
isomer 25.17 min; IR (CH2Cl2) 2956, 2872, 2814, 1717, 1650, 1455
cm−1; 1H NMR (CDCl3, 400 MHz) δ 4.87 (q, 1H, J = 6.7 Hz), 4.72 (br s,
1H), 4.70 (d, 1H, J = 2.2 Hz), 4.13−4.19 (m, 2H), 3.74−3.78 (m, 1H),
3.60−3.66 (m, 1H), 3.54−3.57 (m, 2H), 3.39 (s, 1.7H), 3.38 (s, 1.3H),
2.54 (m, 2H), 2.18 (br s, 1H), 2.15 (br s, 0.4H), 2.11 (br s, 0.6H), 1.55−
1.57 (m, 2H), 1.25−1.34 (m, 8H), 1.08 (dm, 1.2H, J = 6.9 Hz), 1.02
(dm, 0.8H, J = 10.5 Hz); 13C NMR (APT, CDCl3, 100 MHz) major
diastereomer δ 162.4, 161.7, 130.6, 93.7, 71.7, 68.2, 66.8, 59.8, 58.9,
45.96, 45.86, 34.2, 33.6, 30.5, 28.1, 27.9, 19.4, 14.2, minor diastereomer δ
162.4, 161.6, 131.2, 93.8, 71.7, 68.8, 66.9, 59.8, 58.9, 46.9, 45.6, 34.3,
34.0, 30.4, 28.2, 27.8, 19.7, 14.2; HRMS (EI) calcd for C18H28O5 [M]+
324.1937, found 324.1943.
homopropargylic alcohols were also demonstrated, suggesting
that the sterics of substituent groups play an important role in the
diastereoselectivity of cycloaddition.
EXPERIMENTAL SECTION
■
General Information. All glassware was flame- or oven-dried, and
reactions were carried out under an atmosphere of dry nitrogen at
ambient temperature. Standard column chromatography was performed
on 230−400 mesh silica gel using flash column chromatography
techniques.40 Analytical thin-layer chromatography (TLC) was
performed on precoated silica gel 60 F254 plates. Chemical shifts for
1H and 13C NMR spectra are reported in parts per million (ppm) from
tetramethylsilane with the solvent resonance as the internal standard
(deuterochloroform: δ 7.26 ppm for H; δ 77.0 ppm for 13C). GC
1
analyses were performed using an HP-1 (methyl siloxane) column, with
initial temperature 100 °C, helium flow rate 1.6 mL/min, pressure 9.52
psi, ramping 5 °C/min, final temperature 280 °C, hydrogen flow rate 40
mL/min, and air flow rate 450 mL/min. Enantiomeric ratios were
determined by HPLC using the following conditions: Chiralcel OD-H
column, 50/50 hexanes/2-propanol, 0.50 mL/min, 220 nm. Melting
points were measured using a Mel-Temp apparatus and are uncorrected.
Optical rotations were measured using an automatic polarimeter.
Reagents. Commercial reagents were used without purification.
Solvents were purified by distillation under dry nitrogen from CaH2
(dichloromethane and DMF), from molecular sieves (acetone), and
from potassium/benzophenone (THF). Norbornene 1 and alkynes 17,
18a−c, and 19 were purchased from Aldrich. Cp*RuCl(COD) was
prepared according to literature methods.41 For complete experimental
procedures and full characterization data of alkynes, see the Supporting
Information sections of our previous reports.42,43
Cycloadducts (S)-4d and (S)-5d (Table 1, Entry 4). Following the
above general procedure with norbornene 1 (18.1 mg, 0.192 mmol),
alkyne 2d (10.5 mg, 0.045 mmol), THF (0.20 mL) and Cp*RuCl-
(COD) (1.7 mg, 0.004 mmol), the reaction mixture was stirred for 150
h. The crude product was purified by column chromatography (EtOAc/
hexanes 0/1, 1/19, 1/9) to give an inseparable mixture of cycloadducts
4d and 5d (7.0 mg, 0.021 mmol, 47%, dr = 29:71 measured by GC) as a
General Procedure for Ru-Catalyzed [2 + 2] Cycloaddition. A
mixture of norbornene 1 (2.5−5 equiv), alkyne (1 equiv), and THF in
an oven-dried vial was placed via a cannula in an oven-dried screw-cap
vial containing Cp*RuCl(COD) (weighed in a drybox, 5−10 mol %)
under nitrogen. The reaction mixture was stirred in the absence of light
at 60 °C for 43−150 h. The crude product was purified by column
chromatography (ethyl acetate/hexanes mixture) to provide the
cycloadduct.
25
colorless oil: Rf = 0.40 (EtOAc/hexanes 1/9); [α]D = −14.1° (c =
0.085, CHCl3); GC (HP-1 column) retention time for major isomer
28.008 min and retention time for minor isomer 28.241 min; IR (neat)
3031, 2956, 2871, 1747, 1713, 1652, 1558, 1496, 1455, 1368, 1328,
1228, 1190, 1116, 1090 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.34 (s,
1.16H), 7.33 (s, 2.84H), 7.28 (m, 1H), 4.68 (q, 0.29H, J = 6.5 Hz), 4.66
(q, 0.71H, J = 6.6 Hz), 4.58 (d, 0.71H, J = 11.8 Hz), 4.55 (d, 0.29H, J =
11.8 Hz), 4.45 (d, 0.71H, J = 11.8 Hz), 4.41 (d, 0.29H, J = 11.8 Hz),
4.164 (q, 0.58H, J = 7.1 Hz), 4.161 (q, 1.42H, J = 7.1 Hz), 2.60 (s,
0.58H), 2.58 (d, 0.71H, J = 3.4 Hz), 2.56 (d, 0.71H, J = 3.4 Hz), 2.21 (m,
2H), 1.58 (m, 2H), 1.48 (dm, 1H, J = 10.4 Hz), 1.33 (d, 0.87H, J = 6.5
Hz), 1.31 (d, 2.13H, J = 6.6 Hz), 1.26 (t, 3H, J = 7.1 Hz), 1.11 (m,
2.71H), 1.05 (dm, 0.29H, J = 10.4 Hz); 13C NMR (APT, CDCl3, 150
MHz) major isomer δ 162.64, 162.45, 138.6, 131.6, 128.3, 127.7, 127.5,
71.4, 70.7, 59.8, 46.0, 45.9, 34.5, 33.6, 30.9, 28.31, 28.0, 19.5, 14.3, visible
peaks for minor isomer δ 162.60, 162.37, 138.5, 132.4, 128.6, 127.5, 71.1,
71.0, 46.9, 45.8, 34.6, 34.2, 30.6, 28.28, 27.9, 19.7; HRMS calcd for
C21H26O3 [M]+ 326.1882, found 326.1870.
Cycloadducts (S)-4a and (S)-5a (Table 1, Entry 1). Following the
above general procedure with norbornene 1 (42.4 mg, 0.450 mmol),
acetylene 2a (32.1 mg, 0.150 mmol), THF (0.1 mL) and Cp*Ru(COD)
Cl (4.8 mg, 0.016 mmol), the reaction mixture was stirred for 48 h. The
crude product was purified by column chromatography (EtOAc/
hexanes 1/19) to give an inseparable mixture of cycloadducts 4a and 5a
1
(16.3 mg, 0.0523 mmol, 35%, dr = 40:60 measured by H NMR and
GC) as a colorless oil: Rf = 0.36 (EtOAc/hexanes 1/9); GC (HP-1
column) retention time for major isomer 22.04 min, retention time for
minor isomer 22.72 min; IR (CH2Cl2) 3058, 2958, 2873, 1747, 1712,
1655, 1260, 1036 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.73 (q, 0.6H, J
= 6.8 Hz), 5.67 (q, 0.4H, J = 6.8 Hz), 4.12−4.21 (m, 4H), 2.48−2.56 (m,
2H), 2.17 (br s, 1H), 2.15 (br s, 0.4H), 2.01 (br s, 0.6H), 1.52−1.56 (m,
2H), 1.42 (d, 1.2H, J = 6.9 Hz), 1.40 (d, 1.8H, J = 6.8 Hz), 1.25−1.32 (m,
7H), 1.02−1.07 (m, 2.4H), 0.98 (dm, 0.6H, J = 10.5 Hz); 13C NMR
(APT, CDCl3, 100 MHz) major diastereomer δ 162.1, 158.49, 154.38,
130.8, 70.3, 63.93, 60.0, 46.2, 46.0, 34.2, 33.7, 30.46, 28.1, 27.7, 18.8,
14.2, minor diastereomer δ 162.0, 158.54, 154.41, 130.5, 71.4, 63.97,
60.0, 46.9, 45.7, 34.1, 34.0, 30.49, 27.9, 27.7, 19.0, 14.2; HRMS (EI)
calcd for C17H24O5 [M]+ 308.1624, found 308.1630.
Cycloadducts (S)-4b and (S)-5b (Table 1, Entry 2). Following the
above general procedure with norbornene 1 (76.7 mg, 0.81 mmol),
acetylene 2b (50 mg, 0.27 mmol), THF (0.2 mL), and Cp*Ru(COD)Cl
(4.9 mg, 0.013 mmol), the reaction mixture was stirred for 62 h. The
crude product was purified by column chromatography (EtOAc/
hexanes 1/19) to give an inseparable mixture of cycloadducts 4b and 5b
(24.8 mg, 0.0891 mmol, 33%, dr =40:60 measured by 1H NMR and GC)
as a colorless oil: Rf = 0.65 (EtOAc/hexanes 1/4); GC (HP-1 column)
retention time for major isomer = 19.23 min, retention time for minor
isomer 19.65 min; IR (CH2Cl2) 2957, 2872, 1744, 1717, 1653, 1369,
1237 cm−1; 1H NMR (CDCl3, 400 MHz) δ 5.84 (q, 0.6H, J = 6.7 Hz),
Cycloadducts (S)-4e and (S)-5e (Table 1, Entry 5). Following the
above general procedure with norbornene 1 (55.9 mg, 0.594 mmol),
alkyne 2e (25.1 mg, 0.098 mmol), THF (0.20 mL) and Cp*RuCl-
(COD) (3.7 mg, 0.010 mmol), the reaction mixture was stirred for 43 h.
The crude product was purified by column chromatography (EtOAc/
hexanes 0/1, 3/97, 1/19) to give an inseparable mixture of cycloadducts
4e and 5e (22.3 mg, 0.064 mmol, 65%, dr = 32:68 measured by GC) as a
22
colorless oil: Rf = 0.45 (EtOAc/hexanes 1/19); [α]D = +17.1° (c =
0.58, CHCl3); GC (HP-1 column): retention time for major isomer
23.320 min and retention time for minor isomer 22.790 min; IR (neat)
2964, 2933, 2866, 1722, 1655, 1470, 1368, 1336, 1264, 1229, 1192,
1130, 1084, 1048 cm−1; 1H NMR (CDCl3, 400 MHz) δ 4.97 (q, 0.73H, J
= 6.4 Hz), 4.92 (q, 0.27H, J = 6.6 Hz), 4.16 (qd, 2H, J = 7.1, 2.3 Hz), 2.54
(d, 0.27H, J = 3.2 Hz), 2.51 (dm, 1.73H, J = 3.7 Hz), 2.21 (s, 1.27H),
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2.17 (s, 0.73H), 1.53−1.60 (m, 2H), 1.39 (dm, 1H, J = 10.2 Hz), 1.28 (t,
3H, J = 7.1 Hz), 1.27 (d, 0.81H, J = 6.6 Hz), 1.24 (d, 2.19H, J = 6.4 Hz),
1.07 (m, 2H), 0.99 (dm, 1H, J = 10.2 Hz), 0.88 (s, 9H), 0.07 (s, 2.19H),
0.04 (s, 3H), 0.03 (s, 0.81H); 13C NMR (APT, CDCl3, 100 MHz) major
isomer δ 164.3, 162.7, 127.8, 64.5, 59.7, 45.9, 45.7, 34.6, 34.0, 30.6, 28.2,
28.1, 25.8, 22.5, 18.1, 14.3, −4.85, −5.00, visible peaks for minor isomer:
δ 165.2, 65.3, 46.8, 45.3, 34.4, 34.2, 30.5, 28.3, 27.9, 22.9, −4.91, −4.96.
Anal. Calcd for C20H34O3Si: C, 68.52; H, 9.78. Found C, 68.17; H, 9.97.
Cycloadducts (S)-4f and (S)-5f (Table 1, Entry 6). Following the
above general procedure with norbornene 1 (159 mg, 1.69 mmol),
acetylene 2f (80 mg, 0.56 mmol), THF (0.3 mL), and Cp*Ru(COD)Cl
(13.3 mg, 0.035 mmol), the reaction mixture was stirred at 60 °C for 72
h to afford an inseparable mixture of cycloadducts 4f and 5f: 93.1 mg,
0.40 mmol, 71% yellow oil; dr = 81:19 (measured by 1H NMR and GC).
For characterization data, see our previous report.19
Cycloadducts 19g and 20g (Table 2, Entry 3). Following the
above general procedure with norbornene 1 (242.2 mg, 2.572 mmol),
propargylic alcohol 16g (132.1 mg, 0.9036 mmol), THF (1.8 mL), and
Cp*RuCl(COD) (20.4 mg, 0.0537 mmol), the reaction mixture was
stirred for 72 h. The crude product was purified by column
chromatography (EtOAc/hexanes 2/8) to provide a separable mixture
of cycloadducts 19g and 20g (123.3 mg, 0.5130 mmol, 57%, dr = 64:36
measured by GC) as a yellow oil: Rf for major isomer 0.43 (EtOAc/
hexanes 2/8), Rf for minor isomer 0.53 (EtOAc/hexanes 2/8); GC (HP-
1 column) retention time for major isomer 21.65 min, retention time for
minor isomer 21.28 min; IR (CH2Cl2, NaCl) major isomer 3387, 2950,
2869, 1492, 1447, 1368, 1297, 1061 cm−1, minor isomer 3382, 2949,
2920, 2867, 1492, 1447, 1296, 1061 cm−1; 1H NMR (CDCl3, 400 MHz)
major isomer 7.30−7.38 (m, 4H), 7.21−7.25 (m, 1H), 4.86 (q, 1H, J =
6.6 Hz), 2.68−2.69 (m, 1H), 2.62−2.63 (m, 1H), 2.19 (br s, 1H), 2.16
(br s, 1H), 1.67 (br s, 1H), 1.58−1.65 (m, 2H), 1.44−1.46 (m, 1H), 1.40
(d, 3H, J = 6.6 Hz), 1.12−1.19 (m, 2H), 1.00−1.03 (m, 1H), minor
isomer δ 7.39−7.43 (m, 2H), 7.32−7.35 (m, 2H), 7.16−7.25 (m, 1H),
4.83 (q, 1H, J = 6.5 Hz), 2.68−2.69 (m, 1H), 2.54−2.55 (m, 1H), 2.20
(br s, 1H), 2.18 (br s, 1H), 1.58−1.63 (m, 3H), 1.52−1.55 (m, 1H), 1.39
(d, 3H, J = 6.5 Hz), 1.12−1.19 (m, 2H), 1.03−1.05 (m, 1H); 13C NMR
(APT, CDCl3, 75 MHz) major isomer δ 144.4, 138.8, 134.4, 128.4,
127.2, 126.8, 64.8, 45.9, 45.5, 34.9, 34.6, 30.6, 28.6, 28.3, 21.7, minor
isomer δ 144.3, 139.0, 134.4, 128.4, 127.2, 126.8, 65.1, 45.8, 45.5, 35.2,
34.6, 30.6, 28.7, 28.3, 21.4; HRCI calcd for C17H20O [M + H]+
241.1592, found for major isomer 241.1597, found for minor isomer
241.1588.
Cycloadducts 7 and 8 (Scheme 2). Following the above general
procedure with alkene 6 (90.1 mg, 0.349 mmol), alkyne 2f (35.1 mg,
0.246 mmol), THF (0.6 mL), and Cp*Ru(COD)Cl (5.6 mg, 0.015
mmol), the reaction mixture was stirred for 1 h. The crude product was
purified by column chromatography (gradient EtOAc/hexanes 1/19 to
2/3) to provide 7 and 8 as an inseparable mixture (73.2 mg, 0.183 mmol,
1
74%, dr = 91:9 measured by H NMR). 7 (major diastereomer): Rf =
0.19 (EtOAc/hexanes 3/7); IR (CH2Cl2) 3415, 2983, 2907, 1762, 1681,
1673, 1202 cm−1; 1H NMR (CDCl3, 300 MHz) δ 6.78 (m, 2H), 4.79 (br
s, 1H), 4.59 (br q, 1H, J = 6.7 Hz), 4.23 (q, 2H, J = 7.1 Hz), 3.18 (br s,
1H), 3.05 (br s, 1H), 2.76 (br d, 1H, J = 3.1 Hz), 2.70 (br d, 1H, J = 3.2
Hz), 2.31 (s, 3H), 2.30 (s, 3H), 1.77 (br s, 2H), 1.35 (d, 3H, J = 6.6 Hz),
1.32 (t, 3H, J = 7.1 Hz); 13C NMR (CDCl3, 75 MHz) δ 169.2,
169.1,167.9, 163.7, 142.3, 140.3, 139.8, 129.8, 120.5, 120.3, 65.7, 61.0,
44.2, 42.9, 40.6, 38.4, 37.9, 21.5, 20.84, 20.74, 14.1; HRMS (CI) calcd for
C22H24O7 [M + H]+ 401.1600, found 401.1608.
Cycloadducts 9 and 10 (Scheme 2). To a solution of 7 and 8 (42.1
mg, 0.105 mmol) in pyridine (0.3 mL) was added 4-nitrobenzoyl
chloride (38.4 mg, 0.207 mmol). The reaction mixture was stirred at
room temperature for 1.5 h, diluted with ethyl acetate, and washed three
times with saturated copper sulfate aqueous solution and once with
water. The organic layer was dried over Na2SO4, concentrated, and
purified by column chromatography (gradient EtOAc/hexanes 1/10 to
2/3) to give a mixture of 9 and 10 (56.3 mg, 0.102 mmol, 96%) as a
white solid. The pure major diastereomer 9 was obtained through
fractional recrystallization (Et2O/hexanes, three times): IR (CH2Cl2)
2979, 2954, 1763, 1725, 1529, 1269 cm−1; 1H NMR (CDCl3, 300 MHz)
δ 8.26−8.32 (m, 4H), 6.81 (d, 1H, J = 8.8 Hz), 6.77 (d, 1H, J = 8.8 Hz),
6.07 (q, 1H, J = 6.8 Hz), 4.22 (q, 2H, J = 7.1 Hz), 3.27 (s, 1H), 3.16 (s,
1H), 2.85 (br d, 1H, J = 3.4 Hz), 2.82 (br d, 1H, J = 3.4 Hz), 2.32 (s, 3H),
2.18 (s, 3H), 1.84 (m, 2H), 1.63 (d, 3H, J = 6.8 Hz), 1.32 (t, 3H, J = 7.1
Hz); 13C NMR (APT, CDCl3, 75 MHz) δ 169.2, 168.7, 163.8, 161.7,
158.5, 150.6, 142.6, 142.3, 140.1, 139.8, 135.6, 131.5, 130.9, 123.5, 120.7,
120.2, 69.5, 60.4, 44.3, 43.3, 40.6, 38.6, 38.4, 20.9, 20.7, 19.1, 14.3;
HRMS (CI) calcd for C29H27NO10 [M + H]+ 549.1635, found 549.1641.
Oxidized Cycloadducts 11f and 12f (Scheme 4). For character-
ization, see our previous report.19
Cycloadducts 19e and 20e (Table 2, Entry 4). Following the
above general procedure with norbornene 1 (119.5 mg, 1.269 mmol),
propargylic alcohol 16e (50.1 mg, 0.397 mmol), THF (0.8 mL), and
Cp*RuCl(COD) (11.6 mg, 0.0305 mmol), the reaction mixture was
stirred for 72 h. The crude product was purified by column
chromatography (EtOAc/hexanes 1/9) to provide an inseparable
mixture of cycloadducts 19e and 20e (77.8 mg, 0.353 mmol, 88%, dr =
82:12 measured by GC) as a yellow oil: Rf 0.35 (EtOAc/hexanes 1/9);
GC (HP-1 column) retention time for major isomer 14.78 min,
retention time for minor isomer 14.47 min; IR (neat, NaCl) 3328, 2950,
2868, 1449, 1366, 1296, 1316, 1082 cm−1; 1H NMR (CDCl3, 300 MHz)
δ 4.41 (q, 1H, J = 6.5 Hz), 2.39 (br s, 1H), 2.23 (br s, 1H), 1.98−2.06 (m,
3H), 1.95 (br s, 1H), 1.41−1.57 (m, 4H), 1.28−1.40 (m, 4H), 1.25 (d,
0.54H, J = 6.5 Hz), 1.24 (d, 2.46H, J = 6.6 Hz), 0.92−1.01 (m, 3H), 0.88
(t, 3H, J = 7.1 Hz); 13C NMR (APT, CDCl3, 75 MHz) major isomer δ
143.1, 142.5, 64.7, 47.3, 45.4, 34.8, 34.1, 30.4, 29.9, 28.4, 27.2, 22.9, 22.1,
13.9, visible peaks for minor isomer δ 64.2, 47.1, 45.3, 34.7, 27.3, 21.9;
HRCI calcd for C15H24O [M + H]+ 221.1905, found 221.1911.
Cycloadducts 19f and 20f (Table 2, Entry 5). Following the
above general procedure with norbornene 1 (36.5 mg, 0.388 mmol),
propargylic alcohol 16f (18.0 mg, 0.117 mmol), THF (0.2 mL), and
Cp*RuCl(COD) (6.0 mg, 0.016 mmol), the reaction mixture was
stirred for 72 h. The crude product was purified by column
chromatography (EtOAc/hexanes 1/9) to provide an inseparable
mixture of cycloadducts 19f and 20f (13.1 mg, 0.0527 mmol, 44%, dr =
1
77:23 measured by H NMR) as a pale yellow oil: Rf 0.45 (EtOAc/
hexanes 1/9); IR (neat, NaCl) 3303, 2951, 2926, 2869, 1453 cm−1; 1H
NMR (CDCl3, 400 MHz) δ 4.43 (q, 1H, J = 6.6 Hz), 2.40 (br s, 0.77H),
2.34 (br s, 0.23H), 2.24−2.25 (m, 1H), 1.99−2.06 (m, 3H), 1.96 (br s,
1H), 1.60 (br s, 1H), 1.51−1.54 (m, 2H), 1.35−1.43 (m, 2H), 1.25−
1.30 (m, 11H), 0.94−1.03 (m, 2H), 0.88 (t, 3H, J = 7.1 Hz); 13C NMR
(APT, CDCl3, 75 MHz) major isomer δ 143.2, 142.5, 64.3, 47.4, 45.4,
34.9, 34.2, 31.7, 30.5, 29.5, 28.4, 27.7, 27.5, 22.6, 22.1, 14.1, visible peaks
for minor isomer δ 143.1, 64.7, 47.1, 45.3, 34.8, 22.0; HRCI calcd for
C17H28O [M + H]+ 249.2218, found 249.2212.
Cycloadducts 19a and 20a (Table 2, Entry 6). Following the
above general procedure with norbornene 1 (228.9 mg, 2.431 mmol),
propargylic alcohol 16a (80.7 mg, 0.806 mmol), THF (1.0 mL), and
Cp*RuCl(COD) (32.6 mg, 0.0858 mmol), the reaction mixture was
stirred for 72 h. The crude product was purified by column
chromatography (EtOAc/hexanes 4/6) to provide an inseparable
mixture of cycloadducts 19a and 20a (95.4 mg, 0.491 mmol, 61%, dr =
55:45 determined by GC from the acetylated cycloadducts) as a yellow
Cycloadducts 19c and 20c (Table 2, Entry 2). Following the
above general procedure with norbornene 1 (77.1 mg, 0.819 mmol),
propargylic alcohol 16c (45.8 mg, 0.269 mmol), THF (0.4 mL), and
Cp*RuCl(COD) (11.0 mg, 0.0289 mmol), the reaction mixture was
stirred for 72 h. The crude product was purified by column
chromatography (EtOAc/hexanes 1/9) to provide an inseparable
mixture of cycloadducts 19c and 20c (52.9 mg, 0.200 mmol, 74%, dr =
1
78:22 measured by H NMR) as a colorless oil: Rf = 0.38 (EtOAc/
Hexanes 1/9); IR (neat, NaCl) 3446, 2960, 2875, 1714, 1370, 1257
cm−1; 1H NMR (CDCl3, 300 MHz) δ 5.24 (br s, 1H), 4.44 (q, 1H, J =
6.7 Hz), 2.47 (br s, 1H), 2.37−2.38 (m, 0.78H), 2.30−2.31 (m, 0.22H),
2.12 (br s, 1H), 1.99 (br s, 1H), 1.53−1.56 (m, 2H), 1.50 (s, 1.98H),
1.47 (s, 7.02H), 1.28 (d, 3H, J = 6.9 Hz), 0.98−1.11 (m, 4H); 13C NMR
(APT, CDCl3, 75 MHz) major isomer δ 166.5, 163.7, 130.6, 81.4, 65.4,
46.6, 45.8, 33.9, 33.4, 30.43, 28.1, 27.9, 21.3; visible peaks for minor
isomer δ 81.8, 67.1, 47.2, 46.0, 34.1, 33.8, 30.37, 28.0, 21.7; HRCI calcd
for C16H24O3 [M + H]+ 265.1804, found 265.1811.
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oil: Rf 0.23 (EtOAc/hexanes 4/6); IR (neat, NaCl) 3301, 2948, 2869,
28.14, 28.09, 26.1, 14.2; HRCI calcd for C17H26O3 [M + H]+ 279.1960,
found for major isomer 279.1963, found for minor isomer 279.1958.
Cycloadducts 19j and 20j (Table 3, Entry 4). Following the above
general procedure with norbornene 1 (199.0 mg, 2.11 mmol),
propargylic alcohol 16j (153.1 mg, 0.728 mmol), THF (1.0 mL), and
Cp*RuCl(COD) (26.3 mg, 0.0692 mmol), the reaction mixture was
stirred for 72 h. The crude product was purified by column
chromatography (EtOAc/hexanes 1/9) to provide a separable mixture
of cycloadducts 19j and 20j (218.5 mg, 0.7178 mmol, 98%, dr = 88:12
1
1451, 1368, 1318, 1297, 1265 cm−1; H NMR (CDCl3, 400 MHz) δ
4.30−4.36 (m, 1H), 4.085−4.092 (m, 2H), 2.30−2.32 (m, 1H), 2.24 (br
s, 1H), 2.01 (br s, 0.5H), 1.94 (br s, 1.5H), 1.50−1.55 (m, 2.5H), 1.43−
1.46 (m, 0.5H), 1.28 (d, 1.5H, J = 6.4 Hz), 1.26 (d, 1.5H, J = 6.4 Hz),
0.96−1.03 (m, 3H); 13C NMR (APT, CDCl3, 75 MHz) major isomer δ
144.1, 139.1, 64.4, 59.1, 46.1, 45.7, 33.8, 30.4, 28.2, 22.0, visible peaks for
minor isomer δ 143.9, 139.6, 66.2, 59.2, 46.7, 45.9, 34.6, 33.6, 30.3, 28.3,
22.5; HRCI calcd for C12H18O2 [M + H]+ 195.1385, found 195.1380.
Cycloadducts 19b and 20b (Table 2, Entry 7). Following the
above general procedure with norbornene 1 (318.3 mg, 3.380 mmol),
propargylic alcohol 16b (141.9 mg, 1.107 mmol), THF (1.2 mL), and
Cp*RuCl(COD) (32.1 mg, 0.0845 mmol), the reaction mixture was
stirred for 72 h. The crude product was purified by column
chromatography (EtOAc/hexanes 4/6) to provide an inseparable
mixture of cycloadducts 27i and 28i (137.7 mg, 0.6194 mmol, 56%, dr =
50:50 determined by GC from the acetylated cycloadducts) as a yellow
oil: Rf 0.38 (EtOAc/hexanes 4/6); IR (neat, NaCl) 3208, 2958, 2869,
1449, 1374, 1359, 1316, 1004 cm−1; 1H NMR (CDCl3, 400 MHz) δ 4.67
(br s, 2H), 4.28−4.35 (m, 1H), 2.27 (d, 1H, J = 2.5 Hz), 2.18−2.22 (m,
1H), 2.00 (br s, 0.5H), 1.97 (br s, 1H), 1.92 (br s, 0.5H), 1.48−1.59 (m,
3H), 1.32 (s, 1.5H), 1.30 (s, 1.5H), 1.292 (s, 1.5H), 1.290 (s, 1.5H), 1.27
(d, 1.5H, J = 6.7 Hz), 1.24 (d, 1.5H, J = 6.7 Hz), 0.93−1.03 (m, 3H); 13C
NMR (APT, CDCl3, 75 MHz) δ 146.3, 145.8, 141.9, 141.7, 70.5, 66.1,
64.3, 46.0, 45.9, 45.6, 44.9, 34.9, 34.5, 34.4, 33.9, 30.23, 30.18, 30.1, 29.6,
29.2, 28.9, 28.4, 28.3, 22.6, 22.2; HRCI calcd for C14H22O2 [M + H]+
223.1698, found 223.1705.
Cycloadducts 19h and 20h (Table 3, Entry 2). Following the
above general procedure with norbornene 1 (158.0 mg, 1.678 mmol),
propargylic alcohol 16h (111.9 mg, 0.548 mmol), THF (0.80 mL), and
Cp*RuCl(COD) (17.3 mg, 0.0455 mmol), the reaction mixture was
stirred for 72 h. The crude product was purified by column
chromatography (EtOAc/hexanes 1/9) to provide an inseparable
mixture of cycloadducts 19h and 20h (121.3 mg, 0.4065 mmol, 74%, dr
= 90:10 measured by HPLC from the oxidized cycloadducts) as a yellow
oil: Rf = 0.41 (EtOAc/hexanes 1/9); IR (neat, NaCl) 3382, 2956, 2872,
1712, 1679, 1451, 1369, 1285, 1215, 1057, 1026 cm−1; 1H NMR
(CDCl3, 400 MHz, no visible peaks for minor isomer) δ 7.26−7.43 (m,
5H), 6.02 (br s, 1H), 5.32 (s, 1H), 4.25 (q, 2H, J = 7.1 Hz), 2.51 (d, 1H,
2.3 Hz), 2.20 (d, 1H, J = 3.3 Hz), 2.18 (br s, 1H), 2.05 (br s, 1H), 1.47−
1.61 (m, 2H), 1.40−1.44 (m, 1H), 1.33 (t, 3H, J = 7.1 Hz), 0.96−1.08
(m, 3H); 13C NMR (APT, CDCl3, 75 MHz, no visible peaks for minor
isomer) δ 165.7, 164.3, 141.2, 129.3, 128.5, 127.7, 126.4, 72.6, 60.9, 47.2,
45.8, 33.9, 33.5, 30.5, 27.9, 27.8, 14.2; HRCI calcd for C19H22O3 [M +
H]+ 299.1647, found 299.1640.
Cycloadducts 19i and 20i (Table 3, Entry 3). Following the above
general procedure with norbornene 1 (62.2 mg, 0.661 mmol),
propargylic alcohol 16i (41.6 mg, 0.226 mmol), THF (0.30 mL), and
Cp*RuCl(COD) (7.4 mg, 0.019 mmol), the reaction mixture was
stirred for 72 h. The crude product was purified by column
chromatography (EtOAc/hexanes 1/9) to provide a separable mixture
of cycloadducts 19i and 20i (50.5 mg, 0.181 mmol, 75%, dr = 92:8
measured by GC) as a yellow oil: Rf for major isomer 0.47 (EtOAc/
hexanes 1/9), Rf for minor isomer 0.32 (EtOAc/hexanes 1/9); GC (HP-
1 column): retention time for major isomer 20.71 min, retention time
for minor isomer 20.93 min; IR (neat, NaCl) major isomer 3412, 2954,
2871, 1682, 1631, 1367, 1284, 1217 cm−1, minor isomer 3517 (m), 2954
(s), 2871 (m), 1712 (s), 1694 (s), 1642 (m), 1478 (m), 1393 (w), 1367
(m), 1264 (m) cm−1; 1H NMR (CDCl3, 300 MHz) major isomer δ 5.29
(d, 1H, J = 9.3 Hz), 4.20 (dq, 2H, J = 7.1, 2.3 Hz), 3.72 (d, 1H, J = 9.3
Hz), 2.60 (d, 1H, J = 2.6 Hz), 2.44, (d, 1H, J = 2.9 Hz), 2.14 (br s, 1H),
2.09 (br s, 1H), 1.57−1.60 (m, 2H), 1.36−1.39 (m, 1H), 1.30 (t, 3H, J =
7.1 Hz), 1.01−1.09 (m, 3H), 0.95 (s, 9H), minor isomer δ 4.16−4.20
(m, 3H), 3.29 (d, 1H, J = 7.4 Hz), 2.58 (d, 1H, J = 3.1 Hz), 2.51, (d, 1H, J
= 3.1 Hz), 2.21 (br s, 1H), 2.18 (br s, 1H), 1.56−1.59 (m, 2H), 1.40−
1.43 (m, 1H), 1.29 (t, 3H, J = 7.1 Hz), 1.05−1.10 (m, 3H), 0.96 (s, 9H);
13C NMR (APT, CDCl3, 75 MHz) major isomer δ 167.3, 164.3, 131.5,
78.2, 60.7, 50.8, 46.1, 37.3, 33.7, 33.6, 30.5, 28.1, 28.0, 26.0, 14.2, minor
isomer δ 164.3, 163.5, 133.0, 78.0, 60.2, 49.7, 46.2, 36.3, 35.0, 33.8, 30.7,
1
measured by H NMR) as a yellow oil: Rf for major isomer 0.46
(EtOAc/hexanes 1/9), Rf for minor isomer 0.35 (EtOAc/hexanes 1/9);
IR (neat, NaCl) major isomer 3416, 2929, 2870, 2854, 1714, 1682, 1634,
1451, 1369, 1299, 1285 cm−1, minor isomer 3425, 2928, 2869, 2853,
1712, 1682, 1636, 1450, 1369, 1303, 1284, 1214 cm−1; 1H NMR
(CDCl3, 300 MHz) major isomer δ 5.16 (br s, 1H), 4.19 (dq, 2H, J = 7.1,
1.1 Hz), 4.03 (br s, 1H), 2.57 (d, 1H, J = 2.2 Hz), 2.39 (d, 1H, J = 3.1
Hz), 2.15 (br s, 1H), 2.04 (br s, 1H), 1.74−1.78 (m, 2H), 1.46−1.63 (m,
6H), 1.39 (br s, 1H), 1.35 (br s, 1H), 1.29 (t, 3H, J = 7.1 Hz), 1.01−1.22
(m, 7H), minor isomer δ 4.76 (br s, 1H), 4.45 (br s, 1H), 4.18 (q, 2H, J =
7.1 Hz), 2.57 (br s, 1H), 2.43 (d, 1H, J = 2.9 Hz), 2.17 (br s, 1H), 2.11
(br s, 1H), 1.51−1.78 (m, 8H), 1.37−1.50 (m, 3H), 1.29 (t, 3H, J = 7.1
Hz), 1.05−1.23 (m, 6H); 13C NMR (APT, CDCl3, 75 MHz) major
isomer δ 167.6, 164.3, 130.5, 74.2, 60.7, 48.0, 45.8, 43.5, 33.8, 33.6, 30.5,
29.3, 28.0, 27.9, 26.8, 26.4, 26.31, 26.26 14.2, minor isomer δ 166.4,
164.0, 131.1, 75.8, 60.5, 48.0, 45.9, 43.0, 34.6, 33.8, 30.8, 30.2, 28.3, 27.9,
26.6, 26.2, 26.1, 14.2; HRCI calcd for C19H28O3 [M + H]+ 305.2117,
found for major isomer 305.2114, found for minor isomer: 305.2112.
Oxidized Cycloadducts 25 and 26 (Scheme 7). Following the
oxidation protocol from our previous work19 with 23 and 24 (132.8 mg,
0.4451 mmol), the reaction mixture was stirred for 36 h. This was
filtered through a plug of silica and concentrated in vacuo. The crude
product was purified by column chromatography (EtOAc/hexanes 1/9)
to provide the oxidized adduct mixture 25 and 26 (82.6 mg, 0.279 mmol,
62%) as a yellow oil: Rf = 0.46 (EtOAc/hexanes 1/9); [α]24D = +59.8° (c
0.545, CHCl3, 80% ee measured by HPLC); HPLC (OJ-H column, 0.50
i
mL/min, 1% PrOH/hexane, 254 nm) major enantiomer 20.44 min,
minor enantiomer 25.00 min; IR (neat, NaCl) 2959, 2873, 1719, 1645,
1
1449, 1317, 1283, 1203, 1122 cm−1; H NMR (CDCl3, 400 MHz) δ
7.88−7.90 (m, 2H), 7.55−7.59 (m, 1H), 7.43−7.47 (m, 2H), 3.89−3.98
(m, 2H), 2.87 (d, 1H, J = 3.1 Hz), 2.82 (d, 1H, J = 3.0 Hz), 2.35 (s, 2H),
1.56−1.67 (m, 3H), 1.11−1.18 (m, 3H), 0.86 (t, 3H, J = 7.1 Hz); 13C
NMR (APT, CDCl3, 75 MHz) δ 191.5, 161.4, 151.1, 137.8, 136.6, 133.3,
129.2, 128.4, 60.4, 49.5, 47.0, 34.4, 34.3, 30.8, 27.9, 13.5; Anal. Calcd for
C19H20O3: C, 77.00; H, 6.80. Found: C, 76.90; H, 6.94.
Cycloadducts 29a and 30a (Table 4, Entry 1). Following the
above general procedure with norbornene 1 (101.9 mg, 1.082 mmol),
homopropargylic alcohol 27a (59.6 mg, 0.350 mmol), THF (0.50 mL),
and Cp*RuCl(COD) (13.2 mg, 0.0347 mmol), the reaction mixture was
stirred for 72 h. The crude product was purified by column
chromatography (EtOAc/hexanes 2/8) to provide an inseparable
mixture of cycloadducts 29a and 30a (83.9 mg, 0.317 mmol, 91%, dr =
63:37 measured by 1H NMR) as a yellow oil: Rf = 0.48 (EtOAc/hexanes
2/8); IR (neat, NaCl) 3479, 2956, 2872, 1714, 1694, 1650, 1463, 1454,
1370, 1284 cm−1; 1H NMR (CDCl3, 300 MHz) δ 4.16 (q, 2H, J = 7.1
Hz), 3.74−3.76 (m, 1H), 2.97 (br s, 0.37H), 2.76 (br s, 0.63H), 2.54−
2.63 (m, 2H), 2.35−2.46 (m, 2H), 2.16 (br s, 1H), 2.03 (br s, 1H),
1.46−1.62 (m, 4H), 1.28 (t, 3H, J = 7.1 Hz), 1.01−1.08 (m, 4H), 0.95 (t,
3H, J = 7.4 Hz); 13C NMR (APT, CDCl3, 75 MHz) major isomer δ
163.6, 161.1, 132.1, 71.1, 59.89, 48.9, 46.4, 37.0, 33.9, 33.4, 30.6, 30.5,
28.1, 27.9, 14.3, 9.9; visible peaks for minor isomer δ 163.7, 161.2, 32.0,
71.6, 59.94, 49.7, 37.2, 34.0, 33.6; HRCI calcd for C16H24O3 [M + H]+
265.1810, found 265.1804.
Cycloadducts 29b and 30b (Table 4, Entry 2). Following the
above general procedure with norbornene 1 (48.0 mg, 0.510 mmol),
homopropargylic alcohol 27b (53.8 mg, 0.188 mmol), THF (0.30 mL),
and Cp*RuCl(COD) (9.6 mg, 0.025 mmol), the reaction mixture was
stirred for 72 h. The crude product was purified by column
chromatography (EtOAc/hexanes 2/8) to provide an inseparable
mixture of cycloadducts 29b and 30b (66.3 mg, 0.174 mmol, 92%, dr =
56:44 measured by 1H NMR) as a yellow oil: Rf = 0.60 (EtOAc/hexanes
3855
dx.doi.org/10.1021/om500563h | Organometallics 2014, 33, 3847−3856

Organometallics
Article
2/8); IR (neat, NaCl) 3461, 2954, 2870, 2859, 1710, 1646, 1472 cm−1;
1H NMR (CDCl3, 400 MHz) δ 4.16 (q, 0.88H, J = 7.2 Hz), 4.15 (q,
1.12H, J = 7.1 Hz), 3.81−3.89 (m, 1H), 3.54−3.62 (m, 1H), 3.47−3.52
(m, 1H), 2.60−2.64 (m, 1H), 2.58 (br s, 1H), 2.46−2.48 (m, 1H), 2.45−
2.46 (m, 1H), 2.41−2.43 (m, 0.44H), 2.16 (br s, 0.56H), 2.03−2.06 (m,
1H), 1.54−1.57 (m, 2H), 1.27 (t, 3H, J = 7.1 Hz), 1.05−1.08 (m, 2H),
0.98−1.00 (m, 1H), 0.893 (s, 5.04H), 0.891 (s, 3.96H), 0.87−0.88 (m,
1H), 0.063 (s, 3.36H), 0.059 (s, 2.64H); 13C NMR (APT, CDCl3, 75
MHz) major isomer δ 163.2, 160.3, 132.3, 70.0, 67.1, 59.8, 49.0, 46.36,
33.9, 33.5, 33.1, 30.6, 28.1, 27.9, 25.9, 18.3, 14.3, −5.4, visible peaks for
minor isomer δ 163.4, 160.4, 132.1, 70.3, 67.0, 59.7, 49.4, 46.41, 33.6,
33.2; HRCI calcd for C21H36O4Si [M + H]+ 381.2465, found 381.2461.
Cycloadducts 29c and 30c (Table 4, Entry 3). Following the
above general procedure with norbornene 1 (47.5 mg, 0.504 mmol),
homopropargylic alcohol 27c (35.3 mg, 0.162 mmol), THF (0.30 mL),
and Cp*RuCl(COD) (8.6 mg, 0.023 mmol), the reaction mixture was
stirred for 72 h. The crude product was purified by column
chromatography (EtOAc/hexanes 2/8) to provide an inseparable
mixture of cycloadducts 29c and 30c (44.6 mg, 0.143 mmol, 89%, dr =
72:28 measured by 1H NMR) as a yellow oil: Rf = 0.50 (EtOAc/hexanes
2/8); IR (neat, NaCl) 3418, 2952, 2871, 1712, 1694, 1682, 1650, 1454,
1370 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.24−7.40 (m, 5H), 4.91−
4.97 (m, 1H), 4.19 (q, 2H J = 7.1 Hz), 3.49 (br s, 1H), 2.93−2.99 (m,
1H), 2.72−2.85 (m, 1H), 2.62 (d, 0.28H, J = 3.8 Hz), 2.59 (d, 0.72H, J =
3.3 Hz), 2.56 (d, 0.28H, J = 3.0 Hz), 2.38 (d, 0.72H, J = 2.8 Hz), 2.26 (d,
0.28H, J = 3.1 Hz), 2.16 (br s, 0.72H), 2.03 (br s, 0.28H), 1.93 (br s,
0.72H), 1.49−1.60 (m, 2H), 1.30 (t, 3H, J = 7.1 Hz), 1.19−1.22 (m,
1H), 0.93−1.10 (m, 3H); 13C NMR (APT, CDCl3, 75 MHz) major
isomer δ 163.6, 160.3, 144.3, 132.6, 128.4, 127.5, 125.7, 72.1, 60.0, 48.8,
46.4, 39.5, 33.8, 33.3, 30.5, 28.0, 27.8, 14.3, visible peaks for minor
isomer δ 163.7, 160.4, 132.5, 127.4, 125.5, 72.4, 49.6, 39.6, 33.9, 33.5;
HRCI calcd for C20H24O3 [M + H]+ 313.1806, found 313.1804.
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ASSOCIATED CONTENT
■
(32) Lautens, M.; Tam, W.; Lautens, J. C.; Edwards, L. E.; Crudden, C.
M.; Smith, A. C. J. Am. Chem. Soc. 1995, 117, 6863.
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(36) Takami, K.; Kawachi, A.; Shibata, T. Org. Lett. 2006, 8, 1343.
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S
* Supporting Information
1
Text and figures giving H and 13C NMR spectra of all new
compounds and details of the preparation and characterization of
alkynes. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail for W.T.: wtam@uoguelph.ca.
■
(38) Avullon, G.; Bellamy, D.; Brammer, L.; Bruton, E. A.; Orpen, A. G.
Chem. Commun. 1998, 653.
Notes
(39) Liu, Peng; Tam, W.; Goddard, J. D. Tetrahedron 2007, 63, 7659.
(40) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
(41) Fagan, P. J.; Mahoney, W. S.; Calabrese, J. C.; Williams, I. D.
Organometallics 1990, 9, 1843.
(42) Villeneuve, K.; Tam, W. Organometallics 2006, 25, 843.
(43) Villeneuve, K.; Tam, W. Organometallics 2007, 26, 6082.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Natural Sciences and Engineering
Research Council of Canada (NSERC). K.V. thanks the NSERC
for a postgraduate scholarship.
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