Regiochemistry in cobalt-mediated intermolecular Pauson-Khand reactions of unsymmetrical internal heteroaromatic alkynes with norbornene

Article abstract of DOI:10.1021/jo200664m

The intermolecular Pauson-Khand (PK) reactions of sterically comparable (2-phenylethynyl)heteroaromatic compounds with norbornene, mediated by Co ₂(CO)₈ to give cyclopentenone products, were examined in this study. A synthetic protocol utilizing focused-microwave dielectric heating proved indispensable in the efficient synthesis of the PK cyclopentenone products. "π-Deficient" heteroaromatic substrates, e.g., 2-pyrones, and some "π-excessive" heteroaromatics such as 2- and 3-thiophene and 2-furan favor the β-position in the newly formed cyclopentenone ring. Other π-excessive heteroaromatics such as 2-pyrrole or 2-indole favor the α-position. A π-excessive 3-indole derivative gave a nearly equal mixture of regioisomers. The position of the nitrogen in pyridyl-containing alkyne substrates also affects the regiochemical outcome of the PK reaction. A 2-pyridyl alkyne, possessing a proximal nitrogen, influences the regioselectivity relative to a 4-pyridyl variant quite dramatically, favoring the β-position in the newly formed cyclopentenone ring. A 2-pyrimidylalkyne exhibits similar behavior to the 2-pyridylalkyne. Compounds that do not participate in PK reactions with norbornene include (2-phenylethynyl)imidazoles and the related benzimidazoles, which promote rapid decomposition of the in situ generated (μ₂-alkyne)Co₂(CO)₆ complexes. This stands in contrast with other nitrogen-containing heteroaromatics, e.g., pyrrole-, indole-, and pyrimidine-derived compounds, which effectively undergo PK reactions. Overall, the type of heteroaromatic group dramatically influences PK regioselectivity, which can in part be explained by rationalization of the current reaction mechanism, but not fully.

Full text of DOI:10.1021/jo200664m

ARTICLE
pubs.acs.org/joc
Regiochemistry in Cobalt-Mediated Intermolecular PausonꢀKhand
Reactions of Unsymmetrical Internal Heteroaromatic Alkynes with
Norbornene
Benjamin E. Moulton, Adrian C. Whitwood, Anne K. Duhme-Klair, Jason M. Lynam, and Ian J. S. Fairlamb*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, U.K.
S Supporting Information
b
ABSTRACT: The intermolecular PausonꢀKhand (PK) reactions of steri-
cally comparable (2-phenylethynyl)heteroaromatic compounds with norbor-
nene, mediated by Co2(CO)8 to give cyclopentenone products, were
examined in this study. A synthetic protocol utilizing focused-microwave
dielectric heating proved indispensable in the efficient synthesis of the PK
cyclopentenone products. “π-Deficient” heteroaromatic substrates, e.g.,
2-pyrones, and some “π-excessive” heteroaromatics such as 2- and 3-thio-
phene and 2-furan favor the β-position in the newly formed cyclopentenone
ring. Other π-excessive heteroaromatics such as 2-pyrrole or 2-indole favor
the R-position. A π-excessive 3-indole derivative gave a nearly equal mixture
of regioisomers. The position of the nitrogen in pyridyl-containing alkyne
substrates also affects the regiochemical outcome of the PK reaction. A
2-pyridyl alkyne, possessing a proximal nitrogen, influences the regioselec-
tivity relative to a 4-pyridyl variant quite dramatically, favoring the β-position in the newly formed cyclopentenone ring. A
2-pyrimidylalkyne exhibits similar behavior to the 2-pyridylalkyne. Compounds that do not participate in PK reactions with
norbornene include (2-phenylethynyl)imidazoles and the related benzimidazoles, which promote rapid decomposition of the in situ
generated (μ2-alkyne)Co2(CO)6 complexes. This stands in contrast with other nitrogen-containing heteroaromatics, e.g., pyrrole-,
indole-, and pyrimidine-derived compounds, which effectively undergo PK reactions. Overall, the type of heteroaromatic group
dramatically influences PK regioselectivity, which can in part be explained by rationalization of the current reaction mechanism, but
not fully.
Scheme 1. PausonꢀKhand Reaction with Unsymmetrical
’ INTRODUCTION
Terminal and Internal Alkynes
The PausonꢀKhand (PK) reaction,1,2 the [2 þ 2 þ 1] cyclo-
addition reaction of an alkyne, alkene, and CO, the latter from
Co2(CO)8, provides an efficient route to structurally diverse
cyclopentenones, with many examples appearing in natural pro-
duct syntheses.3 Excellentregioselectivities are apparent for certain
intermolecular PK reactions4 (1 f 2, Scheme 1).
Experimental and theoretical studies have provided insight
into the mechanism and origins of the regioselectivity; the latter
aspect is an issue where unsymmetrical mono- (terminal) or
disubstituted (internal) alkynes5 are employed. Mechanistically,
a reaction pathway was proposed by Magnus and Schore in 1985
(Scheme 2)6 that involves CO dissociation from the in situ
generated (μ2-alkynyl)Co2(CO)6 complex (I f II) formed by
reaction of the alkyne with Co2(CO)8 (step 1), creating a vacant
coordination site for alkene coordination (step 2, II f III). The
next step involves an irreversible insertion of the alkene π-bond
into a CoꢀC bond starting from intermediate IV (step 3, IV f
V f VI), followed by CO insertion which generates a 6-mem-
bered cobaltacycle VII (step 4). Reductive elimination (step 5)
and subsequent loss of the dicobalt(0)carbonyl fragment (step 6)
reveals the cyclopentenone product (VII f VIII f IX).
The regiochemistry observed in the cycloadduct product from
the substituted alkyne (and/or alkene) can be explained by the
steric crowding that evolves during CꢀC bond formation in step
3. Considering steric effects alone, larger substituents (RL) appear
at the R-position in the cyclopentenone ring. This has been
observed in reactions of either propyne 1a or ethyl propiolate 1b
Received: March 31, 2011
Published: May 19, 2011
r
2011 American Chemical Society
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Scheme 2. General Accepted Mechanism for the Intermolecular PK Reactiona
a RL = large variable substituent; RS = small variable substituent; trans-eq refers to the equatorial CO ligand which is opposite to the large variable
substituent, RL; cis-eq refers to the equatorial CO ligand which is on the same side as the large variable substituent, RL.
Scheme 3. “Pushꢀpull” Internal Alkyne Leading to a
complex was found to be relatively low and can be overcome at
room temperature (the η2-ethene can move easily between
equatorial and axial sites on cobalt).10 The lowest lying transition
state for alkene insertion affording the most stable cobaltacycle
originates from the complex where the alkene is found inserting
from the axial position.11
Regioselective Intermolecular PK Reaction
Further DFT calculations employing three alkynes (propyne,
methyl 2-butynoate, and methyl propiolate) showed that alkene
insertion is affected by the alkyne bond polarization.12 The alkyne
carbon carrying the most electron density was that involved in
the alkene insertion step (step 3, Scheme 2) and subsequent
CꢀC bond formation, even in cases where geometrical con-
straints were found less favorable.
Direct evidence for the formation of (μ2-alkyne)Co2(CO)5-
(η2-alkene) complexes (e.g., mimicking intermediate IV in
Scheme 2) has attracted recent attention (e.g., by ESI-MS
detection13 or characterization in the solid state). For example,
Evans and McGlinchey reported an arrested intermediate from
an “enyne-type” substrate giving an (μ2-alkyne)Co2(CO)5(η2-
alkene) complex.14 Fox and co-workers reported the highly
regioselective intermolecular PK reactions of chiral cycloprope-
nes,15 which revealed the first examples of Co-complexes derived
from the putative alkene-insertion intermediate. Crucially, the
high regioselectivity was found to not derive from a selective
alkene insertion step. Kinetic discrimination following alkene
insertion affects the regiochemical outcome by allowing a minor
diastereomer to give a ring-opened dinuclear cobalt complex,
which does not deliver a PK product.
with norbornene in the presence of Co2(CO)8 to give 2a and 2b,
respectively (see Scheme 1).7 Electronic effects can also alter the
regiochemical outcome. For example, a similar reaction with
ethyl butynoate 1c resulted in the electron-accepting ester group
residing at the β-position, exclusively (to give 2c).
For a more sterically equivalent “pushꢀpull” internal alkyne,8
ethyl 4-(40-methylphenylethynyl)benzoate 1d (Scheme 3), PK
reaction with Co2(CO)6 and norbornene gave one regioisomer
(2d), where the electron-donating aryl group was found at the
R-positionandtheelectron-deficient aryl group at the β-position.9
Gimbert and Greene determined that electronic differences
imposed by the alkyne substituents of the (μ2-R1C2R2)Co2-
(CO)6 complex leads to the discriminate loss of a CO ligand,
which then controls the regiochemistry of the reaction by
affecting the relative position of alkene coordination (steps
2 f 3 in Scheme 2).9 DFT calculations indicate that the
equatorial CO ligands are the most labile and hence most likely
to dissociate from (μ2-R1C2R2)Co2(CO)6 complexes. Furthermore,
the barrier for rotation in a (μ2-propyne)Co2(η2-ethene)(CO)5
Use of decarbonylation agents (e.g., N-oxides, sulfides and
sulfoxides, including synergistic effects16) under conventional
heating17 or microwave18 and ultrasound19 conditions promote PK
reactions. Pryce, Browne, and co-workers recently reported that
visible light (∼410 nm) promoted the PK reaction of norbornene
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Scheme 4. Intermolecular PausonꢀKhand Reactions of Alkynylated 2-Pyrones
Scheme 5. Intermolecular PausonꢀKhand Reactions of
Internal Alkynes 3 To Give 4r and 4β
The N-methyl derivatives of 2-pyrrole 3a, 2-indole 3b, and
3-indole 3c were prepared in satisfactory yields (entries 1ꢀ3).
The imidazole derivative 3d was accessed in 19% yield (entry 4),
while the benzimidazole 3e was obtained in 58% yield (entry 5).
The pyrimidine derivative 3f, which enables the heteroaromatic
ring size to be evaluated in comparison with 3e, proceeded in
54% yield (entry 6). The three pyridine regioisomers 3gꢀi were
all obtained in good yields (entries 7ꢀ9). These derivatives allow
the relative position of the nitrogen atom to be probed, whereas
quinoline 3j offers a sterically distinct but electronically similar
alternative to the pyridine ring system (88% yield, entry 10).
Thiophenes 3k and 3l were obtained in acceptable yields,
although different catalyst systems were used (entries 11 and
12). A 2-furan derivative 3m needed to be prepared by Stille
coupling of 1-(2,2-dibromovinyl)benzene with (2-tributylstan-
nyl)furan using catalytic Pd2(dba)3 (dba = (E,E)-dibenzylidene
acetone); in situ base-mediated elimination gave 3m in 61% yield
(entry 13). A series of electron-deficient 2-pyrone derivatives
were prepared for comparison with reported alkynes 1eꢀg.21 We
were particularly interested in evaluating terminal alkyne 3o
[available by silyl deprotection of 3n in 56% yield (entry 14)].
Alkyne 3p represents a complementary analogue to 1e (entry
15), as both contain a 2-pyrone group, which was obtained in
91% yield. The “pushꢀpull” pyrrole-2-pyrone derivative 3q
allows a highly polarized alkyne25 to be tested in the reaction,
obtained in an acceptable yield of 55% (entry 16).
PK Reactions of Internal Heteroaromatic Alkynes. The
library of internal alkynes 3aꢀq were reacted with Co2(CO)8
and norbornene under focused microwave dielectric heating
conditions. Norbornene was selected as the primary alkene based
on its high reactivity27 toward cobaltacycle formation. Following
a screen of reaction conditions, we settled on Evans' microwave
conditions18a for the PK reaction. The protocol involves stirring
equimolar quantities of the internal alkyne and Co2(CO)8 in 1,2-
dichloroethane (DCE) at room temperature (ca. 22 °C) for 1 h
in a microwave tube, preforming the (μ2-alkynyl)Co2(CO)6
complex in situ (in all cases). Norbornene (5 equiv) was then
added and the reaction mixture heated to 90 °C in a sealed tube
under microwave irradiation28 until complete consumption of
the (μ2-alkynyl)Co2(CO)6 complex was observed (by TLC). It
is important to note that because of pressure build-up in the
reaction vessel the mixture was vented every 10 min for the first
hour of the reaction.
with terminal alkynes (giving R-cycloadducts, as is the case for
the thermal process).20 The reaction occurs at ambient tempera-
ture, without addition of decarbonylation agents, in nonpolar
solvents (e.g., toluene, hexane). The visible light promotes CO
dissociation, facilitating the alkene insertion step.
Our interest in this area stems from a preliminary study21
detailing the microwave-assisted cobalt-mediated PK reactions of
three internal alkynes containing a 2-pyrone (1eꢀg) with
norbornene to give the regioisomeric cyclopentenone products
2erꢀgr and 2eβꢀgβ (Scheme 4). The π-deficient 2-pyrone
moiety is found to preferentially occupy the β-position in the
cyclopentenone product. Also, the factors affecting CO lability in
various (μ2-alkyne)Co2(CO)6 complexes have been of interest
to us (tangentially as therapeutic CO-releasing molecules).22
Despite the synthetic examples described above, the inter-
molecular PK reactions of unsymmetrical internal alkynes with
appropriate alkenes have yet to be comprehensively investigated.
We have therefore examined a series of sterically equivalent, or
near-equivalent, internal alkynes as substrates for intermolecular
PK reactions. The use of (2-phenylethynyl)heteroaromatic
compounds in PK reactions is fairly rare in the literature, this
despite several (μ2-alkynyl)Co2(CO)6 complexes being known
(Scheme 5).23 From the (2-phenylethynyl)heteroaromatic com-
pounds 3 investigated as part of this study, and other similar
compounds, we can reveal that the type of heteroaromatic group
significantly affects the regiochemical outcome of intermolecular
PK reactions mediated by cobalt (for sterically similar hetero-
aromatic components). Also, the position of the nitrogen atom in
pyridyl-containing alkynes dramatically affects the regiochemical
outcome of the reaction.
’ RESULTS
In the first example, the π-excessive pyrrole alkyne substrate
3a reacted with Co2(CO)8 and norbornene affording a mixture
of both regioisomers in 73% combined yield (entry 1, Table 2).
The major regioisomeric product of the reaction (4ar) formed
crystals suitable for study by X-ray diffraction after being allowed
The internal alkynes, required for the PK reactions, were
prepared by a very useful Sonogashira cross-coupling protocol
(Table 1).24 The precatalyst PdCl2(PPh3)2 (1 mol %) was
employed for most of the couplings, and a Pd/Cu ratio (1:3)
was found to be beneficial.
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Table 1. Synthesis of (2-Phenylethynyl)heteroaromatic Substrates 3aꢀq by Sonogashira Cross-Coupling
a Terminal alkyne (1.1 equiv), PdCl2(PPh3)2 (1 mol %), CuI (3 mol %), Et3N (1.5 equiv), MeCN, reflux, 16 h. b Reaction run at room temperature
(ca. 22 °C). c Reaction run at 110 °C in toluene. d Pd(OAc)2/P(o-C6H4Me)3 (1 mol % Pd; 2 mol % ligand) used in place of PdCl2(PPh3)2. e Pd(PPh3)4
(1 mol %) used in place of PdCl2(PPh3)2.26 f Reaction by Stille coupling, Pd2(dba)3 (0.025 mmol, 2.5 mol % Pd), P(p-C6H4OMe)3 (0.15 mmol), DMF,
80 °C, 10 h. g 10% Pd/C (20 wt.%), PPh3 (25 wt %), CuI (4 mol %), Et3N/CH3CN (5:3, v/v), reflux 16 h. h Deprotection of 3n was accomplished using
TBAF (1 equiv) in THF at ꢀ78 °C for 30 min affording 3o in 56% yield.
to stand in CDCl3 over several weeks (see the Supporting
Information). The X-ray crystal structure shows that the major
regioisomeric product contains the N-methylpyrrole moiety in
the R-position.
norbornene added. In a control reaction, heating Co2(CO)8 and
norbornene at 90 °C for 20 min, under focused microwave
heating, gave 5 in 19% yield. Therefore, under the PK reaction
conditions used, the (μ2-alkynyl)Co2(CO)6 complexes of 3d and
3e are unstable, readily decompose, and do not form PK cyclo-
adducts of norbornene.
The π-excessive 2-indole alkyne substrate 3b reacted with
Co2(CO)8 and norbornene, affording a mixture of regioisomers
in favor of 4br, with 87% combined yield (entry 2). The ratio of
4br:4bβ is similar, but not identical, to reactions of 3a. The
3-indole alkyne substrate 3c gave 4cr and 4cβ in a combined
yield of 76% (entry 3), but surprisingly in an almost equal ratio.
For the imidazole and benzimidazole alkynes 3d and 3e no
reaction was observed (entries 4 and 5); note that the (μ2-
alkynyl)Co2(CO)6 complexes of 3d and 3e can be formed and
characterized. However, a small amount of the known lactone 5
(Figure 1), which is derived from the carbonylative dimerization
of two molecules of norbornene,29 was formed under the reaction
conditions in a yield of 2ꢀ7% with respect to the quantity of
2-Pyrimidylalkyne 3f favors formation of predominantly one
regioisomer (entry 6). Pyrimidine is more electron-deficient than
pyridine,30 and the major regioisomer was assigned as 4fβ (on
1
the basis of 1Hꢀ H NOESY studies).
Three pyridyl-containing alkynes, 3g, 3h and 3i, containing
the nitrogen at each of the 2-, 3-, and 4-positions, respectively,
were investigated (entries 7ꢀ9). The ratio of regioisomers
obtained from these PK reactions was dependent on the position
of the nitrogen atom. For the 2-pyridyl substrate 3g, a 9:1 ratio of
regioisomers was observed in a combined yield of 71% (entry 7),
which mirrors the regioselectivity observed using 3f (entry 6).
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Table 2. Reaction Times and Yields Obtained from PK Reactions of Various (2-Phenylethynyl)heteroaromatic Substrates (3aꢀq
and Reported 3r32)a
a Reaction conditions: (i) Co2(CO)8 (1 equiv), internal alkyne (1 equiv, 3aꢀr), DCE, room temperature, 1 h; (ii) norbornene (5 equiv) added, 90 °C,
MW, reaction time indicated in the internal alkyne column in brackets (cycloadduct numbering correlates with terminal alkyne, e.g., 3a and 4a; unless
otherwise specified, the heteroaromatic group indicates its position in the cycloadduct. b Regioisomeric outcome proven by X-ray crystallography. c No
cyclopentenone products observed (by TLC), only enol lactone 5 in 2ꢀ7% yield (based on consumption of norbornene). d The regiochemistry could
not be determined. e The (μ2-3o)Co2(CO)6 complex was prepared and characterized first and then subjected to the PK reaction (the 2-pyrone group is
found exclusively in the R-position). f Cycloadducts R and β are indicated by the position of the thienyl group. g Cycloadducts R and β are indicated by
the position of the 2-pyrrole group. h Reported PK reaction, see ref 32.
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the cyclopentenone framework, confirming the proposed struc-
ture of the regioisomer.
The PK reactions of 3-thienylalkynyl-2-pyrone 3p and 2-pyr-
rolealkynyl-2-pyrone 3q were conducted for comparison pur-
poses with the other 2-pyrone substrates 3n and 3o (entries 16
and 17), in addition to the reported alkynyl-2-pyrones.21 Alkyne
3p afforded two regioisomeric products in a combined yield of
92% and a surprising 1:1 ratio. Alkyne 3q afforded two regioi-
someric products in a combined yield of 86% and ratio of 19.7:1
in favor of 4qr (entry 17). Two-dimensional Hꢀ H NOESY
spectra of 4pr and 4pβ confirmed contacts between the nor-
bornene unit and the β-positioned 2-pyrone group (in 4pr),
together with cross-peaks between the β-positioned thienyl
group and norbornene (in 4pβ), which allowed the structures
of the regioisomers to be unambiguously assigned.
Figure 1. Side product formed in PK reactions of norbornene, Co2-
(CO)8, and internal alkynes 3d or 3e.
1
1
The 3-pyridyl substrate 3h gave a 91% combined yield and
regioisomeric ratio of 1.8:1, while the 4-pyridyl substrate 3i gave a
yield of 94% and regioisomeric ratio of 2.4:1. The large difference
between the 2-pyridyl substrate and the 3- and 4-pyridyl sub-
strates is of particular note. From the reaction of 3-pyridyl
substrate 3h, crystals of the major regioisomeric product were
found suitable for study by X-ray diffraction (by slow evaporation
from a CH2Cl2 solution), which confirmed the structure as 4hβ
(see the Supporting Information).
’ DISCUSSION
The quinolinyl alkyne derivative 3j (entry 10) was expected to
share similar electronic properties with 2-pyridyl substrate 3g,
although the steric bulk is perhaps increased. The regioisomeric
ratio for 4jr/4jβ was determined to be 1:3, so the larger
quinoline group had diminished the regioselectivity relative to
3g. The minor regioisomeric product gave crystals suitable for
study by X-ray diffraction (after being allowed to stand in
CDCl3), which confirmed the structure as 4jr (see the Support-
ing Information).
For both the 2-thienylalkyne (3k) and 3-thienylalkyne (3l)
derivatives, a regioisomeric ratio of ca. 2:1 was observed; each
reaction also proceeded in good product yield (entries 11 and
12). The X-ray crystal structure of the major regioisomeric
product from the reaction of 3l confirms its structure as 4lβ
(see the Supporting Information). A comparison of the 1H NMR
spectroscopic data of the products from both reactions indicates
that the regiochemical outcome of the reaction is the same for
both 3k and 3l.
The regiochemical outcome of the intermolecular PK reac-
tions of (2-phenylethynyl)heteroaromatic substrates with nor-
bornene mediated by Co2(CO)8 is significantly affected by the
type of heteroaromatic group. Moreover, the reaction times for
the differing alkyne substrates vary significantly, and perhaps
explain the lack of PK reactions reported for these types of
substrates (despite a large number of (μ2-HetAromC2Ph)Co2-
(CO)6 complexes being reported in the literature23). Focused
microwave dielectric heating has allowed us, in most cases, to
synthesize the PK products derived from these internal alkynes,
norbornene and Co2(CO)8, in reasonable reaction times. Steri-
cally comparable heteroaromatic moieties significantly influence
the regioselectivity of the PK reaction. The π-deficient hetero-
aromatics, e.g., 2-pyrones (1e, 3n, 3p and 3q; note: exception of
3o vide infra), favor the β-position in the newly formed
cyclopentenone ring, which is in keeping with the reported PK
reactions of 1eꢀg.21 The regiochemical outcome of 3n, 3p, and
3q is also influenced by the other alkyne substituent. The
π-excessive heteroaromatics, e.g., pyrrole (3a) and indole (3b),
favor the R-position of the newly formed cyclopentenone ring.
The 2- and 3-thiophenyl and 2-furan derivatives generally exhibit
a bias toward the β-regioisomeric cyclopentenone products.
However, indole derivative 3c gave a near 1:1 mixture of
regioisomeric products 4cr and 4cβ. While one could argue
that steric effects are operative in PK reactions of either 3a or 3b,
these steric effects are arguably removed in 3c as the alkyne is at
the 3-position relative to the N-methyl substituent. Therefore, in
this unique case, the π-excessive 3-indole derivative does not give
4cr as the major regioisomer; on the basis of electronic (and
steric) arguments it would be expected to do so.
The presence of a proximal nitrogen on the alkyne hetero-
aromatic group was found to exert a profound effect on the
regiochemical outcome of the PK reaction. For example, the
position of the nitrogen in pyridyl-containing alkyne substrates
(3gꢀi) gave quite different regiochemical outcomes. One may
consider that the electronic character of the pyridyl ring system is
likely affected as a consequence (2- and 4-pyridyl systems being
more electron-deficient than 3-pyridyl systems). The regioselec-
tivity is highest for 2-pyridyl substrate 3g (giving mostly 4 gβ),
which crucially does not mirror the behavior of 3i. The position
of the sulfur atom in 3k and 3l does not affect the regiochemical
outcome in the same way. While not obvious, it is possible that
the proximal nitrogen atom in 3g influences either the alkene
coordination or insertion steps. The regiochemical outcome
2-Furanylalkyne 3m reacted with norbornene in the PK
reaction exceptionally well, affording the products in 88% yield
(ratio of 4mr/4mβ = 1:3.4; entry 13). The regioisomeric
structures of 4mr and 4mβ were confirmed by comparison of
the spectroscopic data of 4kr/4kβ and 4lr/4lβ. Trimethylsilyl-
alkynyl-2-pyrone 3n proved to be a poor substrate for the PK
reaction (entry 14). Loss of the intermediate (μ2-alkynyl)Co2-
(CO)6 was seen only after 24 h of microwave irradiation, with
two products formed, as shown by TLC. However, only one
product could be purified and characterized fully. By comparison
1
of the H NMR spectroscopic data with the reported data
obtained for 2erꢀgr and 2eβꢀgβ,21 it is proposed that the
2-pyrone group is positioned β to the carbonyl group (4nβ).
This regioisomeric product is also biased by the preference for
the bulky TMS group for the R-position in the cyclopentenone
ring system. A negligible amount of the other regioisomer (4nr)
was formed, for which full structural characterization was not
possible.
It is important to note that alkynyl-2-pyrone 3o is quite
unstable. The intermediate (μ2-3o)Co2(CO)6 complex was
purified by flash chromatography on silica gel (in 52% yield).
The reaction of (μ2-3o)Co2(CO)6 (entry 15), under the stan-
dard microwave conditions, led to the isolation of one regioiso-
1
meric product (4or) in 32% yield. A two-dimensional 1Hꢀ H
COSY experiment showed cross-peaks between the proton in
the β-position of the cyclopentenone ring and the H-3a proton of
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a
Scheme 6. Heteroaromatic Group Effects on the Regioselectivity in the Intermolecular PK Reaction Mediated by Co2(CO)8
a The Roman numerals used in this scheme mirror those used in Scheme 2; [Co] = Co(CO)3.
from the reaction of 2-pyrimidylalkyne 3f mirrors that of 3g, giving
preferentially 4fβ. In studies reported by Itami and Yoshida, the
directing effect of the 2-pyridylsilyl group was demonstrated in the
Ru-catalyzed intermolecular PausonꢀKhand-type reaction of
alkenyl(2-pyridyl)silane, alkyne, and carbon monoxide.31 While
the 2-pyridyl group was located on the alkene and not the alkyne, it
serves to highlight that a 2-pyridyl group can affect PK regioselec-
tivity. In our work, it is also interesting to note differences between
the 2-pyridyl and 2-quinoline substrates (3g and 3j, respectively).
It was expected that steric factors could dominate the regioiso-
meric outcome from the PK reaction of 3j with norbornene (e.g.,
the bulky quinoline group ought to give 4jr as the major
regioisomer). However, the major regioisomeric product was still
found to be 4jβ. From the reported reaction of 4-(2-phenyl-
ethynyl)-2H-chromen-2-one 3r with norbornene, mediated by
Co2(CO)8 (Table 2, entry 18),32 we know that the electron-
deficient 2H-chromen-2-one (coumarin) gives more of the
R-regioisomer 4rr (relative to 3j). Therefore, there could be a
subtle steric difference between 3g and 3j, as evidenced by their
regiochemical outcome in the PK reaction. Moreover, a similar
difference is seen for the reported PK reactions of 1e (2-pyrone)
and 3r (coumarin) with norbornene, mediated by Co2(CO)8.
For the (2-phenylethynyl)heteroaromatic substrates that do
not participate in PK reactions with norbornene, e.g., (2-phenyl-
ethynyl)imidazole 3d and the related benzimidazole compound
3e, rapid decomposition of the in situ generated (μ2-HetArom-
C2Ph)Co2(CO)6 complexes33 likely occurs prior to alkene
insertion. 1H NMR spectra of (μ2-3d/3e)Co2(CO)6 complexes
in CD2Cl2 exhibit broad proton signals which we tentatively
attribute to slippage of the cobalt(0) center onto the (benz)imidazole
ring system, leading to decomposition under the microwave
conditions. This stands in contrast to the 2-pyrrole, 2-indole,
3-indole, and pyrimidine substrates (3aꢀc and 3f, respectively),
which effectively undergo PK reactions with norbornene.
The 2-pyrone terminal alkyne 3o gave 4or as the only
regioisomer, which is an expected outcome based on steric
arguments alone (this outcome parallels the reactivity of ethyl
propiolate 1b).7 The modest yield from this reaction is attributed
to the instability of 3o and its associated (μ2-3o)Co2(CO)6
complex under the microwave conditions used.
The regiochemical outcome of the PK reaction of 3-thienylalk-
ynyl-2-pyrone 3p with Co2(CO)8 and norbornene was expected
to mirror the equivalent reaction with 1e. However, a 1:1 mixture
of 4pr and 4pβ were formed. It is unclear why there is no bias for
one particular regioisomer. For 2-pyrrolealkynyl-2-pyrone 3q, the
regiochemical outcome of the PK reaction with Co2(CO)8 and
norbornene behaved as expected, giving4qr as the major product.
We can broadly classify the effect of the different heteroaro-
matic moieties (where the other alkyne substituent is phenyl) in
the current working model for the mechanism of the cobalt(0)ꢀ
carbonyl-mediated intermolecular PK reactions of internal al-
kynes with alkenes (Scheme 6). Alkene insertion likely occurs at
the cis-equatorial sites in complexes II f III (see Scheme 2),34
and pseudorotation then places the alkene in the axial position
(IV, Scheme 6), which is appropriately disposed to insert into
one of two CoꢀC bonds, either distal (via V) or proximal
(via V0) to the heteroaromatic group, which then gives R- and
β-regioisomeric cyclopentenones, respectively.
It would be an understatement to suggest that a subtle combi-
nation of steric and electronic factors control the regioselectivity
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The Journal of Organic Chemistry
ARTICLE
in intermolecular PK reactions of unsymmetrical internal al-
kynes, norbornene, and Co2(CO)8. Dynamic ligand effects could
influence the cobalt center substantially, either by cobalt slippage
on to the organic “heteroaromatic/aromatic” group, or in some
cases, direct coordination. The aromatic stabilization energy of a
given type of heteroaromatic/aromatic group may also be
important.35
Concerning the reaction mechanism, the important findings
reported by Overgaard and Platts36 should perhaps be given
more attention. The study indicates that the traditional view of
the CoꢀCo bond in (μ2-alkyne)Co2(CO)6 complexes may be
incorrect (findings that affect how we view the precise structure
of intermediate species IIꢀIV in the current working mechanism).37
It is suggested that the CoꢀCo bond is better thought of as a
singlet diradical species (CoꢀCo bond order ∼0.25). Together
with our observations, the potential involvement of Co radical/
“pseudoradical” species would have profound implications for
the mechanism of the PK reaction.
was performed at room temperature, with iodobenzene (143 mg,
0.08 mL, 0.76 mmol) and 1-methyl-2-ethynyl-1H-pyrrole (80 mg,
0.70 mmol), to afford the title compound as a dark oil (70 mg, 51%).
1H NMR (400 MHz, CDCl3): δ = 3.74 (s, 3H), 6.12 (dd, J = 3.8, 2.7 Hz,
1H), 6.49 (dd, J = 3.8, 1.7 Hz, 1H), 6.69 (dd, J = 2.7, 1.7 Hz, 1H),
7.31ꢀ7.36 (m, 3H), 7.48ꢀ7.51 (m, 2H). 13C NMR (100.5 MHz,
CDCl3): δ = 34.6 (CH3), 81.3 (4°), 93.0 (4°), 108.2 (CH), 114.8
(CH), 115.7 (4°), 123.4 (4°), 123.8 (CH), 127.9 (CH), 128.3 (CH),
131.1 (CH). IR νmax (CH2Cl2, cmꢀ1): 2961, 2205, 1604, 1322, 1094,
1011. LR(ESI-MS) m/z: 182 {(MH)þ, 100}. HR(ESI-MS) m/z: calcd
for C13H12N 182.0964, found 182.0959 [M þ H]þ.
1-Methyl-2-(2-phenylethynyl)-1H-indole (3b) (Entry 2, Table 1).
Synthesized according to the general Sonogashira procedure, except it
was performed at 60 °C, with 2-iodo-1-methyl-1H-indole (350 mg, 1.4
mmol) and phenylacetylene (153 mg, 0.16 mL, 0.15 mmol) to afford the
title compound as a yellow solid (203 mg, 63%). 1H NMR (400 MHz,
CDCl3): δ = 3.89 (s, 3H), 6.85 (s, 1H), 7.14 (ddd, J = 8.0, 6.3, 1.7 Hz,
1H), 7.26ꢀ7.33 (m, 2H), 7.37ꢀ7.42 (m, 3H), 7.57ꢀ7.63 (m, 3H). 13
C
NMR (100.5 MHz, CDCl3): δ = 30.8 (CH3), 81.2 (4°), 95.3 (4°), 107.5
(CH), 109.5 (CH), 120.2 (CH), 121.1 (CH), 122.2 (4°), 122.8 (4°),
123.1 (CH), 127.4 (CH), 128.6 (CH), 128.7 (4°), 131.5 (CH), 137.4
(4°). LR(ESI-MS) m/z: 232 {(MH)þ, 100}. HR(ESI-MS) m/z: calcd
for C17H14N 232.1121, found 232.1129 [M þ H]þ.
A final comment is required concerning a very recent report38
which shows that a pushꢀpull system, namely methyl 4-(40-
methoxyphenylethynyl)benzoate, reacted with norbornadiene
and Co2(CO)8, which gave a mixture of regioisomeric cycload-
ducts (2.5:1). The major regioisomer was that where the electron
donating aryl group was found in the R-position and the electron-
withdrawing aryl group in the β-position (as expected). How-
ever, this outcome is markedly different from the reaction of 1d,
norbornene,39 and Co2(CO)8 (Scheme 3), where the exclusive
formation of only one regioisomeric product was observed.9
These two outcomes, along with some of the findings detailed in
our study, serve to highlight that the factors governing the
regioselectivity in the intermolecular PK reactions are both subtle
and complex.
In summary, we have probed the regioselectivity of the PK
reaction by altering the heteroaromatic group in a series of
unsymmetrical internal alkynes. Further mechanistic studies are
required to fully understand the regiochemical observations
made in this and in other studies. The following questions are
of interest: (i) How does the heteroaromatic group affect the
CoꢀCo bond order in complexes such as I (and subsequent
intermediate species in the reaction mechanism)? (ii) What is the
relevance and propagation of single electron cobalt species in PK
reactions? (iii) How does varying the alkene substrate affect the
regiochemical outcome from the reaction of “pushꢀpull” inter-
nal alkynes and Co2(CO)8? Our findings relating to these
questions will be reported in due course.
1-Methyl-3-(2-phenylethynyl)-1H-indole (3c) (Entry 3, Table 1).
Synthesized according to the general Sonogashira procedure, except it
was performed at 60 °C, with 3-iodo-1-methyl-1H-indole (350 mg, 1.4
mmol) and phenylacetylene (153 mg, 0.16 mL, 0.15 mmol) to afford the
1
title compound as a dark oil (147 mg, 46%). H NMR (400 MHz,
CDCl3): δ = 3.80 (s, 3H), 7.23 (ddd, J = 7.9, 6.8, 1.3 Hz, 1H), 7.28ꢀ7.37
(m, 6H), 7.55ꢀ7.58 (m, 2H), 7.83 (ddd, J = 7.9, 1.3, 0.8 Hz, 1H). 13C
NMR (100.5 MHz, CDCl3): δ = 33.1 (CH3), 83.1 (4°), 91.0 (4°), 97.0
(4°), 109.5 (CH), 120.2 (CH), 120.3 (CH), 122.7 (CH), 124.3 (4°),
127.4 (CH), 128.3 (CH), 129.1 (4°), 131.2 (CH), 132.2 (CH), 136.2
(4°). LR(ESI-MS) m/z: 232 {MHþ, 100}. HR(ESI-MS) m/z: calcd for
C17H14N 232.1121, found 232.1123 [M þ H]þ.
1-Methyl-2-(2-phenylethynyl)-1H-imidazole (3d) (Entry 4, Table 1).
Synthesized according to the general Sonogashira procedure, with
1-methyl-2-bromo-1H-imidazole (832 mg, 4.0 mmol) and phenylace-
tylene (449 mg, 0.48 mL, 4.4 mmol), and purification by chromatogra-
phy on silica gel using petroleum ether/EtOAc (1:1, v/v) as the eluent to
afford the title compound as a brown solid (137 mg, 19%). Mp =
52ꢀ56 °C. 1H NMR (400 MHz, CDCl3): δ = 3.79 (s, 3H), 6.93ꢀ6.97
(br s, 1H), 7.08ꢀ7.13 (br s, 1H), 7.35ꢀ7.39 (m, 3H), 7.55ꢀ7.57 (m,
2H). 13C NMR (100.5 MHz, CDCl3): δ = 33.7 (CH3), 78.7 (4°), 92.8
(4°), 121.6 (4°-br), 122.0 (CH), 128.6 (CH), 129.1 (CH), 129.9 (CH),
131.8 (CH), 132.6 (4°-br). IR νmax (CH2Cl2, cmꢀ1): 1570, 1458, 1411,
1339, 1108. LR(ESI-MS) m/z: 183 {(MH)þ, 100}. HR(ESI-MS) m/z:
calcd for C12H11N2 183.0917, found 183.0916 [M þ H]þ.
1-Methyl-2-(2-phenylethynyl)-1H-benzo[d]imidazole (3e)40 (Entry
5, Table 1). Synthesized according to the general Sonogashira procedure,
except it was performed at room temperature, with 1-methyl-2-bromo-
1H-benzo[d]imidazole (438 mg, 1.7 mmol) and phenylacetylene (173
mg, 0.21 mL, 1.9 mmol) to afford the title compound as a yellow/brown
solid (229 mg, 58%). 1H NMR (400 MHz, CDCl3): δ = 3.91 (s, 3H),
7.23ꢀ7.34 (m, 3H), 7.36ꢀ7.42 (m, 3H), 7.62ꢀ7.64 (m, 2H), 7.78 (ddd,
J = 7.0, 1.3, 1.3 Hz, 1H). 13C NMR (100.5 MHz, CDCl3): δ = 30.7
(CH3), 78.7 (4°), 94.9 (4°), 109.4 (CH), 120.1 (CH), 121.2 (4°), 122.8
(CH), 123.8 (CH), 128.5 (CH), 129.6 (CH), 132.0 (CH), 134.8 (4°),
137.6 (4°), 143.0 (4°). LR(ESI-MS) m/z: 233 {(MH)þ, 100}. HR(ESI-
MS) m/z: calcd for C16H13N2 233.1073, found 233.1074 [M þ H]þ.
2-(2-Phenylethynyl)pyrimidine (3f)41 (Entry 6, Table 1). Synthesized
according to the general Sonogashira procedure, with 2-bromopyrimi-
dine (477 mg, 3.0 mmol) and phenylacetylene (336 mg, 0.36 mL, 3.3
mmol) but at 110 °C in toluene, to afford the title compound as a brown
’ EXPERIMENTAL SECTION
General Methods. See the Supporting Information.
General Procedure for Sonogashira Cross-Coupling Reactions. The
aryl bromide/iodide (1 equiv), the terminal acetylene (1.1 equiv),
PdCl2(PPh3)2 (precatalyst, 1 mol %), CuI (cocatalyst, 3 mol %), and
dry acetonitrile (1.5 mL/mmol) were added to an oven-dried Schlenk
tube charged with a magnetic stirrer bar. Dry triethylamine (1.5 equiv)
was added, and the reaction was heated at reflux for 16 h. On completion,
the reaction mixture was washed with H2O, extracted with DCM, dried
over MgSO4, and filtered and the solvent removed in vacuo. The crude
products were purified either by chromatography on silica gel, using
hexane/EtOAc (1:0 to 7:3, v/v) as the eluent, or by recrystallization
from hot EtOH.
1-Methyl-2-(2-phenylethynyl)-1H-pyrrole (3a) (Entry 1, Table1).
Synthesized according to the general Sonogashira procedure, except it
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ARTICLE
solid (293 mg, 54%). 1H NMR (400 MHz, CDCl3): δ = 7.23 (dt, J = 4.9,
1.1 Hz, 1H), 7.34ꢀ7.41 (m, 3H), 7.64ꢀ7.67 (m, 2H), 8.75 (dd, J = 4.9,
1.1 Hz, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 87.9 (4°), 88.0 (4°),
119.6 (CH), 121.3 (4°), 128.4 (CH), 129.7 (CH), 132.6 (CH), 153.3
(4°), 157.3 (CH). LR(ESI-MS) m/z: 181 {(MH)þ, 100}. HR(ESI-MS)
m/z: calcd for C12H9N2 181.0760, found 181.0765 [M þ H]þ.
2-(20-Phenylethynyl)pyridine (3g)42 (Entry 7, Table 1). Synthesized
according to the general Sonogashira procedure, except it was performed
at 60 °C, with 2-bromopyridine (632 mg, 0.39 mL, 4.0 mmol) and
phenylacetylene (449 mg, 0.48 mL, 4.4 mmol) to afford the title
compound as a brown oil (716 mg, quant). 1H NMR (400 MHz,
CDCl3): δ = 7.22 (ddd, J = 7.7, 4.9, 1.1 Hz, 1H), 7.33ꢀ7.37 (m, 3H),
7.51 (dt, J = 7.7, 1.1, 1.1 Hz, 1H), 7.57ꢀ7.61 (m, 2H), 7.67 (dt, J = 7.7,
7.7, 1.8 Hz, 1H), 8.61 (ddd, J = 4.9, 1.8, 1.1 Hz, 1H). 13C NMR (100.5
MHz, CDCl3): δ = 88.5 (4°), 89.1 (4°), 122.2 (4°), 122.7 (CH), 127.1
(CH), 128.3 (CH), 128.9 (CH), 132.0 (CH), 136.1 (CH), 143.4 (4°),
150.0 (CH). LRCI-MS m/z: 180 {(MH)þ, 100}.
(1 mol %) as catalyst (in place of PdCl2(PPh31)2), to afford the title
compound as a white solid (368 mg, quant). H NMR (400 MHz,
CDCl3): δ = 7.21 (dd, J = 5.0, 1.2 Hz, 1H), 7.30 (dd, J = 5.0, 3.0 Hz, 1H),
7.32ꢀ7.36 (m, 3H), 7.51ꢀ7.54 (m (with overlapping dd, J = 3.0, 1.2
Hz), 3H). 13C NMR (100.5 MHz, CDCl3): δ = 84.5 (4°), 88.8 (4°),
122.3 (4°), 123.2 (4°), 125.3 (CH), 128.2 (CH), 128.3 (CH), 128.6
(CH), 129.9 (CH), 131.5 (CH). LR(CI-MS) m/z: 184 {(Mþ), 100}.
2-(20-Phenylethynyl)furan (3m) (Entry 13, Table 1). 1-(2,2-Dibro-
movinyl)benzene (262 mg, 1.0 mmol), (2-tributylstannyl)furan (375 mg,
0.33 mL, 1.05 mmol), N,N-diisopropylethylamine (194 mg, 0.26 mL,
1.5 mmol), Pd2(dba)3 (21 mg, 0.025 mmol), and tris(4-methoxyphe-
nyl)phosphine (53 mg, 0.15 mmol) were dissolved in DMF (5 mL) and
the mixture heated at 80 °C for 10 h. The mixture was then diluted with
Et2O (20 mL), washed with H2O (3 ꢁ 15 mL), dried over MgSO4, and
filtered before the solvent was removed in vacuo. Purification by
chromatography on silica gel, using hexane/EtOAc (99:1, v/v) as the
1
eluent, afforded the title compound as a clear oil (103 mg, 61%). H
3-(20-Phenylethynyl)pyridine (3h)42 (Entry 8, Table 1). Synthesized
according to the general Sonogashira procedure, with 3-bromopyridine
(632 mg, 0.39 mL, 4.0 mmol) and phenylacetylene (449 mg, 0.48 mL,
4.4 mmol), to afford the title compound as a brown solid (537 mg, 83%).
1H NMR (400 MHz, CDCl3): δ = 7.28 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H),
7.35ꢀ7.39 (m, 3H), 7.53ꢀ7.57 (m, 2H), 7.81 (ddd, J = 7.9, 2.2, 1.7 Hz,
NMR (400 MHz, CDCl3): δ = 6.44 (dd, J = 3.4, 1.9 Hz, 1H), 6.67 (dd,
J = 3.4, 0.8 Hz, 1H), 7.34ꢀ7.37 (m, 3H), 7.44 (dd, J = 1.9, 0.8 Hz, 1H),
7.51ꢀ7.55 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 79.4 (4°), 93.2
(4°), 111.1 (CH), 115.2 (CH), 122.3 (4°), 128.4 (CH), 128.7 (CH),
131.4 (CH), 137.1 (4°), 143.6 (CH). LR(ESI-MS) m/z: 139 {85}, 168
{Mþ, 100}. HR(ESI-MS) m/z: calcd for C12H8O 168.0575, found
168.0571 [M]þ.
1H), 8.55 (dd, J = 4.9, 1.7 Hz, 1H), 8.77 (dd, J = 2.2, 0.9 Hz, 1H). 13
C
4-Ethynyl-6-methyl-2H-pyran-2-one (3o)47 (Entry 14, Table 1).
Compound 3n (350 mg, 1.7 mmol) was dissolved in THF (1.5 mL)
and cooled to ꢀ78 °C. TBAF (1.8 mL of 1.0 M solution in THF) was
added dropwise and the solution stirred for 30 min with the temperature
maintained at ꢀ78 °C. When TLC showed complete consumption of
starting material, H2O (3 mL) was added and the mixture extracted with
hexane (3 ꢁ 10 mL). The solvent was dried over MgSO4 and filtered and
the solvent removed in vacuo to afford the title compound as a white
solid (126 mg, 0.9 mmol, 56%). 1H NMR (400 MHz, CDCl3): δ = 2.23
(d, J = 0.9, 0.7 Hz, 3H), 3.47 (s, 1H), 5.97 (dq, J = 1.4, 0.9 Hz, 1H), 6.27
(dq, J = 1.4, 0.7 Hz, 1H). 13C NMR (100.5 MHz, CDCl3): δ = 19.9
(CH3), 79.4 (4°), 86.3 (CH), 105.2 (CH), 116.1 (CH), 137.8 (4°),
161.8 (4°), 162.3 (4°). LR(CI-MS) m/z: 135 {(MH)þ, 88}, 152
{(MNH4)þ, 100}.
6-Methyl-4-(2-(thiophene-3-yl)ethynyl)-2H-pyran-2-one (3p) (Entry
15, Table 1). Synthesized according to the general Sonogashira proce-
dure, with 4-bromo-6-methyl-2-pyrone48 (325 mg, 1.7 mmol) and
3-ethynylthiophene (204 mg, 0.19 mL, 1.9 mmol), to afford the title
compound as a pale brown crystalline solid (307 mg, 91%). Mp =
112ꢀ114 °C. 1H NMR (400 MHz, CDCl3): δ = 2.24 (dd, J = 0.9, 0.7 Hz,
3H), 6.03 (dq, J = 1.4, 0.9 Hz, 1H), 6.27 (dq, J = 1.4, 0.7 Hz, 1H), 7.19
(dd, J = 5.0, 1.2 Hz, 1H), 7.34 (dd, J = 5.0, 3.0 Hz, 1H), 7.63 (dd, J = 3.0,
1.2 Hz, 1H). 13C NMR (100.5 MHz, CDCl3): δ = 19.9 (CH3), 85.3
(4°), 93.9 (4°), 105.3 (CH), 114.1 (CH), 120.5 (4°), 126.1 (CH), 129.8
(CH), 131.5 (CH), 138.9 (4°), 161.9 (4°), 162.2 (4°). IR νmax
(CH2Cl2, cmꢀ1): 2211, 1723, 1634, 1547, 1512, 1446, 1384, 1359,
1313, 1216, 1138, 1030. LR(ESI-MS) m/z: 217 {(MH)þ, 100}.
HR(ESI-MS) m/z: calcd for C12H9O2S 217.0318, found 217.0315
[M þ H]þ.
NMR (100.5 MHz, CDCl3): δ = 85.9 (4°), 92.6 (4°), 120.4 (4°), 122.5
(4°), 123.0 (CH), 128.4 (CH), 128.8 (CH), 131.7 (CH), 138.4 (CH),
148.5 (CH), 152.2 (CH). LR(ESI-MS) m/z: 180 {(MH)þ, 100}.
4-(20-Phenylethynyl)pyridine (3i)43 (Entry 9, Table 1). Synthesized
according to the general Sonogashira procedure, except it was performed
at 60 °C, with 4-bromopyridine HCl (583 mg, 3.0 mmol) and pheny-
3
lacetylene (337 mg, 0.36 mL, 3.3 mmol), to afford the title compound as
1
an off-white solid (347 mg, 65%). H NMR (400 MHz, CDCl3): δ =
7.35ꢀ7.39 (m, 5H), 7.53ꢀ7.56 (m, 2H), 8.59 (dd, J = 4.6, 1.4 Hz, 2H).
13C NMR (100.5 MHz, CDCl3): δ = 86.6 (4°), 94.0 (4°), 122.0
(4°),125.5 (CH), 128.5 (CH), 129.20 (CH), 131.5 (4°), 131.8 (CH),
149.7 (CH). LR(CI-MS) m/z: 180 {(MH)þ, 100}.
2-(2-Phenylethynyl)quinoline (3j)44 (Entry 10, Table 1). Synthesized
according to the general Sonogashira procedure, with 2-bromoquinoline
(400 mg, 1.6 mmol) and phenylacetylene (176 mg, 0.19 mL, 1.7 mmol),
to afford the title compound as light brown powder (316 mg, 88%). 1H
NMR (400 MHz, CDCl3): δ = 7.37ꢀ7.40 (m, 3H), 7.55 (ddd, J = 8.1,
6.9, 1.2 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.65ꢀ7.68 (m, 2H), 7.73 (ddd,
J = 8.6, 6.9, 1.6 Hz, 1H), 7.80 (dd, J = 8.1, 1.6 Hz, 1H), 8.12ꢀ8.15 (m,
2H). 13C NMR (100.5 MHz, CDCl3): δ = 89.3 (4°), 89.9 (4°), 122.1
(4°), 124.3 (CH), 127.1 (CH), 127.1 (4°), 127.5 (CH), 128.4 (CH),
129.1 (CH), 129.3 (CH), 130.0 (CH), 132.2 (CH), 136.1 (CH), 143.6
(4°), 148.2 (4°). LR(ESI-MS) m/z: 230 {(MH)þ, 100}. HR(ESI-MS)
m/z: calcd for C17H12N 230.0964, found 230.0967 [M þ H]þ.
2-(20-Phenylethynyl)thiophene (3k)45 (Entry 11, Table 1). Synthe-
sized according to the general PK procedure, except it was performed at
60 °C, with 2-bromothiophene (652 mg, 0.39 mL, 4.0 mmol), phenyl-
acetylene (449 mg, 0.48 mL, 4.4 mmol), and Pd(OAc)2 (1 mol %) and
tri-o-tolylphosphine (2 mol %) as catalyst system (in place of PdCl2-
(PPh3)2), to afford the title compound as a white solid (392 mg, 53%).
1H NMR (400 MHz, CDCl3): δ = 7.01ꢀ7.04 (m, 1H), 7.29 (s, 1H),
7.31 (dd, J = 1.7, 1.2 Hz, 1H), 7.34ꢀ7.38 (m, 3H), 7.53ꢀ7.54 (m, 2H).
13C NMR (100.5 MHz, CDCl3): δ = 82.6 (4°), 93.0 (4°), 122.9 (4°),
123.3 (4°), 127.1 (CH), 127.2 (CH), 128.3 (CH), 128.4 (CH), 131.4
(CH), 131.9 (CH). LR(CI-MS) m/z: 184 {Mþ, 100}, 202 {(MNH4)þ,
21}.
6-Methyl-4-(2-(1-methyl-1H-pyrr-2-yl)ethynyl)-2H-pyran-2-one (3q)
(Entry 16, Table 1). Synthesized according to the general Sonogashira
procedure, with 4-bromo-6-methyl-2-pyrone48 (229 mg, 1.2 mmol) and
1-methyl-2-ethynyl-1H-pyrrole (140 mg, 1.3 mmol), to afford the title
compound as a brown powder (143 mg, 55%). Mp = 109ꢀ113 °C. 1H
NMR (400 MHz, CDCl3): δ = 2.24 (dd, J = 0.9, 0.7 Hz, 3H), 3.72 (s,
3H), 5.99 (dq, J = 1.4, 0.9 Hz, 1H), 6.15 (dd, J = 3.9, 2.6 Hz, 1H), 6.18
(dq, J = 1.4, 0.7 Hz, 1H), 6.61 (dd, J = 3.9, 1.7 Hz, 1H), 6.77 (dd, J = 2.6,
1.7 Hz, 1H). 13C NMR (100.5 MHz, CDCl3): δ = 19.9 (CH3), 34.7
(CH3), 91.0 (4°), 91.8 (4°), 104.9 (CH), 109.2 (CH), 111.9 (CH),
113.9 (4°), 118.3 (CH), 126.2 (CH), 139.0 (4°), 161.7 (4°), 162.4 (4°).
3-(20-Phenylethynyl)thiophene (3l)46 (Entry 12, Table 1). Synthe-
sized according to the general Sonogashira procedure, except it was
performed at 60 °C, with 3-bromothiophene (326 mg, 0.19 mL, 2.0
mmol), phenylacetylene (250 mg, 0.24 mL, 2.2 mmol), and Pd(PPh3)4
5328
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ARTICLE
LR(ESI-MS) m/z: 214 {(MH)þ, 100}. HR(ESI-MS) m/z: calcd for
C13H12NO2 214.0863, found 214.0870 [M þ H]þ.
HR(ESI-MS) m/z: calcd for C25H24NO 354.1852, found 354.1854
[M þ H]þ. Data for (3aRS,4SR,7RS,7aSR)-3-(1-Methyl-1H-inden-2-yl)-
2-phenyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-1-one (4bβ).
General Procedure for the PausonꢀKhand (PK) Reactions. The
alkyne (0.5 mmol), dicobalt(0) octacarbonyl (0.171 g, 0.5 mmol), and
DCE (2 mL) were added to a microwave tube and charged with a
magnetic stirrer bar. The reagents were stirred for 1 h at ambient
temperature, after which time norbornene (0.235 g, 2.5 mmol) was
added and the reaction was placed in the microwave reactor (100 W,
90 °C). Any pressure build-up was released from the vessel at 10 min
intervals during the first hour of the reaction. The reaction was followed
by TLC analysis (silica gel) and heated until the intermediate (μ2-
alkyne)Co2(CO)6 complex was no longer detected. On completion of
the reaction, the solvent was removed in vacuo and the reaction mixture
purified by chromatography on silica gel, using hexane/EtOAc (1:0 to
7:3, v/v) as the eluent, to afford the desired cycloadduct(s).
1
Mp = >71 °C dec. H NMR (400 MHz, CDCl3): δ = 1.06 (d, J =
10.5 Hz, 1H), 1.28 (d, J = 10.5 Hz, 1H), 1.42ꢀ1.53 (m, 2H), 1.61ꢀ1.78
(m, 2H), 2.24 (br, 1H), 2.58 (d, J = 5.5 Hz, 1H), 2.65 (br, 1H), 3.30 (s,
3H), 3.36 (d, J = 5.5 Hz, 1H), 6.50 (s, 1H), 7.10 (ddd, J = 8.1, 6.9, 1.2 Hz,
1H), 7.21 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.24ꢀ7.35 (m, 6H), 7.60 (d, J =
7.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ = 28.8 (CH2), 28.9
(CH2), 31.4 (CH3), 31.7 (CH2), 38.8 (CH), 39.6 (CH), 52.2 (CH),
54.2 (CH), 104.4 (CH), 109.9 (CH), 120.3 (CH), 121.1 (CH), 123.2
(CH), 127.9 (4°), 128.1 (CH), 128.4 (CH), 128.8 (CH), 132.0 (4°),
136.0 (4°), 139.0 (4°), 142.0 (4°), 161.3 (4°), 207.9 (4°). IR νmax
(CH2Cl2, cmꢀ1): 2962, 2876, 1690, 1616, 1597, 1462, 1393, 1317.
LR(ESI-MS) m/z: 354 {(MH)þ, 61}, 376 {(MNa)þ, 100}. HR(ESI-
MS) m/z: calcd for C25H23NNaO 376.1675, found 376.1672 [M þ Na]þ.
Compounds 4cr and 4cβ from 3c (Entry 3, Table 2). Synthesized
according to the general PK procedure, except on 2.5 mmol scale, with
3c (58 mg, 2.5 mmol), to afford 4cr as a yellow solid (34 mg, 39%) and
4cβ as a yellow solid (33 mg, 37%). Data for (3aRS,4SR,7RS,7aSR)-2-(1-
Methyl-1H-inden-3-yl)-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-
methanoinden-1-one (4cr). Mp = >188 °C dec. 1H NMR (400 MHz,
CDCl3): δ = 1.00 (d, J = 10.4 Hz, 1H), 1.24 (d, J = 10.4 Hz, 1H),
1.43ꢀ1.50 (m, 2H), 1.64ꢀ1.71 (m, 2H), 2.17 (br, 1H), 2.52 (d, J = 5.4
Hz, 1H), 2.62 (br, 1H), 3.27 (d, J = 5.4 Hz, 1H), 3.82 (s, 3H), 6.64 (d, J =
8.0 Hz, 1H), 6.77 (t, J = 7.5 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.22ꢀ7.27
(m, 4H), 7.46 (d, J = 6.9 Hz, 2H), 7.51 (s, 1H). 13C NMR (125 MHz,
CDCl3): δ = 28.90 (CH2), 28.94 (CH2), 31.7 (CH2), 33.0 (CH3), 38.8
(CH), 39.5 (CH), 50.5 (CH), 54.0 (CH), 105.4 (4°), 109.1 (CH), 119.1
(CH), 121.2 (CH), 121.3 (CH), 125.5 (4°), 128.3 (CH), 128.4 (CH),
129.1 (CH), 130.3 (CH), 135.9 (4°), 136.3 (4°), 137.0 (4°), 166.0 (4°),
209.5 (4°). νmax (CH2Cl2, cmꢀ1): 2962, 2875, 1687, 1620, 1608, 1524,
1469, 1386, 1336, 1303, 1200, 1069. LR(ESI-MS) m/z: 354 {(MH)þ,
63}, 376 {(MNa)þ, 100}. HR(ESI-MS) m/z: calcd for C25H23NNaO
376.1672, found 376.1673 [M þ Na]þ. Data for (3aRS,4SR,7RS,7aSR)-
3-(1-Methyl-1H-inden-3-yl)-2-phenyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-
methanoinden-1-one (4cβ). Mp = >192 °C dec. 1H NMR (400 MHz,
CDCl3): δ = 1.00 (d, J = 10.4 Hz, 1H), 1.31 (d, J = 10.4 Hz, 1H),
1.42ꢀ1.57 (m, 2H), 1.68ꢀ1.73 (m, 2H), 2.33 (br, 1H), 2.52 (d, J = 5.5
Hz, 1H), 2.61 (br, 1H), 3.45 (d, J = 5.5 Hz, 1H), 3.68 (s, 3H), 6.97 (s,
1H), 7.09 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.22ꢀ7.26 (m, 1H), 7.27ꢀ7.33
(m, 4H), 7.34ꢀ7.39 (m, 2H), 7.42 (d, J = 8.2 Hz, 1H). 13C NMR (125
MHz, CDCl3): δ = 29.0 (CH2), 29.1 (CH2), 31.6 (CH2), 33.3 (CH3),
39.4 (CH), 39.6 (CH), 50.7 (CH), 54.0 (CH), 109.8 (CH), 110.8 (4°),
121.1 (CH), 121.7 (CH), 122.4 (CH), 126.2 (4°), 127.5 (CH), 128.8
(CH), 129.3 (CH), 132.8 (CH), 134.5 (4°), 137.2 (4°), 138.2 (4°),
165.8 (4°), 207.8 (4°). νmax (CH2Cl2, cmꢀ1): 2962, 2875, 1673, 1613,
1584, 1570, 1522, 1474, 1465, 1366, 1317. LR(ESI-MS) m/z: 354
{(MH)þ, 100}, 376 {(MNa)þ, 81}. HR(ESI-MS) m/z: calcd for
C25H24NO 354.1852, found 354.1855 [M þ H]þ.
Compounds 4ar and 4aβ from 3a (Entry 1, Table 2). Synthesized
according to the general PK procedure except on 2.8 mmol scale, with 3a
(50 mg, 2.8 mmol), to afford 4ar as a yellow solid (45 mg, 54%) and 4aβ
as a light brown solid (16 mg, 19%). Data for (3aRS,4SR,7RS,7aSR)-
2-(1-Methyl-1H-pyrr-2-yl)-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-
methanoinden-1-one (4ar). Mp = 122ꢀ125 °C. 1H NMR (500 MHz,
CDCl3): δ = 1.03 (d, J = 10.6 Hz, 1H), 1.20 (d, J = 10.6 Hz, 1H),
1.40ꢀ1.47 (m, 2H), 1.63ꢀ1.73 (m, 2H), 2.19 (br, 1H), 2.50 (d, J = 5.6
Hz, 1H), 2.60 (br, 1H), 3.14 (s, 3H), 3.25 (d, J = 5.6 Hz, 1H), 6.10 (dd,
J = 3.6, 1.9 Hz, 1H), 6.18 (dd, J = 3.6, 2.6 Hz, 1H), 6.65 (dd, J = 2.6, 1.9
Hz, 1H), 7.27ꢀ7.29 (m, 2H), 7.30ꢀ7.35 (m, 3H). 13C NMR (125 MHz,
CDCl3): δ = 28.8 (CH2), 29.0 (CH2), 31.8 (CH2), 34.4 (CH3), 39.0
(CH), 39.4 (CH), 50.2 (CH), 54.0 (CH), 108.4 (CH), 110.4 (CH),
123.4 (CH), 124.2 (4°), 128.2 (CH), 128.6 (CH), 129.9 (CH), 135.1
(4°), 135.3 (4°), 170.0 (4°), 208.7 (4°). IR νmax (CH2Cl2, cmꢀ1): 2962,
2876, 1691, 1620, 1526, 1445, 1336, 1198, 1157, 1088. LR(ESI-MS) m/
z: 304 {(MH)þ, 100}. HR(ESI-MS) m/z: calcd for C21H22NO
304.1696, found 304.1696 [M þ H]þ. Data for (3aRS,4SR,7RS,7aSR)-
3-(1-Methyl-1H-pyrr-2-yl)-2-phenyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-
1
methanoinden-1-one (4aβ). Mp = >89 °C dec. H NMR (500 MHz,
CDCl3): δ = 1.03 (d, J = 10.5 Hz, 1H), 1.19 (d, J = 10.5 Hz, 1H),
1.42ꢀ1.38 (m, 2H), 1.69ꢀ1.64 (m, 2H), 2.19 (br, 1H), 2.48 (d, J = 5.6
Hz, 1H), 2.60 (br, 1H), 2.86 (s, 3H), 2.86 (d, J = 5.6 Hz, 1H), 6.24 (dd,
J = 3.8, 2.6 Hz, 1H), 6.47 (dd, J = 3.8, 1.7 Hz, 1H), 6.63 (dd, J = 2.6, 1.7
Hz, 1H), 7.24ꢀ7.21 (m, 3H), 7.31ꢀ7.26 (m, 2H). 13C NMR (125 MHz,
CDCl3): δ = 28.86 (CH2), 28.91 (CH2), 31.7 (CH2), 35.3 (CH3), 39.0
(CH), 39.5 (CH), 51.8 (CH), 54.2 (CH), 109.2 (CH), 112.7 (CH),
126.7 (CH), 127.6 (CH), 128.4 (CH), 128.8 (CH), 129.6 (4°), 133.0
(4°), 139.2 (4°), 161.9 (4°), 207.8 (4°). νmax (CH2Cl2, cmꢀ1): 2960,
2876, 1790, 1685, 1613, 1595, 1492, 1374, 1343, 1291, 1199, 1162.
LR(ESI-MS) m/z: 304 {(MH)þ, 100}. HR(ESI-MS) m/z: calcd for
C21H22NO 304.1696, found 304.1704 [M þ H]þ.
Compounds 4br and 4bβ from 3b (Entry 2, Table 2). Synthesized
according to the general PK procedure, except on 2.5 mmol scale, with
3b (58 mg, 2.5 mmol), to afford 4br as a yellow solid (51 mg, 58%) and
4bβ as a yellow solid (26 mg, 29%). Data for (3aRS,4SR,7RS,7aSR)-2-
(1-Methyl-1H-inden-2-yl)-3-phenyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-
methanoinden-1-one (4br). Mp = >165 °C dec. 1H NMR (400 MHz,
CDCl3): δ = 1.09 (d, J = 10.5 Hz, 1H), 1.28 (d, J = 10.5 Hz, 1H),
1.42ꢀ1.53 (m, 2H), 1.61ꢀ1.78 (m, 2H), 2.24 (br, 1H), 2.58 (d, J = 5.5
Hz, 1H), 2.65 (br, 1H), 3.30 (s, 3H), 3.36 (d, J = 5.5 Hz, 1H), 6.50 (s,
1H), 7.10 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.21 (ddd, J = 8.1, 6.9, 1.2 Hz,
1H), 7.24ꢀ7.35 (m, 6H), 7.60 (d, J = 7.9 Hz, 1H). 13C NMR (100.5
MHz, CDCl3): δ = 28.8 (CH2), 29.0 (CH2), 30.7 (CH3), 31.9 (CH2),
39.1 (CH), 39.5 (CH), 50.5 (CH), 54.1 (CH), 103.1 (CH), 109.5
(CH), 119.5 (CH), 120.9 (CH), 121.6 (CH), 128.2 (4°), 128.4 (CH),
128.7 (CH), 130.4 (CH), 131.5 (4°), 134.4 (4°), 134.7 (4°), 137.8 (4°),
171.0 (4°), 208.3 (4°). IR νmax (CH2Cl2, cmꢀ1): 2962, 2876, 1694,
1626, 1527, 1465, 1393, 1344. LR(ESI-MS) m/z: 354 {(MH)þ, 100}.
Compounds 4fr and 4fβ from 4f (Entry 6, Table 2). Synthesized
according to the general PK procedure, with 3f (90 mg, 5.0 mmol), to
afford 4fr as an off-white solid (4 mg, 3%) and 4fβ as a white solid
(114 mg, 75%). Data for (3aRS,4SR,7RS,7aSR)-3-Phenyl-2-(pyrimidin-
2-yl)-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-1-one (4fr). 1H
NMR (400 MHz, CDCl3): δ = 1.06 (d, J = 10.9 Hz, 1H), 1.38ꢀ1.48
(m, 3H), 1.63ꢀ1.73 (m, 2H), 2.17 (br, 1H), 2.58 (d, J = 5.4 Hz, 1H),
2.65 (br, 1H), 3.33 (d, J = 5.4 Hz, 1H), 7.22ꢀ7.30 (m, overlapped with
residual CDCl3, 5H), 7.33ꢀ7.36 (m, 3H), 8.79 (s, 2H). 13C NMR (125
MHz, CDCl3): δ = 28.9 (CH2), 29.1 (CH2), 31.9 (CH2), 38.6 (CH),
39.7 (CH), 51.0 (CH), 54.7 (CH), 119.6 (CH), 128.5 (CH), 130.2
(CH), 157.4 (CH), 173.3 (4°). Remaining carbon peaks could not be
observed even after extended collection times. IR νmax (CH2Cl2, cmꢀ1):
2962, 1696, 1624, 1559, 1424, 1354. LR(ESI-MS) m/z: 303 {(MH)þ,
5329
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ARTICLE
46}, 325 {(MNa)þ, 100). HR(ESI-MS) m/z: calcd for C20H19N2O
303.1492, found 303.1498 [M þ H]þ. Data for (3aRS,4SR,7RS,7aSR)-2-
Phenyl-3-(pyrimidin-2-yl)-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-
1-one (4fβ). Mp = >175 °C dec. 1H NMR (400 MHz, CDCl3): δ = 1.10
(d, J = 10.6 Hz, 1H), 1.34 (d, J = 10.6 Hz, 1H), 1.38ꢀ1.49 (m, 2H),
1.61ꢀ1.74 (m, 2H), 2.31ꢀ2.35 (m, 1H), 2.53 (d, J = 5.5 Hz, 1H),
2.61ꢀ2.63 (m, 1H), 3.39 (d, J = 5.5 Hz, 1H), 7.18ꢀ7.20 (m, 3H),
7.25ꢀ7.29 (m, 3H), 8.72 (d, J = 4.9 Hz, 2H). 13C NMR (125 MHz,
CDCl3): δ = 28.6 (CH2), 29.1 (CH2), 31.6 (CH2), 38.3 (CH), 39.9
(CH), 50.2 (CH), 54.2 (CH), 120.0 (CH), 127.9 (CH), 127.9 (CH),
129.1 (CH), 131.4 (4°), 146.3 (4°), 156.9 (CH), 164.1 (4°), 166.5 (4°),
209.6 (4°). IR νmax (CH2Cl2, cmꢀ1): 2962, 2876, 1698, 1566, 1556,
1421, 1359, 1244, 1198, 1170. LR(ESI-MS) m/z: 303 {(MH)þ, 100},
325 {(MNa)þ, 25). HR(ESI-MS) m/z: calcd for C20H19N2O 303.1492,
found 303.1500 [M þ H]þ.
(CH2), 31.6 (CH2), 38.2 (CH), 39.5 (CH), 51.2 (CH), 54.1 (CH),
123.2 (CH), 128.1 (4°), 128.3 (CH), 128.7 (CH), 129.9 (CH), 134.6
(4°), 136.8 (CH), 139.2 (4°), 148.7 (CH), 150.1 (CH), 171.9 (4°),
208.1 (4°). IR νmax (CH2Cl2, cmꢀ1): 2963, 2876, 1692, 1621, 1583,
1565, 1350, 1329, 1200, 1170, 1028. LR(ESI-MS) m/z: 302 {(MH)þ,
100}. HR(ESI-MS) m/z: calcd for C21H20NO 302.1539, found 302.1544
[M þ H]þ. Data for (3aRS,4SR,7RS,7aSR)-2-Phenyl-3-(pyridin-3-yl)-
>136 °C dec. 1H NMR (500 MHz, CDCl3): δ = 1.06 (d, J = 10.7 Hz,
1H), 1.23 (d, J = 10.7 Hz), 1.43 (m, 2H), 1.62ꢀ1.75 (m, 2H), 2.12 (br,
1H), 2.54 (d, J = 5.4 Hz, 1H), 2.63 (br, 1H), 3.22 (d, J = 5.4, Hz, 1H),
7.16 (dd, J = 7.7, 1.6 Hz, 2H), 7.23 (br s, 1H), 7.29ꢀ7.33 (m, 3H), 7.55
(d, J = 7.8 Hz, 1H), 8.62 (br s, 2H). 13C NMR (125 MHz, CDCl3): δ =
28.7 (CH2), 29.0 (CH2), 31.6 (CH2), 38.2 (CH), 39.5 (CH), 50.4
(CH), 54.1 (CH), 123.4 (br, CH), 128.2 (CH), 128.6 (CH), 129.2
(CH), 131.4 (4°), 135.7 (CH), 144.3 (4°), 149.3 (CH), 150.3 (4°),
165.9 (4°), 208.0 (4°). IR νmax (CH2Cl2, cmꢀ1): 2962, 2876, 1695,
1624, 1597, 1493, 1474, 1411, 1349, 1200, 1166, 1024. LR(ESI-MS)
m/z: 302 {(MH)þ, 100}. HR(ESI-MS) m/z: calcd for C21H20NO
302.1539, found 302.1536 [M þ H]þ.
3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-1-one (4hβ). Mp
=
Compounds 4gr and 4gβ from 4g (Entry 7, Table 2). Synthesized
according to the general PK procedure, with 3g (90 mg, 5.0 mmol),
except purification. On completion of the reaction, the mixture was
filtered through Celite with DCM (20 mL) and the solvent removed in
vacuo. Chromatography on silica gel using DCM/MeOH (99:1, v/v) as
the eluent afforded 4gr as a white solid (11 mg, 7%) and 4gβ as a white
solid (96 mg, 64%). Data for (3aRS,4SR,7RS,7aSR)-3-Phenyl-2-(pyridin-
2-yl)-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-1-one (4gr).
Mp = 138ꢀ142 °C. 1H NMR (500 MHz, CDCl3): δ = 1.04 (d, J = 10.6
Hz, 1H), 1.32 (d, J = 10.6 Hz, 1H), 1.40ꢀ1.46 (m, 2H), 1.63ꢀ1.72 (m,
2H), 2.15 (br, 1H), 2.54 (d, J = 5.5 Hz, 1H), 2.63 (br, 1H), 3.28 (d,
J = 5.5, Hz, 1H), 7.20 (ddd, J = 7.7, 5.0, 0.9 Hz, 1H), 7.24ꢀ7.30 (m, 5H),
7.31ꢀ7.34 (m, 1H), 7.67 (ddd, J = 7.8, 7.7 Hz, 1.9 Hz, 1H), 8.59 (ddd,
J = 5.0, 1.9, 0.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ = 28.9 (CH2),
29.1 (CH2), 31.8 (CH2), 38.6 (CH), 39.5 (CH), 50.9 (CH), 54.4 (CH),
122.6 (CH), 124.9 (CH), 128.3 (CH), 128.7 (CH), 129.9 (CH), 134.6
(4°), 136.2 (CH), 142.4 (4°), 149.9 (CH), 152.5 (4°), 172.3 (4°), 208.0
(4°). IR νmax (CH2Cl2, cmꢀ1): 2962, 2876, 1691, 1623, 1583, 1472,
1428, 1350, 1200, 1179. LR(ESI-MS) m/z: 302 {(MH)þ, 100}. HR-
(ESI-MS) m/z: calcd for C21H20NO 302.1539, found 302.1538 [M þ
H]þ. Data for (3aRS,4SR,7RS,7aSR)-2-Phenyl-3-(pyridin-2-yl)-3a,4,5,6,
7,7a-hexahydro-1H-4,7-methanoinden-1-one (4gβ). Mp = 129ꢀ131
°C. 1H NMR (500 MHz, CDCl3): δ = 1.02 (d, J = 10.5 Hz, 1H), 1.25
(d, J = 10.5 Hz, 1H), 1.39ꢀ1.51 (m, 2H), 1.61ꢀ1.71 (m, 2H), 2.21 (br,
1H), 2.51 (d, J = 5.4 Hz, 1H), 2.61 (br, 1H), 3.49 (d, J = 5.4 Hz, 1H), 7.01
(ddd, J = 7.8, 1.0, 1.0 Hz, 1H), 7.18ꢀ7.121 (m, 3H), 7.30ꢀ7.34 (m, 3H),
7.45 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H), 8.73 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H).
13C NMR (125 MHz, CDCl3): δ = 28.7 (CH2), 29.1 (CH2), 31.6
(CH2), 38.4 (CH), 39.8 (CH), 50.0 (CH), 54.0 (CH), 123.5 (CH),
125.1 (CH), 128.1 (CH), 128.5 (CH), 129.2 (CH), 131.8 (4°), 135.7
(CH), 144.2 (4°), 149.9 (CH), 154.3 (4°), 169.0 (4°), 209.3 (4°). IR
νmax (CH2Cl2, cmꢀ1): 2961, 2876, 1692, 1585, 1566, 1493, 1353, 1198,
1167. LR(ESI-MS) m/z: 302 {(MH)þ, 100}. HR(ESI-MS) m/z: calcd
for C21H20NO 302.1539, found 302.1532 [M þ H]þ.
Compounds 4ir and 4iβ from 3i (Entry 9, Table 2). Synthesized
according to the general PK procedure, with 3i (90 mg, 0.5 mmol), to
afford 4ir as a white solid (42 mg, 28%) and 4iβ as a white solid (100
mg, 66%). Data for (3aRS,4SR,7RS,7aSR)-3-Phenyl-2-(pyridin-4-yl)-
3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-1-one (4ir). Selected
peaks. 1H NMR (500 MHz, CDCl3): δ = 1.00ꢀ1.06 (overlapping d’s,
J = 10.7 Hz, 1H), 1.16ꢀ1.22 (overlapping d’s, J = 10.7 Hz, 1H),
1.35ꢀ1.44 (m, 2H), 1.59ꢀ1.74 (m, 2H), 2.05ꢀ2.10 (m, 1H), 2.53 (d,
J = 5.5 Hz, 1H), 2.58ꢀ2.63 (br, 1H), 3.21 (d, J = 5.5 Hz, 1H), 7.10ꢀ7.20
(m, 3H), 7.22ꢀ7.37 (m, 4H), 8.50ꢀ8.80 (br s, 2H). 13C NMR (125
MHz, CDCl3): δ = 28.7 (CH2), 28.9 (CH2), 31.6 (CH2), 38.2 (CH),
39.5 (CH), 51.1 (CH), 54.1 (CH), 128.3 (CH), 128.3 (CH), 128.6
(CH), 130.8 (CH), 134.3 (4°), 139.9 (4°), 141.8 (4°), 150.1 (CH),
172.6 (4°), 207.3 (4°). IR νmax (CH2Cl2, cmꢀ1): 2963, 2877, 1695,
1623, 1591, 1543, 1489, 1445, 1350, 1198, 1167. LR(ESI-MS) m/z: 302
{(MH)þ, 100}, 324 {(MNa)þ, 73}. HR(ESI-MS) m/z: calcd for
C21H20NO 302.1539, found 302.1544 [M þ H]þ. Data for (3aRS,
4SR,7RS,7aSR)-2-Phenyl-3-(pyridin-4-yl)-3a,4,5,6,7,7a-hexahydro-1H-
1
4,7-methanoinden-1-one (4iβ). Mp = >148 °C dec. H NMR (500
MHz, CDCl3): δ = 1.06 (d, J = 10.7 Hz, 1H), 1.21 (d, J = 10.7 Hz, 1H),
1.38ꢀ1.44 (m, 2H), 1.62ꢀ1.74 (m, 2H), 2.09 (br, 1H), 2.53 (d, J = 5.5
Hz, 1H), 2.63 (br, 1H), 3.15 (d, J = 5.5 Hz, 1H), 7.12ꢀ7.22 (m, 4H),
7.28ꢀ7.32 (m, 3H), 8.50ꢀ8.80 (br s, 2H). 13C NMR (125 MHz,
CDCl3): δ = 28.7 (CH2), 28.9 (CH2), 31.6 (CH2), 38.0 (CH), 39.6
(CH), 50.5 (CH), 54.1 (CH), 122.8 (br, CH), 128.4 (CH), 128.5 (CH),
129.1 (CH), 130.9 (4°), 143.0 (CH), 144.9 (4°), 150.3 (4°), 166.3 (4°),
208.1 (4°). IR νmax (CH2Cl2, cmꢀ1): 2963, 2877, 1695, 1623, 1591,
1543, 1489, 1445, 1350, 1198, 1167. LR(ESI-MS) m/z: 302 {(MH)þ,
100}. HR(ESI-MS) m/z: calcd for C21H20NO 302.1539, found 302.1543
[M þ H]þ.
Compounds 4hr and 4hβ from 3h (Entry 8, Table 2). Synthesized
according to the general PK procedure, with 3h (90 mg, 0.5 mmol),
except purification. After chromatography on silica gel using DCM/
MeOH (99:1, v/v) as the eluent, the solvent was removed in vacuo to
give crude 4hr first, which was passed through a small pad of silica using
hexane/EtOAc (2:3, v/v) as the eluent to afford pure 4hr as a white
solid (50 mg, 33%). 4hβ eluted from the first column, following 4hr,
affording an off-white solid (87 mg, 58%). Data for (3aRS,4SR,7RS,
7aSR)-3-Phenyl-2-(pyridin-3-yl)-3a,4,5,6,7,7a-hexahydro-1H-4,7-metha-
noinden-1-one (4hr). Mp = 116ꢀ119 °C. 1H NMR (400 MHz,
CDCl3): δ = 1.03 (d, J = 10.6 Hz, 1H), 1.21 (d, J = 10.6 Hz, 1H),
1.39ꢀ1.44 (m, 2H), 1.64ꢀ1.69 (m, 2H), 2.11 (br, 1H), 2.53 (d, J = 5.5
Hz, 1H), 2.61 (br, 1H), 3.23 (d, J = 5.5 Hz, 1H), 7.23ꢀ7.37 (m, 6H),
7.62 (ddd, J = 7.9, 2.1, 1.7 Hz, 1H), 8.36 (d, J = 1.7 Hz, 1H), 8.49 (dd, J =
4.8, 1.7 Hz, 1H). 13C NMR (100.5 MHz, CDCl3): δ = 28.8 (CH2), 28.9
Compounds 4jr and 4jβ from 3j (Entry 10, Table 2). Synthesized
according to the general PK procedure, with 3j (115 mg, 5.0 mmol), to
afford 4jr as an off-white solid (33 mg, 19%) and 4jβ as a white solid (99
mg, 57%). Data for (3aRS,4SR,7RS,7aSR)-3-Phenyl-2-(quinolyn-2-yl)-
3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-1-one (4jr). Mp
=
1
206ꢀ211 °C. H NMR (500 MHz, CDCl3): δ = 1.08 (br d, J = 10.7
Hz, 1H), 1.40 (br d, J = 10.7 Hz, 1H), 1.42ꢀ1.50 (m, 2H), 1.67ꢀ1.75
(m, 2H), 2.22 (br, 1H), 2.59 (d, J = 5.6 Hz, 1H), 2.68 (br, 1H), 3.35 (d,
J = 5.6 Hz, 1H), 7.20ꢀ7.24 (m, 2H), 7.28ꢀ7.32 (m, 3H), 7.52 (ddd, J =
7.8, 6.9, 0.9 Hz, 1H), 7.65 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.81 (d, J = 8.1
Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H). 13C NMR
(125 MHz, CDCl3): δ = 28.8 (CH2), 29.1 (CH2), 32.0 (CH2), 38.7
(CH), 39.5 (CH), 51.0 (CH), 54.5 (CH), 122.6 (CH), 126.6 (CH),
127.3 (4°), 127.5 (CH), 128.3 (CH), 128.9 (CH), 129.3 (CH), 129.6
5330
dx.doi.org/10.1021/jo200664m |J. Org. Chem. 2011, 76, 5320–5334

The Journal of Organic Chemistry
ARTICLE
(CH), 130.0 (CH), 134.4 (CH), 136.2 (4°), 142.8 (4°), 148.3 (4°),
153.3 (4°), 172.8 (4°), 208.2 (4°). IR νmax (CH2Cl2, cmꢀ1): 2964, 2876,
1693, 1594, 1501, 1354. LR(ESI-MS) m/z: 352 {(MH)þ, 100}.
HR(ESI-MS) m/z: calcd for C25H22NO 352.1696, found 352.1703
[M þ H]þ. Data for (3aRS,4SR,7RS,7aSR)-2-Phenyl-3-(quinolyn-2-yl)-
137.1 (4°), 169.5 (4°), 208.5 (4°). IR νmax (CH2Cl2, cmꢀ1): 2962, 2876,
1691, 1619, 1491, 1445, 1416, 1327, 1199. LR(ESI-MS) m/z: 307
{(MH)þ, 100}. HR(ESI-MS) m/z: calcd for C20H19OS 307.1151,
found 307.1157 [M þ H]þ. Data for (3aRS,4SR,7RS,7aSR)-2-Phenyl-
3-(thiophene-3-yl)-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-1-
one (4lβ). Mp = 159ꢀ162 °C. 1H NMR (500 MHz, CDCl3): δ = 1.07
(d, J = 10.6 Hz, 1H), 1.26 (d, J = 10.6 Hz, 1H), 1.40ꢀ1.51 (m, 2H),
1.65ꢀ1.78 (m, 2H), 2.37ꢀ2.39 (m, 1H), 2.49 (d, J = 5.6 Hz, 1H),
2.58ꢀ2.61 (m, 1H), 3.14 (d, J = 5.6 Hz, 1H), 6.91 (dd, J = 5.1, 1.3 Hz,
1H), 7.19 (dd, J = 5.1, 3.0 Hz, 1H), 7.21ꢀ7.24 (m, 2H), 7.33ꢀ7.36 (m,
1H), 7.37ꢀ7.41 (m, 2H), 7.48 (dd, J = 3.0, 1.3 Hz, 1H). 13C NMR (125
MHz, CDCl3): δ = 28.7 (CH2), 29.3 (CH2), 31.9 (CH2), 39.2 (CH),
39.6 (CH), 50.6 (CH), 54.0 (CH), 125.5 (CH), 127.6 (CH), 128.0
(CH), 128.0 (CH), 128.6 (CH), 129.2 (CH), 133.1 (4°), 136.5 (4°),
141.7 (4°), 162.9 (4°), 208.6 (4°). IR νmax (CH2Cl2, cmꢀ1): 2962, 2875,
1667, 1619, 1592, 1417, 1329, 1199, 1164. LR(ESI-MS) m/z: 307
{(MH)þ, 100}. HR(ESI-MS) m/z: calcd for C20H19OS 307.1151,
found 307.1152 [M þ H]þ.
3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-1-one (4jβ). Mp
=
167ꢀ168 °C. 1H NMR (500 MHz, CDCl3): δ = 1.05 (d, J = 10.6 Hz,
1H), 1.31 (d, J = 10.6 Hz, 1H), 1.41ꢀ1.54 (m, 2H), 1.65ꢀ1.69 (m, 2H),
2.30 (br, 1H), 2.56 (d, J = 5.5 Hz, 1H), 2.65 (br, 1H), 3.66 (d, J = 5.5, Hz,
1H), 7.05 (d, J = 8.5 Hz, 1H), 7.23 (dd, J = 6.7 Hz, 3.0 Hz, 2H),
7.28ꢀ7.32 (m, 3H), 7.55ꢀ7.58 (m, 1H), 7.73ꢀ7.78 (m, 2H), 7.89 (d,
J = 8.5 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H). 13C NMR (125 MHz, CDCl3):
δ = 28.7 (CH2), 29.2 (CH2), 31.6 (CH2), 38.6 (CH), 39.9 (CH), 50.4
(CH), 54.2 (CH), 122.3 (CH), 127.3 (CH), 127.5 (4°), 127.6 (CH),
128.2 (CH), 128.4 (CH), 129.4 (CH), 129.7 (CH), 130.0 (CH), 131.7
(4°), 135.4 (CH), 144.8 (4°), 148.3 (4°), 154.9 (4°), 169.4 (4°), 209.4
(4°). IR νmax (CH2Cl2, cmꢀ1): 2962, 2876, 1695, 1604, 1592, 1556,
1493, 1357, 1306, 1227, 1198, 1164. LR(ESI-MS) m/z: 352 {(MH)þ,
100}. HR(ESI-MS) m/z: calcd for C25H22NO 352.1696, found
352.1695 [M þ H]þ.
Compounds 4mr and 4mβ from 3m (Entry 13, Table 2). Synthe-
sized according to the general PK procedure, with 3m (84 mg, 5.0
mmol), to afford 4mr as a cream solid (29 mg, 20%) and 4mβ as a cream
solid (98 mg, 68%). Data for (3aRS,4SR,7RS,7aSR)-2-(Fur-2-yl)-3-
phenyl-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-1-one (4mr).
Compounds 4kr and 4kβ from 3k (Entry 11, Table 2). Synthesized
according to the general PK procedure, with 3k (92 mg, 5.0 mmol), to
afford 4kr as a white solid (35 mg, 23%) and 4kβ as a cream solid (80
mg, 52%). Data for (3aRS,4SR,7RS,7aSR)-3-Phenyl-2-(thiophene-2-yl)-
3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-1-one (4kr). Mp >
1
Mp = >134 °C dec. H NMR (400 MHz, CDCl3): δ = 0.97 (d, J =
10.6 Hz, 1H), 1.16 (d, J = 10.6 Hz, 1H), 1.32ꢀ1.41 (m, 2H), 1.59ꢀ1.65
(m, 2H), 2.06 (br, 1H), 2.47 (d, J = 5.5 Hz, 1H), 2.58 (br, 1H), 3.12 (d,
J = 5.5 Hz, 1H), 6.41 (dd, J = 3.4, 1.8 Hz, 1H), 7.02 (ddd, J = 3.4, 0.6, 0.5
Hz, 1H), 7.24 (dd, J = 1.8, 0.6 Hz, 1H), 7.37ꢀ7.42 (m, 5H). 13C NMR
(125 MHz, CDCl3): δ = 28.9 (CH2), 28.9 (CH2), 31.7 (CH2), 35.3
(CH3), 39.0 (CH), 39.5 (CH), 51.8 (CH), 54.2 (CH), 109.2 (CH),
112.7 (CH), 126.7 (CH), 127.6 (CH), 128.4 (CH), 128.8 (CH), 129.6
(4°), 133.0 (4°), 39.2 (4°), 161.9 (4°), 207.8 (4°). IR νmax (CH2Cl2,
cmꢀ1): 2962, 2876, 1785, 1696, 1547, 1473, 1392, 1340, 1291, 1200,
1146. LR(ESI-MS) m/z: 313 {(MNa)þ, 100}. HR(ESI-MS) m/z: calcd
for C20H18NaO2 313.1199, found 313.1189 [M þ Na]þ. Data for
(3aRS,4SR,7RS,7aSR)-3-(Fur-2-yl)-2-phenyl-3a,4,5,6,7,7a-hexahydro-
1
165 °C dec. H NMR (500 MHz, CDCl3): δ = 0.99 (d, J = 10.6 Hz,
1H), 1.23 (d, J = 10.6 Hz, 1H), 1.31ꢀ1.41 (m, 2H), 1.60ꢀ1.68 (m, 2H),
2.12 (br, 1H), 2.49 (d, J = 5.5 Hz, 1H), 2.61 (br, 1H), 3.03 (d, J = 5.5 Hz,
1H), 6.92 (dd, J = 5.0, 3.8 Hz, 1H), 7.22ꢀ7.25 (m, 2H), 7.34ꢀ7.37 (m,
2H), 7.41ꢀ7.44 (m, 3H). 13C NMR (125 MHz, CDCl3): δ = 28.7
(CH2), 28.9 (CH2), 31.6 (CH2), 37.9 (CH), 39.6 (CH), 52.5 (CH),
54.0 (CH), 126.5 (CH), 126.5 (CH), 127.4 (CH), 127.6 (CH), 128.8
(CH), 129.2 (CH), 132.2 (4°), 135.6 (4°), 136.4 (4°), 169.4 (4°), 207.5
(4°). IR νmax (CH2Cl2, cmꢀ1): 2964, 2877, 1694, 1614, 1532, 1444,
1426, 1372, 1307, 1199. LR(ESI-MS) m/z: 307 {(MH)þ, 100}. HR-
(ESI-MS) m/z: calcd for C20H19OS 307.1151, found 307.1157
[M þ H]þ. Data for (3aRS,4SR,7RS,7aSR)-2-Phenyl-3-(thiophene-2-
yl)-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-1-one (4kβ). Mp =
106ꢀ111 °C. 1H NMR (500 MHz, CDCl3): δ = 0.99 (d, J = 10.7 Hz,
1H), 1.31 (d, J = 10.7 Hz), 1.40ꢀ1.46 (m, 1H), 1.48ꢀ1.54 (m, 1H),
1.66ꢀ1.72 (m, 1H), 1.74ꢀ1.80 (m, 1H), 2.12 (d, J = 5.6 Hz, 1H), 2.55
(m, 1H), 2.59 (m, 1H), 3.17 (d, J = 5.6 Hz, 1H), 7.01 (dd, J = 5.1, 3.8 Hz,
1H), 7.23 (dd, J = 8.1, 1.5 Hz, 2H), 7.33 (dd, J = 3.8, 1.1 Hz, 1H), 7.38
(dd, J = 5.1, 1.1 Hz, 1H), 7.39ꢀ7.45 (m, 3H). 13C NMR (125 MHz,
CDCl3): δ = 28.7 (CH2), 29.3 (CH2), 32.1 (CH2), 39.1 (CH), 40.2
(CH), 50.5 (CH), 54.2 (CH), 127.2 (CH), 128.4 (CH), 128.9 (CH),
129.5 (CH), 130.3 (CH), 130.4 (CH), 132.6 (4°), 138.0 (4°), 141.3
(4°), 161.2 (4°), 207.9 (4°). IR νmax (CH2Cl2, cmꢀ1): 2962, 2876, 1686,
1617, 1590, 1489, 1420, 1357, 1198, 1162. LR(ESI-MS) m/z: 307
{(MH)þ, 100}. HR(ESI-MS) m/z: calcd for C20H19OS 307.1151,
found 307.1153 [M þ H]þ.
1
1H-4,7-methanoinden-1-one (4mβ). Mp = >133ꢀ136 °C. H NMR
(400 MHz, CDCl3): δ = 1.06 (d, J = 10.6 Hz, 1H), 1.26 (d, J = 10.6 Hz,
1H), 1.36ꢀ1.43 (m, 1H), 1.47ꢀ1.53 (m, 1H), 1.61ꢀ1.69 (m, 1H),
1.72ꢀ1.79 (m, 1H), 2.49 (d, J = 5.5 Hz, 1H), 2.52 (m, 1H), 2.56 (m,
1H), 3.14 (d, J = 5.5 Hz, 1H), 6.38 (dd, J = 3.6, 1.8 Hz, 1H), 6.43 (dd, J =
3.6, 0.7 Hz, 1H), 7.24ꢀ7.27 (m, 2H), 7.33ꢀ7.37 (m, 1H), 7.39ꢀ7.43
(m, 2H), 7.50 (dd, J = 1.8, 0.7 Hz, 1H). 13C NMR (100.5 MHz, CDCl3):
δ = 28.6 (CH2), 29.3 (CH2), 31.7 (CH2), 39.5 (CH), 39.8 (CH), 48.3
(CH), 53.7 (CH), 112.2 (CH), 115.7 (CH), 128.1 (CH), 128.5 (CH),
129.1 (CH), 132.7 (4°), 139.8 (4°), 144.8 (CH), 150.5 (4°), 156.6 (4°),
208.1 (4°). IR νmax (CH2Cl2, cmꢀ1): 2962, 2876, 1685, 1620, 1594,
1492, 1476, 1342, 1215, 1171, 1023. LR(ESI-MS) m/z: 313 {(MNa)þ,
100}. HR(ESI-MS) m/z: calcd for C20H18NaO2 313.1199, found
313.1199 [M þ Na]þ.
Compound 4nβ from 3n (Entry 14, Table 2). Synthesized according
to the general PK procedure, with 3n (89 mg, 5.0 mmol), to afford 4nβ
as a white solid (28 mg, 17%). While another product was observed by
TLC analysis, it could not be isolated and characterized. Data for
(3aRS,4SR,7RS,7aSR)-4-(1-Oxo-2-trimethylsilyl-3a,4,5,6,7,7a-hexahydro-
Compounds 4lr and 4lβ from 3l (Entry 12, Table 2). Synthesized
according to the general PK procedure, with 3l (92 mg, 5.0 mmol), to
afford 4lr as a cream solid (46 mg, 30%) and 4lβ as a white solid (95 mg,
62%). Data for (3aRS,4SR,7RS,7aSR)-3-Phenyl-2-(thiophene-3-yl)-
3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-1-one (4lr). Mp = 142ꢀ
146 °C. 1H NMR (500 MHz, CDCl3): δ = 0.99 (d, J = 10.5 Hz, 1H),
1.20 (d, J = 10.5 Hz, 1H), 1.34ꢀ1.42 (m, 2H), 1.64ꢀ1.66 (m, 2H), 2.09
(br, 1H), 2.47 (d, J = 5.5 Hz, 1H), 2.60 (br, 1H), 3.10 (d, J = 5.5 Hz), 6.80
(dd, J = 5.1, 1.1 Hz, 1H), 7.14 (dd, J = 5.1, 3.0 Hz, 1H), 7.32ꢀ7.36 (m,
2H), 7.36ꢀ7.39 (m, 3H), 7.66 (dd, J = 3.0, 1.1 Hz, 1H). 13C NMR (125
MHz, CDCl3): δ = 28.8 (CH2), 28.9 (CH2), 31.6 (CH2), 38.1 (CH),
39.5 (CH), 51.5 (CH), 54.1 (CH), 124.5 (CH), 125.4 (CH), 127.7
(CH), 128.0 (CH), 128.6 (CH), 129.3 (CH), 131.3 (4°), 136.2 (4°),
1H-4,7-methanoinden-3-yl)-2H-pyran-2-one (4nβ). Mp
=
161ꢀ
1
166 °C. H NMR (400 MHz, CDCl3): δ = 0.11 (s, 9H), 0.95 (d, J =
10.6 Hz, 1H), 0.99 (d, J = 10.6 Hz, 1H), 1.22ꢀ1.31 (m, 2H), 1.55ꢀ1.68
(m, 2H), 2.12 (br, 1H), 2.24 (d, J = 5.6 Hz, 1H), 2.30 (s, 1H), 2.47 (br,
1H), 2.74 (d, J = 5.6 Hz, 1H), 5.86ꢀ5.87 (m, 1H), 5.92ꢀ5.94 (m, 1H).
13C NMR (100.5 MHz, CDCl3): δ = ꢀ0.80 (CH3). 20.2 (CH3), 28.2
(CH2), 28.7 (CH2), 31.2 (CH2), 37.4 (CH), 39.5 (CH), 54.5 (CH),
54.6 (CH), 103.4 (CH), 109.6 (CH), 147.2 (4°), 155.1 (4°), 161.8 (4°),
162.7 (4°), 178.5 (4°), 213.4 (4°). IR νmax (CH2Cl2, cmꢀ1): 2962, 2876,
5331
dx.doi.org/10.1021/jo200664m |J. Org. Chem. 2011, 76, 5320–5334

The Journal of Organic Chemistry
ARTICLE
1727, 1690, 1641, 1588, 1544, 1383, 1315, 1249, 1215, 1198. LR(ESI-
MS) m/z: 329 {(MH)þ, 40}, 351 {(MNa)þ, 100). HR(ESI-MS) m/z:
calcd for C19H24O3SiNa 351.1387, found 351.1396 [M þ Na]þ.
Compound 4or from 3o (Entry 15, Table 2). Synthesized according
to the general PK procedure except on 3.75 mmol scale, with 3o (50 mg,
3.75 mmol) (note: the intermediate complex was purified first; see
characterization data below), to afford 4or as a cream solid (31 mg,
32%). Data for (3aRS,4SR,7RS,7aSR)-4-(1-Oxo-3a,4,5,6,7,7a-hexahy-
dro-1H-4,7-methanoinden-2-yl)-6-methyl-2H-pyran-2-one (4or). Mp =
142ꢀ147 °C. 1H NMR (500 MHz, CDCl3): δ = 1.00 (d, J = 10.8 Hz,
1H), 1.03 (d, J = 10.7 Hz, 1H), 1.29ꢀ1.41 (m, 2H), 1.62 (dddd, J = 11.3,
11.3, 3.9, 3.9 Hz, 1H), 1.73 (dddd, J = 11.3, 11.3, 4.0, 4.0 Hz, 1H), 2.25
(s, 3H), 2.31 (br, 1H), 2.36 (d, J = 5.4 Hz, 1H), 2.49 (br d, 1H), 2.74 (dd,
J = 5.4, 3.0 Hz, 1H), 6.26 (s, 1H), 6.71 (s, 1H), 7.80 (d, J = 3.0 Hz, 1H).
13C NMR (125 MHz, CDCl3): δ = 20.0 (CH3), 28.2 (CH2), 29.2
(CH2), 31.4 (CH2), 38.4 (CH), 39.6 (CH), 48.2 (CH), 55.0 (CH),
102.2 (CH), 109.5 (CH), 141.9 (4°), 145.6 (4°), 161.8 (4°), 163.1 (4°),
165.1 (CH), 207.2 (4°). IR νmax (CH2Cl2, cmꢀ1): 2963, 2877, 1722,
1638, 1608, 1548, 1411, 1332, 1305, 1185, 1131. LR(ESI-MS) m/z: 257
{(MH)þ, 100}, 279 {(MNa)þ, 43). HR(ESI-MS) m/z: calcd for
C16H17O3: 257.1172, found 257.1166 [M þ H]þ. Data for the Inter-
mediate Complex [μ2-4-Ethynyl-6-methyl-2H-pyran-2-one]hexacarbonyl
Dicobalt. 1H NMR (500 MHz, CDCl3): δ = 2.27 (s, 3H), 5.93 (s, 1H),
6.28 (s, 1H), 6.33 (s, 1H). 13C NMR (125 MHz, CDCl3): δ = 20.0
(CH3), 73.8 (CH), 82.9 (4°), 105.6 (CH), 110.8 (CH), 155.9 (4°),
161.6 (4°), 162.8 (4°), 198.2 (br, MꢀCO). IR νmax (CH2Cl2, cmꢀ1):
2101, 2065, 2037, 1713, 1632, 1567, 1363, 1310, 1273, 1263, 1223.
LR(ESI-MS) m/z: 421 {(MH)þ, 100}. HR(ESI-MS) m/z: calcd for
C14H7Co2O8 420.8799, found 420.8791 [M þ H]þ. Anal. Calcd for
C14H6Co2O8: C, 40.03; H, 1.44. Found: C, 39.96; H, 1.48.
afford the 4qr as an orange solid (138 mg, 82%) and 4qβ as an orange
solid (7 mg, 4%). Data for (3aRS,4SR,7RS,7aSR)-4-[1-Oxo-2-(1-methyl-
1H-pyrr-2-yl)-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-3-yl]-2H-
pyran-2-one (4qr). Mp = 141ꢀ144 °C. 1H NMR (500 MHz, CDCl3):
δ = 1.09 (s, 2H), 1.36ꢀ1.43 (m, 2H), 1.63ꢀ1.75 (m, 2H), 2.12 (t, J = 0.7
Hz, 3H), 2.27 (br, 1H), 2.48 (d, J = 5.6 Hz, 1H), 2.58 (br, 1H), 3.01 (d,
J = 5.6 Hz, 1H), 3.35 (s, 3H), 5.49 (dq, J = 1.5, 0.9 Hz, 1H), 6.09 (dd, J =
3.7, 1.8 Hz, 1H), 6.16 (dd, J = 3.7, 2.7 Hz, 1H), 6.29 (dq, J = 1.5, 0.7 Hz,
1H), 6.72 (dd, J = 2.7, 1.8 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ =
20.1 (CH3), 28.5 (CH2), 28.9 (CH2), 31.8 (CH2), 34.9 (CH3), 38.7
(CH), 39.4 (CH), 49.5 (CH), 53.9 (CH), 102.4 (CH), 109.0 (CH),
111.5 (CH), 112.4 (CH), 122.6 (4°), 125.1 (CH), 139.6 (4°), 150.6
(4°), 161.8 (4°), 162.7 (4°), 162.9 (4°), 207.9 (4°). IR νmax
(CH2Cl2, cmꢀ1): 2963, 2877, 1720, 1701, 1637, 1548, 1484, 1315,
1227, 1197. LR(ESI-MS) m/z: 336 {(MH)þ, 3), 358 {(MNa)þ, 100}.
HR(ESI-MS) m/z: calcd for C21H21NNaO3 358.1414, found 358.1420
[M þ H]þ. Data for (3aRS,4SR,7RS,7aSR)-4-[1-Oxo-3-(1-methyl-1H-
pyrr-2-yl)-3a,4,5,6,7,7a-hexahydro-1H-4,7-methano-inden-2-yl]-2H-
pyran-2-one (4qβ). 1H NMR (500 MHz, CDCl3): δ = 1.04ꢀ1.06 (m,
2H), 1.38ꢀ1.41 (m, 2H), 1.65ꢀ1.69 (m, 2H), 2.15 (s, 3H), 2.17 (br,
1H), 2.47 (d, J = 5.8 Hz, 1H), 2.57 (br, 1H), 3.08 (d, J = 5.8 Hz, 1H), 3.33
(s, 3H), 5.72ꢀ5.73 (br s, 1H), 6.24ꢀ6.25 (s, 1H), 6.27 (dd, J = 3.9, 2.5
Hz, 1H), 6.53 (dd, J = 3.9, 1.8 Hz, 1H), 6.82 (dd, J = 2.5, 1.8 Hz, 1H). 13C
NMR (100.5 MHz, CDCl3): δ = 20.1 (CH3), 28.7 (CH2), 28.9 (CH2),
31.8 (CH2), 35.9 (CH3), 39.5 (CH), 39.7 (CH), 51.9 (CH), 54.3 (CH),
103.7 (CH), 110.3 (CH), 111.5 (CH), 115.0 (CH), 128.6 (4°), 129.1
(CH), 133.9 (4°), 148.6 (4°), 161.6 (4°), 163.1 (4°), 165.5 (4°), 205.6
(4°). IR νmax (CH2Cl2, cmꢀ1): 2963, 2876, 1717, 1636, 1597, 1543,
1458, 1424, 1316, 1196. LR(ESI-MS) m/z: 336 {(MH)þ, 14}, 358
{(MNa)þ, 100). HR(ESI-MS) m/z: calcd for C21H21NNaO3 358.1414,
found 358.1417 [M þ Na]þ.
Compounds 4pr and 4pβ from 3p (Entry 16, Table 2). Synthesized
according to the general PK procedure, with 3p (108 mg, 5.0 mmol), to
afford 4pr as an orange solid (79 mg, 47%) and 4pβ as a white solid (76
mg, 45%). Data for (3aRS,4SR,7RS,7aSR)-4-[1-Oxo-2-(thiophene-3-
yl)-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-3-yl]-2H-pyran-2-
one (4pr). Mp = >163 °C dec. 1H NMR (500 MHz, CDCl3): δ = 1.08
(d, J = 10.6 Hz, 1H), 1.09 (d, J = 10.6 Hz, 1H), 1.34ꢀ1.40 (m, 2H),
1.62ꢀ1.71 (m, 2H), 2.20 (s, 4H overlapping with H-4), 2.45 (d, J = 5.6
Hz, 1H), 2.59 (br, 1H), 2.91 (d, J = 5.6 Hz, 1H), 5.76 (s, 1H), 6.22 (s,
1H), 7.02 (dd, J = 5.0, 1.2 Hz, 1H), 7.28 (dd, J = 5.0, 3.0 Hz, 1H), 7.72
(dd, J = 3.0, 1.2 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ = 20.1 (CH3),
28.5 (CH2), 28.8 (CH2), 31.6 (CH2), 38.0 (CH), 39.6 (CH), 50.5
(CH), 53.9 (CH), 103.3 (CH), 110.9 (CH), 125.4 (CH), 126.7 (CH),
127.4 (CH), 129.9 (4°), 139.7 (4°), 152.4 (4°), 162.2 (4°), 162.4 (4°),
162.6 (4°), 207.5 (4°). IR νmax (CH2Cl2, cmꢀ1): 2963, 2877, 1726,
1701, 1638, 1544, 1297, 1205, 1144. LR(ESI-MS) m/z: 339 {(MH)þ,
100}, 361 {(MNa)þ, 59). HR(ESI-MS) m/z: calcd for C20H19O3S1
339.1049, found 339.1055 [M þ H]þ. Data for (3aRS,4SR,7RS,7aSR)-
4-[1-Oxo-3-(thiophene-3-yl)-3a,4,5,6,7,7a-hexahydro-1H-4,7-metha-
’ ASSOCIATED CONTENT
S
Supporting Information. General experimental details,
b
1H and 13C NMR spectra (images) for new compounds, and a
summary of the X-ray diffraction data (four structures). This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: (þ44) 1904 324091. Fax: (þ44) 1904 322516. E-mail: ian.
fairlamb@york.ac.uk.
’ ACKNOWLEDGMENT
We are grateful to the EPSRC (DTA studentship to B.E.M.),
the Royal Society (I.J.S.F.) for funding. Dr. Mary Pryce (Dublin
City University, Dublin, Ireland) and Dr. Paul Evans (University
College, Dublin, Ireland) are both thanked for detailed discus-
sions concerning this and related projects. We are also grateful to
Dr. Jamie Platts (Cardiff University, U.K.) for discussion con-
cerning the singlet diradical nature of (μ2-alkyne)Co2(CO)6
complexes.
1
noinden-2-yl]-2H-pyran-2-one (4pβ). Mp = 158ꢀ161 °C. H NMR
(500 MHz, CDCl3): δ = 1.06 (d, J = 10.9 Hz, 1H), 1.11 (d, J = 10.9 Hz,
1H), 1.36ꢀ1.49 (m, 2H), 1.64ꢀ1.75 (m, 2H), 2.22 (s, 3H), 2.33 (br,
1H), 2.47 (d, J = 5.6 Hz, 1H), 2.56 (br, 1H), 3.13 (d, J = 5.6 Hz, 1H), 5.82
(s, 1H), 6.11 (s, 1H), 7.17 (d, J = 3.9 Hz, 1H), 7.36 (br s, 1H), 7.67 (br s,
1H). 13C NMR (100.5 MHz, CDCl3): δ = 20.1 (CH3), 28.5 (CH2), 29.1
(CH2), 31.9 (CH2), 39.3 (CH), 39.7 (CH), 51.1 (CH), 54.2 (CH),
104.8 (CH), 112.6 (CH), 126.8 (CH), 127.3 (CH), 129.20 (CH), 135.1
(4°), 137.0 (4°), 149.4 (4°), 162.3 (4°), 162.6 (4°), 165.7 (4°), 206.3
(4°). IR νmax (CH2Cl2, cmꢀ1): 2963, 2877, 1723, 1692, 1640, 1606,
1547, 1418, 1321, 1294, 1198, 1145. LR(ESI-MS) m/z: 339 {(MH)þ,
100}, 361 {(MNa)þ, 75). HR(ESI-MS) m/z: calcd for C20H19O3S
339.1049, found 339.1055 [M þ H]þ.
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Compounds 4qr and 4qβ from 3q (Entry 17, Table 2). Synthesized
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5332
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The Journal of Organic Chemistry
ARTICLE
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