Au(I)-catalyzed cycloisomerization reaction of amide- or ester-tethered 1,6-enynes to bicyclo[3.2.0]hept-6-en-2-ones

Article abstract of DOI:10.1021/jo901771p

(Chemical Equation Presented) The cycloisomerization reaction of N-allyl-2-(2′-arylethyne-2-yl)amides or allylic 2-alkynoates in the presence of cationic triphenylphosphinegold(I) produced bicyclo[3.2.0]hept-6-en- 2-ones under mild conditions. Computation

Full text of DOI:10.1021/jo901771p

pubs.acs.org/joc
Au(I)-Catalyzed Cycloisomerization Reaction of Amide- or
Ester-Tethered 1,6-Enynes to Bicyclo[3.2.0]hept-6-en-2-ones
Young Tak Lee,† Youn Kyung Kang,*,‡ and Young Keun Chung*,†
†Intelligent Textile System Research Center, Department of Chemistry, College of Natural Sciences, Seoul
National University, Seoul 151-747, Korea, and ‡Division of Chemistry and Molecular Engineering,
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Korea
ykchung@snu.ac.kr
Received August 25, 2009
The cycloisomerization reaction of N-allyl-2-(20-arylethyne-2-yl)amides or allylic 2-alkynoates in the
presence of cationic triphenylphosphinegold(I) produced bicyclo[3.2.0]hept-6-en-2-ones under mild
conditions. Computational investigations with a density functional theory (DFT) revealed that a
stepwise 6-endo-dig cyclization of 1,6-enyne systems, followed by a skeletal rearrangement to form
bicyclo[3.2.0]hept-6-en-2-one species represents the most probable reaction pathway. This can be
further supported by employing N-(10,10-dimethyl-1-propen-3-yl)-2-(100-phenylethyne-200-yl)amide
as a substrate, which exclusively produced 4-phenyl-5-(prop-1-en-2-yl)-5,6-dihydropyridino-2(1H)-
one unambiguously via 6-endo-dig cyclization. Theoretical calculations suggest both an aryl group at
the terminal alkyne and a keto carbonyl at the C(5) position of the 1,6-enyne system play a
complementary role for the reactivity.
Introduction
strate has been accepted as the origin for this diversity.2,6-10
A subtle change in the structure of the substrate, through its
interplay with the catalyst system, modulates the reactivity of
the system and thus leads to different reaction pathways.11,12
In the electrophilic transition metal-catalyzed cycloisome-
rization reaction of enynes, the formation of cyclobutenes is
quite limited13-19 although it has been considered one of the
Recently, transition metal-catalyzed cycloisomerization
reactions of enyne systems have been a subject of intense
research due to their impact on synthetic methodologies of a
range of structurally diverse products. A variety of structural
frameworks can be constructed utilizing these chemical
procedures by proper choice of the catalyst and the sub-
strates.1-5 Among many factors that affect the reaction
pathways, the formation of a stabilized carbocationic inter-
mediate between the transition metal catalyst and the sub-
(6) Furstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J. Am. Chem. Soc.
1998, 120, 8305–8314.
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69, 8018–8023.
(11) Kim, S. M.; Lee, S. I.; Chung, Y. K. Org. Lett. 2006, 8, 5425–5427.
(12) Lee, S. I.; Kim, S. M.; Choi, M. R.; Kim, S. Y.; Chung, Y. K.; Han,
W. S.; Kang, S. O. J. Org. Chem. 2006, 71, 9366–9372.
(13) Marion, F.; Coulomb, J.; Courillon, C.; Fensterbank, L.; Malacria,
M. Org. Lett. 2004, 6, 1509–1511.
*To whom correspondence should be addressed. Y.K.C.: phone (þ82)
2-880-6662; fax (þ82) 2-889-0310.
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7922 J. Org. Chem. 2009, 74, 7922–7934
Published on Web 09/22/2009
DOI: 10.1021/jo901771p
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2009 American Chemical Society

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accessible products.6,20-27 Since there are a handful of pre-
cedents for the synthesis of cyclobutenes,28-35 finding a
synthetic protocol selectively producing this structural motif
is still challenging.
SCHEME 1. Transition Metal-Catalyzed Cycloisomerization
of Allylpropargylmalonates
While we were studying the Au(I)-catalyzed cycloisome-
rization reactions of heteroatom-tethered 1,6-enynes, we
found that the introduction of a keto carbonyl at the C(5)
position could alter the reaction pathway from its nonketo
analogues giving rise to the formation of bicyclobutenes
instead of many other cycloisomerization products such as
1,3-diene derivatives or cyclopropanated compounds. Here-
in, we report our results along with the theoretical rationale
for the observed selectivity through a DFT calculation.
aReference 22. bReference 25.
derivative (4) under the conditions exerted by the PtCl215 or
by the Au(PPh3)þ catalysts (eq 2),36 the apparent difference
observed in this result clearly showed that the introduction of
the keto carbonyl group at the C(5) position of the 1,6-enyne
substrate completely changed the reaction pathway.
Results and Discussions
Synthesis of the Bicyclo[3.2.0]hept-6-en-2-one System from
Amide- or Ester-Tethered 1,6-Enynes. A cycloisomerization
reaction of N-allyl-2-alkynylamide (1) in the presence of
Au(PPh3)þ (generated from a reaction of [Au(PPh3)Cl]
(5 mol %) with AgSbF6 (7 mol %)) was studied initially
(eq 1). The reaction went to completion within 30 min at
room temperature. A bicyclobutene compound (2) was iso-
lated in 63% yield. When the same substrate was reacted with
PtCl2, on the contrary, no reaction was observed.
Encouraged by this result, we attempted to probe whether
this chemistry can be expanded to other 1,6-enyne systems
(eq 3). In the case of allylic 2-alkynoate (5), the reaction was
rather inefficient; the cyclobutene derivative (6) was ob-
tained in only 45% yield even with an increased amount of
the catalyst (10 mol %) and a prolonged reaction time (12 h).
Moreover, a 1,3-diene compound (7) was also produced in
8% yield.
Considering the fact that a similar type of substrate with a
simple NTs-tether (3) gave rise to a bicyclo[4.1.0]hept-4-ene
(14) Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am. Chem.
Soc. 2005, 127, 6178–6179.
(15) Furstner, A.; Davies, P. W.; Gress, T. J. Am. Chem. Soc. 2005, 127,
8244–8245.
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3810.
Enynes with a carbon tether are known to give bicyclic
cyclobutenes in platinum- or gold(I)-catalyzed cycloisomeri-
zation reactions (Scheme 1).14,17 However, when a keto car-
bonyl was introduced to a carbon tethered 1,6-enyne system, a
corresponding cyclobutene was not produced at all (eq 4).
Instead, a 1,3-diene compound was obtained in 52% yield.
(23) Furstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122,
6785–6786.
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2668–2670.
Knowing that the formation of cyclobutenes by the Au(I)-
catalyzed cycloisomerization reaction is confined only to the
amide- and ester-tethered 1,6-enyne systems, we further
screened the reaction with various substrates. The results
are compiled in Table 1. The introduction of a mono sub-
stitution to the alkene in the enyne substrate did not change
the reaction pathway. The treatment of amide-tethered
enynes 10 and 12 with a methyl group at the alkene group
(entries 1 and 2) led to the isolation of the corresponding
(34) Xu, H. D.; Zhang, W.; Shu, D. X.; Werness, J. B.; Tang, W. P.
Angew. Chem., Int. Ed. 2008, 47, 8933–8936.
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Am. Chem. Soc. 2008, 130, 269–279.
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2260.
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TABLE 1. Au(I)-Catalyzed Cycloisomerization Reactions of Amide- or
SCHEME 2. Proposed Au(I)-Catalyzed Cycloisomerization Re-
actions of Amide- or Ester-Tethered 1,6-Enynes
Ester-Tethered 1,6-Enynesa
SCHEME 3. Reaction Flow Chart of Au(I)-Catalyzed Cycloi-
somerization Reactions of Amide- or Ester-Tethered 1,6-Enynes
Prepared for the DFT Computational Study
a0.5 mmol of a reactant was reacted with 10 mol % of [Au(PPh3)]SbF6
in CH2Cl2 at room temperature for 12 h. bIsolated yields. c0.5 mmol of a
reactant was reacted with 5 mol % of [Au(PPh3)]SbF6 in CH2Cl2 at room
temperature for 0.5 h. dA 1,3-diene (16) obtained in 7% yield.
cyclobutene derivatives 11 and 13 in 77% and 73% yields,
respectively. The formation of 13 was confirmed by X-ray
diffraction analysis (see the SI). In the same way, ester-
tethered enynes (entries 3-7) gave cyclobutenes in
70-85% yields. It should be noted that the concomitant
formation of 1,3-diene (7%) in addition to the cyclobutene
was observed when substrate 14 was employed (entry 3) as in
the case of eq 4. The use of cyclohexenyl alkynes (entries
8-10) led to the isolation of 4.5.6-tricyclic cyclobutene
compounds in 82-91% yield.
Proposed Mechanisms. The studies of the Au(I)-catalyzed
cycloisomerization reaction of 1,6-enyne systems are docu-
mented in a number of reviews.7,37,38 Especially its mechanistic
investigation via DFT calculation has been well studied by the
Echavarren group.19,35,39,40 While there have been a number of
mechanistic suggestions for the formation of cyclobutenes by
transition metal-catalyzed cycloisomerization reactions, which
include the involvement of the cyclopropyl metal carbenes pre-
pared via 5-exo-26,40,41 or 6-endo-cyclization mode,15 Echavarren
et al. reported that the former is favorable for carbon tethered
1,6- or 1,7-enyne systems.39,40 Given their established framework
as a benchmark, we propose plausible reactions in Scheme 2.
As mentioned by Echavarren in his recent review,25 all the
results of gold(I)-catalyzed cycloisomerization reactions of
enyne systems reported to date can be explained in terms of a
selective activation of the alkyne by gold(I) although gold-
(I)-alkene complexes are likely formed in equilibrium with
the gold(I)-alkyne ones.27 Under this scope, reactions start-
ing from gold(I)-alkene are not considered in this work. The
mechanism toward product A, which can be formed by an
Alder-ene cycloisomerization, is also precluded given the fact
that both amide- and ester-tethered 1,6-enynes with methyl
group at the terminal alkene (entries 2, 3, 6, and 7 in Table 1)
did not produce this type of products at all (Scheme 2). Thus
our mechanistic investigation will be focused on products B
and D.42 The corresponding reaction flowchart covered by
(37) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180–3211.
(38) Zhang, L. M.; Sun, J. W.; Kozmin, S. A. Adv. Synth. Catal. 2006, 348,
2271–2296.
(39) Nieto-Oberhuber, C.; Munoz, M. P.; Bunuel, E.; Nevado, C.;
Cardenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43,
2402–2406.
(40) Nieto-Oberhuber, C.; Lopez, S.; Munoz, M. P.; Cardenas, D. J.;
Bunuel, E.; Nevado, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2005, 44,
6146–6148.
(41) Peppers, B. P.; Diver, S. T. J. Am. Chem. Soc. 2004, 126, 9524–9525.
(42) The synthesis of C-type compound will be discussed in later part of
this paper.
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FIGURE 1. Reaction diagram of 5-exo-syn- (to the left) and 5-exo-anti-cyclization (to the right) of amide-tethered 6-phenyl-1,6-enyne.
Geometries of stationary points are optimized structures via DFT at the B3LYP/6-31G(d) and LANL2DZ levels. Zero point energy (ZPE)
corrected free energies are given in kcal/mol. Arrows (sky blue) in the transition state geometries indicate displacement vectors of vibrational
mode possessing an imaginary frequency.
FIGURE 2. Reaction diagram of 6-endo-cyclization of amide-tethered 6-phenyl-1,6-enyne. Geometries of stationary points are optimized
structures via DFT at the B3LYP/6-31G(d) and LANL2DZ levels. ZPE corrected free energies are given in kcal/mol. Arrows (sky blue) in the
transition state geometries indicate displacement vectors of vibrational mode possessing an imaginary frequency.
computational study in this work is shown in Scheme 3. It
should be addressed that the reactant state in which
phosphinegold(I) is bound to both alkyne and alkene (R2)
is also considered to probe the pathway involving metalla-
cycle intermediate (I4). Besides two forms of cyclopropyl
metal carbene complexes, I1 (via 5-exo-anti-cyclization) and
I3 (via 6-endo-cyclization), the intermediate I2 (via 5-exo-
syn-cyclization) is also considered because reaction barriers
for both a 5-exo-cyclization step (R1_I1 or I2) and its further
rearrangement to a cyclobutene (I1_B1 or I2_B2) can be
energylevel ofI1 (ΔG = -6.3kcal/mol) isslightly morestable
than that of I2 (ΔG = -2.8 kcal/mol).39 However, in contrast
to Echavarren’s case, where the energy level of 6-endo-cycli-
zation product is residing below those of 5-exo-ones, I3 in this
work becomes destabilized (ΔG = 1.8 kcal/mol) and thus lies
above the level of I2 by 4.6 kcal/mol. This reversion of energy
order between I2 and I3 leads the major difference of mechan-
istic pathway for the formation of cyclobutene, which will be
discussed in the next part of this paper.
In Echavarren’s work, the transition state for the 5-exo-
anti-process served as the lowest reaction barrier with near
zero activation energy. In our result, however, the free energy
barrier for the 6-endo-cyclization (TS_RI3) was slightly
lower (ΔGq = 15.2 kcal/mol) than that for the 5-exo-anti-
one (TS_RI1, ΔGq = 17.6 kcal/mol). TS_RI2 has a much
higher free energy barrier than the other two (ΔGq = 29.2
kcal/mol); the first step of the reaction is thus most likely
toward I3 or I1 and the possibility of its being toward I2 can
be practically excluded.
largely affected by the relative orientation of
a
phosphinegold(I) moiety in the cyclopropyl metal carbene
complex.40 Three types of cyclobutenes and two types of
dienes are corresponding products derived from I1-I4 inter-
mediates.
Mechanisms from R to I. The energetics and the structures
of each stationary point for the formation of cyclopropyl
metal carbene intermediates are illustrated in Figures 1 (5-
exo) and 2 (6-endo). Similar to the case of Echavarren et al., in
which eithera keto carbonyl group ora phenyl ringatthe C(5)
and C(7) atoms, respectively, were not introduced, the free
Mechanisms toward Cyclobutenes or 1,3-Dienes. The trans-
formations from cyclopropyl metal carbene intermediates to
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FIGURE 3. Reaction diagram of transformations from the cyclopropyl metal carbene intermediate (I1) to the 1,3-diene (D1, to the left) and
cyclobutene (B1, to the right). Geometries of stationary points are optimized structures via DFT at the B3LYP/6-31G(d) and LANL2DZ
levels. ZPE corrected free energies are given in kcal/mol. Arrows (sky blue) in the transition state geometries indicate displacement vectors of
vibrational mode possessing an imaginary frequency.
FIGURE 4. Reaction diagram of the transformation from the cyclopropyl metal carbene intermediate (I2) to the cyclobutene (B2). Geometries
of stationary points are optimized structures via DFT at the B3LYP/6-31G(d) and LANL2DZ levels. ZPE corrected free energies are given in
kcal/mol. Arrows (sky blue) in the transition state geometries indicate displacement vectors of vibrational mode possessing an imaginary
frequency.
FIGURE 5. Reaction diagram of the transformation from the cyclopropyl metal carbene intermediate (I3) to the cyclobutene (B3). Geometries
of stationary points are optimized structures via DFT at the B3LYP/6-31G(d) and LANL2DZ levels. ZPE corrected free energies are given in
kcal/mol. Arrows (sky blue) in the transition state geometries indicate displacement vectors of vibrational mode possessing an imaginary
frequency.
their corresponding cyclobutene or 1,3-diene complexes are
illustrated in Figures 3-5. The 5-exo-anti-product I1 could
evolve to either cyclobutene (B1) via TS_I1B1 or 1,3-diene
(D1) via TS_I1D1 (Figure 3). The structure of TS_I1B1
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FIGURE 6. Reaction diagram of the direct transformation from the reactant (R1) to the cyclobutene (B2). Geometries of stationary points are
optimized structures via DFT at the B3LYP/6-31G(d) and LANL2DZ levels. ZPE corrected free energies are given in kcal/mol. Arrows (sky
blue) in the transition state geometries indicate displacement vectors of vibrational mode possessing an imaginary frequency.
clearly shows the smooth ring expansion process from I1
˚
to B1 exhibiting the lengthened (1.904 A) and the shor-
tened (1.556 A) bond distances for the cleaved (C(1)-C(6))
computational investigation, we found the transition state
that directly connects R1 and B2. Interestingly, the structure,
the energy level, the magnitude of the imaginary vibrational
frequency, as well as the vibrational mode of this transition
state (TS_RB2) were virtually identical with those of TS_RI3
implying that the reaction pathway bifurcation may possibly
be involved in this state44 (Figure 6).
˚
and the newly formed (C(1)-C(7)), respectively. The struc-
ture of TS_I1D1 seems to be similar to that of TS_I1B1 yet
more close to that of the 1,3-diene product. The bond
distances of C(2)-C(6) and C(1)-C(7) are 1.361 and 1.414
˚
A, respectively, indicating apparent double bond characters.
As illustrated in Figures 5 and 6, the displacement vectors
for the vibrational mode possessing imaginary frequency of
this transition state demonstrate that the C(7) atom ap-
peared to fluctuate on the C(1)-C(2) ethylene plane. When
two units (C(7) and C(1)-C(2) double bond) approach each
other, either C(1)-C(2)-C(7) cyclopropane or C(1)-C(2)-
C(6)-C(7) cyclobutene is likely to form. Due to this addi-
tional pathway, the possibility for the formation of cyclo-
butene product is augmented. As a result, the competition
between the pathway toward the 1,3-diene and that toward
the cyclobutene ends up with the victory of the latter.
Mechanism through Metallacycle Intermediate. Although
oxidative additions involving phosphinegold(I) complexes
are known to be difficult,45 it was possible to locate the
metallacycle intermediate I4 in the computational calcula-
tion (Figure 7). This state is most likely derived from R2 in
which phosphinegold(I) binds to both alkyne and alkene
since, as we already confirmed, R1 gave rise to cyclopropyl
metal carbene intermediates rather than a metallacycle. The
structure of R2 exhibits that the Au-alkyne distance
A notable difference from TS_I1B1 is the C(1)-C(2) dis-
tance (2.809 A), showing there is no more bonding character
between these two atoms. The free energy barrier from I1 to
D1 (ΔGq = 6.3 kcal/mol) is ca. 16 kcal/mol lower than that to
B1 (ΔGq = 22.3 kcal/mol). Thus the evolution from I1 is
most likely to the 1,3-diene product.
˚
On the other hand, the 5-exo-syn-product I2 gave rise to
the formation of cyclobutene (B2) via TS_I2B2 with the
activation free energy of 21.4 kcal/mol (Figure 4). In spite of
extensive computational searching, however, we were not
able to find the transition state for the I2_D2 process.
Interestingly, the 6-endo-cyclization product I3 did evolve
to the cyclobutene (B2) through TS_I3B243 (Figure 5).
The structure of the transition state displays the bond
˚
cleavage between C(2) and C(7) (1.807 A) with the concomi-
˚
tant bond formation between C(2) and C(6) (1.969 A). The
free energy level of TS_I3B2 was 8.2 kcal/mol, which is
slightly higher than that of TS_I1D1. However, the activa-
tion free energy for this process was only 6.4 kcal/mol due to
the highly destabilized I3 state as previously mentioned.
Considering the fact that the magnitude of the activation
barrier of this process is the smallest among three processes
(I1_TS_I1B1_B1, I2_TS_I2B2_B2, and I3_TS_I3B2_B2)
and TS_RI3 served as the lowest barrier from the reactant
state (R1) to the cyclopropyl metal carbene intermediates,
the most probable reaction pathway for the formation of
cyclobutene is thus the R1_I3_B2 route. Moreover the
activation barrier for the I3_B2 process is much smaller than
that for the I1_D1 one demonstrating that the formation of
cyclobutene is more favorable than that of 1,3-diene.
˚
(Au-C(6), 2.295 A) is shorter than the Au-alkene one
˚
˚
(Au-C(1), 2.457 A or Au-C(2), 2.486 A) assuring the
alkynophilicity of gold. Bond distances of C(1)-C(2) and
˚
C(6)-C(7) are 1.368 and 1.248 A, indicating that the double
and the triple bond characters for the former and the latter,
respectively, still persist. In metallacycle I4, these distances
˚
are lengthened to 1.521 and 1.335 A exhibiting that those two
bonds are turning into the single and the double bonds,
respectively.
The structure of the transition state TS_R2I4 suggests
that the formation of metallacycle is stepwise rather than
Mechanism via Direct Transformation from R1 to B2: The
Possibility of Reaction Pathway Bifurcation. During the
(44) Ess, D. H.; Wheeler, S. E.; Iafe, R. G.; Xu, L.; Celebi-Olcum, N.;
Houk, K. N. Angew. Chem., Int. Ed. 2008, 47, 7592–7601.
(43) The evolution to the 1,3-diene compound from I3 is not likely from
the studies of many other scientist, and thus was not considered.
(45) Cheong, P. H. Y.; Morganelli, P.; Luzung, M. R.; Houk, K. N.;
Toste, F. D. J. Am. Chem. Soc. 2008, 130, 4517–4526.
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FIGURE 7. Reaction diagram of transformations from R2 to the cyclobutene (B3) via metallacycle intermediate (I4). Geometries of stationary
points are optimized structures via DFT at the B3LYP/6-31G(d) and LANL2DZ levels. ZPE corrected free energies are given in kcal/mol.
Arrows (sky blue) in the transition state geometries indicate displacement vectors of vibrational mode possessing an imaginary frequency.
concerted (Figure 7). At this point, the phosphinegold(I)
moiety is attached only to the terminal alkene with a Au-C-
tion of an aryl group at the terminal alkyne position cannot
drive the reaction to the cyclobutene product. However, it is
somewhat hasty to conclude that the formation of cyclobu-
tene product is solely due to the effect of the keto carbonyl
group at the C(5) position. Hence, we performed DFT
calculations for both no-carbonyl (Figure 9) and no-phenyl
(Figure 10) systems to interrogate the relative effect of the
keto carbonyl and the terminal aryl group on the reactivity of
gold(I)-catalyzed cycloisomerization reaction.
˚
(1) bond length of 2.157 A. The Au-C(1)-C(2) angle is
obtuse (117.0°) with the phosphinegold(I) moiety being
positioned outward from the potential metallacycle plane.
Displacement vectors of this transition state display major
fluctuation between C(2) and C(6). Therefore, it appears that
Au-C(7) bond formation to complete the metallacycle
might occur after the C(2)-C(6) bond is formed.
The free energy of R2 and I4 is 10.1 and 9.4 kcal/
mol higher than those of R1 and I3, respectively. Likewise,
the transition state TS_R2I4 resides at 25.7 kcal/mol,
which is 10.5 kcal/mol higher than that of TS_RI3; this
step is obviously disadvantageous relative to the R1_I3
pathway.
In the system without keto carbonyl (Figure 9), the 6-endo-
cyclization via TS_NRI3 has the lowest free energy barrier
(ΔGq = 11.4 kcal/mol). The free energy barriers for 5-exo-
cyclizations were 15.4 kcal/mol (TS_NRI1) and 25.1 kcal/
mol (TS_NRI2). This result suggests that a careful control of
the reaction under mild conditions might lead to the forma-
tion of NI3 exclusively although TS_NRI3 lies only 4 kcal/
mol lower than TS_NRI1. Interestingly, NI3 (ΔG = -5.8
kcal/mol) was similarly stable with NI1 (ΔG = -3.4 kcal/
mol) or NI2 (ΔG = -6.3 kcal/mol). This pattern clearly
differs from that of the amide-tethered analogue in which I3
was mostly destabilized. Consequently, the activation free
energy from NI3 to NB2 becomes as high as 15.2 kcal/mol
even though the free energy of TS_NI3B2 (ΔGq = 9.4 kcal/
mol) is in a similar level with that of TS_I3B2 (ΔGq = 8.2
kcal/mol). Note that the magnitudes of the activation free
energies for both the forward and the reverse reactions from
NI3 are higher than that for the first step (NR_NI3), which
drives the reaction entrapped at the NI3 stage.36
For the system without a phenyl group at the terminal
alkyne position (Figure 10), calculation results were signifi-
cantly different from those discussed above. First of all, the
5-exo-anti-cyclization via TS_PRI1 has the lowest activation
barrier from PR1 to cyclopropyl metal carbene intermedi-
ates. The free energy barrier of this state (ΔGq = 6.6 kcal/
mol) is ca. 5 and 7 kcal/mol smaller than those of TS_PRI3
(ΔGq = 11.3 kcal/mol) and TS_PRI2 (ΔGq = 13.3 kcal/
mol), respectively; the first step of the reaction is thus most
likely toward PI1 and the possibility of its being toward I2 or
I3 is low.
It was necessary to suppose a third type of cyclobutene
product that is different from B1 or B2 in terms of positions
of phosphinegold(I) moiety and protons. If a C(1)-C(7)
bond is formed from I4, the phosphinegold(I) moiety can be
destined toward either C(7) or C(1). When we considered
the former assumption, the resulting structure optimized by
the DFT calculation was B2. B3 was the optimized structure
based on the assumption for the latter. It is important to note
that a sequential repositioning of protons was prerequisite to
adopt B3 as a product as shown in Figure 7. B3 has a similar
free energy level with B2. The activation free energy from I4
to B3 was, however, prohibitively high (ΔGq = 31.6 kcal/
mol) probably due to the proton movements. We also
located the transition state that connects I4 and B2 (not
shown). However, its activation free energy was 30.8 kcal/
mol (ΔGq = 46.0 kcal/mol), which is even higher than that of
TS_I4B3. From this result, the pathway through I4 is
obviously unfavorable. Figure 8 displays an overall free
energy profile of cyclobutene formation of the amide-teth-
ered 1,6-enyne system.
Comparison of the Effects of Carbonyl Group (C(5)) vs.
Phenyl Group (C(7)). Virtually all examples of the cyclobu-
tene formation by the transition metal-catalyzed cycloisome-
rization reaction of 1,6-enynes feature an aryl group at the
terminal alkyne position.14,17 However, as we previously
reported,36 compound 3 gave rise to a bicyclo[4.1.0]hept-4-
ene derivative 4 (eq 2) demonstrating that a mere introduc-
The 5-exo-anti product PI1 could evolve to either cyclo-
butene (PB1) via TS_PI1B1 or 1,3-diene (PD1) via TS_I1D1.
Whereas the process toward PD1 is highly exothermic
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FIGURE 8. Free energy reaction profile of Au(I)-catalyzed cycloisomerization reactions of amide-tethered 7-phenyl-1,6-enyne. Numbers in
red denote free energies in kcal/mol. Green dotted lines signify most probable reaction pathways. For details of structures of all compounds
listed in this diagram, see the SI.
FIGURE 9. Free energy reaction profile of Au(I)-catalyzed cycloisomerization reactions of N-tethered 7-phenyl-1,6-enyne. Numbers in red
denote free energies in kcal/mol. Green dotted lines signify most probable reaction pathway. For details of structures of all compounds listed in
this diagram, see the SI.
(ΔGrxn = 37.9 kcal/mol), the PI1_PB1 process is 9.5 kcal/
mol uphill. Moreover, the activation free energy of the
PI1_PB1 process is 16.7 kcal/mol while that for the PI1_PD1
process is only 2.1 kcal/mol. Thus the evolution from PI1 is
most likely to the 1,3-diene product.
Unlike the system possessing both the keto carbonyl and
phenyl groups at C(5) and C(7), respectively, the 5-exo-syn
product PI2 gave rise to the formation of both cyclobutene
(PB2) via TS_PI2B2 or 1,3-diene (PD2) via TS_I2D2. The
activation free energies for both processes are similar to each
other; they are 9.5 and 7.4 kcal/mol for TS_PI2B2 or
TS_PI2D2, respectively. However, these values are still
much higher than that of the PI1_PD1 process. Thus the
process involving the I2 intermediate could not affect the
overall reaction pathway. Likewise, the reaction pathway
involving I3 did not alter the destination of the reaction as
shown in Figure 10. These results clearly show that the
selective formation of a cyclobutene by the gold(I)-catalyzed
cycloisomerization reaction of amide tethered 1,6-enyene
systems can be ascribed to the interplay of both the keto
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Lee et al.
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FIGURE 10. Free energy reaction profile of Au(I)-catalyzed cycloisomerization reactions of amide-tethered 1,6-enyne. Numbers in red denote
free energies in kcal/mol. Green dotted lines signify the most probable reaction pathway. For details of structures of all compounds listed in this
diagram, see the SI.
FIGURE 11. Free energy reaction profile of Au(I)-catalyzed cycloisomerization reactions of ester-tethered 7-phenyl-1,6-enyne. Numbers in
red denote free energies in kcal/mol. Green dotted lines signify the most probable reaction pathway. For details of structures of all compounds
listed in this diagram, see the SI.
carbonyl group and the aryl substituent at C(5) and C(7)
positions, respectively.
(ΔG‡=19.6 kcal/mol) than that to the 5-exo-anti product
(OI1, ΔGq = 18.4 kcal/mol) in this case. Thus the first step of
the reaction cannot distinguish the 5-exo-anti and the 6-endo
processes clearly. The differentiation between these two
processes is made only in the second step.
OI1 can evolve either to D1 or B1 with the former being
preferred. The activation free energy for the OI1_OD1
process is 11.9 kcal/mol while that for the OI1_OB1 process
is 30.6 kcal/mol. On the other hand, OI3 can be easily
Mechanism of the Ester-Tethered System. We also inves-
tigated the ester-tethered 1,6-enyne system. The overall
feature of the reaction pathway obtained from the calcula-
tion is similar to that for the amide-tethered one (Figure 11).
However, a number of points deserve comments. First,
the free energy barrier from the reactant state (OR) to
the 6-endo-cyclization product (OI3) was slightly higher
7930 J. Org. Chem. Vol. 74, No. 20, 2009

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FIGURE 12. Free energy reaction profile of Au(I)-catalyzed cycloisomerization reactions of amide-tethered 1,1-dimethyl-7-phenyl-1,6-enyne.
Numbers in red denote free energies in kcal/mol. Green dotted lines signify the most probable reaction pathway. For details of structures of all
compounds listed in this diagram, see the SI.
transformed into OB2 with only 3.8 kcal/mol of activation
free energy. Therefore, the formation of cyclobutene is still
advantageous to that of 1,3-diene in the ester-tethered
system.
Second, the magnitude of the activation free energy of the
OR_OI3 step (ΔGq = 19.6 kcal/mol) is ca. 4 kcal/mol larger
than that of the R1_I 3 step in the amide-tethered system
(ΔGq = 15.2 kcal/mol). Since this step is rate-determining,
this result implies that the ester-tethered system requires
more time to complete the reaction than the amide-tethered
one. Actually, the ester-tethered system requires 12 h of
average reaction time while the amide-tethered one requires
only half an hour.
thus we can safely exclude the pathway involving MI2. Since
TS_MRI1 and TS_MRI3 are virtually isoenergetic, both the
5-exo- and the 6-endo-cyclizations have an equal opportu-
nity. However, it is important to note that the MR_MI1
process is endothermic by 4.3 kcal/mol while the MR_MI3
process is slightly exothermic (ΔGrxn = -1.9 kcal/mol).
Third, the reaction pathway bifurcation was not observed
in this case. TS_ORI3 could not connect R1 to OB2. This
point combined with the fact that the lowest barrier of the
first step is not TS_ORI3 but TS_ORI1 drives the situation
where the formation of OI1 is unavoidable, which gives rise
to the formation of 1,3-diene as a minor product in some
cases (Table 1, entries 4 and 5).
The structure of MI1 resembles its archetypal I1 except
that the C(1)-C(2) and the C(1)-C(6) bond distances of
MI1 are slightly longer than those of I1 (see the SI for
detailed structural information). Notable differences were
observed in the structure of MI3. The comparison of two
structures (I3 and MI3) is depicted in Figure 13.
˚
Mechanism of the 1,1-Dimethyl-1,6-enyne Systems. When
both protons at the terminal alkenyl position were substi-
tuted with methyl groups, the desired cyclobutene was not
synthesized. Instead, the 5,6-dihydropyridin-2(1H)-one de-
rivative was obtained (eq 5). The identity of the product was
verified by X-ray crystallography (see the SI). This result is in
sharp contrast to those observed in allylpropargylmalonate
systems in which cationic gold(I) led to the formation of
2,3,9,9a-tetrahydro-1H-cyclopenta[b]naphthalenes by intra-
molecular [4þ2] cycloadditions.14,17
In MI3, the C(1)-C(7) distance was 2.095 A indicating
that there is no more bonding character between two carbon
atoms. The C(1)-C(2)-C(7) angle (86.9°) of MI3 also
exhibits the breakdown of the cyclopropyl skeleton. As a
result, the positive charge was built at the C(1) atom. The
Mulliken charge at this position of MI3 obtained by DFT
calculation was 0.221 while that of I3 was -0.288. Never-
theless, the free energy level of MI3 (ΔG = -1.9 kcal/mol)
lies lower than those of MI1 (ΔG = 4.3 kcal/mol) or MI2
(ΔG = 5.5 kcal/mol). Considering the fact that I3 has a
higher free energy than I1 or I2, this result was noteworthy. It
is probably due to the stabilization of the positive charge by
the two adjacent methyl groups. This structural variation
gave rise to a completely different consequence. The trans-
formation from MI3 to the cyclobutene was no longer
possible. In TS_I3B2, the C(1)-C(7) bond plays a pinning
To investigate the background of this result, we performed
DFT calculations. Figure 12 illustrates the whole profiles of
reaction energetics. Both the 5-exo-anti- and the 6-endo-
cyclizations have similar activation free energies (∼12 kcal/
mol). The activation free energy of the 5-exo-syn-cyclization
is a factor of 2 larger than the other two (24.3 kcal/mol) and
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Lee et al.
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FIGURE 13. Geometry comparison of I3 and MI3.
role during the bond-forming fluctuation between C(2) and
C(6). However, this type of fluctuation cannot be accom-
plished in MI3 because the C(1)-C(7) bond is no longer
available. As expected, the transition state between MI3 and
MB2 could not be located in spite of the elaborate computa-
tional search. On the other hand, MI1 could evolve to
cyclobutene MB1 with 19.3 kcal/mol of activation barrier.
Note that the formation of 5,6-dihydropyridin-2(1H)-one by
demetalation requires only 16.6 kcal/mol of energy. Hence,
the gold(I)-catalyzed cycloisomerization reaction of amide-
tethered 1,1-dimethyl-1,6-enyne substrate resulted in the
formation of 5,6-dihydropyridin-2(1H)-one.
7-Phenyl-3-tosyl-3-aza-bicyclo[3.2.0]hept-6-en-2-one (2): 1H
NMR (CDCl3, 300 MHz) δ 2.39 (s, 3 H), 3.33 (dd, J = 3.9, 8.0
Hz, 1 H), 3.86 (dd, J = 8.0, 10.5 Hz, 1 H), 3.86 (m, 1 H), 4.03 (d,
J = 10.5 Hz, 1 H), 6.43 (s, 1 H), 7.27 (d, J = 8.3 Hz, 2 H), 7.31
(m, 3 H), 7.46 (m, 2 H), 7.90 (d, J = 8.3 Hz, 2 H); 13C NMR
(CDCl3, 75 MHz) δ 21.6, 32.9, 48.5, 49.4, 125.2, 128.1, 128.4,
128.9, 129.2, 129.5, 131.7, 134.8, 145.0, 148.4, 171.9; IR νCO
(CHCl3) 1723.2 cm-1; HRMS (EI) calcd for C19H17N1O3S1 (Mþ)
339.0929, found 339.0929.
6-Methyl-7-phenyl-3-oxa-bicyclo[3.2.0]hept-6-en-2-one (6):
1H NMR (CDCl3, 500 MHz) δ 2.10 (t, J = 1.5 Hz, 3 H), 3.45
(m, 1 H), 3.83 (dq, J = 1.8, 3.6 Hz, 1 H), 4.34 (m, 2 H), 7.27 (m, 1
H), 7.37 (m, 2 H), 7.53 (m, 2 H); 13C NMR (CDCl3, 125 MHz)
δ 14.1, 40.7, 43.6, 67.5, 126.2, 127.9, 128.6, 133.2, 140.2, 141.1,
175.7; IR νCO (CHCl3) 1748.8 cm-1; HRMS (EI) calcd for
C13H12O2 (Mþ) 200.0837, found 200.0834.
Conclusion
(E)-3-(1-Phenylprop-1-enyl)furan-2(5H)-one (7): 1H NMR
(CDCl3, 500 MHz) δ 1.67 (d, J = 7.1 Hz, 3 H), 4.72 (m, 2 H),
6.67 (m, 1 H), 7.16 (m, 2 H), 7.25 (q, J = 7.1 Hz, 1 H), 7.34 (m, 1
H), 7.41 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 15.3, 68.9,
127.3, 128.5, 129.2, 129.7, 132.1, 132.6, 138.1, 144.1, 172.0; IR
The Au(I)-catalyzed cycloisomerization of amide- or es-
ter-tethered 1,6-enynes gave bicyclo[3.2.0]hept-6-en-2-ones
in reasonable to high yields. A subtle change in the substrate
completely alters the reaction pathway. This reaction can be
complementary to the platinum- or gold(I)-catalyzed forma-
tion of cyclobutenes from enynes with a carbon chain.
Calculations carried out on the Au(I)-catalyzed formation
of cyclobutenes also support this experimental observation.
Further work on amide- or ester-tethered enynes in other
transition metal-catalyzed processes is underway in our
laboratories.
ν
200.0837, found 200.0836.
CO (CHCl3) 1748.0 cm-1; HRMS (EI) calcd for C13H12O2 (Mþ)
Diethyl 2-(2-methylallyl)-2-(3-phenylpropioloyl)malonate (8):
1H NMR (CDCl3, 500 MHz) δ 1.28 (t, J = 7.1 Hz, 6 H), 1.76 (s,
3 H), 3.09 (s, 2 H), 4.28 (q, J = 7.1 Hz, 4 H), 4.81 (s, 1 H), 4.87 (s,
1 H), 7.39 (m, 2 H), 7.48 (m, 1H), 7.57 (m, 2 H); 13C NMR
(CDCl3, 125 MHz) δ 13.9, 23.4, 40.2, 62.2, 71.3, 86.5, 94.5,
115.7, 119.6, 128.7, 131.1, 133.1, 140.3, 166.2, 178.6; IR νCO
(CHCl3) 1672.0, 1737.6 cm-1; HRMS (EI) calcd for C20H22O5
(Mþ) 342.1467, found 342.1470.
Experimental Section
General Procedure for the Au(I)-Catalyzed Cycloisomeriza-
tion Reaction of Amide- or Ester-Tethered 1,6-Enynes. To a
flame-dried 15-mL Schlenk flask capped with a rubber septum
was injected via a syringe 5 mL of dichloromethane under N2
flow. Au(PPh3)Cl (25 mg, 10 mol %) and AgSbF6 (24 mg, 14
mol %) were added sequentially. The solution was stirred for
10 min. A 1,6-enyne bearing a keto carbonyl (0.5 mmol) was put
into the flask under N2 flow. The reaction was monitored by
thin-layer chromatography. After the reactant disappeared, the
solvent was removed under reduced pressures. Flash chroma-
tography on a silica gel eluting with hexane and ethyl acetate
(v/v, 10:1) gave the product.
Diethyl 4-methyl-2-oxo-3-(1-phenylvinyl)cyclopent-3-ene-1,1-
dicarboxylate (9): H NMR (CDCl3, 500 MHz) δ 1.30 (t, J =
1
7.1 Hz, 6 H), 2.00 (s, 3 H), 3.28 (m, 2 H), 4.28 (q, J = 7.1 Hz, 4
H), 5.26 (d, J = 1.1 Hz, 1 H), 5.84 (d, J = 1.1 Hz, 1 H), 7.28 (m, 5
H); 13C NMR (CDCl3, 125 MHz) δ 13.9, 18.1, 41.3, 62.4, 65.3,
118.2, 126.1, 127.8, 128.4, 138.6, 138.7, 138.8, 167.0, 171.6,
194.8; IR νCO (CHCl3) 1636.8, 1718.4 cm-1; HRMS (EI) calcd
for C20H22O5 (Mþ) 342.1467, found 342.1466.
N-(2-Methylallyl)-3-phenyl-N-tosylpropiolamide (10): 1H
NMR (CDCl3, 500 MHz) δ 1.81 (s, 3 H), 2.43 (s, 3 H), 4.63 (s,
2 H), 5.00 (s, 1 H), 5.02 (s, 1 H), 7.30 (d, J = 8.3 Hz, 2 H), 7.38
(m, 2 H), 7.46 (m, 1 H), 7.50 (m, 2 H), 7.93 (d, J = 8.3 Hz, 2 H);
7932 J. Org. Chem. Vol. 74, No. 20, 2009

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13C NMR (CDCl3, 125 MHz) δ 20.2, 21.6, 52.4, 81.5, 92.6,
112.9, 119.4, 128.7, 128.9, 129.3, 130.9, 132.7, 135.7, 139.8,
145.1, 152.9; IR νCO (CHCl3) 1664.0 cm-1; HRMS (EI) calcd
for C20H19N1O3S1 (Mþ) 353.1086, found 353.1089.
5-Methyl-7-phenyl-3-tosyl-3-aza-bicyclo[3.2.0]hept-6-en-2-one
(11): 1H NMR (CDCl3, 500 MHz) δ 1.43 (s, 3 H), 2.40 (s, 3 H),
3.44 (s, 1 H), 3.59 (d, J = 10.5 Hz, 1 H), 4.06 (d, J = 10.5 Hz, 1
H), 6.47 (s, 1 H), 7.27 (d, J = 6.8 Hz, 2 H), 7.32 (m, 3 H), 7.46 (m,
2 H), 7.90 (d, J = 6.8 Hz, 2 H); 13C NMR (CDCl3, 125 MHz) δ
21.6 (2 C), 40.1, 54.1, 54.9, 125.3, 128.1, 128.4, 128.8, 129.5,
131.8, 133.5, 134.9, 145.0, 146.2, 172.3; IR νCO (CHCl3) 1726.4
cm-1; HRMS (EI) calcd for C20H19N1O3S1 (Mþ) 353.1086,
found 353.1088.
cm-1; HRMS (EI) calcd for C14H14O2 (Mþ) 214.0994, found
214.0996.
5-Methyl-7-p-tolyl-3-oxa-bicyclo[3.2.0]hept-6-en-2-one (20):
1H NMR (CDCl3, 500 MHz) δ 1.48 (s, 3 H), 2.34 (s, 3 H),
3.52 (s, 1 H), 4.09 (d, J = 9.6 Hz, 1 H), 4.33 (d, J = 9.6 Hz, 1 H),
6.45 (s, 1 H), 7.16 (d, J = 7.9 Hz, 2 H), 7.42 (d, J = 7.9 Hz, 2 H);
13C NMR (CDCl3, 125 MHz) δ 20.3, 21.4, 44.8, 51.2, 74.7,
125.1, 129.2 (2 C), 132.4, 139.0, 146.0, 175.6; IR νCO (CHCl3)
1747.2 cm-1; HRMS (EI) calcd for C14H14O2 (Mþ: 214.0994,
found 214.0993.
(E)-2-Methylbut-2-enyl 3-phenylpropiolate (21): 1H NMR
(CDCl3, 500 MHz) δ 1.66 (dq, J = 1.0, 10 Hz, 3 H), 1.72 (q, J
= 1.0 Hz, 3 H), 4.62 (s, 2 H), 5.64 (m, 1 H), 7.37 (m, 2 H), 7.45
(m, 1 H), 7.59 (m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 13.3,
13.7, 71.9, 80.6, 86.2, 119.7, 125.6, 128.5, 139.9, 130.6, 133.0,
154.1; IR νCO (CHCl3) 1700.8 cm-1; HRMS (EI) calcd for
C14H14O2 (Mþ) 214.0994, found 214.0991.
1
N-(But-2-enyl)-3-phenyl-N-tosylpropiolamide (12): H NMR
(CDCl3, 500 MHz) δ 1.73 (trans) (d, J = 6.3 Hz, 3 H), 1.8 (cis)
(d, J = 6.9 Hz, 3 H), 2.41 (s, 3 H), 4.62 (trans) (d, J = 6.0 Hz, 2
H), 4.75 (cis) (d, J = 6.4 Hz, 2 H), 5.55 (cis) (m, 1 H), 5.62 (trans)
(m, 1 H), 5.73 (cis) (m, 1 H), 5.86 (trans) (m, 1 H), 7.29 (d, J = 7.1
Hz, 2 H), 7.38 (m, 2 H), 7.46 (m, 1 H), 7.51 (m, 2 H), 7.89 (d, J =
7.1 Hz, 2 H); 13C NMR (CDCl3, 125 MHz) δ 17.6, 21.5, 48.9,
81.6, 92.7, 119.4, 125.2, 128.6, 129.2, 129.3, 130.8, 130.9, 132.6,
136.0, 144.9, 152.5; IR νCO (CHCl3) 1660.8 cm-1; HRMS (EI)
calcd for C20H19N1O3S1 (Mþ) 353.1086, found 353.1089.
6-Methyl-7-phenyl-3-tosyl-3-aza-bicyclo[3.2.0]hept-6-en-2-one
(13): 1H NMR (CDCl3, 500 MHz) δ 2.07 (s, 3 H), 2.40 (s, 3 H),
3.19 (dd, J = 3.9, 8.3 Hz, 1 H), 3.69 (m, 1 H), 3.77 (d, J = 8.3,
10.6 Hz, 1 H), 4.04 (d, J = 10.6 Hz, 1 H), 7.23 (m, 1 H), 7.27 (d, J
= 8.0 Hz, 2 H), 7.31 (m, 2 H), 7.43 (m, 2 H), 7.89 (d, J = 8.3 Hz,
2 H); 13C NMR (CDCl3, 125 MHz) δ 13.9, 21.6, 35.7, 46.5, 47.4,
126.3, 127.8, 128.1, 128.4, 129.5, 133.1, 135.0, 140.3, 140.8,
145.0, 172.5; IR νCO (CHCl3) 1728.0 cm-1; HRMS (EI) calcd
for C20H19N1O3S1 (Mþ) 353.1086, found 353.1089.
5,6-Dimethyl-7-phenyl-3-oxa-bicyclo[3.2.0]hept-6-en-2-one (22):
1H NMR (CDCl3, 500 MHz) δ 1.44 (s, 3 H), 2.04 (d, J = 1.8 Hz,
3 H), 3.45 (q, J = 1.8 Hz, 1 H), 4.00 (d, J = 9.7 Hz, 1 H), 4.33 (d,
J = 9.7 Hz, 1 H), 7.27 (m, 1 H), 7.37 (m, 2 H), 7.53 (m, 2 H); 13
C
NMR (CDCl3, 125 MHz) δ 11.5, 18.3, 46.2, 49.9, 72.4, 126.2,
127.8, 128.5, 133.2, 137.9, 144.5, 176.0; IR νCO (CHCl3) 1752.8
cm-1; HRMS (EI) calcd for C14H14O2 (Mþ) 214.0994, found
214.0992.
(E)-2-Methylbut-2-enyl 3-p-tolylpropiolate (23): 1H NMR
(CDCl3, 300 MHz) δ 1.66 (d, J = 6.6 Hz, 3 H), 1.71 (s, 3 H),
2.38 (s, 3 H), 4.61 (s, 2 H), 5.63 (q, J = 6.6 Hz, 2 H), 7.17 (d, J =
8.1 Hz, 2 H), 7.48 (d, J = 8.1 Hz, 2 H); 13C NMR (CDCl3, 75
MHz) δ 13.3, 13.7, 21.7, 71.8, 80.3, 86.7, 116.6, 125.5, 129.3,
130.0, 133.0, 141.2, 154.2; IR νCO (CHCl3) 1696.8 cm-1; HRMS
(EI) calcd for C15H16O2 (Mþ) 228.1150, found 228.1151.
5,6-Dimethyl-7-p-tolyl-3-oxa-bicyclo[3.2.0]hept-6-en-2-one (24):
1H NMR (CDCl3, 500 MHz) δ 1.42 (s, 3 H), 2.01 (d, J = 1.8 Hz,
3 H), 2.34 (s, 3 H), 3.41 (q, J = 1.8 Hz, 1 H), 3.99 (d, J = 9.6 Hz,
1 H), 4.31 (d, J = 9.6 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 2 H), 7.41 (d,
J = 8.0 Hz, 2 H); 13C NMR (CDCl3, 125 MHz) δ 11.5, 18.4, 21.3,
46.2, 49.9, 72.5, 126.1, 129.2, 130.5, 137.8, 137.9, 143.2, 176.2; IR νCO
(CHCl3) 1748.8 cm-1; HRMS (EI) calcd for C15H16O2 (Mþ)
228.1150, found 228.1149.
But-2-enyl 3-p-tolylpropiolate (14): 1H NMR (CDCl3, 500
MHz) δ 1.75 (d, J = 6.5 Hz, 3 H), 2.38 (s, 3 H), 4.65 (trans) (d, J
= 6.7 Hz, 2 H), 4.80 (cis) (d, J = 7.0 Hz, 2 H), 5.62 (cis) (m, 1 H),
5.65 (trans) (m, 1 H), 5.79 (cis) (m, 1 H), 5.88 (trans) (m, 1 H),
7.17 (d, J = 8.0 Hz, 2 H), 7.47 (d, J = 8.0 Hz, 2 H); 13C NMR
(CDCl3, 125 MHz) δ 21.6, 21.7, 66.6, 80.2, 86.8, 116.5, 124.2,
129.3, 132.7, 133.0, 141.2, 154.0; IR νCO (CHCl3) 1705.6 cm-1
;
HRMS (EI) calcd for C14H14O2 (Mþ) 214.0994, found 214.0995.
6-Methyl-7-p-tolyl-3-oxa-bicyclo[3.2.0]hept-6-en-2-one (15):
1H NMR (CDCl3, 500 MHz) δ 2.07 (t, J = 1.5 Hz, 3 H), 2.34
(s, 3 H), 3.43 (m, 1 H), 3.80 (dq, J = 1.7, 3.6 Hz, 1 H), 4.33 (m, 2
H), 7.17 (d, J = 8.2 Hz, 2 H), 7.42 (d, J = 8.2 Hz, 2 H); 13C
NMR (CDCl3, 125 MHz) δ 14.0, 21.3, 40.6, 43.5, 67.5, 126.1,
129.2, 130.4, 137.9, 139.8, 140.1, 175.8; IR νCO (CHCl3) 1746.4
cm-1; HRMS (EI) calcd for C14H14O2 (Mþ) 214.0994, found
214.0996.
N-(Cyclohexenylmethyl)-3-phenyl-N-tosylpropiolamide (25):
1H NMR (CDCl3, 500 MHz) δ 1.58 (m, 4 H), 1.93 (m, 2 H),
2.06 (m, 2 H), 2.43 (s, 3 H), 4.61 (s, 2 H), 5.77 (m, 1 H), 7.30 (d, J
= 8.2 Hz, 2 H), 7.38 (m, 2 H), 7.46 (m, 1 H), 7.51 (m, 2 H), 7.91
(d, J = 8.2 Hz, 2 H); 13C NMR (CDCl3, 125 MHz) δ 21.7, 22.1,
22.4, 25.0, 26.1, 52.9, 81.7, 92.7, 119.5, 125.7, 128.7, 128.9, 129.2,
130.9, 132.3, 132.7, 135.9, 144.9, 153.1; IR νCO (CHCl3) 1660.8
cm-1; HRMS (FAB) calcd for C23H24N1O3S1 ([M þ H]þ)
394.1477, found 394.1480.
2-Tosyl-4-phenylbenzo[1,4]cyclobuta[1,2-c]pyrrole-3(3aH)-one,
pentahydro (26): 1H NMR (CDCl3, 500 MHz) δ 1.35 (m, 2 H),
1.67 (m, 1 H), 1.77 (m, 1 H), 1.98 (m, 1 H), 2.03 (m, 1 H), 2.30 (m,
1 H), 2.40 (s, 3 H), 2.81 (m, 1 H), 3.43 (d, J = 2.3 Hz, 1 H), 3.52
(d, J = 10.2 Hz, 1 H), 4.17 (d, J = 10.2 Hz, 1 H), 7.22 (m, 1 H),
7.28 (d, J = 8.2 Hz, 2 H), 7.31 (m, 2 H), 7.41 (m, 2 H), 7.90 (d, J
= 8.2 Hz, 2 H); 13C NMR (CDCl3, 125 MHz) δ 21.7, 22.5, 24.6,
26.2, 35.4, 39.9, 52.2, 53.9, 126.2, 127.7, 128.1, 128.4, 129.5,
133.2, 135.0, 135.4, 144.9, 147.4, 172.6; IR νCO (CHCl3) 1716.0
cm-1; HRMS (FAB) calcd for C23H24N1O3S1 ([M þ H]þ)
394.1477, found 394.1478.
(E)-3-(1-p-Tolylprop-1-enyl)furan-2(5H)-one (16): 1H NMR
(CDCl3, 500 MHz) δ 1.67 (d, J = 7.0 Hz, 3 H), 2.39 (s, 3 H), 4.71
(m, 1 H), 4.72 (m, 1 H), 6.69 (m, 1 H), 7.04 (d, J = 7.9 Hz, 2 H),
7.21 (d, J = 7.9 Hz, 2 H), 7.22 (q, J = 7.0 Hz, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 15.3, 21.2, 68.9, 129.1, 129.2, 129.6, 132.3,
132.5, 135.0, 137.0, 144.1, 172.0; IR νCO (CHCl3) 1733.6 cm-1
;
HRMS (EI) calcd for C14H14O2 (Mþ) 214.0994, found 214.0998.
5-Methyl-7-phenyl-3-oxa-bicyclo[3.2.0]hept-6-en-2-one (18):
1H NMR (CDCl3, 500 MHz) δ 1.49 (s, 3 H), 3.55 (s, 1 H),
4.10 (d, J = 9.6 Hz, 1 H), 4.34 (d, J = 9.6 Hz, 1 H), 6.52 (s, 1 H),
7.30 (m, 1 H), 7.36 (m, 2 H), 7.53 (m, 2 H); 13C NMR (CDCl3,
125 MHz) δ 20.2, 44.9, 51.3, 74.6, 125.2, 128.5, 128.9, 131.9,
133.6, 146.1, 175.4; IR νCO (CHCl3) 1766.4 cm-1; HRMS (EI)
calcd for C13H12O2 (Mþ) 200.0837, found 200.0839.
Cyclohexenylmethyl-3-phenylpropiolate (27): 1H NMR
(CDCl3, 500 MHz) δ 1.61 (m, 2 H), 1.69 (m, 2 H), 2.07 (m, 4
H), 4.61 (s, 2 H), 5.84 (m, 1 H), 7.38 (m, 2 H), 7.46 (m, 1 H), 7.60
(m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 22.0, 22.3, 25.0, 25.9,
70.5, 80.6, 86.2, 119.7, 127.8, 128.5, 130.6, 132.1, 133.0, 154.1;
IR νCO (CHCl3) 1700.8 cm-1; HRMS (EI) calcd for C16H16O2
(Mþ) 240.1150, found 240.1148.
2-Methylallyl 3-p-tolylpropiolate (19): 1H NMR (CDCl3, 500
MHz) δ 1.81 (s, 3 H), 2.36 (s, 3 H), 4.64 (s, 2 H), 4.99 (s, 1 H), 5.06
(s, 1 H), 7.17 (d, J = 7.9 Hz, 2 H), 7.47 (d, J = 7.9 Hz, 2 H); 13
C
NMR (CDCl3, 125 MHz) δ 19.3, 21.5, 68.9, 80.1, 86.9, 113.8,
116.3, 129.2, 132.8, 139.0, 141.2, 153.7; IR νCO (CHCl3) 1705.6
J. Org. Chem. Vol. 74, No. 20, 2009 7933

Lee et al.
JOCArticle
1H-4-Phenylbenzo[1,4]cyclobuta[1,2-c]furan-3(3aH)-one, pe-
F
calcd = 1.360 g/cm-3, absorption coefficient = 0.326 mm-1, total
reflections collected 7514, unique 4360 (Rint = 0.0261), GOF =
1
ntahydro (28):. H NMR (CDCl3, 500 MHz) δ 1.27 (m, 1 H),
1.40 (m, 1 H), 1.81 (m, 2 H), 1.99 (m, 1 H), 2.16 (m, 1 H), 2.31 (m,
1 H), 2.86 (m, 1 H), 3.57 (d, J = 2.3 Hz, 1 H), 4.11 (d, J = 9.4 Hz,
1 H), 4.47 (d, J = 9.4 Hz, 1 H), 7.26 (m, 1 H), 7.36 (m, 2 H), 7.50
(m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 22.9, 24.8, 26.0, 34.0,
44.6, 50.0, 72.9, 126.1, 127.8, 128.6, 133.3, 135.2, 147.4, 175.7;
IR νCO (CHCl3) 1753.6 cm-1; HRMS (EI) calcd for C16H16O2
(Mþ) 240.1150, found 240.1148.
1.043, R1 = 0.0466, Rw = 0.1116 (I > 2σ(I)).
Crystal data for 32: C46H50N2O7S2 (295 K); M = 807.00,
˚
triclinic, space group P1, a = 6.3711(3) A, b = 13.0727(6) A, c =
˚
˚
13.8394(5) A, R = 66.842(2)°, β = 79.983(3)°, γ = 83.492(2)°,
V = 1042.33(8) A , Z = 1, Fcalcd = 1.286 g/cm-3, absorption
3
˚
coefficient = 0.181 mm-1, total reflections collected 7213,
unique 7213 (Rint = 0.0000), GOF = 1.044, R1 = 0.0517,
Rw = 0.1370 (I > 2σ(I)). A disordered THF molecule was
observed in difference Fourier maps and refined as occupying
two positions. All atoms of the THF molecules were isotropically
treated, and C-C and C-O bond lengths of the THF molecule
were idealized by using the 1,2-distance constraint “DFIX 1.54”
and “DFIX 1.40”, respectively. The hydrogen atoms were
assigned to idealized positions and were allowed to ride.
Cyclohexenylmethyl 3-p-tolylpropiolate (29):. 1H NMR
(CDCl3, 300 MHz) δ 1.64 (m, 4 H), 2.05 (m, 4 H), 2.38 (s, 3
H), 4.59 (s, 2 H), 5.82 (m, 1 H), 7.17 (d, J = 8.0 Hz, 2 H), 7.48 (d,
J = 8.0 Hz, 2 H); 13C NMR (CDCl3, 75 MHz) δ 21.7, 22.0, 22.3,
25.1, 25.9, 70.4, 80.3, 86.8, 116.6, 127.7, 129.3, 132.2, 133.0,
141.2, 154.2; IR νCO (CHCl3) 1692.8 cm-1; HRMS (EI) calcd for
C17H18O2 (Mþ) 254.1307, found 254.1306.
1H-4-(4-Methylphenyl)benzo[1,4]cyclobuta[1,2-c]furan-3(3aH)-
one, pentahydro (30):. 1H NMR (CDCl3, 500 MHz) δ 1.24 (m, 1
H), 1.38 (m, 1 H), 1.79 (m, 2 H), 1.96 (m, 1 H), 2.13 (m, 1 H), 2.28
(m, 1 H), 2.34 (s, 3 H), 2.82 (m, 1 H), 3.53 (d, J = 2.3 Hz, 1 H),
4.09 (d, J = 9.4 Hz, 1 H), 4.45 (d, J = 9.4 Hz, 1 H), 7.15 (d, J =
8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H); 13C NMR (CDCl3, 125
MHz) δ 21.3, 22.9, 24.7, 26.0, 34.0, 44.5, 50.0, 73.0, 126.0, 129.2,
CCDC reference numbers CCDC-716233 (13) and CCDC-
716234 (32) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Computational Method. The calculations were performed
with the Gaussian 03 program package.48 In the computational
model, the PPh3 ligand was represented by PH3. The tosyl group
at the nitrogen atom in the amide-tethered 1,6-enyne substrate
was replaced with H. All the results were obtained at the DFT
level of theory, using the B3LYP hybrid functional.49-51 The
gold atom was described by using the LANL2DZ basis set,
which includes the relativistic effective core potential (ECP) of
Hay and Wadt52-54 for the inner electrons and a double-ζ basis
set for the outer electrons. The standard 6-31G(d) basis set was
used for the remaining atoms. All geometries of stationary states
were fully optimized without any symmetry restriction. Fre-
quency calculations were performed to characterize the station-
ary points as minima or transition states and to obtain the zero-
point energies (ZPE) and thermal corrections at 298.15 K.
Transition states were identified by using a single negative
eigenvalue in the Hessian matrix. Intrinsic reaction coordinate
calculations (IRC) were performed to ensure that the transition
states actually connect the proposed reactants and products.
130.5, 135.1, 137.7, 146.1, 175.8; IR νCO (CHCl3) 1745.6 cm-1
;
HRMS (EI) calcd for C17H18O2 (Mþ) 254.1307, found 254.1303.
N-(3-Methylbut-2-enyl)-3-phenyl-N-tosylpropiolamide (31):.
1H NMR (CDCl3, 500 MHz) δ 1.76 (s, 3 H), 1.81 (s, 3 H),
2.42 (s, 3 H), 4.69 (d, J = 6.8 Hz, 2 H), 5.29 (m, 1 H), 7.29 (d, J =
8.4 Hz, 2 H), 7.38 (m, 2 H), 7.46 (m, 1 H), 7.52 (m, 2 H), 7.88 (d, J
= 8.4 Hz, 2 H); 13C NMR (CDCl3, 125 MHz) δ 18.2, 21.7, 25.7,
45.6, 81.7, 93.0, 119.4, 128.5, 128.6, 128.7, 129.3, 129.7, 130.9,
132.7, 137.3, 144.9, 152.7; IR νCO (CHCl3) 1664.0 cm-1; HRMS
(EI) calcd for C21H21N1O3S1 (Mþ) 367.1242, found 367.1241.
4-Phenyl-5-(prop-1-en-2-yl)-1-tosyl-5,6-dihydropyridin-2(1H)-
one (32):. 1H NMR (CDCl3, 500 MHz) δ 1.99 (s, 3 H), 2.42 (s, 3
H), 3.50 (m, 1 H), 3.87 (dd, J = 4.2, 12.8 Hz, 1 H), 4.66 (dd, J =
2.1, 12.8 Hz, 1 H), 4.73 (s, 1 H), 4.99 (s, 1 H), 6.32 (s, 1 H), 7.30
(d, J = 8.2 Hz, 2 H), 7.38 (m, 3 H), 7.45 (m, 2 H), 7.91 (d, J = 8.4
Hz, 2 H); 13C NMR (CDCl3, 125 MHz) δ 21.6, 22.0, 44.3, 47.5,
116.1, 119.9, 126.4, 128.7, 128.9, 129.1, 130.3, 135.7, 135.9,
140.2, 144.6, 155.0, 163.1; IR νCO (CHCl3) 1674.4 cm-1; HRMS
(EI) calcd for C21H21N1O3S1 (Mþ) 367.1242, found 367.1244.
X-ray Structures of 13 and 32. Single crystals of compounds 13
and 32 were grown by slow evaporation of CH2Cl2 and THF
solutions. Diffraction data were collected on an Enraf-Nonius
CCD single crystal X-ray diffractometer at room temperature,
using graphite-monochromated Mo KR radiation (λ = 0.71073
Acknowledgment. This work was supported by the Kor-
ean Government (MOEHRD) (KRF-2008-341-C00022),
and the Korea Science and Engineering Foundation
(KOSEF) grant funded by the Korea Government (MEST)
(R11-2005-065). Y.T.L. thanks the Brain Korea 21 fellow-
ship and the Seoul Science Fellowship.
˚
A). Preliminary orientation matrices and unit cell parameters
were obtained from the peaks of the first 10 frames and then
refined by using the whole data set. Frames were integrated and
corrected for Lorentz and polarization effects by using DEN-
ZO. Structures were solved by direct methods with use of
SHELXS-9746 and refined by full-matrix least-squares with
SHELXL-97.47 All non-hydrogen atoms were refined anisotro-
pically and hydrogen atoms except some were treated as idea-
lized contributions.
Supporting Information Available: Photocopies of 1H NMR
and 13C NMR spectra of all new compounds; ORTEP drawing
of comopounds 13 and 32; Cartesian coordinates, energies, and
thermodynamic data for all model compounds for computa-
tional study; and a complete ref 48. This material is available free
of charge via the Internet at http://pubs.acs.org.
Crystal data for 13: C20.5H20Cl1N1O3S1 (295 K); M = 389.898,
(48) Frisch, M. J. et al. Gaussian 03, Revision C.02; Gaussian, Inc.:
Wallingford, CT, 2004. For the full reference, see the SI.
(49) Lee, C. T.; Yang, W. T.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.
(50) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
˚
monoclinic, space group C2/c, a = 26.8036(7) A, b = 6.1821(2) A,
˚
3
˚
˚
c = 24.8527(8) A, β = 110.146(2)°, V = 3866.2(2) A , Z = 8,
(51) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J.
Phys. Chem. 1994, 98, 11623–11627.
(52) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270–283.
(53) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284–298.
(54) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299–310.
(46) Sheldrick, G. M. Program for the Solution of Crystal Structure;
University of Gottingen: Gottinger, Germany, 1997.
(47) Sheldrick, G. M. Program for Crystal Structure Refinement; Uni-
versity of Gottingen: Gottinger, Germany, 1997.
7934 J. Org. Chem. Vol. 74, No. 20, 2009