Gold(III)-catalyzed enynamine-cyclopentadiene cycloisomerization with chirality transfer: An experimental and theoretical study indicating involvement of dual au(iii) push-pull assisted cis - Trans isomerism

Article abstract of DOI:10.1021/jo501905q

A synthetic approach for asymmetric ring-fused cyclopentadienes (Cps) with a chiral carbon at the ring junction has been established from chiral enynamines by achiral Au(III) catalysis. On the basis of experimental and theoretical data, the proposed mechanistic pathway from enynamines to Cps occurs via a Au(III) ene cis-trans isomerization step. Computational studies at DFT and NEVPT2 levels advocate that the cis-trans isomerization step proceeds via a dual Au(III) push-pull assisted intermediate with a low computed rotation barrier. The chirality transfer occurs through a helical-shaped transition state with allenic character. The scope of the catalysis encompasses sterically bulky enynamines including terpene natural products.

Full text of DOI:10.1021/jo501905q

Article
pubs.acs.org/joc
Gold(III)-Catalyzed Enynamine−Cyclopentadiene Cycloisomerization
with Chirality Transfer: An Experimental and Theoretical Study
Indicating Involvement of Dual Au(III) Push−Pull Assisted cis−trans
Isomerism
Tom Wirtanen,‡ Mikko Muuronen,‡ Michele Melchionna, Michael Patzschke,* and Juho Helaja*
Department of Chemistry, University of Helsinki, A.I. Virtasen aukio 1, P.O. Box 55, Helsinki, Finland
S
* Supporting Information
ABSTRACT: A synthetic approach for asymmetric ring-fused
cyclopentadienes (Cps) with a chiral carbon at the ring
junction has been established from chiral enynamines by
achiral Au(III) catalysis. On the basis of experimental and
theoretical data, the proposed mechanistic pathway from
enynamines to Cps occurs via a Au(III) ene cis−trans
isomerization step. Computational studies at DFT and
NEVPT2 levels advocate that the cis−trans isomerization
step proceeds via a dual Au(III) push−pull assisted
intermediate with a low computed rotation barrier. The
chirality transfer occurs through a helical-shaped transition
state with allenic character. The scope of the catalysis encompasses sterically bulky enynamines including terpene natural
products.
1-ethynyl-2-propenyl pivalates by cationic Au(I) catalysis,
where the asymmetry from the pivalate moiety is transferred
to the carbon at the β-ketoposition.23 On the other hand, in the
pioneering Au(I)-catalyzed cyclopentadiene synthesis reported
by Toste and Lee, chiral enallene led to a racemic mixture of
product.24 Remarkably, a fresh report by Sanz and co-workers
describes the synthesis of asymmetric β-alkoxy-Cps for many
substrates with good yields and with high to excellent e.r. by use
of cationic Au(I) catalysts bearing chiral biphosphine ligands.11
In our previous work, we documented a Au(III) salt-
catalyzed synthetic route from enynamines to Cps through a
Au(III)metallacycle intermediate, whose existence was also
confirmed by single-crystal X-ray diffraction.25 In the present
work, after optimizing the reaction conditions and improving
yields to synthetically significant levels, we have established the
center-to-center chirality transfer and studied the scope and
mechanism of the reaction. A combination of extensive
experimental work and thorough theoretical study allowed us
to confidently reveal the features of the key cis−trans
isomerization step.
1. INTRODUCTION
Cyclopentadienes (Cps) are key synthetic intermediates, widely
used in organic and organometallic chemistry. Most notably,
they are the direct ligand precursors in the assembly of
metallocenes, a very important and well-known class of metal
complexes, extensively employed as homogeneous catalysts in
many single- or multistep chemical processes. In addition to
simpler symmetrical metallocenes, access to more sophisticated
asymmetric derivatives is often achieved by endowing the
cyclopentadiene ligand precursors with a chiral center.1
Significantly, there are several natural products possessing
cyclopentadiene moieties, which can be foreseen as a functional
Cp ligand in metallocene assembly.2−4 Another prominent area
of application of Cps is in the construction of complex natural
and related biologically active products, where Cps can offer a
phase selective platform for intermolecular Diels−Alder
cycloadditions; once again, enantiopurity of the chiral Cp
moiety represents an extraordinary advantage in terms of
stereocontrol over the resulting chiral product.2,5−8 Despite
their relevance and multipurpose roles, there are very few direct
accesses to chiral Cps from acyclic substrates,9−12 with most
synthetic protocols still relying on multistep postmodification
of cyclic derivatives.5,6,13−16
2. RESULTS AND DISCUSSION
Synthetic Scope. We began our study by screening
different reaction conditions for the cyclopentadiene (2a)
synthesis from chiral enynamines (1a), which were prepared
from alkenyltriflates (3) and propargylic amines (4) (Scheme
Homogeneous Au(I) and Au(III) catalysis has been shown
to be a powerful tool in various asymmetric cycloisomerization
reactions, where alkyne or allene groups may be activated for
internal nucleophilic addition by, e.g., alkenes or heteroa-
toms.17−22 For instance, related compounds to Cps, cyclo-
pentenones, have been enantioselectively cycloisomerized from
Received: August 18, 2014
Published: October 13, 2014
© 2014 American Chemical Society
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Scheme 1. Synthesis of Enynamines and Cyclopentadienes
Table 1. Screening of Reaction Conditions
entry
solvent
catalyst (mol %)
R
conditions (equiv)
time (h)
yield (%)
1
2
MeCN
MeCN
MeCN
TCE
KAuCl4 (10)
KAuCl4 (10)
KAuCl4 (10)
KAuCl4 (10
KAuCl4 (10
KAuCl4 (10)
KAuCl4 (5)
KAuCl4 (10)
KAuCl4 (10)
KAuCl4 (10)
KAuCl4 (10)
HAuCl4 (5)
HAuCl4 (10)
HAuCl4 (15)
HAuCl4 (10)
KAuCl4 (10)
KAuCl4 (10)
KAuCl4 (10)
HAuCl4 (10)
H
16
16
16
18
18
16
20
20
18
20
18
18
18
18
16
18
18
18
18
15
11
<4
a
NO2
NMe2
NO2
NMe2
H
3
4
5
TCE
6
DCE
DCE
DCE
AcOH
PhMe
TCE
42
21
52
7
H
8
H
AcOH (10)
9
H
10
11
12
13
14
15
16
17
18
19
H
12
35
36
56
59
70
67
43
52
52
H
TCE
H
TCE
H
TCE
H
TCE
H
dg
TCE
H
dg
TCE
H
0.01 M, dg
0.1 M, dg
dg, r.t.
TCE
H
TCE
H
a
1
Yield Determined by H NMR, dg = degassed, r.t. = room temperature
1). The propargylic amines were synthesized from propargylic
acetates (5) with enantioselective copper-catalyzed amina-
tion.26 To our delight, we observed chirality transfer from the
propargylic position of the enynamine to the ring junction of
the cyclopentadiene, which inspired us to further study the
scope and mechanism of the reaction.
Initial screening results (Table 1) revealed that the
chlorinated solvents, in particular tetrachloroethane, afford
best yields, whereas poor product recovery was obtained in
nonchlorinated media (entries 1−14).
Tuning the electronics of the isoquinoline moiety with either
an electron withdrawing (NO2) or donating group (NMe2)
lowered the yield in MeCN (entries 2, 3), whereas, in
tetrachloroethane, no formation of cyclopentadiene was
observed (entries 4, 5). Interestingly, enallene was obtained
as a major product (1.0:0.3) when the NMe2 derivative was
used as a starting material in MeCN. The optimum catalyst
loading was found to be 10 mol %. Higher loadings had only
little effect on the yield (entry 14), whereas lower loadings
resulted in decreased yields (entry 12). Chloroauric acid,
HAuCl4, gave slightly better yields than KAuCl4, but the latter
was chosen as catalyst because, in some cases, the use of
HAuCl4 (entry 15) led to undesired double bond isomer-
ization. The reaction turned out to be moderately sensitive to
concentration and temperature (entries 17−19), while careful
degassing of the reaction solvent almost doubled the yield
(entries 11, 16). We conclude that the removal of air is
beneficial due to the sensitivity of the starting material that
readily decomposes on standing at room temperature.
Investigation of the scope of the reaction (Table 2) indicates
that the reaction is applicable to the synthesis of various acyclic
and ring-fused chiral Cps from low to good yields. The best
yields and highest retention of chirality were associated with
cyclohexene rings substituted with alkyl groups. Remarkably,
the highest chirality retention was obtained for 2e, where a
quaternary stereocenter is formed. The electronic nature of the
aromatic ring was found to have an impact on both
enantioselectivity and yield (2b and 2c). Both electron
withdrawing and donating substituents in the para-position
decrease the yield, whereas a decrease in enantioselectivity is
associated only with electron donating groups. Formation of
enallene as a side product in a 1:1 ratio with the Cp was
observed only with 1f as the starting material. Remarkably, the
reaction could also be applied to the synthesis of the extended
ring-fused system of natural betuline (2j). As expected, for the
betuline derivative, the stereochemistry of the formed
asymmetric carbon was fully dictated by the rigid terpene
scaffold.
The absolute configuration of cyclopentadienes was estab-
lished with NMR NOE experiments using substrates 2h and 2i
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a
As discussed above, the formation of the enallene was only
observed in the Au(III) catalysis of substrate 1f. In this case, the
chirality transfer was also significantly lower. Previously, Toste
et al. have demonstrated that a rasemic mixture of cyclo-
pentadiene is obtained in Au(I)-catalytic cyclization of chiral
enallene.24 In addition, Che et al. have synthesized IV-f from
similar enynamine using Au(III)- and Ag-salts as catalysts;
noteworthy, the Ag-based system led to 99% enantiomeric
excess, whereas the latter only gave 50% ee with no reported
formation of cyclopentadiene.27,28 This finding implies that
KAuCl4 is capable of racemizing IV-f under similar reaction
conditions prior to cyclization. Moreover, we observed slightly
more racemized enallene (e.r. 54:46) than the Cp (e.r. 58:42)
in the reaction mixture of IV-f (Scheme 4). We consider that
the formation of the enallene occurs enantioselectively by the
cleavage of gold and 3,4-dihydroisoquinoline, while the
racemization is caused by a recoordination/decoordination
process of gold to enallene. In agreement with this hypothesis,
several other studies have shown the occurrence of rapid
isomerization of allenes under Au(I)/Au(III) catalysis in
ambient conditions.29−35 In our fresh computational study,
we discovered that the racemization of enallene IV-f occurs
through a gold-activated intermediate in the cis-conformation
prior to the cyclization from the trans-conformation.36 When
the system was studied according to the transition state theory
using several methods, and with molecular dynamics at the
DFT level without any constrains, the results pointed out that
the time scale for racemization is fast compared to that of the
cyclization.
Table 2. Scope of Reaction
a
Products with isolated yields (NMR yields in parentheses) and
Considering again the enallene formation from 1f, we note
that this starting substrate only differs from 1a by the R2-
substitution (Scheme 3). In this respect, if the two-step route
through enallene would be operational in all of the cases, one
could anticipate to observe at least some of the other
corresponding enallenes, too. To rule out the involvement of
enallene in the reaction mechanism, we pursued the synthesis
of enantiopure enallene IV-a. Unfortunately, we were only able
to receive a complex mixture of products in a minor yield when
1a was reacted together with AgBF4. Changing the hydride
source to prolinol and catalyst to KAuCl4 led to the formation
of cyclopentadiene 2a exclusively. This is somewhat surprising
as 1f has been successfully converted to enallene in the same
reaction conditions.27,28 Despite that all our other numerous
attempts to obtain IV-a were not successful, we consider the
two-step allene route to be an improbable pathway for all the
substrates based on the discussion above.
On the basis of the experimental data (see additional data in
the Supporting Information), an alternative mechanism is
considered to justify the chirality transfer and the absence of
enallenes. In this route, the gold is protodeaurated as the last
step, after diastereoselective formation of V. However, prior to
this, the vinyl−Au(III) complex II-cis should isomerize to the
corresponding II-trans for steric reasons. On the basis of these
stereomeric ratio of enynamine (EA) and cyclopentadiene (CP).
(Supporting Information), which were prepared from com-
mercially available enantiopure (+)-methyl-(R)-3-(1-methyl-2-
oxocyclohexyl)propionate (6) by protecting the carbonyl group
as a 1,3-dioxolane (7), followed by reduction with LAH (8)
(Scheme 2). The formed alcohol was then methylated with
NaH/MeI and deprotected to afford ketoether (9), which was
then converted to the corresponding triflate (10). The triflate
(10) was coupled with chiral ynamines (4) to form (R,R) and
(R,S)-enynamines that gave two diastereomeric Cps (2h, 2i)
upon treatment with KAuCl4 in TCE.
Mechanistic Aspects. Previously, we have shown that the
reaction proceeds from activated enyneamine I via 1,5-hydride
shift to form a vinyl−Au(III)complex II-cis, which can C−H
activate R1 to form Au(III)−metallacycle III (Scheme 3).25 We
have ruled out the involvement of this species in the
mechanism by performing successfully the reaction with the
methylated analogue where R1 = Me (2e, Table 2). Thus, the
complex III is not likely a reactive intermediate in the catalytic
cycle. On the other hand, the cleavage of AuCl3 at this stage
together with 3,4-dihydroisoquinoline elimination would lead
to formation of enallene IV.
Scheme 2. Preparation of Starting Materials for Determining Absolute Configuration
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Scheme 3. Possible Pathways to Resting State Au(III)−Metallacycle, Enallene, and Chiral Cyclopentadiene via cis−trans
Isomerization Step
outcome of the reaction. The II-trans cyclizes via two
diastereomeric TS TSII-V-syn and TSII-V-anti, with activation
free energies of 19.3 and 24.8 kcal/mol, respectively (Figure 1).
These TS seem to predict a wrong stereochemical outcome;
namely, the formed product should be R-2a, whereas we
experimentally found S-2a as the main product (88%). Closer
examination of the TS showed the 3,4-dihydroisoquinoline
leaving group to be already over 3.1 Å away from the reaction
center. The analysis of vibrational frequencies of the TS
confirmed that the leaving group has diverged the system. We
consider that, in our model, the 3,4-dihydroisoquinoline moiety
stays loosely attached by dispersions with the AuCl3 group
because of the unsuitable description of the competitive van der
Waals forces of the solvent environment. Optimization of these
transition states without D3-dispersion correction, and, there-
fore, neglecting the internal attractive dispersions, inverted the
ΔΔG value between the corresponding transition states, and,
therefore, gave a “better” result. However, we do not consider
this to be a satisfactory option to improve our model.
Scheme 4
findings, we performed computational studies to provide
theoretical insights into the cis−trans isomerization and the
enantioselectivity determining cyclization step. All computa-
tions were carried out using TPSS-D3/def2-TZVP37−39 in
tetrachloroethane (COSMO) unless otherwise noted (see the
Experimental Section for details). The corresponding computa-
tional level has provided an accurate description of gold
complexes compared to high-level ab initio benchmark data as
well as experimental results.40−42
In order to disclose a more realistic description of the
transition states, the system was optimized without the 3,4-
dihydroisoquinoline group. The removal of this group allowed
the TSII-V-anti to relax into a helical-shaped TS. Interestingly,
Transfer of Chirality. To examine our hypothesis on the
required cis−trans isomerization step, we began by exploring
the transition states (TS) that determine the stereochemical
Figure 1. TPSS-D3/def2-TZVP optimized structures of TSII-V-anti and TSII-V-syn.
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Figure 2. TPSS-D3/def2-TZVP optimized transition states TSII-V-anti and TSII-V-syn without the isoquinolone group.
b
Table 3. Comparison of Experimental and Computed Values for Transfer of Chirality
a
substrate
ΔG⧧ (syn−anti) (kcal/mol)
computed (%)
experimental (%)
1a
1c
1e
1f
1.5
2.5
4.2
1.5
92
98
88
72
98
64
100
92
a
b
TPSS-D3/def2-TZVP in solution. Populations are calculated from ΔG (298 K) values according to Boltzmann distribution at 313 K.
Scheme 5
a similar conformation has also been reported previously in the
enantioselective Rautenstrauch cyclization (Figure 2).43 The
ΔG⧧ value for the cyclization to the S-enantiomer is 13.6 kcal/
mol, and the respective value for the R-enantiomer is 15.1 kcal/
mol. The computed enantiomeric ratio according to Boltzmann
distribution at 313.5 K is 92%, which is in excellent
correspondence with the experimental value for the studied
substrate (88%). This was also verified using a number of
dispersion corrected DFT-D3 functionals (Supporting In-
formation).
center. The TS itself is identical to that of the gold-activated
enallene, but we reason that the late cleavage of the 3,4-
dihydroisoquinoline prevents the racemization.
Experimentally, slightly different enantioselectivities were
observed for substrates 1a and 1e, whereas distinctly lower
selectivities were received for 1c and 1f (Table 3). Satisfactorily,
the computed values correlate excellently with the values for
substrates 1a and 1e, but poorly for 1c and 1f (Table 3). The
drop in the transfer of chirality for 1c and 1f compared to 1a
(72% and 64% vs 88%) is somewhat unexpected, while the only
exclusive difference between the compounds lies in the R2
substitutions (R2 = H/Me) or in the para-substitution of the
phenyl, both of which are located relatively far away from the
According to our computational analysis, the 3,4-dihydroi-
soquinoline group is cleaved from the system just prior to the
transition state, providing a Au-stabilized cationic reaction
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Figure 3. Structures showing the carbene behavior from II-cis via protonation to the transition state (TPSS-D3/def2-TZVP).
reaction center. Therefore, we considered alternative mecha-
nistic routes that could explain the decreased enantioselectivity
for 1c and 1f.
binding, in which stabilization takes place through resonance
with the Au(I)−allenylidene form.47 In these cases, the back-
donation from the filled d-shell occurs, thus stabilizing the
cationic system. We investigated computationally the acid-
activated pathways A and C to yield a carbocation on the γ- or
α-position compared to gold, by activation of the C1−C2 (VIa,
VIc) or C3−C4 (VIb, VId) π-system, respectively. As acid
additives, we took into consideration a simple protonation or
activation of the π-system with another Lewis acidic AuCl3.
Route A. The protonation of C1 to yield a carbocation at the
γ-position (VIa and VIc) increases the back-donation (Figure
3). The Au−C4 bond length is decreased by 3 pm, and the C3−
C4 bond length is increased by 4 pm. Overall, the whole
conjugated π-system is affected, and we do not consider this
Au−C4 bond length shortening to correspond to “true” gold−
For this purpose, we inspected the cyclopentadiene−enallene
ratio in the catalysis: the 1a yielded high selectivity on
cyclopentadiene with no enallene observed, whereas, for the
substrate 1f (R2 = H), this ratio is 50:50 (Scheme 4). Together,
this suggests that, for substrate 1f, there are two operating
pathways: one proceeding through the enallene intermediate,
leading to a racemic mixture of cyclopentadiene, and the other
progressing through the cis−trans isomerization that provides
the chiral product. The competing enallene route explains,
therefore, the poor enantioselectivity for substrate 1f. For 1c,
we did not observe any enallene in the product mixture, but this
might be due to a more rapid activation of electron rich
enallene compared to enynamine. An alternative explanation is
that the methoxy-substituted phenyl ring assists earlier cleavage
of the 3,4-dihydroisoquinoline moiety in the cyclization step
through resonance effects and allows partial racemization.
Meanwhile, the excellent correlation of the chirality transfer
between computational and experimental studies for substrates
1a and 1e suggests that, in these cases, the mechanism operates
chiefly through a chirality transferring cis−trans isomerization
step in the optimized reaction conditions.
Mechanism of Au−Vinyl cis−trans isomerization. We
envisioned that the cis−trans isomerization can, in principle,
proceed via three possible pathways A−C in Scheme 5. First,
we considered the most straightforward route B, i.e., direct
rotation around the π-system to find out if Au(III), as a formal
d8 metal, would be able to stabilize the triplet character of such
a transformation. Because of the pseudo-Jan−Teller origin of
the isomerization,44 this step was studied with the NEVPT2-
(6,6)/def2-TZVP method in gas phase (see comprehensive
data and discussion in the Supporting Information). We found
a high activation energy barrier of 43.1 kcal/mol that seems to
exclude this route. Also, light-induced direct rotation of an
excited state of the system can be ruled out as the reactions
were also performed in the dark.
carbene, as was also recently proposed by Seidel and Furstner.48
̈
However, while studying the TS for the cis−trans isomerization
(TSVIa-VIIa), we observed a more pronounced carbene
character: The Au−C4 distance is shortened by an additional
3 pm, which makes the total decrease of the bond length to be
6 pm when considering II-cis. The C2−C3 and C3−C4 distances
are also notably affected. On the basis of these computational
findings, we consider the carbene character to be more likely a
phenomenon related to the TS rather than the ground state in
this studied system.
The observed TS behavior accounts for the relatively low
rotational energy barrier: the ΔG⧧ value for the proton-assisted
route A is 20.2 kcal/mol. When considering the same activation
as described, but with another AuCl3, we noted the carbene
character not to be as pronounced as in the case of proton
assistance. This is in accordance with the calculated bond
lengths and higher activation free energy, which, in the dual
AuCl3 route A, is 27.9 kcal/mol.
Route C. In this route, intermediates VIb or VId are formed
when the C3−C4 π-system of II-cis is activated with a proton or
another AuCl3, respectively. Intermediate VIb is 16.1 kcal/mol
higher in energy than VIa (route A), and similarly, VId is 11.8
kcal/mol higher in energy than VIc when considering the dual
gold activation. From a thermodynamic point of view, it is,
therefore, clear that the acid (proton or AuCl3) favors the
coordination to the C1−C2 over the C3−C4 π-system, but on
the other hand, the sp3-hybridization of C3 should provide a
low activation energy barrier for this rotation. In this respect,
both proton-assisted routes should have similar energetics. The
dual gold activation in route C provides a low rotational barrier
of 10 kcal/mol, when the reaction is overall exothermic by 4.4
kcal/mol (Supporting Information). The transition state for the
rotation (Figure 4, TSVId-VIId) suggests the covalently bound
Thus far, several mechanistic studies have focused on the
nature of the gold-carbocation species, where either a carbene
or a carbenoid character is possible.45−48 Experimental and
theoretical investigations have suggested that cationic liganded
Au(I) predominantly stabilizes the carbocation in an electro-
static carbenoid manner rather than via genuine carbene
bonding.46 The cis−trans isomerization in the Ph3P−Au(I)−
vinyl ketal cation has been proven conclusively by NMR
evidence. Respectively, a nonclassical propargylic gold stabilized
carbocation has been reported for alkynes with terminal Au(I)
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gold to act as a Lewis base, pushing electrons, whereas the new
additive is a coordinative Lewis acid.
Scheme 7. Push−Pull Effect by Electron Withdrawing and
Donating Groups Lowers Ethylene Rotation Barrier49−51
Figure 4. TPSS-D3-def2-TZVP optimized dual gold transition state.
Energetically, we can rule out the dual-activated route A as
the activation energy of 28 kcal/mol is too high when
compared to experimental reaction conditions. On the other
hand, the same activation to route C goes through route A (VIc
→ VId → TSVId-VIId), giving a total activation energy of
approximately 22 kcal/mol. Both proton-assisted routes have
barriers of approximately 20 kcal/mol. The energy required for
the acid activation itself was not computed because it is
dependent on the acid species present in the reaction media. In
particular, the nature of gold species in the solution has been
shown to depend on the concentration of reagents that can
compete for the coordination.35 Some potential reagents or
byproducts in our system include the 3,4-dihydroisoquinoline
and the final product cyclopentadiene.
Figure 5. Electron density effect of the second gold (blue [Au] in the
inset = AuCl3, of which the influence on the electron density is
visualized) to the total electron density of the system in dual gold
ground state intermediate VId. Blue indicates increased and red
decreased electron density.
zwitterionic character, which may significantly lower the
rotational barrier.49−51
In Figure 5, we present the computed effect of the second
AuCl3 on the electron density of VId. Inspection of this
electron density difference plot reveals polarization of the bond
in a similar manner to that represented in Scheme 7; a decrease
in electron density is observed in the p-orbital close to the
carbon bound covalently to gold, whereas an increase in
electron density appears in the surrounding of the carbon of the
second coordinated gold. This leads to a weakening of the π-
system. Furthermore, an addition of electron density to σ-type
orbitals of the carbon atom is observed. The second gold gains
electron density in the Au−C3 region, and this is an indication
of the Lewis acidity of this unit. The covalently bound gold is
also affected. Electron density is lost from its filled 5d orbital,
and the surrounding toward C4 is slightly negatively polarized.
Taking into account the small change in Au−C4 bond length by
addition of the second gold, and the small polarization effect,
we regard the covalently bound gold as a carbocation stabilizing
center. The carbene behavior was only observed in the
transition state of the computationally studied proton-assisted
route A.
The Toste, Nolan, Zhang, and Hashmi groups have recently
reported dual gold activation pathways for allenyne and 1,2-
bialkynephenyl cycloisomerizations.52−56 A common feature for
these reactions is that (at least) one Au(I) converts a terminal
alkyne to a nucleophile, while another Au(I) activates the
neighboring π-system for this nucleophile. The present
experimental and computational evidence implies that a distinct
dual Au(III) push−pull activation pathway operates for the
studied cis−trans isomerization. Unfortunately, the fast
decomposition of the catalyst and inability to monitor the
concentration of gold in the reaction mixture prevented us to
perform reliable kinetic studies. However, this investigation
takes into account all the feasible pathways, which pinpoint the
dual activation as the most probable.
Although the proton assistance seems to be a plausible
solution for the cis−trans isomerization, this was ruled out on
2
the basis of H-labeling experiments (Scheme 6). Experimen-
Scheme 6. Deuterolabeling Experiments
tally, under catalysis conditions using D2O as an additive, no
proton−deuterium exchange was observed in either C1 or C3
positions. The fact that C4 became labeled indicates only that
the protodeauration step is solvent-assisted. For additional
evidence, we also performed the reaction in the presence of
pyridine as a proton sequestering agent and still observed the
successful proceeding of the reaction, which is in contrast with
a possible proton-assisted catalysis.
On the basis of the presented data, we propose the dual-
activated route C with a second gold species as the operating
pathway. The role of the second gold in the cis−trans
isomerization can be rationalized in analogy with the push−
pull effect in ethylene substituted with an electron donating and
an electron withdrawing group at the two ends to the double
bond (Scheme 7). Such a double bond exhibits some
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a
Scheme 8. Proposed Reaction Mechanism
a
All energies are ΔG (298.15 K) values in kcal/mol, except rotation is reported as ΔE.
Overall, the computational and experimental results support
the mechanism presented in Scheme 8. The gold-activated
complex I is converted to structure II-cis via 1,5-hydride shift.
This may lead to metallacycle III or the catalysis proceeds from
the cis-Au−vinyl complex to the corresponding trans-complex
by a dual gold activation of II-cis when another AuCl3
coordinates to the vinyl group producing intermediate VId.
For this complex, the cis−trans isomerization is possible with a
low rotational energy barrier of 10 kcal/mol, although the total
activation energy needed for this transformation is 22 kcal/mol
due to gold favoring thermodynamically the C1−C2 π-system.
The following cyclization step determines the chirality of the
product. A diastereomeric intermediate V-anti/syn is formed
with the ΔG⧧ value for V-anti of 13.6 kcal/mol. The last step of
the mechanism involves cleavage of the benzylic proton to the
reaction media (Supporting Information, Scheme S3) and
solvent-assisted protodeauration.
cis by the second gold depending on the concentration of free
gold in solution.
3. CONCLUSIONS
We have established a Au(III) catalytic methodology to convert
enynamines to various acyclic and cyclic cyclopentadiene
derivatives with low to good yields. The chirality of the
propargylic position of the enynamine is transferred to the ring
junction of the cyclopentadiene through a helical-shaped
transition state with allenic character, at its best with a high
degree of preservation. Our extensive experimental and
computational studies indicate the cis−trans isomerization to
involve two Au(III) species in a traditional push−pull manner.
We expect that these symmetric or asymmetric cyclo-
pentadiene derivatives have the potential to be attractive
synthetic platforms in phase-selective Diels−Alder retro-Diels−
Alder cascades in natural product synthesis, as key
intermediates in organic synthesis or utilizing ring extended
terpene natural products, e.g., betuline as a bulky asymmetric
ligand in metallocene assembly.
Inspection of the computed energetics at the different stages
of the mechanism indicates that the cis−trans isomerization step
is the rate-limiting step. The fact that we failed to
experimentally detect any intermediates after the hydride shift
4. EXPERIMENTAL SECTION
1
in the H NMR studies is in agreement with our studied free
General Remarks. Unless otherwise specified, all commercial
materials were used as received without further purification. Reactions
involving use of air- and moisture-sensitive materials were carried out
in an atmosphere of dry argon using Schlenk techniques or in a
conventional argon-filled glovebox. THF and methanol were distilled,
respectively, from sodium/benzophenoneketyl and CaH2 under a
energy profile for the catalytic cycle. Practically all reactions are
endothermic after formation of II-cis, indicating that the
population of these species is small and, therefore, out of H
NMR detection range at the tested concentration levels.
Alternatively, the rate-limiting step may be the activation of II-
1
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positive pressure of argon prior to use or taken directly from the
°C under Ar. After 16 h, the resulting mixture of regioisomers
(1.0:0.38:0.07) was analyzed with NMR using 1,3,5-trimethoxyben-
zene as internal standard. NMR yield 42%. 1H NMR (300 MHz,
CDCl3): Common peaks: δ 7.59−7.44 (m), 7.35−7.23 (m), 7.21−
7.11 (m). Common peaks of regioisomers 1 + 2: 3.40−3.26 (m).
Regioisomer 1: 6.75 (dt, J = 2.3, 1.1 Hz), 6.20 (dt, J = 2.3, 1.1 Hz),
1.22 (s). Regioisomer 2: 6.94 (dd, J = 2.7, 1.5 Hz), 5.98 (q, J = 1.5
Hz), 1.21 (s). Regioisomer 3: 6.56−6.54 (m, 1H), 6.48 (dd, J = 3.5,
1.9 Hz), 3.16 (dd, J = 1.9, 1.1 Hz), 1.23(s). 13C NMR (75 MHz,
CDCl3) δ 159.5, 143.9, 136.7, 128.7, 128.0, 127.3, 126.7, 126.3, 126.0,
125.0, 124.8, 124.7, 122.2, 40.7, 40.0, 33.5, 31.0, 29.9. IR (cm−1, neat):
3060, 2961, 750, 691. HRMS (EI+) calcd for [C15H18]+ m/z 198.1409,
found: 198.1400.
1
solvent purifier. H and 13C{1H} NMR spectra were recorded with
1
either a 300 or a 500 MHz spectrometer. H spectra were referenced
to tetramethylsilane (TMS, 0.00 ppm) and are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet). Chemical shifts of the 13C{1H} NMR spectra
were referenced to CDCl3 (77.16 ppm). NMR yields were determined
using nitrobenzene or 1,3,5-trimethoxybenzene as an internal standard.
HR-MS spectral data were acquired with EI ionization mode with a
sector analyzer. Column chromatographic purifications were per-
formed on silica gel (230−400 mesh). Brine refers to a saturated water
solution of NaCl. Known compounds were prepared according to the
literature procedures.
(S)-3a,7,7-Trimethyl-3-phenyl-4,5,6,7-tetrahydro-3aH-indene
(2e). Following the general procedure with 27.7 mg (0.0750 mmol) of
1e, with 2.8 mg (0.0074 mmol) of KAuCl4 and with 2.8 mL of TCE.
Purification of the crude by column chromatography using n-hexane
and ethyl acetate (40:1) as eluent afforded 8 mg of product and
unknown side/decomposition product that could not be separated
with column chromatography. The analytical sample was purified with
preparative HPLC, and the yield was determined with NMR using
General Procedure for Cyclopentadiene Synthesis. Freshly
purified enynamine (1 equiv) was dissolved in tetrachloroethane
(0.03M), and the mixture was degassed with three freeze−pump−thaw
cycles and by keeping the solution exposed to high vacuum (oil pump)
for a minute. The solution was added to gold salt (0.1 equiv), and the
temperature was brought to 40 °C under Ar in the absence of light.
After 16 h, the solvent was evaporated. Purification of the crude by
column chromatography using n-hexane or pentane and ethyl acetate
as eluent afforded the desired product.
1
PhNO2 as an internal standard. H NMR (300 MHz, CDCl3) δ 7.46
(d, J = 7.5 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.19 (t, J = 7.5 Hz, 1H),
6.62 (s, 1H), 6.06 (s, 1H), 2.44 (d, J = 12.9 Hz, 1H), 2.02−1.82 (m,
1H), 1.69−1.58 (m, 2H), 1.26 (s, 3H), 1.24 (s, 3H), 1.23 (s, 3H),
1.20−1.02 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 165.1, 155.8,
136.8, 128.4, 126.7, 126.3, 125.8, 120.8, 54.8, 43.0, 37.9, 35.8, 31.5,
25.8, 21.0, 20.0. IR (cm−1, neat): 3057, 2926, 839, 759, 692. HRMS
(EI+) calcd for [C18H22]+ m/z 238.1722, found: 238.1715. e.r.
(HPLC): 86:14.
(S)-3-(4-Bromophenyl)-7,7-dimethyl-4,5,6,7-tetrahydro-3aH-in-
dene (2b). Following the general procedure with 68.2 mg (0.157
mmol) of 1b, with 5.9 mg (0.0157 mmol) of KAuCl4 and with 5.3 mL
of TCE. Purification of the crude by column chromatography using n-
hexane and ethyl acetate (40:1) as eluent afforded 25.3 mg (0.0832
mmol, 53%) of the desired product.1H NMR (300 MHz, CDCl3) δ
7.46−7.38 (m, 2H), 7.30−7.24 (m, 2H), 6.72 (dd, J = 2.2, 0.9 Hz,
1H), 6.05 (d, J = 2.2 Hz, 1H), 3.22 (dd, J = 12.8, 5.8 Hz, 1H), 2.42−
2.22 (m, 1H), 1.90−1.58 (m, 4H), 1.26 (s, 3H), 1.19 (s, 3H), 0.72
(qd, J = 12.8, 3.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 162.5,
148.2, 135.0, 131.7, 127.3, 127.1, 120.4, 119.8, 49.0, 43.7, 35.3, 34.2,
28.8, 28.5, 22.7. IR (cm−1, neat): 3059, 2958, 2926, 1537, 1484, 1073,
1007, 812. HRMS (EI+) calcd for [C17H19Br]+ m/z 302.0670, found:
302.0672. e.r. (HPLC): 76:24.
(S)-7,7-Dimethyl-3-phenyl-4,5,6,7-tetrahydro-3aH-indene (2a).
Following the general procedure (with 18 h heating) with 42.9 mg
(0.121 mmol) of 1a, with 4.6 mg (0.0122 mmol) of KAuCl4 and with
4.2 mL of TCE. Purification of the crude by column chromatography
using n-hexane and ethyl acetate (40:1) as eluent afforded 17.8 mg
(0.0799 mmol, 66%) of the desired product. Spectral data were found
to match literature values.12 Missing spectroscopic data are reported:
IR (cm−1, neat): 3057, 2956, 2924, 2858, 872, 753, 691. e.r. (HPLC
A): 79:21.
(S)-3-Phenyl-4,5,6,7-tetrahydro-3aH-indene (2f). Following the
general procedure with 36.6 mg (0.112 mmol) of 1f, with 4.3 mg
(0.0114 mmol) of KAuCl4 and with 3.7 mL of TCE. Purification of the
crude by column chromatography using n-hexane and ethyl acetate
(40:1) as eluent afforded 13.8 mg (0.0694 mmol, 62%) of the desired
product and the corresponding enallene as a 1:1 mixture. The pure
analytical sample was then purified with column chromatography using
1
n-hexane as eluent. H NMR (300 MHz, CDCl3) δ 7.46−7.37 (m,
2H), 7.36−7.26 (m, 2H), 7.21−7.12 (m, 1H), 6.74−6.72 (m, 1H),
6.08 (t, J = 1.9 Hz 1H), 3.08 (dd, J = 12.8, 5.9 Hz, 1H), 2.79−2.64 (m,
1H), 2.50−2.26 (m, 2H), 2.09−1.94 (m, 1H), 1.88−1.74 (m, 1H),
1.63−1.41 (m, 1H), 1.37−1.14 (m, 1H), 0.82 (qd, J = 12.8, 3.4 Hz,
1H). 13C NMR (75 MHz, CDCl3) δ 153.7, 149.3, 136.0, 128.7, 127.0,
126.1, 125.6, 122.4, 51.6, 33.9, 30.0, 29.5, 25.8. IR (cm−1, neat): 3055,
2929, 2853, 2350, 1597, 1541, 1491, 1444, 829, 756, 692. HRMS (EI+)
calcd for [C15H16]+ m/z 196.1252, found: 196.1254. e.r. (HPLC):
58:42.
(S)-3-(4-Methoxyphenyl)-7,7-dimethyl-4,5,6,7-tetrahydro-3aH-in-
dene (2c). Following the general procedure with 82.8 mg (0.215
mmol) of 1c, with 8.1 mg (0.0215 mmol) of KAuCl4 and with 7.2 mL
of TCE. Purification of the crude by column chromatography using n-
hexane and ethyl acetate (20:1) as eluent afforded 25.3 mg (0.125
7-(tert-Butyl)-3-phenyl-4,5,6,7-tetrahydro-3aH-indene (2g). Meth-
od A: Following the typical procedure with 100.2 mg (0.261 mmol) of
1g, with 9.9 mg (0.0261 mmol) of KAuCl4 and with 8.7 mL of TCE.
Purification of the crude by column chromatography using n-hexane
and ethyl acetate (40:1) as eluent afforded 34.3 mg (0.136 mmol,
52%) of the desired product as a mixture of diastereomers (62:38).
Method B: Following the general procedure (with 15 h heating) with
81.5 mg (0.212 mmol) of 1g, with 8.5 mg (0.0213 mmol) of NaAuCl4
× 2H2O and with 7.1 mL of TCE. Purification of the crude by column
chromatography using n-hexane and ethyl acetate (40:1) as eluent
afforded 40.1 mg (0.159 mmol, 75%) of the desired product as a
mixture of diastereomers (62:38). Spectroscopic data for the mixture
1
mmol, 58%) of the desired product. H NMR (300 MHz, CDCl3) δ
7.39−7.31 (m, 2H), 6.92−6.83 (m, 2H), 6.58 (dd, J = 2.2, 0.8 Hz,
1H), 6.03 (d, J = 2.2 Hz, 1H), 3.80 (s, 3H), 3.22 (dd, J = 12.8, 5.8 Hz,
1H), 2.41−2.30 (m, 1H), 1.90−1.60 (m, 4H), 1.26 (s, 3H), 1.19 (s,
3H), 0.72 (qd, J = 12.8, 3.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ
160.8, 158.3, 149.2, 129.2, 126.7, 124.6, 120.3, 114.1, 55.4, 49.1, 43.9,
35.2, 34.4, 28.9, 28.5, 22.9. IR (cm−1, neat): 3055, 2927,1609, 1505,
1277, 1250, 1177, 1040, 819. HRMS (EI+) calcd for [C18H22O]+ m/z
254.1671, found: 254.1665. e.r. (HPLC): 58:42.
(4-(tert-Butyl)cyclopenta-1,3-dien-1-yl)benzene (2d). Method A:
Following the general procedure (with 18 h heating) with 47 mg
(0.143 mmol) of 1d, with 5.7 mg (0.0143 mmol) of NaAuCl4 × 2H2O
and with 4.8 mL of TCE. Purification of the crude by column
chromatography using n-pentane as eluent afforded 12 mg (0.058
mmol, 41%) of the desired product as a mixture of regioisomers
(1.0:0.5:0.07). Method B: Freshly purified 1d (10.5 mg, 0.029 mmol)
was dissolved in d2-tetrachloroethane (1 mL, 0.03 M), and the mixture
was degassed by three freeze−pump−thaw cycles and keeping the
solution exposed to high vacuum for a minute. The solution was added
to KAuCl4 (1.2 mg, 0.031 mmol), and temperature was brought to 40
1
of diastereomers: H NMR (300 MHz, CDCl3) Diastereomer 1: 6.73
(s), 6.22 (s), 3.04 (dd, J = 12.7, 5.6 Hz), 1.10 (s). Diastereomer 2: 6.78
(s), 6.14 (s), 3.28 (dd, J = 12.2, 6.2 Hz), 0.98 (s). Undistinguished
peaks: δ 7.46−7.26 (m), 7.15 (t, J = 7.2 Hz), 2.57 (d, J = 6.9 Hz),
2.43−2.31 (m), 2.22 (d, J = 12.4 Hz), 2.12 (d, J = 12.8 Hz), 1.84
(1.95−1.70), 1.66−1.38 (m), 0.93−0.67 (m). 13C NMR (75 MHz,
CDCl3) δ 154.6, 154.5, 150.2, 148.3, 136.0, 135.8, 128.6, 127.2, 126.7,
126.6, 126.1, 125.7, 125.5, 122.5, 54.3, 51.9, 50.4, 48.2, 34.9, 34.4, 33.0,
31.5, 29.7, 28.9, 28.7, 28.5, 28.3, 26.9, 24.1. IR (cm−1, neat): 3055,
2942, 2863, 832, 755, 692. HRMS (EI+) calcd for [C19H24]+ m/z
252.1878, found: 252.1884. d.r. (1H NMR): 62:38.
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(3aS,7R)-7-(3-Methoxypropyl)-7-methyl-3-phenyl-4,5,6,7-tetrahy-
dro-3aH-indene (2h). Following the general procedure with 38.5 mg
(0.093 mmol) of 1h, with 3.5 mg (0.0093 mmol) of KAuCl4 and with
3.1 mL of TCE. Purification of the crude by column chromatography
using n-hexane and ethyl acetate (20:1 → 10:1 → 5:1) as eluent
afforded 13.4 mg (0.0474 mmol, 51%) of the desired product as a
mixture of diastereomers. The major diastereomer was separated with
preparative HPLC. 1H NMR (500 MHz, CDCl3, −5 °C) δ 7.43 (d, J =
7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H), 6.75 (d,
J = 1.5 Hz, 1H), 6.09 (d, J = 1.5 Hz, 1H), 3.38−3.32 (m, 2H), 3.31 (s,
3H), 3.19 (dd, J = 13.0, 5.8 Hz, 1H), 2.41−2.34 (m, 1H), 1.89−1.73
(m, 3H), 1.64−1.51 (m, 2H), 1.39 (td, J = 12.6, 4.3 Hz, 1H), 1.33−
1.22 (m, 2H), 1.23−1.17 (m, 3H), 0.74 (qd, J = 13.0, 3.5 Hz, 1H). 13C
NMR (126 MHz, CDCl3, −5 °C) δ 160.2, 149.3, 135.8, 128.6, 126.4,
126.1, 125.5, 122.5, 73.5, 58.7, 48.5, 42.8, 38.1, 36.3, 33.9, 25.4, 24.9,
22.1. IR (cm−1, neat): 3057, 2927, 2858, 1596, 1447, 1117, 891, 756,
693. HRMS (EI+) calcd for [C20H26O]+ m/z 282.1984, found:
282.1981. d.r. (1H NMR): 75:35.
(PPh3)PdCl2 (18 mg, 0.0256 mmol), CuI (9.8 mg, 0.0515 mmol),
and 6,6-dimethylcyclohex-1-en-1-yl trifluoromethanesulfonate (131
mg, 0.507 mmol) were dissolved in 4 mL of degassed THF:DEA
(50:50). After 5 min, propargylic amine (166 mg, 0.671 mmol) in 2
mL of THF:DEA (50:50) was added to the mixture, and the
temperature was brought to 40 °C. After 16 h, the solvent was
evaporated. Purification of the crude by column chromatography
(SiO2) using n-hexane and ethyl acetate as eluent (20:1) afforded 168
1
mg (0.294 mmol, 58%) of the desired product. H NMR (300 MHz,
CDCl3) δ 7.58−7.52 (m, 2H), 7.49−7.44 (m, 2H), 7.12−7.06 (m,
3H), 7.01−6.95 (m, 1H), 6.10 (t, J = 4.1 Hz, 1H), 4.92 (s, 1H), 3.75,
3.74 (ABq, J = 14.9 Hz, 2H), 2.95−2.74 (m, 4H), 2.11−2.01 (m, 2H),
1.68−1.56 (m, 2H), 1.55−1.47 (m, 2H), 1.15 (s, 6H). 13C NMR (75
MHz, CDCl3) δ 138.2, 135.4, 134.8, 134.5, 131.4, 130.3, 130.0, 128.8,
126.8, 126.1, 125.7, 121.6, 89.0, 82.9, 61.1, 52.4, 47.3, 37.7, 33.8, 29.8,
29.1, 26.3, 19.0. IR (cm−1, neat): 3023, 2928, 1689, 1588, 1484, 1455,
1071, 1011, 739. HRMS (EI+) calcd for [C26H28NBr]+ m/z 433.1405,
found: 433.1417. e.r. (HPLC): 90:10.
(3aR,7R)-7-(3-Methoxypropyl)-7-methyl-3-phenyl-4,5,6,7-tetra-
hydro-3aH-indene (2i). Following the general procedure with 42.1 mg
(0.102 mmol) of 1i, with 3.9 mg (0.0103 mmol) of KAuCl4 and with
3.4 mL of TCE. Purification of the crude by column chromatography
using n-hexane and ethyl acetate (20:1 → 10:1 → 5:1) as eluent
afforded 6.7 mg (0.0235 mmol, 23%) of the desired product as a
mixture of diastereomers. The major diastereomer was separated with
preparative HPLC. 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 7.6 Hz,
2H), 7.31 (t, J = 7.6 Hz, 2H), 7.16 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 1.9
Hz, 1H), 6.07 (d, J = 1.9 Hz, 1H), 3.44 (t, J = 6.3 Hz, 2H), 3.38 (s,
3H), 3.29 (dd, J = 12.9, 5.7 Hz, 1H), 2.43−2.33 (m, 1H), 1.89−1.55
(m, 8H), 1.19 (s, 3H), 0.73 (qd, J = 12.9, 3.6 Hz, 1H). 13C NMR (75
MHz, CDCl3) δ 161.1, 149.4, 136.0, 128.6, 126.5, 126.2, 125.6, 120.8,
73.9, 58.8, 49.2, 40.9, 37.8, 37.7, 34.3, 25.8, 24.2, 22.6. IR (cm−1, neat):
3056, 2925, 2855, 1738, 1445, 1116, 1018, 837, 754, 692. HRMS (EI+)
calcd for [C20H26O]+ m/z 282.1984, found: 282.1977. d.r. (1H NMR):
77:33.
(R)-2-(3-(6,6-Dimethylcyclohex-1-en-1-yl)-1-(4-methoxyphenyl)-
prop-2-yn-1-yl)-1,2,3,4-tetrahydro-3,4-dihydroisoquinoline (1c).
(PPh3)PdCl2 (24 mg, 0.0342 mmol), CuI (12.6 mg, 0.0662 mmol),
and 6,6-dimethylcyclohex-1-en-1-yl trifluoromethanesulfonate (173
mg, 0.670 mmol) were dissolved in 4 mL of degassed THF:DEA
(1:1). After 5 min, propargylic amine (186 mg, 0.725 mmol) in 2 mL
of THF:DEA (1:1) was added, and the temperature was brought to 40
°C. After 16 h, the solvent was evaporated. Purification of the crude by
column chromatography (SiO2) using n-hexane and ethyl acetate as
eluent (20:1) afforded 213 mg (0.550 mmol, 82%) of the desired
1
product. H NMR (300 MHz, CDCl3) δ 7.60−7.54 (m, 2H), 7.10−
7.05 (m, 3H), 7.01−6.95 (m, 1H), 6.91−6.85 (m, 2H), 6.09 (t, J = 4.1
Hz, 1H), 4.93 (s, 1H), 3.79 (s, 3H), 3.76 (s, 2H), 2.97−2.73 (m, 4H),
2.10−2.01 (m, 2H), 1.67−1.57 (m, 2H), 1.55−1.47 (m, 2H), 1.16 (s,
6H). 13C NMR (75 MHz, CDCl3) δ 159.1, 135.7, 134.7, 134.4, 131.1,
130.2, 129.7, 128.8, 126.9, 126.0, 125.6, 113.6, 88.3, 83.9, 61.1, 55.4,
52.3, 47.2, 37.8, 33.8, 29.9, 29.1, 26.3, 19.0. IR (cm−1, neat): 3022,
2929, 1610, 1585, 1508, 1455, 1245, 1172, 1036, 739. HRMS (EI+)
calcd for [C27H31NO]+ m/z 385.2406, found: 385.2398. e.r. (HPLC):
81:19.
Betulonic Acid Methyl Ester 3-Phenyl Cyclopentadiene (2j).
Following the typical procedure with 70 mg (0.101 mmol) of 1j, with
3.8 mg (0.0101 mmol) of KAuCl4 and with 3.3 mL of TCE.
Purification of the crude by column chromatography using n-hexane
and ethyl acetate (20:1) as eluent afforded 32.5 mg (0.0576 mmol,
57%) of the desired product as a mixture of regioisomers. The
2-(5,5-Dimethyl-4-methylene-1-phenylhex-2-yn-1-yl)-1,2,3,4-
tetrahydro-3,4-dihydroisoquinoline (1d). (PPh3)PdCl2 (14 mg,
0.0199 mmol) and CuI (7.6 mg, 0.0399 mmol) were dissolved in 2
mL of degassed THF:DEA (1:1). 6,6-Dimethylcyclohex-1-en-1-yl
trifluoromethanesulfonate (99.5 mg, 0.428 mmol) was added in 2 mL
of THF:DEA (1:1), followed by propargylic amine (104 mg, 0.420
mmol) in 1.05 mL of THF after 5 min. The temperature was brought
to 40 °C. After 19 h, the solvent was evaporated. Purification of the
crude by column chromatography (SiO2) using n-hexane and ethyl
acetate as eluent (40:1) afforded 101 mg (0.308 mmol, 72%) of the
1
regioisomers were separated with preparative HPLC. Fraction 3: H
NMR (500 MHz, CDCl3, −5 °C) δ 7.37−7.30 (m), 7.17 (t, J = 7.1
Hz), 6.73 (d, J = 1.6 Hz), 6.12 (d, J = 1.6 Hz), 4.67 (s), 4.51 (s), 3.68
(s), 3.44 (dd, J = 13.2, 5.5 Hz), 3.05−2.92 (m), 2.33 (dd, J = 12.6, 5.6
Hz), 2.26−2.13 (m), 1.92−1.80 (m), 1.69−1.62 (m), 1.62−1.57 (m),
1.55−1.45 (m), 1.44−1.19 (m), 1.18−1.13 (m), 1.08 (s), 0.97 (s),
0.88 (t, J = 6.9 Hz), 0.85 (s), 0.79 (d, J = 11.6 Hz), 0.35 (t, J = 13.2
Hz). 13C NMR (126 MHz, CDCl3, −5 °C) δ 176.8, 163.7, 150.5,
150.2, 135.6, 128.7, 126.3, 126.2, 125.5, 120.5, 109.9, 59.7, 56.4, 51.5,
50.2, 49.3, 47.1, 45.2, 42.5, 41.0, 38.8, 38.1, 38.1, 37.0, 34.3, 32.2, 31.7,
30.4, 29.7, 28.2, 25.3, 24.9, 22.8, 21.0, 19.1, 16.6, 16.2, 14.5, 14.4. IR
(cm−1, neat): 3061, 2944, 2868, 1727, 1490,1135, 863, 760, 739, 693.
HRMS (EI+) calcd for [C40H54O2]+ m/z 566.4124, found: 566.4113.
Fraction 1: 1H NMR (300 MHz, CDCl3) δ 7.37−7.33 (m), 6.27 (t, J =
1.6 Hz), 4.74 (d, J = 2.5 Hz), 4.61 (dd, J = 2.5, 1.4 Hz), 3.67 (s), 3.00
(d, J = 2.8 Hz), 2.38−2.17 (m), 1.88 (dd, J = 13.5, 6.0 Hz), 1.73−1.65
(m), 1.50−1.37 (m), 1.21 (t, J = 8.8 Hz), 1.14 (s), 1.04 (s), 1.00 (s),
0.95 (s), 0.77 (s). IR (cm−1, neat): 2944, 2869, 1726, 1451, 1376,
1364, 1153, 886, 735, 698. HRMS (EI+) calcd for [C40H54O2]+ m/z
1
desired product. H NMR (300 MHz, CDCl3) δ 7.70−7.64 (m, 2H),
7.39−7.27 (m, 3H), 7.13−7.06 (m, 3H), 7.02−6.97 (m, 1H), 5.38 (d, J
= 1.4 Hz, 1H), 5.29 (d, J = 1.4 Hz, 1H), 5.00 (s, 1H), 3.79 (s, 2H),
2.96−2.77 (m, 4H), 1.18 (s, 9H). 13C NMR (75 MHz, CDCl3) δ
141.6, 138.8, 135.6, 134.7, 128.8, 128.6, 128.3, 127.7, 126.9, 126.1,
125.6, 118.1, 88.5, 85.7, 61.7, 52.4, 47.4, 36.1, 29.9, 29.3. IR (cm−1,
neat): 3025, 2965, 1602, 1449, 899, 737, 700. HRMS (EI+) calcd for
[C24H27N]+ m/z 329.2143, found: 329.2144.
(R)-2-(1-Phenyl-3-(2,6,6-trimethylcyclohex-1-en-1-yl)prop-2-yn-1-
yl)-1,2,3,4-tetrahydro-3,4-dihydroisoquinoline (1e). (PPh3)PdCl2
(7.7 mg, 0.0110 mmol), TEA (67 mg, 0.67 mmol), and propargylic
amine (56 mg, 0.226 mmol) were dissolved in 3 mL of degassed DMF.
2,6,6-Trimethylcyclohex-1-en-1-yl trifluoromethanesulfonate (60 mg,
0.220 mmol) in 3 mL of DMF was added to the mixture, and the
temperature was brought to 75 °C. After 23 h, the solvent was
evaporated. Purification of the crude by column chromatography
(SiO2) using n-hexane and ethyl acetate as eluent (20:1) afforded 62
1
566.4124, found: 566.4113. Fraction 2: H NMR (300 MHz, CDCl3)
δ 7.37−7.31 (m), 6.14 (s), 4.76 (d, J = 1.5 Hz, 1H), 4.67−4.62 (m),
3.67 (s), 3.57−3.45 (m), 3.22−3.11 (m), 3.07−2.93 (m), 2.35−2.16
(m), 2.01−1.82 (m), 1.74−1.66 (m), 1.49−1.36 (m), 1.22 (s), 1.14
(s), 1.05−1.00 (m), 0.98 (s), 0.94 (s), 0.77 (d, J = 3.3 Hz), 0.69 (s). IR
(cm−1, neat): 2945, 2869, 1727, 1492, 1453, 1187, 1173, 1154, 884,
755, 740, 696. HRMS (EI+) calcd for [C40H54O2]+ m/z 566.4124,
found: 566.4111.
1
mg (0.167 mmol, 76%) of the desired product. H NMR (500 MHz,
CDCl3) δ 7.72−7.68 (m, J = 7.5 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H),
7.28 (t, J = 7.5 Hz, 1H), 7.12−7.06 (m, 3H), 6.99 (d, J = 7.0 Hz, 1H),
5.05 (s, 1H), 3.81, 3.79 (ABq, J = 15.1 Hz, 2H), 2.96−2.80 (m, 4H),
2.03 (t, J = 6.2 Hz, 2H), 1.92 (s, 3H), 1.64−1.58 (m, 2H), 1.50−1.46
(R)-2-(1-(4-Bromophenyl)-3-(6,6-dimethylcyclohex-1-en-1-yl)-
prop-2-yn-1-yl)-1,2,3,4-tetrahydro-3,4-dihydroisoquinoline (1b).
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(m, 2H), 1.15 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 140.9, 139.3,
135.7, 134.7, 128.8, 128.7, 128.2, 127.6, 126.9, 126.0, 125.6, 124.0,
88.4, 87.3, 61.9, 52.4, 47.4, 37.9, 34.1, 32.1, 29.9, 29.4, 29.4, 23.2, 19.1.
IR (cm−1, neat): 3293, 2960 2926, 2864, 1493, 1450, 1262, 1086,
1049, 1029, 798, 740, 700, 648. HRMS (EI+) calcd for [C27H31N]+ m/
z 369,2457, found: 369.2454. e.r. (HPLC): 88:12.
evaporated. Purification of the crude by column chromatography
(SiO2) using n-hexane and ethyl acetate as eluent (10:1) afforded 41.1
mg (0.0938 mmol, 79%) of the desired product. 1H NMR (300 MHz,
CDCl3) δ 7.68−7.63 (m, 2H), 7.38−7.24 (m, 3H), 7.11−7.05 (m,
2H), 7.01−6.95 (m, 1H), 6.17 (t, J = 4.1 Hz, 1H), 4.97 (s, 1H), 3.77
(s, 2H), 3.33−3.25 (m, 1H), 3.23 (s, 3H), 2.93−2.74 (m, 2H), 2.11−
1.95 (m, 1H), 1.70−1.33 (m, 8H), 1.14 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 139.0, 135.8, 135.6, 134.6, 129.3, 128.8, 128.6, 128.2, 127.6,
126.9, 126.0, 125.6, 88.5, 83.6, 73.7, 61.7, 58.6, 52.4, 47.4, 37.5, 36.6,
33.6, 29.9, 27.5, 26.2, 24.73, 18.8. IR (cm−1, neat): 2930, 2866, 2826,
1263, 1493, 1117, 739, 700. HRMS (EI+) calcd for [C29H35NO]+ m/z
413.2719, found: 413.2722. d.r. (NMR): 88:12.
1-Phenylprop-2-yn-1-yl-1,2,3,4-tetrahydro-3,4-dihydroisoquino-
line Betulonic Acid Methyl Ester (1j). (PPh3)PdCl2 (27.3 mg, 0.0389
mmol) and CuI (16.6 mg, 0.0871 mmol) were dissolved in 5 mL of
DMF, after which propargylic amine (164 mg, 0.663 mmol) and TEA
(101.7 mg) were added in 5 mL of DMF. This mixture was added to
3j (400 mg, 0.666 mmol) in 27 mL of DMF and stirred for 10 min,
after which the temperature was brought to 80 °C. After 11/2 h, 30 mL
of water was added to the mixture, which was extracted with 3 × 30
mL of diethyl ether. The combined ethers were washed with 15 mL of
water and 15 mL of brine and dried over Na2SO4. Purification of the
crude by column chromatography (SiO2) using n-hexane and ethyl
acetate as eluent (20:1) afforded 336 mg (0.477 mmol, 72%) of the
desired product. 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 7.1 Hz),
7.38−7.25 (m), 7.13−7.04 (m), 7.02−6.95 (m), 6.00 (dd, J = 6.4, 2.1
Hz), 4.98 (s), 4.74 (d, J = 2.1 Hz), 4.60 (dd, J = 2.2, 1.4 Hz), 3.78 (s),
3.67 (s), 3.06−2.76 (m), 2.24 (qd, J = 8.1, 3.6 Hz), 2.08 (dd, J = 17.9,
6.6 Hz), 1.96−1.81 (m), 1.77−1.72 (m), 1.68 (s), 1.60 (dd, J = 15.4,
7.2 Hz), 1.53−1.29 (m), 1.21−1.18 (m), 1.17 (s), 1.14−1.08 (m), 1.06
(s), 1.05−1.00 (m), 0.97 (s), 0.95 (s), 0.86 (s). 13C NMR (75 MHz,
CDCl3) δ 176.8, 150.7, 139.1, 135.7, 134.7, 132.3, 129.9, 128.8, 128.6,
128.2, 127.6, 126.9, 126.0, 125.6, 109.7, 89.0, 83.0, 61.7, 56.7, 52.4,
51.4, 49.6, 49.4, 47.4, 47.1, 42.5, 42.1, 40.7, 38.5, 37.1, 37.0, 36.3, 33.6,
32.3, 31.7, 30.8, 30.6, 29.8, 25.7, 22.8, 21.7, 21.4, 20.0, 19.5, 16.6, 15.7,
14.9, 14.3. IR (cm−1, neat): 2944, 1726, 1445, 1377, 1143, 883, 739,
699. HRMS (EI+) calcd for [C49H63NO2]+ m/z 697.4859, found:
697.4874.
2-(1-(4-Methoxyphenyl)prop-2-yn-1-yl)-1,2,3,4-tetrahydro-3,4-
dihydroisoquinoline (4c). Cu(OTf)·(benzene)0.5 (24 mg, 0.954
mmol) and R(+)-BINAP (118 mg, 0.190 mmol) were dissolved in 7
mL of anhydrous methanol under an argon atmosphere and stirred for
21/2 h at 60 °C. The temperature was lowered to 0−5 °C (ice bath),
and a solution of 5c (388 mg, 1.90 mmol), DIPEA (288 mg, 2.23
mmol), and 1,2,3,4-tetrahydroisoquinoline (285 mg, 2.14 mmol) in
anhydrous methanol (7 mL) was added to the mixture. The mixture
was stirred for 20 h at 0−5 °C, after which the solution was filtered
and washed with MeOH. The filtrate was removed under reduced
pressure. Purification of the crude by column chromatography (SiO2)
using n-hexane and ethyl acetate as eluent (10:1) afforded 163 mg
(0.589 mmol, 31%) of the desired product. 1H NMR (500 MHz,
CDCl3) δ 7.55 (d, J = 8.2 Hz, 2H), 7.12−7.05 (m, 3H), 6.97 (d, J = 6.7
Hz, 1H), 6.88 (d, J = 8.2 Hz, 2H), 4.78 (s, 1H), 3.79 (s, 2H), 3.73 (s,
1H), 2.95−2.70 (m, 2H), 2.55−2.53 (m, 1H). 13C NMR (126 MHz,
CDCl3) δ 159.3, 135.3, 134.5, 129.9, 129.5, 128.8, 126.8, 126.0, 125.6,
113.7, 79.6, 75.9, 60.4, 55.4, 52.1, 47.0, 29.7. IR (cm−1, neat): 3285,
2908, 2834, 1609, 1508, 1245, 1171, 1033, 839, 734, 689. HRMS (EI+)
calcd for [C19H19NO]+ m/z 277.1467, found: 277.1476.
2-(1-(4-Bromophenyl)prop-2-yn-1-yl)-1,2,3,4-tetrahydro-3,4-
dihydroisoquinoline (4b). Cu(OTf)·(benzene)0.5 (17.6 mg, 0.0700
mmol) and R(+)-BINAP (87 mg, 0.140 mmol) were dissolved in 7 mL
of anhydrous methanol under an argon atmosphere and stirred for 2 h
at 60 °C. The temperature was lowered to 0−5 °C (ice bath), and a
solution of 5b (354 mg, 1.40 mmol), DIPEA (212 mg, 1.64 mmol),
and 1,2,3,4-tetrahydroisoquinoline (373 mg, 2.80 mmol) in anhydrous
methanol (7 mL) was added to the mixture. The mixture was stirred
for 63 h, and during this time, the temperature was let to rise to room
temperature. The solution was filtered and washed with MeOH. The
filtrate was removed under reduced pressure. Purification of the crude
by column chromatography (SiO2) using n-hexane and ethyl acetate as
(R)-2-(3-(Cyclohex-1-en-1-yl)-1-phenylprop-2-yn-1-yl)-1,2,3,4-
tetrahydro-3,4-dihydroisoquinoline (1f). (PPh3)PdCl2 (14 mg,
0.0199 mmol) and CuI (7.6 mg, 0.0399 mmol) were dissolved in 2
mL of degassed THF:DEA (1:1). Cyclohex-1-en-1-yltrifluoromethane-
sulfonate (92 mg, 0.400 mmol) was added in 2 mL of THF:DEA
(1:1), followed by propargylic amine (104 mg, 0.420 mmol) in 1.05
mL of THF after 5 min. The temperature was brought to 40 °C. After
48 h, the solvent was evaporated. Purification of the crude by column
chromatography (SiO2) using n-hexane and ethyl acetate as eluent
(40:1) afforded the 99.7 mg (0.304 mmol, 76%) of the desired
1
product. H NMR (300 MHz, CDCl3) δ 7.68−7.62 (m, 2H), 7.38−
7.22 (m, 3H), 7.12−7.04 (m, 3H), 7.01−6.94 (m, 1H), 6.18−6.13 (m,
1H), 4.94 (s, 1H), 3.76 (s, 2H), 2.96−2.71 (m, 4H), 2.25−2.02 (m,
4H), 1.70−1.49 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 138.8, 135.6,
134.8, 134.6, 128.8, 128.6, 128.3, 127.7, 126.9, 126.0, 125.6, 120.6,
90.6, 82.0, 61.6, 52.3, 47.3, 29.8, 25.7, 22.5, 21.7. IR (cm−1, neat):
3024, 2925, 1492, 1448, 733, 698. e.r. (HPLC): 90:10.
2-(3-(6-(tert-Butyl)cyclohex-1-en-1-yl)-1-phenylprop-2-yn-1-yl)-
1,2,3,4-tetrahydro-3,4-dihydroisoquinoline (1g). (PPh3)PdCl2 (17
mg, 0.0242 mmol) and CuI (9 mg, 0.0473 mmol) were dissolved in 2
mL of degassed THF:DEA (1:1). 6-(tert-Butyl)cyclohex-1-en-1-yl
trifluoromethanesulfonate (140 mg, 0.486 mmol) was added in 2 mL
of THF:DEA (1:1), followed by propargylic amine (129 mg, 0.522
mmol) in 1.3 mL of THF after 5 min. The temperature was brought to
40 °C. After 19 h, the solvent was evaporated. Purification of the crude
by column chromatography (SiO2) using n-hexane and ethyl acetate as
eluent (40:1) afforded 137.6 mg (0.360 mmol, 74%) of the desired
product as a mixture of diastereomers. Spectral data for the mixture of
1
diastereomers: H NMR (300 MHz, CDCl3) δ 7.68−7.62 (m, 2H),
7.38−7.26 (m, 3H), 7.12−7.06 (m, 3H), 7.01−6.95 (m, 1H), 6.40−
6.34 (m, 1H), 4.92 (s, 1H), 3.77 (s, 2H), 2.94−2.75 (m, 4H), 2.17−
1.99 (m, 3H), 1.80−1.41 (m, 4H), 1.07 (s, 9H). 13C NMR (75 MHz,
CDCl3) δ 140.0, 139.9, 139.1, 135.6, 134.7, 128.8, 128.6, 128.2, 127.6,
126.9, 126.0, 125.6, 123.3, 92.8, 83.6, 61.8, 52.5, 47.5, 47.5, 46.9, 46.9,
34.6, 29.9, 29.5, 26.1, 25.6, 20.8. IR (cm−1, neat): 2952, 1449, 740,
698. HRMS (EI+) calcd for [C28H33N]+ m/z 383.2615, found:
383.2598. d.r. (HPLC): 90:10.
2-((R)-3-((R)-6-(3-Methoxypropyl)-6-methylcyclohex-1-en-1-yl)-1-
phenylprop-2-yn-1-yl)-1,2,3,4-tetrahydro-3,4-dihydroisoquinoline
(1h). (PPh3)PdCl2 (4.4 mg, 0.00627 mmol) and CuI (2.4 mg, 0.0126
mmol) were dissolved in 4 mL of degassed THF:DEA (1:1). 9 (39.5
mg, 0.125 mmol) was added in 2 mL of THF, followed by propargylic
amine (39 mg, 0.158 mmol) in 2 mL of THF after 5 min. The
temperature was brought to 50 °C. After 15 h, the solvent was
evaporated. Purification of the crude by column chromatography
(SiO2) using n-hexane and ethyl acetate as eluent (10:1) afforded 49.2
mg (0.0938 mmol, 75%) of the desired product. 1H NMR (500 MHz,
CDCl3) δ 7.66 (d, J = 7.5 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.28 (t, J =
7.5 Hz, 1H), 7.12−7.06 (m, 3H), 6.99 (d, J = 6.3 Hz, 1H), 6.17 (t, J =
3.9 Hz, 1H), 4.97 (s, 1H), 3.78, 3.76 (ABq, 2H, JAB = 15.1 Hz), 3.34−
3.26 (m, 2H), 3.25−3.23 (m, 3H), 2.94−2.76 (m, 4H), 2.10−1.98 (m,
2H), 1.68−1.37 (m, 8H), 1.14 (s, 3H). 13C NMR (126 MHz, CDCl3)
δ 139.0, 135.8, 135.6, 134.6, 129.2, 128.8, 128.6, 128.2, 127.6, 126.9,
126.0, 125.6, 88.5, 83.6, 73.7, 61.7, 58.6, 52.4, 47.3, 37.5, 36.6, 33.6,
29.9, 27.5, 26.2, 24.7, 18.8. IR (cm−1, neat): 2928, 2866, 2826, 1493,
1449, 1261, 1115, 1086, 802, 737, 699. HRMS (EI+) calcd for
[C29H35NO]+ m/z 413.2719, found: 413.2719. d.r. (NMR): 89:11.
2-((S)-3-((R)-6-(3-Methoxypropyl)-6-methylcyclohex-1-en-1-yl)-1-
phenylprop-2-yn-1-yl)-1,2,3,4-tetrahydro-3,4-dihydroisoquinoline
(1i). (PPh3)PdCl2 (4.4 mg, 0.00627 mmol) and CuI (2.4 mg, 0.0126
mmol) were dissolved in 4 mL of degassed THF:DEA (1:1). 9 (39.5
mg, 0.125 mmol) was added in 2 mL of THF, followed by propargylic
amine (39 mg, 0.158 mmol) in 2 mL of THF after 5 min. The
temperature was brought to 50 °C. After 15 h, the solvent was
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eluent (10:1) afforded 142.6 mg (0.434 mmol, 31%) of the desired
product. 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 8.1 Hz, 2H), 7.47
(d, J = 8.1 Hz, 2H), 7.13−7.06 (m, 3H), 6.97 (d, J = 6.4 Hz, 1H), 4.78
(s, 1H), 3.74, 3.71 (ABq, 2H, JAB = 14.7 Hz), 2.96−2.68 (m, 4H),
2.60−2.54 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 137.0, 135.0,
134.4, 131.5, 130.1, 128.8, 126.8, 126.2, 125.7, 121.9, 78.6, 76.7, 60.4,
52.1, 47.1, 29.7. IR (cm−1, neat): 3294, 2921, 1485, 1071, 1012, 951,
783, 740. HRMS (EI+) calcd for [C18H16BrN]+ m/z 325.0466, found:
325.0473.
(R)-Methyl 3-(6-Methyl-1,4-dioxaspiro[4.5]decan-6-yl)pro-
panoate (7). Ketone (6) (199 mg, 1.00 mmol), p-TsOH (19.1 mg,
0.100 mmol), and ethylene glycol (624 mg, 10.1 mmol) were dissolved
to 20 mL of toluene, and the mixture was refluxed in a Dean−Stark
setup fitted with a drying tube (CaCl2) for 21/2 h. The reaction was
quenched with 5 mL of 2 N NaOH and diluted with 50 mL of EtOAc.
The organic fraction was washed with 30 mL of water and 30 mL of
brine and dried over Na2SO4. Purification of the crude by column
chromatography (SiO2) using n-hexane and ethyl acetate (10:1) as
eluent afforded 176 mg (0.730 mmol, 73%) of the desired product. 1H
NMR (300 MHz, CDCl3) δ 4.00−3.85 (m, 4H), 3.66 (s, 3H), 2.39−
2.25 (m, 2H), 1.91−1.65 (m, 2H), 1.67−1.47 (m, 4H), 1.44−1.35 (m,
4H), 0.92 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 175.2, 112.8, 65.1,
64.8, 51.6, 40.9, 34.8, 30.6, 30.3, 29.4, 23.6, 20.9, 19.41. IR (cm−1,
neat): 2933, 2866, 1736, 1436, 1172, 1088, 948, 878. HRMS (EI+)
calcd for [C13H22O4]+ m/z 242.1518, found: 242.1513.
(R)-3-(6-Methyl-1,4-dioxaspiro[4.5]decan-6-yl)propan-1-ol (8).
To stirred solution of LiAlH4 (58 mg, 1.53 mmol) in 10 mL THF
was added protected ester (7) (167 mg, 0.689 mmol) in 10 mL of
THF, and the mixture was stirred at room temperature for 2 h 15 min.
The reaction mixture was quenched with Rochelle’s Salt, and the
organic fraction was separated. The water phase was extracted with
Et2O (3 × 50 mL) and washed with 50 mL of H2O and 50 mL brine
and dried over Na2SO4. Purification of the crude by column
chromatography (SiO2) using n-hexane and ethyl acetate (1:1) as
eluent afforded 121 mg (0.565 mmol, 82%) of the desired product. 1H
NMR (300 MHz, CDCl3) δ 4.00−3.85 (m, 4H), 3.66−3.58 (m, 2H),
1.67−1.34 (m, 12H), 0.92 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
113.1, 65.1, 64.9, 64.2, 41.1, 34.4, 30.6, 30.5, 27.2, 23.8, 21.0, 19.6. IR
(cm−1, neat): 3360, 2931, 2865, 1467, 1448, 1174, 1126, 1089, 1054,
1026, 951, 879. HRMS (EI+) calcd for [C12H22O3]+ m/z 214.1569,
found: 214.1579.
quenched with water. THF was evaporated, and the residue was
dissolved in 40 mL of DCM. DCM was washed with 20 mL of water
and 20 mL of brine and dried with Na2SO4. Purification of the crude
by column chromatography (SiO2) using n-hexane and ethyl acetate
(10:1) as eluent afforded 225 mg (0.715 mmol, 55%) of the desired
1
product. H NMR (300 MHz, CDCl3) δ 5.72 (t, J = 4.1 Hz, 1H),
3.41−3.34 (m, 2H), 3.33 (s, 3H), 2.20−2.11 (m, 2H), 1.80−1.43 (m,
8H), 1.14 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 155.4, 118.6 (d, J =
318 Hz), 117.1, 73.2, 58.7, 38.1, 35.4, 35.1, 24.9, 24.8, 24.3, 18.5. IR
(cm−1, neat) 2942, 2868, 1408, 1141, 1016, 894, 866, 603.
6-(tert-Butyl)cyclohex-1-en-1-yl Trifluoromethanesulfonate (3g).
To 2-(t-butyl)cyclohexanone (154 mg, 1 mmol) in 3 mL of THF was
added LiHMDS (167 mg, 1 mmol) as a 1 M solution in THF at −78
°C. The mixture was stirred for 30 min, after which PhNTf2 (357 mg,
1 mmol) was added as a 1 M solution in THF. The mixture was then
stirred overnight, and the temperature was let to rise to room
temperature during the stirring. The next day, the reaction was
quenched with H2O and THF was evaporated. The residue was
dissolved in DCM, and the DCM was washed with H2O and brine and
dried over Na2SO4. Purification of the crude by column chromatog-
raphy using pentane as eluent afforded 159 mg (0.560 mmol, 56%) of
1
the desired product. H NMR (300 MHz, CDCl3) δ 5.92−5.86 (m,
1H), 2.37−2.29 (m, 1H), 2.25−2.03 (m, 2H), 1.91−1.79 (m, 1H),
1.79−1.60 (m, 2H), 1.57−1.41 (m, 1H), 1.01 (s, 9H). 13C NMR (75
MHz, CDCl3) δ 152.2, 121.8, 118.7 (q, J = 320.3 Hz), 47.4, 34.2, 29.1,
26.8, 24.5, 20.4. IR (cm−1, neat): 2962, 2874, 1671, 1414, 1244, 1200,
1140, 1014. HRMS (EI+) calcd for [C11H17F3O3S]+ m/z 286.0850,
found: 286.0830.
((2S)-1-(1-Phenylprop-2-yn-1-yl)pyrrolidin-2-yl)methanol (4d).
Cu(OTf)·(benzene)0.5 (16 mg, 0.064 mmol) and S-(−)-Cl-MeO-
BIPHEP (84 mg, 0.13 mmol) were dissolved in 3 mL of anhydrous
methanol under an argon atmosphere and stirred for 1 h at 60 °C. The
temperature was lowered to 0−5 °C (ice bath), and a solution of L-
prolinol (131 mg, 1.3 mmol), DIPEA (335 mg, 2.6 mmol), and 1-
phenylprop-2-yn-1-yl acetate (226 mg, 1.3 mmol) in anhydrous
methanol (3 mL) was added to the mixture. The mixture was stirred
for 22 h at 0−5 °C, after which the solution was filtered and washed
with MeOH. The filtrate was removed under reduced pressure.
Purification of the crude by column chromatography (SiO2) using n-
hexane and ethyl acetate as eluent (5:1) afforded 53 mg (0.589 mmol,
1
19%) of the desired product. H NMR (300 MHz, CDCl3) δ 7.57−
(R)-2-(3-Methoxypropyl)-2-methylcyclohexanone (9). Protected
alcohol (8) (105 mg, 0.490 mmol) in 10 mL of THF was added to
a 55% NaH suspension (78 mg, 1.96 mmol) in 10 mL of THF at 0 °C.
The reaction mixture was stirred for 21/2 h, after which MeI (556 mg,
3.92 mmol) was added and the mixture was stirred overnight. The next
day, the reaction was quenched with water. THF was evaporated, and
to the residue was added 10 mL of water, which was extracted with 3 ×
20 mL of DCM. DCM was washed with 10 mL of H2O and
evaporated. The mixture was dissolved in 30 mL of 2:1 (THF:H2O),
and a catalytic quantity of p-TsOH was added. The mixture was heated
to 70 °C, and after the disappearance of starting material (TLC), THF
was evaporated. The residue was extracted with 3 × 20 mL of DCM.
DCM was washed with 15 mL of sat. NaHCO3 and 15 mL of brine
and dried over Na2SO4. Purification of the crude by column
chromatography (SiO2) using n-hexane and ethyl acetate (3:1) as
7.51 (m, 2H), 7.38−7.24 (m, 3H), 4.92 (d, J = 1.9 Hz, 1H), 3.77 (dd, J
= 11.0, 3.6 Hz, 1H), 3.51 (dd, J = 11.0, 2.4 Hz, 1H), 3.17 (dd, J = 6.0,
2.8 Hz, 1H), 2.75−2.64 (m, 1H), 2.62−2.49 (m, 3H), 2.03−1.55 (m,
4H). 13C NMR (75 MHz, CDCl3) δ 138.6, 128.4, 128.0, 127.7, 79.70,
75.5, 62.0, 61.7, 55.7, 47.8, 28.0, 23.5. IR (cm−1, neat): 3410, 3291,
3030, 2963, 2872, 1493, 1117, 1029, 701, 640. HRMS (EI+) calcd for
[C14H17NO − CH3O]+ m/z 184.1126, found: 184.1129.
((2S)-1-(3-(6,6-Dimethylcyclohex-1-en-1-yl)-1-phenylprop-2-yn-
1-yl)pyrrolidin-2-yl)methanol (1k). (PPh3)PdCl2 (8.8 mg, 0.0125
mmol), CuI (4.8 mg, 0.025 mmol), and 6,6-dimethylcyclohex-1-en-1-
yl trifluoromethanesulfonate (64.5 mg, 0.25 mmol) were dissolved in 2
mL of degassed THF:DEA (1:1). After 5 min, 4d (53 mg, 0.25 mmol)
in 2 mL of THF:DEA (1:1) was added and temperature was brought
to 40 °C. After 22 h, the solvent was evaporated. Purification of the
crude by column chromatography (SiO2) using n-hexane and ethyl
acetate as eluent (5:1) afforded 37.6 mg (0.117 mmol, 47%) of the
1
eluent afforded 78 mg (0.421 mmol, 86%) of the desired product. H
1
desired product. H NMR (300 MHz, CDCl3) δ 7.60−7.51 (m, 2H),
NMR (500 MHz, CDCl3) δ 3.35 (t, J = 6.2 Hz, 2H), 3.32 (s, 2H),
2.46−2.30 (m, 2H), 1.93−1.64 (m, 6H), 1.62−1.43 (m, 4H), 1.40−
1.31 (m, 1H), 1.06 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 215.9,
73.1, 58.6, 48.4, 39.5, 38.8, 34.1, 27.6, 24.2, 22.6, 21.1. IR (cm−1, neat):
2932, 2863, 2827, 1703, 1452, 1116. HRMS (EI+) calcd for
[C11H20O2]+ m/z 184.1463, found:184.1469.
7.39−7.21 (m, 3H), 6.10 (t, J = 4.1 Hz, 1H), 5.03 (s, 1H), 3.80 (dd, J
= 10.9, 3.5 Hz, 1H), 3.51 (dd, J = 10.9, 2.2 Hz, 1H), 3.27−3.17 (m,
1H), 2.80−2.69 (m, J = 9.2, 7.3 Hz, 1H), 2.62−2.51 (m, 2H), 2.11−
2.01 (m, 2H), 2.00−1.57 (m, 6H), 1.58−1.49 (m, 2H), 1.17 (s, 6H).
13C NMR (75 MHz, CDCl3) δ 139.8, 134.6, 130.1, 128.3, 128.2, 127.5,
(R)-6-(3-Methoxypropyl)-6-methylcyclohex-1-en-1-yl Trifluoro-
methanesulfonate (10). To a stirred solution of ketone (9) (240
mg, 1.30 mmol) in 6 mL of THF was added LiHMDS (350 mg, 2.10
mmol) in 6 mL of THF at −84 °C. After 30 min, N,N-
bis(trifluoromethylsulfonyl)-5-chloro-2-pyridylamine (561 mg, 1.43
mmol) was added in 9 mL of THF. The reaction mixture was brought
to room temperature and left overnight. The next day, the reaction was
87.8, 83.9, 61.9, 61.8, 56.4, 47.9, 37.8, 33.8, 29.0, 28.2, 26.3, 23.7, 19.0.
IR (cm−1, neat): 3421, 2961, 2930, 2929, 2866, 2829, 1451, 1360,
1075, 1030, 703. HRMS (EI+) calcd for [C22H29NO − CH3O]+ m/z
292.2065, found: 292.2075.
(S)-7-Nitro-2-(1-phenylprop-2-yn-1-yl)-1,2,3,4-tetrahydro-
isoquinoline (4e). Cu(OTf)·(benzene)0.5 (2 mg, 0.008 mmol) and R-
(+)-Cl-MeO-BIPHEP (11 mg, 0.016 mmol) were dissolved in 3 mL of
10280
dx.doi.org/10.1021/jo501905q | J. Org. Chem. 2014, 79, 10269−10283

The Journal of Organic Chemistry
Article
1
anhydrous methanol under an argon atmosphere, and the mixture was
stirred for 1 h at 60 °C. The temperature was lowered to 0−5 °C (ice
bath), and a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline (61 mg,
0.34 mmol), DIPEA (88 mg, 0.68 mmol), and 1-phenylprop-2-yn-1-yl
acetate (30 mg, 0.17 mmol) in 3 mL of anhydrous methanol was
added to the mixture. The mixture was stirred overnight, after which
the solution was filtered and washed with MeOH. The filtrate was
removed under reduced pressure. Purification of the crude by column
chromatography (SiO2) using n-hexane and ethyl acetate as eluent
(10:1) afforded 37 mg (0.126 mmol, 74%) of the desired product. 1H
NMR (300 MHz, CDCl3) δ 7.95 (dd, J = 8.4, 2.4 Hz, 1H), 7.87 (d, J =
2.2 Hz, 1H), 7.66−7.60 (m, 2H), 7.42−7.30 (m, 3H), 7.22 (d, J = 8.4
Hz, 1H), 4.88 (d, J = 2.2 Hz, 1H), 3.82 3.78 (ABq, J = 15.4 Hz, 2H),
3.06−2.77 (m, 4H), 2.61 (d, J = 2.3 Hz, 1H). 13C NMR (75 MHz,
CDCl3) δ 146.2, 142.6, 137.2, 136.9, 129.7, 128.5, 128.4, 128.2, 122.0,
121.1, 78.7, 77.2, 76.6, 60.8, 51.7, 46.5, 30.0. IR (cm−1, neat): 3290,
1592, 1346, 1101, 752, 697. HRMS (EI+) calcd for [C18H16N2O2]+ m/
z 292.1212, found: 292.1211.
mmol, 74%) of the desired product. H NMR (500 MHz, CD3CN) δ
7.63 (d, J = 7.6 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.3 Hz,
1H), 6.91 (d, J = 8.4 Hz, 1H), 6.56 (dd, J = 8.4, 2.5 Hz, 1H), 6.37 (d, J
= 2.3 Hz, 1H), 6.08 (t, J = 4.1 Hz, 1H), 4.95 (s, 1H), 3.70 3.62 (ABq, J
= 14.7 Hz, 2H), 2.81 (s, 6H), 2.77−2.65 (m, 4H), 2.08−2.01 (m, 2H),
1.65−1.59 (m, 2H), 1.54−1.49 (m, 2H), 1.16 (s, 6H). 13C NMR (126
MHz, CD3CN) δ 150.3, 140.4, 136.7, 135.5, 131.1, 130.1, 129.4, 129.3,
128.6, 123.6, 118.3, 112.7, 111.7, 89.3, 85.1, 62.4, 53.6, 49.0, 41.2, 38.5,
34.5, 29.5, 29.5, 27.0, 19.7. IR (cm−1, neat): 2963, 2928, 2851, 1617,
1515, 1338, 796, 749, 698. HRMS (EI+) calcd for [C28H34N2]+ m/z
398.2722, found: 398.2723.
tert-Butyl 7-(Dimethylamino)-3,4-dihydroisoquinoline-2(1H)-
carboxylate (11). tert-Butyl 7-nitro-3,4-dihydroisoquinoline-2(1H)-
carboxylate (140 mg) and 5% Pd/C (14.8 mg) in 5 mL of MeOH
were stirred at room temperature under a balloon of H2. After 2 h,
formalin (1 mL) and 0.1 mL of 3 N HCl was added to the mixture and
the stirring was continued for 2 h. The reaction was quenched with
saturated NaHCO3 and filtered through a pad of Celite, which was
washed with acetone. After evaporation of organic solvents, water was
added to the residue. The water phase was extracted with 3 × 20 mL
of DCM, and the organic phase was washed with brine. After drying
the organic phase over Na2SO4, the solvent was evaporated.
Purification of the crude by column chromatography (SiO2) using n-
hexane and ethyl acetate as eluent (3:1) afforded 82.9 mg (0.3 mmol,
60%) of the desired product. 1H NMR (500 MHz, CDCl3) δ 7.02 (d, J
= 8.4 Hz, 1H), 6.63 (d, J = 7.2 Hz, 1H), 6.48 (s, 1H), 4.55 (s, 2H),
3.64 (s, 2H), 2.92 (s, 6H), 2.77 (d, J = 18.5 Hz, 2H), 1.51 (s, 9H). 13C
NMR (75 MHz, CDCl3) δ 155.0, 149.5, 129.3, 123.1, 111.8, 110.2,
79.6, 40.9, 28.6, 28.0. IR (cm−1, neat): 2974, 2800, 1689, 1617, 1513,
1414, 1363, 1290, 1237, 1163, 1120, 730. HRMS (EI+) calcd for
[C16H24N2O2]+ m/z 276.1838, found: 276.1840.
(R)-2-(3-(6,6-Dimethylcyclohex-1-en-1-yl)-1-phenylprop-2-yn-1-
yl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (1l). (PPh3)PdCl2 (5.3 mg,
0.0075 mmol) and CuI (3,2 mg, 0.017 mmol) were dissolved in 6 mL
of degassed THF:DEA (1:1). After 5 min, 6,6-dimethylcyclohex-1-en-
1-yl trifluoromethanesulfonate (78 mg, 0.275 mmol) in 3 mL of THF
was added to the mixture, followed by (after 5 min stirring) 4e (61 mg,
0.25 mmol) dissolved in 3 mL of THF. After stirring overnight at 40
°C, the solvent was evaporated. Purification of the crude by column
chromatography (SiO2) using n-hexane and ethyl acetate as eluent
1
(20:1) afforded 64 mg (0.16 mmol, 64%) of the desired product. H
NMR (300 MHz, CDCl3) δ 7.95 (dd, J = 8.4, 2.4 Hz, 1H), 7.88 (d, J =
2.2 Hz, 1H), 7.74−7.55 (m, 2H), 7.42−7.27 (m, 3H), 7.23 (d, J = 8.4
Hz, 1H), 6.12 (t, J = 4.1 Hz, 1H), 5.02 (s, 1H), 3.85 3.80 (ABq, J =
15.4 Hz, 2H), 3.06−2.75 (m, 4H), 2.18−2.00 (m, 2H), 1.73−1.42 (m,
4H), 1.17 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 146.1, 142.7,
138.4, 137.2, 134.9, 130.0, 129.7, 128.5, 128.4, 127.9, 122.1, 121.1,
89.0, 82.9, 61.5, 52.0, 46.8, 37.7, 33.8, 30.1, 29.06, 29.05, 26.3, 19.0. IR
(cm−1, neat): 2959, 2928, 2851, 1523, 1346, 1100, 750, 712, 696.
HRMS (EI+) calcd for [C26H28N2O2]+ m/z 400.2151, found:
400.2154.
N,N-Dimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine (12). 11
(150 mg, 0.54 mmol) was stirred in 6 mL of TFA:DCM overnight.
The next day, solvents were evaporated and 20 mL of 2 N NaOH was
added to the residue, which was extracted with 3 × 20 mL of Et2O and
washed with brine. After drying the organic phase with Na2SO4, the
solvent was evaporated. Purification of the crude by column
chromatography (SiO2) using DCM and MeOH as eluent (1:1 →
1:3 → 0:1) afforded 97.7 mg (0.55 mmol, >99%) of the desired
product. 1H NMR (300 MHz, CDCl3) δ 6.95 (d, J = 8.4 Hz, 1H), 6.60
(dd, J = 8.4, 2.7 Hz, 1H), 6.38 (d, J = 2.7 Hz, 1H), 3.96 (s, 2H), 3.10
(t, J = 6.0 Hz, 2H), 2.88 (s, 6H), 2.68 (t, J = 6.0 Hz, 2H), 2.22 (s, 1H).
13C NMR (75 MHz, CDCl3) δ 149.2, 136.3, 129.9, 123.1, 111.8, 110.3,
(S)-N,N-Dimethyl-2-(1-phenylprop-2-yn-1-yl)-1,2,3,4-tetrahydro-
isoquinolin-7-amine (4f). Cu(OTf)·(benzene)0.5 (6.9 mg, 0.0275
mmol) and R-(+)-Cl-MeO-BIPHEP (35.8 mg, 0.055 mmol) were
dissolved in 5 mL of anhydrous methanol under an argon atmosphere
and stirred for 1 h at 60 °C. The temperature was lowered to 0−5 °C
(ice bath), and a solution of 7-dimethylamino-1,2,3,4-tetrahydro-
isoquinoline (98 mg, 0.55 mmol), DIPEA (284 mg, 2.22 mmol), and
1-phenylprop-2-yn-1-yl acetate (96 mg, 0.55 mmol) in 5 mL of
anhydrous methanol was added to the mixture. The mixture was
stirred overnight, after which the solution was filtered and washed with
MeOH. The filtrate was removed under reduced pressure. Purification
of the crude by column chromatography (SiO2) using n-hexane and
ethyl acetate as eluent (20:1) afforded 84.7 mg (0.292 mmol, 53%) of
48.7, 44.3, 41.0, 28.2. IR (cm−1, neat): 2924, 2798, 1676, 1513, 1345,
801. HRMS (EI+) calcd for [C11H16N2]+ m/z 176.1313, found:
176.1310.
Computational Methods. All computations at the DFT level
were performed using the Turbomole 6.4 program package.57
Solvation effects were taken into account using the COSMO solvation
model in all DFT computations with a dielectric constant of 1,1,2,2-
tetrachloroethane (ε = 8.42) unless otherwise noted.58 The TPSS-
D337,38 functional was chosen with the triple ζ quality basis set, def2-
TZVP.39 Grid m4 was used in all computations. The MARI-J
approximation was used in all computations with a suitable auxiliary
basis set.59−62 The scalar relativistic effects for gold were taken into
account using the def2-ecp from the Stuttgart group.63 Vibrational
frequencies were calculated numerically for all complexes to obtain the
chemical potential at 298.15 K (chem. pot.) and to confirm the nature
of the stationary point (minima or TS). The Gibbs free energies were
then calculated: G = E(0) + chem. pot. All multireference calculations
(CASSCF and NEVPT2) were performed using the ORCA 2.9.1
program package.64
The enantioselectivity determining cyclization step was also
computed using various different DFT methods, namely, PBE-D3,65
PBE0-D3,65,66 TPSSh-D3,37,67 B3LYP-D3,68−70 and a double-hybrid
functional B2PLYP-D3.71 The D3 empirical dispersion corrections
were used with zero damping. Pictures were generated with
CYLview,72 Gabedit,73 and VMD.74 Density differences were
calculated using DGrid.75
1
the desired product. H NMR (300 MHz, CDCl3) δ 7.74−7.66 (m,
2H), 7.44−7.29 (m, 3H), 7.00 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 8.4,
2.7 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 4.87 (d, J = 2.0 Hz, 1H), 3.76
3.73 (ABq, J = 14.7 Hz, 2H), 2.89 (s, 6H), 2.83 (d, J = 5.8 Hz, 4H),
2.61−2.58 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 149.2, 138.1,
135.7, 129.3, 128.4, 128.3, 127.8, 123.0, 112.0, 111.0, 79.5, 76.1, 61.1,
52.4, 47.8, 41.1, 28.8. IR (cm−1, neat): 3285, 2912, 2798, 1616, 1514,
1339, 1088, 721, 698, 649. HRMS (EI+) calcd for [C20H22N2]+ m/z
290.1783, found: 290.1780.
(R)-2-(3-(6,6-Dimethylcyclohex-1-en-1-yl)-1-phenylprop-2-yn-1-
yl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine (1m).
(PPh3)PdCl2 (10 mg, 0.00145 mmol) and CuI (3.2 mg, 0.017
mmol) were dissolved in 10 mL of degassed THF:DEA (1:1). After 5
min, 6,6-dimethylcyclohex-1-en-1-yl trifluoromethanesulfonate (83
mg, 0.29 mmol) in 5 mL of THF was added to the mixture, followed
by (after 5 min stirring) 4f (75 mg, 0.25 mmol) dissolved in 5 mL of
THF. After stirring overnight at 40 °C, the solvent was evaporated.
Purification of the crude by column chromatography (SiO2) using n-
hexane and ethyl acetate as eluent (10:1) afforded 86 mg (0.215
10281
dx.doi.org/10.1021/jo501905q | J. Org. Chem. 2014, 79, 10269−10283

The Journal of Organic Chemistry
Article
(26) Hattori, G.; Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. Angew.
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(27) Lo, V. K.-Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2008, 10, 517.
(28) Lo, V. K.-Y.; Zhou, C.-Y.; Wong, M.-K.; Che, C.-M. Chem.
Commun. 2010, 46, 213.
ASSOCIATED CONTENT
* Supporting Information
NMR spectra, HPLC chromatograms, computational data, and
xyz parameters. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(29) Deutsch, C.; Gockel, B.; Hoffmann-Roder, A.; Krause, N. Synlett
̈
2007, 2007, 1790.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: juho.helaja@helsinki.fi (J.H.).
*E-mail: michaelp@chem.helsinki.fi (M.P.).
(30) Nishina, N.; Yamamoto, Y. Tetrahedron Lett. 2008, 49, 4908.
(31) Nishina, N.; Yamamoto, Y. Tetrahedron 2009, 65, 1799.
(32) Zhang, Z.; Widenhoefer, R. A. Org. Lett. 2008, 10, 2079.
(33) Kung, K. K.-Y.; Lo, V. K.-Y.; Ko, H.-M.; Li, G.-L.; Chan, P.-Y.;
Leung, K.-C.; Zhou, Z.; Wang, M.-Z.; Che, C.-M.; Wong, M.-K. Adv.
Synth. Catal. 2013, 355, 2055.
(34) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
(35) Wang, Z. J.; Benitez, D.; Tkatchouk, E.; Goddard, W. A., III;
Toste, F. D. J. Am. Chem. Soc. 2010, 132, 13064.
(36) Muuronen, M.; Wirtanen, T.; Patzschke, M.; Helaja, J.
Unpublished data; a manuscipt in preparation.
(37) Tao, J.; Perdew, J. P.; Staroverov, V. N.; Scuseria, G. E. Phys.
Rev. Lett. 2003, 91, 146401.
(38) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys.
2010, 132, 154104.
(39) Weigend, F.; Ahlrichs, R. Phys. Chem. Chem. Phys. 2005, 7, 3297.
(40) Nava, P.; Hagebaum-Reignier, D.; Humbel, S. ChemPhysChem
2012, 13, 2090.
■
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Academy of Finland [J.H. No.
258348]. T.W. is grateful to Finnish Cultural and Magnus
Ehrnrooth Foundations for funding. M.M. expresses gratitude
to the Emil Aaltonen foundation for funding. M.P. wishes to
acknowledge support by the Academy of Finland through its
Computational Science Research Programme (LASTU/
258258).
(41) Muuronen, M.; Perea-Buceta, J. E.; Nieger, M.; Patzschke, M.;
Helaja, J. Organometallics 2012, 31, 4320.
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