Synthesis and application of β-substituted Pauson-Khand adducts: Trifluoromethyl as a removable steering group

Article abstract of DOI:10.1002/anie.201300907

Against the rules: The synthesis of the previously unknown β-substituted regioisomers of the intermolecular Pauson-Khand reaction of terminal alkynes is reported. This regiochemistry was achieved by using the trifluoromethyl group as a removable directing group on the alkyne. Copyright

Full text of DOI:10.1002/anie.201300907

Angewandte
Chemie
DOI: 10.1002/anie.201300907
Synthetic Methods
Synthesis and Application of b-Substituted Pauson–Khand Adducts:
Trifluoromethyl as a Removable Steering Group**
Nuria Aiguabella, Carlos del Pozo, Xavier Verdaguer, Santos Fustero, and Antoni Riera*
The Pauson–Khand reaction (PKR) is a well-established
methodology for the construction of cyclic and polycyclic
structures containing five-membered rings.[1,2] Since its dis-
covery in 1973 this reaction has been widely used in organic
synthesis. The intramolecular PKR has been extensively
applied to build polycyclic compounds. In this case, both the
stereo- and regioselectivity are controlled by the substrate.
The intermolecular version of the reaction has been less
exploited because of its smaller range of reactive alkenes,[3]
although it has the advantage that in many cases the
Scheme 1. General trends of the regioselectivity of intermolecular PKR.
stereochemistry can be controlled by the presence of either
chiral auxiliaries[4] (bound to the alkyne or the alkene) or
chiral ligands[5] (bound to the intermediate cobalt complex).
However, one of the difficulties encountered with the
intermolecular PKR is the control of the regiochemical
outcome.[6–10] While this control is achieved when dealing with
terminal alkynes (in this case only the a-substituted cyclo-
pentenone I is formed[8]), with internal nonsymmetric alkynes
the regiochemistry of the PK adducts depends on a combina-
tion of steric and electronic effects, which are difficult to
predict (Scheme 1).[7–10] In the absence of steric effects,
electron-donating groups (EDGs) show preference for the
a-position, whereas electron-withdrawing groups (EWGs)
tend to displace to the b-position.[9] However, recent studies
have shown that the electronic effects are much less
significant than previously described and can, therefore, be
overcome by the steric effects.[10]
impact on the regioselectivity.[11] Unexpectedly, these frag-
ments ended up in the a-position of the PK adduct. To
ascertain whether this was a purely steric effect, herein we
studied the regioselectivity of the PKR of a family of
trifluoromethylacetylenes. In all cases the regioselectivity
was complete, being the PK adduct with the trifluoromethyl
in a-position the only one observed. The subsequent study of
the reactivity of these adducts allowed us to find an efficient
procedure to remove the trifluoromethyl group. Therefore we
uncovered a new procedure, outlined in Scheme 2, to prepare
In previous studies of the intermolecular PKR of non-
symmetric fluorinated alkynes we observed that the electron-
withdrawing effect of the fluorinated substituents had little
[*] N. Aiguabella, Prof. X. Verdaguer, Prof. A. Riera
Institute for Research in Biomedicine (IRB Barcelona)
Baldiri i Reixac, 10, 08028 Barcelona (Spain)
E-mail: antoni.riera@irbbarcelona.org
Scheme 2. Standard intermolecular PKR for internal alkynes affording
adducts I and the sequence for the synthesis of the regioisomers II
described here. The trifluoromethylation Cu reagent CF3-Cu(Phen) was
prepared as described in the Experimental Section.
Prof. X. Verdaguer, Prof. A. Riera
Dept. de Quꢀmica Orgꢁnica, Universitat de Barcelona
Martꢀ i Franquꢂs, 1, 08028 Barcelona (Spain)
the previously unknown b-substituted PK adducts II. Here we
describe the first synthesis of the regioisomeric PK adducts of
terminal alkynes II and their practical application to the
formal synthesis of a-cuparenone.
We chose p-methoxyphenylacetylene 1a as a model
substrate to explore our synthetic proposal, since the elec-
tron-donating nature of the p-methoxyphenyl group and its
medium size should favor to end up at the a-position. The
trifluoromethylated alkyne was synthesized from 1a by
following the procedure described by F.-L. Qing and co-
workers.[12] This alkyne was difficult to purify, because of its
volatility and highly lipophilic character. These features
Dr. C. del Pozo, Prof. S. Fustero
Dept. de Quꢀmica Orgꢃnica, Universidad de Valencia
46100 Burjassot (Spain)
and
Laboratorio de Molꢂculas Orgꢃnicas, Centro de Investigaciꢄn
Prꢀncipe Felipe
46012 Valencia (Spain)
[**] We thank the Spanish Ministerio de Economia y Competitividad
(CTQ2011-23620), the Generalitat de Catalunya (2009SGR 00901),
and IRB Barcelona for financial support. N.A. thanks the MICINN
for a fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300907.
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hindered the chromatographic separation of the desired
product from the homocoupling byproducts. To overcome
these problems, we proceeded to treat the crude reaction
mixture of the alkyne in hexanes with [Co2(CO)8]. The
resulting dicobalt hexacarbonyl complex 2a was purified by
chromatography without further problems (Scheme 3). The
pure complex 2a was subjected to the thermal PKR (toluene,
of 3a could be thus determined[14] (Scheme 4), and conse-
quently the regiochemistry of the previous PKR was con-
firmed.
The remaining PK adducts were treated under the same
conditions yielding products 4b–k in satisfactory yields
(Table 2) except for adduct 3j. In this case, although the
final product was detected by NMR spectroscopy, it could not
be purified from the reaction by-products.
1
708C) with norbornadiene. Both H and 19F NMR spectra of
Although the mechanism of this novel reaction is
unknown, we hypothesized that the removal of the CF3
group could take place after a Michael addition of nitro-
methane, which would afterwards be removed. Adduct 3c was
selected to perform experiments to shed light on the
mechanism. As expected, treatment of 3c with DBU/nitro-
methane/H2O afforded cyclopentenone 4c in good yield. The
essential role of nitromethane was readily confirmed, since
the reaction did not take place in toluene or in dioxane. In
a mixture of toluene/nitromethane, the reaction occurred at
a lower rate and yield. Small amounts of water also play an
essential role in the reaction. Its complete removal by using
dry nitromethane led to a dramatic decrease of the con-
version, which did not reach completion even after 18 h.
Addition of 5 equivalents of water to dry nitromethane gave
the same reaction yield as using nitromethane directly
without purification. Other nucleophiles such as 1,4-
diazabicyclo[2.2.2]octane (DABCO) or cyanide in acetoni-
trile (without nitromethane) were successful only in the latter
case, but with a lower conversion or yield. The base was
substituted by tetrabutylammonium fluoride (TBAF) and the
same dependence of nitrometane/water was observed (a
summary of these experiments is shown in the Supporting
Information). These experiments are consistent with the
observation that the loss of fluoride occurred after the
Michael addition of nitromethane to the enone. Since a loss
of fluoride in a-trifluoromethyl ketones had been reported by
Mikami and Itoh,[15] and also took place in a related
compound reported by our group,[11] we propose a plausible
mechanism for this reaction (Scheme 5). After conjugate
addition of nitromethane, elimination of fluoride would give
a difluoroenone 5, which, after conjugate addition of water
followed by a retro-aldol reaction would afford an inter-
mediate enol 6. Retro-Michael reaction of nitromethane on
this substrate would yield the observed product 4. None of the
proposed intermediates (5, 6) were detectable by NMR
Scheme 3. Synthesis and PKR of trifluoromethyl acetylene 2a.
the reaction crude showed only one PK adduct, which was
isolated in 81% yield.[13] The NMR spectra led us to assign the
product to the a-trifluoromethylated PK adduct 3a. The
regiochemical outcome, which was the opposite of the
standard selectivity on the basis of electronic criteria, led us
to propose that the electronic effect of the trifluoromethyl
substituent is much weaker than expected, so the reaction
outcome is determined by steric effects.
To check the scope of our approach, we tested a series of
terminal alkynes 1b–k (Table 1). The substitution pattern
included aliphatic, olefinic, and aromatic groups with a large
range of substituents with distinct electronic properties. The
trifluoromethyl group was introduced to these alkynes by
following Qingꢀs procedure[12] with minor modifications (see
the Supporting Information). The reaction crude products of
the trifluoromethylated alkynes were complexed with
[Co2(CO)8] and purified by silica gel chromatography to
afford complexes 2b–k in good to excellent yield. The
corresponding PKR of these complexes with norbornadiene
proceeded smoothly by heating the toluene solution at 708C.
In all cases, a single regioisomer was obtained in good to
excellent yield.
We next tackled the removal of the trifluoromethyl group.
After some experimentation we found that treatment of PK
adduct 3a with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
nitromethane with a small amount of water afforded enone 4a
in good yield (Scheme 4). Although the yield was not
quantitative, the reaction was clean, and cyclopentenone 4a
was easily purified. Crystals suitable for X-ray diffraction
were obtained from dichloromethane/hexanes. The structure
Scheme 4. Removal of the CF3 group from the PKR adduct 3a and
ORTEP drawing of cyclopentenone 4a with the thermal ellipsoids set
at 50% probability.
Scheme 5. Postulated mechanism for the CF3 elimination.
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Table 1: Synthesis and PKR of trifluoromethylated alkynes 2b–k.
spectroscopy. Attempts to trap enol 6 with an
electrophile were unsuccessful.
To demonstrate the synthetic potential of these
newly available compounds, a formal synthesis of a-
cuparenone was envisaged. a-Cuparenone is a bicy-
clic sesquiterpene that belongs to the cuparene
family. It was isolated from Thuja orientalis, an
evergreen coniferous tree endemic to Asia, by Dev
and Chetty in 1964.[16] Its synthesis has been tackled
using various approaches.[17] The final steps of
several of them involve the alkylation and reduction
of the key intermediate 7.[18] We set about to obtain
this intermediate by a retro-Diels–Alder reaction of
8, which in turn would be prepared by methyl
conjugate addition on the corresponding regioiso-
meric PK adduct 4c (Scheme 6).
The methyl conjugate addition to enone 4c
required some experimentation. Lithium dimethyl-
cuprate afforded only the 1,2-addition product.[19]
The conjugate addition of dialkyl zinc species
catalyzed by nickel(II)[20] to 4c was also fruitless.
Finally, the nickel-catalyzed addition of trimethyl-
aluminium[21] yielded the desired 1,4-addition prod-
uct 8 as a single diastereomer in a satisfactory 67%
yield (Scheme 7). The final step, the retro-Diels–
Alder reaction, was carried out under microwave
conditions and yielded key intermediate 7 in high
yield and purity. The spectroscopic data coincided
with those reported.[18c]
In conclusion, under thermal conditions, the
PKR of norbornadiene with internal trifluoromethyl
alkynes provided the PK adducts with complete
regioselectivity in good to excellent yields. A wide
variety (11 examples) of internal trifluoromethyl
alkynes including aromatic, aliphatic, and olefinic
substituents was tested, affording in all cases the
regioisomer bearing the CF3 group attached to the a-
position. Treatment of these PK adducts with DBU
in nitromethane/water resulted in the loss of the CF3
group, thereby providing the b-substituted cyclo-
pentenones that correspond to the regioisomers of
the normal PKR of terminal alkynes. The unprece-
dented reaction for removal of the trifluoromethyl
group proved to be general (10 examples), and
a reasonable mechanism has been proposed. The
overall process constitutes the first example of
a PKR with terminal alkynes with inverse regio-
chemistry. This methodology was successfully
applied to the formal synthesis of a-cuparenone.
Entry Alkyne
Complex 2
Yield 2 PK adduct 3 Yield 3
[%]
[%]
1
55
77
2
3
91
70
95
74
4
5
6
69
44
62
99
70
81
7
70
80
8
9
87
60
79
77
Experimental Section
General preparation of cobalt complexes 2: To a Schlenk
flask, Ag2CO3 (1 mmol, 2 equiv), phenantroline (1 mmol,
2 equiv), CuCl (1 mmol, 2 equiv), tBuOK (1 mmol,
2 equiv), and anhydrous DMF (10 mL) were added under
nitrogen. The red-brown solution was stirred at room
temperature for 30 min. Trifluoromethyltrimethylsilane
(TMSCF3; 2.5 mmol, 5 equiv) was added, and the reaction
heated one hour at 408C. A solution of the terminal alkyne
10
70
70
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General preparation of cylopentenones 4: To a solution of 3
(0.11 mmol, 1 equiv) in nitromethane (7 mL), water (0.01 mL,
0.55 mmol, 5 equiv) and DBU (0.11 mmol, 1 equiv) were added
under nitrogen. The mixture was heated to reflux and the reaction
monitored by TLC. When finished (approximately 1.5 h), the solvent
was removed under vacuum and the crude was purified by chroma-
tography (SiO2/hexanes/AcOEt) to afford cyclopentenones 4.
Table 2: Removal of the trifluoromethyl group from PK adducts 3.
Entry
PK
R
Product
Yield
[%]
adduct
Received: February 1, 2013
Published online: April 10, 2013
1
2
3
4
5
6
7
8
9
3b
3c
3d
3e
3 f
3g
3h
3i
phenyl
tolyl
4b
4c
4d
4e
4 f
4g
4h
4i
55
64
51
68
57
59
58
61
n.d.
40
2-methoxyphenyl
4-pentylphenyl
4-(trifluoromethyl)phenyl
4-fluorophenyl
6-methoxynaphtalene-2-yl
undecyl
Keywords: directing group · Pauson–Khand reaction ·
.
regioselectivity · synthetic methods · trifluoromethyl alkynes
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Scheme 7. Synthesis of key intermediate 7. MW=microwave,
acac=acetylacetonate.
1 (0.5 mmol, 1 equiv) in DMF (3 mL) was slowly added to the mixture
with a syringe pump (addition rate: 0.5 mLhÀ1). The reaction was
stirred overnight and quenched by addition of water and hexanes.
While stirring vigorously in open air, a solution of NH3/NH4Cl (1:3)
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organic layer was washed with water, dried (MgSO4), and filtered. To
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monitored by TLC. When finished (approximately 24 h), the solvent
was removed under reduced pressure and the crude purified by
chromatography (SiO2, hexanes/AcOEt) to afford trifluoromethylcy-
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