Calcium(II)- And Triflimide-Catalyzed Intramolecular Hydroacyloxylation of Unactivated Alkenes in Hexafluoroisopropanol

Article abstract of DOI:10.1021/acs.orglett.9b02705

We report an efficient intramolecular hydroacyloxylation of unactivated alkenes, offering a streamlined access to relevant γ-lactones, which features the utilization of either a calcium(II) salt or triflimide as a catalyst in hexafluoroisopropanol. This method could be applied to the synthesis of natural products and the late-stage functionalization of natural and bioactive molecules. Additionally, DFT computations were used to elucidate the twist of reactivity observed between the hydroamidation and hydroacyloxylation of unactivated alkenes regarding the formation of 5- and 6-membered rings.

Full text of DOI:10.1021/acs.orglett.9b02705

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Calcium(II)- and Triflimide-Catalyzed Intramolecular
Hydroacyloxylation of Unactivated Alkenes in
Hexafluoroisopropanol
Chenxiao Qi,† Shengwen Yang,†,‡ Vincent Gandon,*,†,‡ and David Lebœuf*,†
†
́
́
́
́
Institut de Chimie Moleculaire et des Materiaux d’Orsay (ICMMO), CNRS UMR 8182, Universite Paris-Sud, Universite
̂
Paris-Saclay, Batiment 420, Orsay 91405 Cedex, France
‡
́
Laboratoire de Chimie Moleculaire (LCM), CNRS UMR 9168, Ecole Polytechnique, Institut Polytechnique de Paris, route de
Saclay, Palaiseau 91128 Cedex, France
S
* Supporting Information
ABSTRACT: We report an efficient intramolecular hydro-
acyloxylation of unactivated alkenes, offering a streamlined
access to relevant γ-lactones, which features the utilization of
either a calcium(II) salt or triflimide as a catalyst in
hexafluoroisopropanol. This method could be applied to the
synthesis of natural products and the late-stage functionalization
of natural and bioactive molecules. Additionally, DFT
computations were used to elucidate the twist of reactivity observed between the hydroamidation and hydroacyloxylation of
unactivated alkenes regarding the formation of 5- and 6-membered rings.
ntramolecular hydroacyloxylation of unactivated alkenes
represents in theory one of the most efficient and atom-
to expand the reactivity of unactivated alkenes, this reaction
piqued our attention. In previous studies, we have demonstrated
that the association of a catalytic amount of calcium(II) salts5
with hexafluoroisopropanol (HFIP)6,7 was a powerful synthetic
tool regarding the hydroamidation of unactivated alkenes8 and
the hydroarylation of highly deactivated styrenes.9 In these
reactions, the role of calcium is not to act as a traditional Lewis
acid that will activate either the nucleophile or the olefin but,
instead, to strengthen the acidity of H-bond clusters of HFIP
and trigger the hydrofunctionalization process.10 Moreover,
what makes this strategy enticing is the remarkable hydrogen-
donor ability of HFIP, which prevents an unwanted coordina-
tion between the substrate and the catalyst by substituting itself
to the catalyst. As a result, it usually enables an extended reaction
scope with respect to prior reports.8,9 In this context, we believed
that our approach could open a new door to rapidly forge γ-
lactones while being compatible with a large variety of
precursors. In addition, by means of DFT computations, we
tried to shed some light on the difference of selectivity observed
between hydroacyloxylation and hydroamidation processes, a
common trend often overlooked in the hydrofunctionalization
of alkenes.
I
economical processes to provide γ-lactones, notably γ-
butyrolactones. Taking into account the wide range of
applications exhibited by these motifs, whether as agro-
chemicals, drugs, fragrances, or food additives,1 tremendous
endeavors have been dedicated to the development of new and
effective protocols for the synthesis of these derivatives,2 bearing
in mind that they have to be compatible with a large array of
functional groups to be truly meaningful. Yet, to date, most of
the methods reported, which feature transition metals or Lewis
or Brønsted acids as catalysts, suffer from a lack of versatility and
flexibility in terms of reactivity (Scheme 1).3 In addition, in
comparison with the hydroamination and hydroalkoxylation of
unactivated alkenes,4 only a few catalytic systems have been
described. Although the reason behind remains unclear, one
could argue that an unwanted coordination between the catalyst
and the carboxylic acid might come into play, which makes this
reaction still highly challenging. As part of our continuing efforts
Scheme 1. Hydroacyloxylation of Unactivated Alkenes
As a first step, we conducted the hydroacyloxylation of 4-
pentenoic acid 1a (Table 1) using our standard conditions,
Ca(NTf2)2/nBu4NPF6 (5 mol %) in HFIP (0.2 M) at 80 °C,
which proved to be highly effective in the hydroamidation of
unactivated alkenes.8 These conditions led to γ-valerolactone 2a
in 92% yield within 2 h (entry 1). Other common solvents were
Received: August 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02705
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Organic Letters
Letter
Table 1. Reaction Optimization for the Formation of γ-
a
Butyrolactone 2a
time conversion 2a (%)
entry
catalyst
additive
solvent
(h)
(yield, %)
1
2
3
4
5
6
7
8
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
HNTf2
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
HFIP
2
5
5
5
1
2
2
2
2
6
100 (92)
40 (33)
NR (−)
100 (79)
100 (63)
<10
NR
NR
<10
100 (91)
1,2-DCE
toluene
MeNO2
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
Ca(NTf2)2
nBu4NPF6
9
b
Ca(OTf)2
Ca(NTf2)2
nBu4NPF6
nBu4NPF6
a
Reaction conditions: 4-pentenoic acid 1a (0.3 mmol) in HFIP (0.2
M) in the presence of catalyst (5 mol %) with or without nBu4NPF6
b
(5 mol %) at 80 °C for the indicated time. 4-Pentenoic acid 1a (6
mmol).
also screened (entries 2−4) but they were far less efficient than
HFIP, with the exception of nitromethane (entry 4). The
reaction could be also carried out in the presence of triflimide11
(entry 5) as a catalyst, but with a lower yield (63%).
Additionally, control experiments were conducted to confirm
the importance of each parameter for the transformation
(catalyst, ligand, and additive) (entries 6−9). More importantly,
the reaction, albeit slower, could be conducted on a larger scale
(6 mmol) without any drop in yield (entry 10).
With optimal conditions in hand, we started to explore the
scope of the reaction toward the preparation of various γ-
lactones (Figure 1). Our standard reaction conditions were
applied to a large variety of substrates and provided access to the
targeted γ-butyrolactones and δ-valerolactones in good to
excellent yields (up to 98%). During the course of our
investigations, we were able to make several observations.
First, the reaction was tolerant to the presence of substituents at
the positions C2 and C3 of the 4-pentenoic derivatives to furnish
the corresponding γ-butyrolactones in good yields (2c−2e).
However, in these examples, it remains challenging to control
the diastereoselectivity, which is unfortunately not uncommon
with such processes.3 Polycyclic structures could be also easily
accessed (2f and 2g, in 94% and 60% yields, respectively), and
the creation of quaternary centers was not an issue either (2h).
Moreover, the reaction was not limited to terminal alkenes but
was also compatible with the presence of aryl and alkyl
substituents (2i−2l). For instance, peach-flavored γ-decalactone
2l was afforded in 82% yield. However, in the case of a longer
carbon chain (2k and 2l), the reaction required a prolonged
heating at 100 °C to reach the full conversion, which might
result from unfavorable steric repulsion during the cyclization.
Interestingly, our reaction conditions were also applicable to
more complex natural products such as mycophenolic acid and
ursolic acid (2m and 2n, in 74% and 75% yields, respectively),
with even the presence of a free alcohol in the latter case,
increasing the synthetic value of this method. In addition, the
reaction could be performed in the presence of a second alkene
functionality, delivering α-methylene-γ-butyrolactone 3o in 82%
yield, which is even more interesting with respect to the
importance of these motifs in medicinal chemistry.2a To further
Figure 1. Scope of intramolecular hydroacyloxylation of unactivated
alkenes. (a) In the presence of Ca(NTf2)2 (10 mol %) and nBu4NPF6
(10 mol %). (b) In HFIP/CH2Cl2 (3:1).
illustrate the utility of this method, substrate 1p was successfully
converted into the corresponding cognac lactones (coconut
flavor)12 2p in a 63% combined yield.13
We then turned our attention to the preparation of 6-
membered rings. In these cases, the gem-disubstituent effect is
not negligible. In its absence, a mixture of δ-valerolactone and γ-
butyrolactone products was obtained (3r/2r and 3t/2t), even if
the δ-valerolactone adduct was still largely predominant. On the
other hand, in its presence, the δ-valerolactones were obtained as
sole products (3s and 3q). Finally, the reaction proceeded
B
DOI: 10.1021/acs.orglett.9b02705
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Organic Letters
Letter
particularly well to generate isochromanone derivatives such as
3v in 94% yield. Our promoter system was, however, fraught
with some limitations in terms of reactivity. Indeed, in the
presence of strong electron-withdrawing groups at the α-
position of the carboxylic acid (1w−1z), no reaction occurred
with the combination Ca(NTf2)2/nBu4NPF6. A plausible
explanation is the formation of a strong H-bonding between
the hydroxyl group of the carboxylic acid and the electron-
withdrawing group, which might prevent the hydroacyloxylation
as the carboxylic acid is no more available for the transformation.
However, this issue could be addressed by conducting the
reaction in the presence of triflimide that could disrupt this H-
bonding by protonation, so that the expected products were
delivered in good to excellent yields (65−95%). In this way, we
could access molecules of interest such as homoserine lactones
(2w)14 and fluorinated derivatives (2y) as well as enable the
introduction of useful functional groups such as carboxylic acids
(2x) and phosphonates (2z) for further potential derivatiza-
tions.15,16
Scheme 2. Comparison between Hydroacyloxylation and
Hydroamidation of Unactivated Alkenes
replaced by NHTs, the 9:1 ratio between 6- and 5-membered
rings becomes 1:6, all with a similar reaction rate.
To address this question, DFT computations were carried out
at the ωB97-XD/6-31+G(d,p) level of theory including solvent
correction using 1t and the corresponding tosylamide 13 as
substrates (see the Supporting Information for computational
details and additional computations). Since such reactions are
protocatalyzed by HNTf2, or even by the [Ca(NTf2)+/(HFIP)n]
system as previously reported,7,8 H+ has been taken as model
catalyst. The cyclizations were studied in the gas phase at 353.15
K. Scheme 3 shows the formation of 6- and 5-membered
On the other hand, to our delight, this transformation could
be also extended to geraniol-derived substrate 4 to furnish the
corresponding bicyclic γ-lactones 5 in 66% at room temperature
(eq 1). Of note, performing the reaction at a higher temperature
proved to be detrimental to the success of the transformation as
a complex mixture of products was obtained in that case.
Scheme 3. Computed Free Energy Profile Corresponding to
the H+-Catalyzed Hydroacyloxylation of 1t (ΔG353, kcal/
mol)
Another interesting feature of this method is the fact that the
reaction is not only limited to the utilization of carboxylic acids
but could be also applied to esters (eq 2), making this method
even more practical for applications in synthesis.17 The
transformation proceeded at a slower rate but the desired γ-
valerolactone 2a was still generated in high yields.
products from A, which corresponds to the protonation of 1t to
give a secondary carbocation. The cyclization can be achieved by
the hydroxy oxygen to give B through TSAB or by the carbonyl
oxygen to give C through TSAC. The latter pathway is favored
kinetically (3.4 vs 2.7 kcal/mol) and thermodynamically (−3.4
vs −19.2 kcal/mol). A 1,2-proton shift to give the secondary
carbocation D was achieved via TSAD at a low free energy cost of
2.7 kcal/mol and D is less stable than A by 2.3 kcal/mol. The
cyclization of D into the 5-membered ring intermediates E and F
is achieved across higher barriers than in the 6-membered ring
case (4.7/6.0 vs 3.4/2.7 kcal/mol). This time, the C−O bond
formation via the hydroxy group is faster (4.7 vs 6.0 kcal/mol)
but remains less favored thermodynamically (−1.4 vs −17.5
kcal/mol). One can expect than E can easily be transformed into
F by prototropy. However, the 6-membered ring formation
remains kinetically more favorable (2.7 vs 4.7 kcal/mol).
As stated above (Figure 1), the reaction was quite efficient to
afford α-phosphono-γ-butyrolactones. However, this type of
compound represents a formidable platform to give access to α-
alkylidene-butyrolactone derivatives via olefination.18 As an
example, compound 2z could be engaged in a Horner−
Wadsworth−Emmons reaction with piperonal to lead to the
targeted product 7 in 70% along with an excellent selectivity in
favor of the E-product (eq 3).
Similar calculations were then carried out in the hydro-
amidation series (Scheme 4). No direct connection between
carbocations G and J and the 6- and 5-membered nitrogen
heterocycles I and L could be established. These carbocations
are first easily trapped by the sulfonyl group to give the oxygen-
stabilized species H and K, lying at −9.5 and −9.2 kcal/mol on
the energy surface, respectively. The formation of H requires 8.9
kcal/mol of free energy of activation, which is much higher than
the one required for forming K from J (2.6 kcal/mol between J
and TSJK). The preorganized carbocations then cyclize through
During the course of our investigations, a point clearly puzzled
us, namely the difference of reactivity between the hydro-
acyloxylation of alkenes and the related hydroamidation
regarding the selectivity between 6- and 5-membered rings.
Indeed, while 6-membered rings can be easily obtained with the
title reaction from α,δ-ene-carboxylic acids, 5-membered rings
were found as major products with α,δ-ene-amides in a previous
study (Scheme 2).7 In particular, if the CO2H group in 1t is
C
DOI: 10.1021/acs.orglett.9b02705
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ORCID
Scheme 4. Computed Free Energy Profile for the Cyclization
of the NHTs Analogue of 1t (ΔG353, kcal/mol; Selected
Distances d in Å)
Vincent Gandon: 0000-0003-1108-9410
David Lebœuf: 0000-0001-5720-7609
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully thank the China Scholarship Council (CSC), the
CNRS, the Ecole Polytechnique and the Universite Paris-Sud
for their support of this work.
■
́
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ASSOCIATED CONTENT
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■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02705.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: david.leboeuf@u-psud.fr.
*E-mail: vincent.gandon@u-psud.fr.
D
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DOI: 10.1021/acs.orglett.9b02705
Org. Lett. XXXX, XXX, XXX−XXX