Micellar Catalysis for Sustainable Hydroformylation

Article abstract of DOI:10.1002/cctc.202100181

It is here reported a fully sustainable and generally applicable protocol for the regioselective hydroformylation of terminal alkenes, using cheap commercially available catalysts and ligands, in mild reaction conditions (70 °C, 9 bar, 40 min). The process can take advantages from both micellar catalysis and microwave irradiation to obtain the linear aldehydes as the major or sole regioisomers in good to high yields. The substrate scope is largely explored as well as the application of hydroformylation in tandem with intramolecular hemiacetalization thus demonstrating the compatibility with a broad variety of functional groups. The reaction is efficient even in large scale and the catalyst and micellar water phase can be reused at least 5 times without any impact in reaction yields. The efficiency and sustainability of this protocol is strictly related to the in situ transformation of the aldehyde into the corresponding Bertagnini's salt that precipitates in the reaction mixture avoiding organic solvent mediated purification steps to obtain the final aldehydes as pure compounds.

Full text of DOI:10.1002/cctc.202100181

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Micellar Catalysis for Sustainable Hydroformylation
Francesca Migliorini,[a] Filippo Dei,[a] Massimo Calamante,[b] Samuele Maramai,[a] and
Elena Petricci*[a]
It is here reported a fully sustainable and generally applicable
protocol for the regioselective hydroformylation of terminal
alkenes, using cheap commercially available catalysts and
thus demonstrating the compatibility with a broad variety of
functional groups. The reaction is efficient even in large scale
and the catalyst and micellar water phase can be reused at least
5 times without any impact in reaction yields. The efficiency
and sustainability of this protocol is strictly related to the in situ
transformation of the aldehyde into the corresponding Bertag-
nini’s salt that precipitates in the reaction mixture avoiding
organic solvent mediated purification steps to obtain the final
aldehydes as pure compounds.
°
ligands, in mild reaction conditions (70 C, 9 bar, 40 min). The
process can take advantages from both micellar catalysis and
microwave irradiation to obtain the linear aldehydes as the
major or sole regioisomers in good to high yields. The substrate
scope is largely explored as well as the application of hydro-
formylation in tandem with intramolecular hemiacetalization
Introduction
autoclaves, for long reaction times (1–4 days), at high temper-
°
atures (80–200 C), in not properly eco-friendly media such as
Hydroformylation reaction is one of the most useful methods
for the preparation of aldehydes by addition of hydrogen (H2)
and carbon monoxide (CO) to double bonds.[1–3] Aldehydes are
very versatile and reactive functional groups usually used as
intermediates for further transformations into alcohols, amines
or condensation products, by also using domino and tandem
protocols.[2] The oxo process, as called by Otto Roelen,[1a–b] is the
most applied catalytic atom-economic transformation in bulk
and fine chemical industries for the synthesis of fine chemicals
including Active Pharmaceutical Ingredients[4–5] (i.e. Ilepatril,
Omapatrilat,[6] Zincophorin Methyl Ester,[7] Naproxen[8]), fragran-
ces (i.e. linalool, β-citronellene),[9] detergents and natural
products (i.e. Lepadiformine,[10] (S)-anabasine, (S)-nicotine,
(+)-lupinine[11]). This homogeneous catalytic process can be
mediated by different transition metals such as Co,[1a,12] Ru,[13]
Pt,[14] Fe[15] and Rh[16] in the presence of a specific ligands tuning
the regio- and the chemoselectivities.[2,17] Double bond hydro-
genation and isomerization usually are the main side reactions
in hydroformylation conditions.[18] Classical hydroformylations
require high pressures (10–100 bar) of H2 and CO mixtures
(syngas) in different ratios (i.e. 1:1, 2:1, 4:1) in stainless steel
toluene or THF.[1–3,19–20]
Since several years, our interest is focused on the develop-
ment of processes for olefin hydroformylation in mild and more
sustainable conditions, at low pressure of syngas, including
taking advantages of microwave (MW) irradiation.[21–22] These
transformations have been successfully extended to heteroge-
neous catalytic systems,[23] as well as to tandem and domino
processes.[24] However, the main limitation of the developed
protocols is still represented by the use of toluene as the
solvent, in pretty diluted conditions (i.e. 0.1 M), unsuitable for
industrial applications. To overcome these limitations, we
figured out that micellar catalysis could represent a valid option
for our purposes.[25–26] Water is a safe and non-toxic solvent
used in a few transformations because of the low solubility of
most organic compounds in it.[27] This problem can be over-
come by the use of surfactants generating supramolecular
aggregates, such as micelles, able to solubilize organic lipophilic
molecules in water.[25–26,28] Moreover, micelles act as nano-
reactors, containing all reactants and catalyst in very high
concentrations, thus speeding up the reaction rates[25–26] of
many different metal-catalysed reactions, such as Suzuki-
Miyaura and Heck cross-coupling,[26] hydrogen borrowing
processes,[29] and others.[28–30]
Hydroformylation in biphasic olefin/water system has been
firstly reported 1975 in the patented OXEA process using the
water soluble trisulfonated triphenylphoshine ligand (TPPTS).[31]
Contemporary, Johnson Matthey patented the use of cationic
surfactants in hydroformylation processes by using similar
sulfonated phosphine ligands.[32] Since the 80’s, many efforts
have been dedicated to find optimal catalysts and conditions
for aqueous (or aqueous/organic biphasic) hydroformylation,[32]
with only few of them leading to industrial applications.[34] As
indicated by Kamer and Laan: “There is still a need for an
approach that meets all of the strict requirements of a technical
two-phase process, such as complete catalyst retention, high
activity and stability, high aldehyde selectivity, simple phase
[a] F. Migliorini, F. Dei, Dr. S. Maramai, Prof. E. Petricci
Department of Biochemistry, Chemistry and Pharmacy
University of Siena
Via A. Moro
53100 Siena (Italy)
E-mail: petricci@unisi.it
[b] M. Calamante
CNR – ICCOM
Dipartimento di Chimica
Università degli Studi di Firenze
Via Madonna del Piano, 10
50019 Sesto Fiorentino, Firenze (Italy)
© 2021 The Authors. ChemCatChem published by Wiley-VCH GmbH. This is
an open access article under the terms of the Creative Commons Attribution
Non-Commercial NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non-
commercial and no modifications or adaptations are made.
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separation, and low ligand costs in order to be economically
competitive with the currently used processes”.[35] The most
recently reported and efficient protocols are mediated by
surfactants in 3 phases microemulsions systems, involving not
sustainable solvents (i.e. toluene, 1,4-dioxane), although finding
very interesting industrial applications.[36–38] The real micellar
catalytic hydroformylation protocols reported still suffer from
many limitations including low yields (30–73%),[39] the use of
expensive ligands such as SulfoXantphos (260 E/g versus the
less expensive Xantphos 45 E/g),[39–40] 6DPPon (130 E/g),[41]
tailor-made surfactants,[40,42] or modified cyclodestrines[43] usu-
ally associated with high syngas pressures (15–100 bar). In
some cases, the process is just apparently green as extraction
and column chromatography using high quantities of toxic
solvents (i.e. Et2O) are necessary, and no catalyst recover and
recycle is investigated, thus negatively impacting in the E-
Factor.[41] The most challenging reports are represented by the
tandem application of hydroformylation with biocatalysis for
the synthesis of nonanitrile,[44] still needing high syngas
pressures and occurring with poor regioselectivity, and the use
of supramolecular ion pairs for 1-octene hydroformylation in
water.[45] The substrate scope of all these reports is limited to 1-
octene, 1-dodecene or styrene without investigating any
general application to functionalized olefins thus needing a
further investigation for a completely green hydroformylation
protocol of general applicability.
Figure 1. 1 (0.75 mmol), 1-dodecanal (internal standard, 0.075 mmol), Rh(CO)
H(PPh3)3 (0.015 mmol), Xantphos (0.06 mmol), salt (0.0075 mmol), TPGS-750-
°
M 5 wt% in H2O (3 mL), MW 110 C, 10 min. Conversions are determined by
GC/MS (%) as reported in SI.
50% conversion with a good 9:1 regioselectivity towards liner
aldehyde 2a (Figure 1).
Even the use of different salts such as MgBr or CsF had a
low impact on both conversions and regioselectivities probably
caused by the use of a non-ionic surfactant in the reaction
medium.[35]
Irradiation at higher temperatures in the presence of
different ligands (Figure 2A) or for longer reaction times
(Figure 2B) only enhance reduction or isomerization of the
starting allylbenzene, together with the reduction of aldehyde 2
into the corresponding alcohol.
We here reported our contribution to a fully sustainable and
generally applicable approach to the regioselective hydro-
formylation of terminal alkenes in water through the use of the
commercially available surfactant DL-α-Tocopherol meth-
oxypolyethylene glycol succinate (TPGS-750-M), commercially
available Rh(CO)H(PPh3)3 catalyst and the cheap ligand Xant-
phos under MW-irradiation at low pressures of syngas (9 bar).
This green method allows to obtain linear aldehydes in mild
°
conditions (70 C and 9 bar) and short reaction times (40–60
minutes), with high isolated yields and regioselectivities and no
purification step or extraction with organic solvents. All of this
independently from the substituents present on the starting
olefins and with a full recovery of the catalyst and the micellar
phase, that can be reused for at least 5 times without any
impact in reaction yields.
Results and Discussion
Allylbenzene (1) was selected as the model substrate for
optimizing the hydroformylation process. At first, reaction
conditions similar to the one we already developed in toluene
were tested:[7] a suspension of 1 in TPGS-750-M (5 wt%) in H2O
was irradiated with MW in the presence of a 1:1 CO/H2 mixture
°
(9 bar), Rh(CO)H(PPh3)3 (2 mol%), Xantphos (Rh/L 1:4) at 110 C
for 10 min obtaining a 53% conversion into the corresponding
aldehyde with a good regioselectivity (Figure 1). Starting from
Pogrzeba and co-workers’ observations,[39] NaCl (1 mol%) was
added to obtain better performances in term of catalyst stability
and reaction yields. The expected product 2 were obtained in a
Figure 2. A) 1 (0.75 mmol), 1-dodecanal (internal standard, 0.075 mmol),
Rh(CO)H(PPh3)3 (0.015 mmol), L (0.06 mmol), TPGS-750-M (5 wt%) in H2O
(3 mL), MW (max power 300 Watt), 10 min. Conversion determined by GC/
MS (%) as report in ESI. B) 1 (0.75 mmol), 1-dodecanal (internal standard,
0.075 mmol), Rh(CO)H(PPh3)3 (0.015 mmol), Xantphos (0.06 mmol), TPGS-750-
°
M (5 wt%) in H2O (3 mL), MW (max power 300 Watt), 70 C. Conversion
determined by GC/MS (%) as reported in SI.
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By using Biphephos as the ligand, an improvement in the
Table 1. Optimization of reaction conditions with MW constant irradiation.
conversion paralleled by a lower 4:1 regioselectivity was
observed (Figure 2B). Surprisingly, the best results in terms of
both conversion and selectivity were obtained lowering the
°
temperature to 70 C and irradiating for 40 minutes (Figure 2B
Entry Catalyst
(Cat:L)
Surfactant
Time Conv
[min] [%][a]
2a/
and Table S1). Despite the different ligands tested (i.e.
Biphephos, DPEphos, Dppf, 6-DPPon), the best performances in
term of both conversions and regioselectivities towards the
linear aldehyde 2a were obtained by using Xantphos. As
expected, using PPh3 as the ligand or running the reaction in
ligand free conditions, a drastic lower-down in regioselectivities
was observed with similar conversions with respect to the ones
observed with Xantphos (Table S1). It is interesting to note that
the conversions are directly proportional to the logP of the
different ligands used, 6-DPPon (logP=3.51) being the worst
2b[a]
1[b]
2[c]
3[c]
4[d]
5[e]
6[c]
7[c]
8[c]
9[c]
10[f]
11
Rh(CO)H(PPh3)3
TPGS-750-M
5 wt%
40
40
40
40
40
40
40
40
40
40
40
40
>99
>99
98
97
25
56
55
63
51
–
24:1
24:1
24:1
24:1
3:1
13:1
13:1
16:1
6:1
–
2 mol% (1:4)
Rh(CO)H(PPh3)3
1 mol% (1:4)
Rh(CO)H(PPh3)3
1 mol% (1:4)
Rh(CO)H(PPh3)3
1 mol% (1:4)
Rh(CO)H(PPh3)3
1 mol% (1:8)
Rh(CO)2acac 1 mol%
(1:4)
TPGS-750-M
2.5 wt%
°
and Xantphos (logP=10.39) the best one. Irradiating at 50 C,
RhCl(cod)2 1 mol%
(1:4)
shortening reaction times (30 minutes) or repeating 4 cycles of
irradiation for 10 min each, negatively impacted the conver-
sions (Figure 2A and Table S1). It is worth noting that a
temperature reduction is possible and necessary thanks to the
particular combination of the MW effect on the triphasic
micellar catalysis system: a gas-liquid-solid dispersion (see SI for
reactions performed with traditional heating). We can probably
associate the lower conversions observed at higher temper-
Rh(CO)H(PPh3)3
1 mol% (1:4)
Rh(CO)H(PPh3)3
1 mol% (1:4)
Rh(CO)H(PPh3)3
1 mol% (1:4)
–
SDS 2.5 wt%
CITAB 2.5 wt%
–
TPGS-750-M
2.5 wt%
–
–
12[g]
Rh(CO)H(PPh3)3
1 mol% (1:4)
–
–
°
atures than 70 C to the minor interface area related to a lower
down in droplet size responsible for a difficult mass transfer
[a] Conversion determined by GC/MS. [b] 1 (0.75 mmol), 1-dodecanal
(internal standard, 0.075 mmol), Rh cat (0.015 mmol), Xantphos
(0.06 mmol), TPGS-750-M 5 wt% in H2O (3 mL), MW dielectric heating at
into the micelles.[39] The best conditions observed for these
°
transformations are: irradiation for 40 minutes at 70 C in
°
70 C with fixed power irradiation at 300 Watt, cooling while heating (max
presence of Rh(CO)H(PPh3)3, and Xantphos at 9 bar of syngas.
The impact of MW irradiation on the reaction outcome was
investigated by using a fixed power irradiation at 300 Watt
°
T 70 C). [c] 1 (0.75 mmol), 1-dodecanal (internal standard, 0.075 mmol), Rh
(CO)H(PPh3)3 (0.0075 mmol), Xantphos (0.03 mmol), TPGS-750-M 2.5 wt%
°
in H2O (3 mL) if not differently reported, MW dielectric heating at 70 C with
°
fixed power irradiation at 300 Watt, cooling while heating (max T 70 C). [d]
1 (1.5 mmol), 1-dodecanal (internal standard, 0.15 mmol), Rh(CO)H(PPh3)3
(0.015 mmol), Xantphos (0.03 mmol), TPGS-750-M 2.5 wt% in H2O (3 mL),
MW dielectric heating at 70 C with fixed power irradiation at 300 Watt,
cooling while heating (max T 70 C). [e] 1 (1.5 mmol), 1-dodecanal (internal
standard, 0.15 mmol), Rh(CO)H(PPh3)3 (0.0075 mmol), Xantphos
(0.06 mmol), TPGS-750-M 2.5 wt% in H2O (3 mL), MW dielectric heating
°
(maximum temperature settled 70 C), thus obtaining a full
conversion (>99%) and high regioselectivity (2a/2b 24:1). The
effect of lowering down the amount of catalyst from 2 to
1 mol% (Entries 1–2, Table 1) was also evaluated. Lowering the
amount of TPGS-750-M to 2.5 wt% had no impact on
conversion (Entry 3, Table 1). No differences were observed at
higher concentrations (Entry 4, Table 1), while the addition of
sustainable co-solvents such as 2Me-THF worsened the reaction
rate (Table S1) as well as a change in the catalyst to ligand ratio
(Entry 5, Table 1).
Different catalysts (Entries 6–7, Table 1) and ionic surfactants
(Entries 8–9, Table 1) were tested, with no improvements
observed. It is interesting to note that the structure of the
surfactant directly impacts both on yield and regioselectivity,
therefore demonstrating its active role in the reaction. This is
further confirmed by the absence of any aldehyde while
performing the transformation just in water without any
surfactant (Entry 10, Table 1). Blank tests were also carried out
to demonstrate the catalyst, the surfactant and the syngas roles
in this transformation (Entries 10–12, Table 1).
°
°
°
at 70 C with fixed power irradiation at 300 Watt, cooling while heating
°
(max T 70 C). [f] same as [c] without TPGS-750-M. [g] Without syngas.
raphy, in 90% isolated yields (2b was isolated in 3% yield).
With the aim of overcoming an organic work-up, thus avoiding
the use of organic solvents in purification, the reaction was
repeated by adding 1.5 eq. of NaHSO3 directly in the reaction
mixture. In these conditions, 2 was directly obtained after
microwave irradiation as the corresponding Bertagnini’s salt
that precipitates in micellar suspension (Figure S1).
The reaction mixture was filtered and the Bertagnini’s salt
treated with 1 equivalent of NaOH 10 M, with a full recovery of
2 as an oil in >99% isolated yields by centrifugation and
decantation. The possible catalyst recycle was evaluated by
adding 1 and NaHSO3 to the micellar phase recovered after
filtration and exposing the suspension to MW irradiation at
In order to evaluate the sustainability of the overall process,
a pilot reaction involving allylbenzene was performed in larger
scale (10 mmol of allylbenzene). By using the best reaction
conditions reported so far (Entry 3, Table 1 and Figure S1) at
0.5 mmol/mL concentration, the linear aldehyde 2a was
recovered after extraction with AcOEt and column chromatog-
°
70 C, for 40 minutes in the presence of syngas (9 bar). The
conversion into 2 was complete (>99%) and the process has
been repeated for further 3 times without almost any impact in
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reaction yields, demonstrating a full recyclability of the catalyst
(Figure 3 and S1).
reference 41). We decide to further investigate micellar
structure by DLS and TEM analysis to have a characterization of
micelles after microwave irradiation and the catalyst recycling
process, as a single example applying TPGS-750-M under
microwave irradiation has been previously reported lacking for
this data.[29b] As reported in Figure 3 and in S4, after microwave
irradiation of the micellar suspension or the reaction mixture,
we observe a higher homogeneity in micellar size together with
The TON for a single reaction cycle is 99.1 while the TOF at
70% of conversion is 280 hÀ 1 (for a confront of TOF values with
other reported protocols see Table S2). The E-Factor for a single
hydroformylation run on 1-octene is only 1.08 (Table S2); this
value is comparable to the ones considered as suitable for the
scale-up of industrial hydroformylation processes[39–40] and
better than the one reported in literature for 1-octene hydro-
formylation in the presence of surfactants (i.e. E-Factor 1035 in
a
higher Z-potential value indicating an overall micellar
stabilization. TEM analysis of the reaction mixture after irradi-
°
ation at 70 C shows a multi-micelle structure in agreement
with the data reported in the literature for traditional heating
conditions.[25d] This structure is maintained after 4 cycles of
catalyst recycle (Figure 4 B and C).
Rh nanoparticles are not formed in the reaction conditions,
°
while irradiating at higher temperatures (i.e. 120 C) lower
reaction yields contemporary with nanoparticles formation are
observed together with micelles destabilization (Z-potential in
Figure S3). These last findings demonstrate that Rh nanoparticle
formation is detrimental for hydroformylation reactions and
occurs irradiating at high temperature (>100 C). 31P-NMR
°
analysis of the reaction mixture after irradiation, after recycling,
and after irradiation in previously reported hydroformylation
conditions[21] indicated the presence of a stable catalytic species
Figure 3. Catalyst and micelles recycle, work-up and purification
Figure 4. TEM analysis of: A) reaction mixture before irradiation: 1 (0.75 mmol), Rh(CO)H(PPh3)3 (0.015 mmol), Xantphos (0.06 mmol), TPGS-750-M (2.5 wt%) in
°
°
H2O (3 mL); B) reaction mixture after MW dielectric heating at 70 C with fixed power irradiation at 300 Watt, cooling while heating (max T 70 C) for 40 min; C)
°
reaction mixture after recycling micellar phase for 3 times; D) reaction mixture after MW dielectric heating at 120 C for 40 min. The TEM images are
200×200 nm.
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formed during MW heating different than the one obtained by
using toluene as the reaction media (Figure S4–7).
Syngas solubility in micellar media has been found to be
higher (1.6 mmol/L) than the observed in water at 1 atm
(1 mmol/L), although this slight difference cannot be consid-
ered as responsible for the different reaction outcome in the
different media.
With these findings in hands, we decided to explore the
reaction versatility by using different terminal alkenes as
substrates (Table 2).
We demonstrated that these MW assisted hydroformylation
conditions are very tolerant to different functional groups (i.e.
ester, amide, acetal, ether).
It is worth noting that the hydroformylation of industrially
valuable long chain olefins, such as 1-octene 3, occurs very
efficiently producing linear nonanal in 95% isolated yields
(Entry 1, Table 2). The process is chemoselective as it can be
successfully performed even in the presence of reduction-
sensitive functional groups such as nitrile (Entry 2, Table 2),
benzyl ether (Entry 9, Table 2), and internal alkenes (Entry 18,
Table 2). Only terminal alkenes react even in the presence of
internal ones (Entry 18, Table 2). Amides 9–14 react with
variable yields and regioselectivities depending on the sub-
stituents on the aromatic ring. Particularly, electron withdraw-
ing groups seem to negatively impact on reaction yields. The
most difficult compounds to be hydroformylated are the solid
ones (i.e. 7, 9, 11, 13, 19). In fact, most of the micellar catalysed
processes reported in the literature have liquid starting
materials or solid water soluble substrates.[25–27]
We figure out after many attempts (Table S3) that is
possible to obtain linear aldehydes in good yields even starting
from solid alkenes by using 2 mol% of the catalyst instead of 1
(Entries 5, 7, 9, 11 and 17, Table 2). The reaction is compatible
with the presence of silyloxy derivatives (Entries 13–12, Table 2),
the performances being dependent on the hydrophobicity of
the starting material. As expected, styrene 18 furnish the
branched aldehyde 36 as the main reaction product in good
yields (Entry 16, Table 2). Starting form quinoline 19, containing
an hydroxy group, the 9-member cyclic hemiacetal is directly
isolated in 53% yields with a full regioselectivity (Entry 17,
Table 2). Similar results were obtained starting from linalool 20:
the cyclic hemiacetal is directly formed in 78% isolated yields
from the linear aldehyde as the only reaction product (Entry 18,
Table 2).
Scheme 1. Tandem hydroformylation and hemiacetalization
micellar catalysis and microwave irradiation. The process is fully
eco-sustainable tanks to the use of NaHSO3 as additive that
consents a full recovery of the final aldehydes and the active
catalytic water-micellar phase without the use of any organic
solvent (to see the impact on NaHSO3 on hydroformylation
process see TLCs on Figure 2S). The process occurs with high
regioselectivity towards linear aldehydes at low pressure of
°
syngas (9 bar) and low temperature (70 C) for an hydro-
formylation process, in only 40 minutes. The reaction can be
done in 10 mmol scale without affecting yields and selectivity
and the micelles-catalyst system can be efficiently reused at
least 5 times. The optimized protocol is compatible with
different functional groups (i.e. amides, nitrile, nitro, ester, etc.)
and can be used in tandem with intramolecular hemiacetaliza-
tion for the synthesis of 5 or 6 member cyclic hemiacetals
starting from hydroxy group containing starting alkenes. This
work demonstrates how effective can be the coupling of
micellar catalysis with microwave irradiation for the develop-
ment of very efficient and sustainable hydroformylation proto-
cols of general applicability. Micelles appear to be stable and
more homogenous in term f size distribution after irradiation.
The process can be easily applied in lab scale by using
commercial microwaves and we hope that it should find future
applications in industrial scale as the hydroformylation in
microemulsion has been recently investigated in miniplants[37]
and as microwave technology already found some applications
in chemical production.[47–52]
Starting form this interesting finding, we decided to
investigate the possibility to obtain cyclic hemiacetals by
hydroformylating alkenes containing alcohol moieties in β
position (Scheme 1).
Hemiacetals are obtained in good to acceptable yields.
Again, the presence of electron donating moieties in the
aromatic ring is usually associated with higher reaction yields.
Experimental Section
Conclusion
All reagents were used as purchased from commercial suppliers
(i.e. Merk for surfactant and ligand, TCI for Rh catalyst) without
further purification. Flash column chromatography was performed
in glass columns using Merk silica gel 60 Å, 230–400 mesh particle
We here demonstrate that is possible to perform hydroformyla-
tion reaction in water media taking advantages from both
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Table 2. Substrate scope.
Table 2. continued
Entry[a] Alkene
Entry[a] Alkene
Product
Yield [%]
(l:b)
Product
Yield [%]
(l:b)
95
(100:0)
78
(200:1)
1
2
18
30[b] (6:1)
72 (49:1)
[a] Alkene (1.5 mmol), Rh(CO)H(PPh3)3 (0.015 mmol), Xantphos (0.03 mmol),
NaHSO3 (1.72 mmol), TPGS-750-M 2.5 wt% in H2O (3 mL), CO/H2 (9 bar),
MW dielectric heating at 70 C with fixed power irradiation at 300 Watt,
cooling while heating (max T 70 C) for 40 min. [b] Conversion determined
by GC/MS. [c] Alkene (1.5 mmol), Rh(CO)H(PPh3)3 (0.03 mmol), Xantphos
(0.06 mmol), NaHSO3 (1.72 mmol), TPGS-750-M 2.5 wt% in H2O (3 mL), CO/
°
3
4
°
81
(100:0)
°
H2 (9 bar), MW dielectric heating at 70 C with fixed power irradiation at
°
300 Watt, cooling while heating (max T 70 C) for 60 min.
83
(100:0)
5[c]
size Merck aluminum backed plates pre-coated with silica gel 60
(UV254) were used for analytical thin-layer chromatography and
were visualized by staining with a solution p-anisaldehyde in EtOH
or a KMnO4 solution. 1H NMR, 13C and 31P NMR spectra were
recorded on 400 MHz, 600 MHz, and 243 MHz Bruker Advance NMR
spectrometers. Deuterated chloroform and methanol were used as
the solvents and chemical shift values (δ) are reported in parts per
million (ppm) referring to the residual signals of the deuterated
solvent (δ 7.26 for 1H and δ 77.6 for 13C in CDCl3, δ 3.34 for 1H and δ
49.00 for 13C in CD3OD). For 31P NMR spectra (δ) are reported in
parts per million (ppm) referring to triethylphosphate (δ=À 0.82) in
6
76 (2:1)
78 (4:1)
7[c]
1
CDCl3. 31P NMR spectra were acquired with H decoupling. Data are
8
65 (8:1)
represented as follows: chemical shift, multiplicity (s=singlet, d=
doublet, dd=doublet of doublets, dt=doublet of triplets, t=
triplet, q=quartet, m=multiplet or multiple resonances, bs=broad
singlet), coupling constant (J) in Hertz and the integration in ppm.
Mass spectrometry data were collected on Varian Saturn 2000 GC/
MS spectrometer with ion trap detector and equipped with 30 m
37
(100:0)
9[c]
10
°
OV-101 capillary column, splitting injector at 240 C.
76 (6:1)
°
°
°
Methods for GC analysis: A) 40 C – 3 min, 40–200 C 10 C/min –
°
°
°
°
17 min, 200–240 C 20 C/min – 5 min; B) 40 C – 3 min, 40–200 C
10 C/min – 16 min, 200–240 C 20 C/min – 8 min, 240–280 C
20 C/min, 8 min. Reactions carried out under MW dielectric heating
°
°
°
°
11[c]
12
–
–
°
were performed with
a
modified Discover microwave oven
equipped with the 80 mL vial for reaction under pressure.[21]
Scanning transmission electron microscopy (STEM) and Energy-
dispersive X-ray spectroscopy (EDS) analysis was done using a FIB/
SEM TESCAN GAIA 3 installed at the Microscopy Center (Ce.me.) at
ICCOM-CNR (Florence). DLS, Z-potential measurements were done
using a Zetasizer NanoZS90 instrument (Malvern, Worcestershire,
UK).
11[b]
(100:1)
13
14
81[b]
(100:1)
General method for 31P NMR samples preparation
61
(100:0)
15
16
A sample (0.500 mL) of the reaction mixture carried out on
allylbenzene in toluene[21] was evaporated under reduced pressure,
dissolved in 0.400 mL of CDCl3 and analyzed by 31P NMR (ns=
2048). A sample (0.500 mL) of the reaction mixture carried out on
allylbenzene as reported in Method A was extracted with AcOEt
(0.500 mL), evaporated under reduced pressure dissolved in
0.400 mL of CDCl3 and analyzed by 31P NMR (ns=2048). The
micellar solution left was recovered and reused 3 times, and finally
a sample (0.500 mL) of the reaction mixture was extracted with
AcOEt (0.500 mL), evaporated under reduced pressure dissolved in
0.400 mL of CDCl3 and analyzed by 31P NMR (ns=2048). Data are
reported in Figures S5–8.
76 (1:4)
53
(100:0)
17[c]
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Preparation of not commercially available starting alkenes 2-
(Dec-9-en-1-yl)-1,3-dioxolane (5). 10-undecenal (2.38 mL,
N-Allylbenzamide (12). The crude was purified by means of flash
chromatography on silica gel using a petroleum ether/CH2Cl2
1
12.0 mmol) was dissolved in anhydrous ethylene glycol (136 mL,
2436.0 mmol) and a catalytic amount of pTSA (193 mg, 1.02 mmol)
in 40 mL of anhydrous toluene was added. The resulting mixture
was heated at reflux for 1 h. The mixture was extracted with CH2Cl2
(3×50 mL), and the organic layer was evaporated after drying with
anhydrous Na2SO4 furnishing the protected aldehyde. Yield: 81%.
GC-MS (m/z): 212; Rt =16.563 (Method A). 1H NMR (600 MHz, CDCl3)
δ 5.83–5.68 (m, 1H), 4.95 (d, J=17.1 Hz, 1H), 4.89 (d, J=10.0 Hz,
1H), 4.80 (t, J=4.5 Hz, 1H), 3.98–3.87 (m, 2H), 3.85–3.77 (m, 2H),
2.00 (q, J=6.5 Hz, 2H), 1.66–1.59 (m, 2H), 1.41–1.22 (m, 12H). 13C
NMR (151 MHz, CDCl3) δ 139.1, 114.1, 104.7, 64.8, 33.9, 33.7, 29.5,
29.5, 29.3, 29.1, 28.9, 24.0. The spectral data were identical to those
reported in the literature.[53]
mixture as the eluent. Yield: 78%. H NMR (400 MHz, CDCl3) δ 7.75
(d, J=7.6 Hz, 2H), 7.50–7.35 (m, 3H), 6.21 (bs, 1H), 5.91 (qd, J=10.8,
5.7 Hz, 1H), 5.23 (dd, J=17.3, 1.4 Hz, 1H), 5.15 (dd, J=10.2, 1.2 Hz,
1H), 4.11–4.02 (m, 2H). 13C NMR (101 MHz, CDCl3): δ 167.5, 134.6,
134.3, 131.6, 128.7, 127.1, 116.7, 42.5. The spectral data were
identical to those reported in the literature.[55]
N-Allyl-4-nitrobenzamide (13). The product was purified by means
of flash chromatography using EtOAc in petroleum ether mixture as
the eluent. Yield: 78%. 1H NMR (600 MHz, CDCl3) δ 8.28 (d, J=
8.4 Hz, 2H), 7.96 (d, J=8.4 Hz, 2H), 6.45 (s, 1H), 6.01–5.88 (m, 1H),
5.28 (d, J=17.1 Hz, 1H), 5.22 (d, J=10.2 Hz, 1H), 4.11 (t, J=5.3 Hz,
2H). 13C NMR (151 MHz, CDCl3) δ 165.4, 149.6, 140.0, 133.4, 128.2,
123.9, 117.4, 42.8. The spectral data were identical to those
reported in the literature.[56]
2-Allylisoindoline-1,3-dione (7). To a solution of phthalimide (1.5 g,
10.2 mmol) in DMF (10 mL) were added K2CO3 (1.41 g, 10.2 mmol)
and allyl bromide (882 μL, 10.2 mmol). After the solution was stirred
for 16 h at room temperature, EtO2 (30 mL) was added to the
reaction mixture, and this latter was then washed with NaClss (3×
15 mL). The organic layer was evaporated under reduced pressure
after drying with anhydrous Na2SO4 to afford the desired com-
pound. Yield: 87%. GC-MS (m/z): 187; Rt =16.697 (Method A). 1H
NMR (600 MHz, CDCl3) δ 7.86 (dd, J=5.3, 3.1 Hz, 2H), 7.72 (dd, J=
5.3, 3.1 Hz, 2H), 5.95–5.81 (m, 1H), 5.25 (dd, J=17.0, 0.9 Hz, 1H),
5.20 (d, J=10.2 Hz, 1H), 4.30 (d, J=5.7 Hz, 2H). 13C NMR (151 MHz,
CDCl3) δ 167.9, 134.0, 132.1, 131.5, 123.3, 117.8, 40.1. The spectral
data were identical to those reported in the literature.[54]
N-Allylacetamide (14). Allylamine (2.63 mL, 35.0 mmol) was dis-
solved in dry CH2Cl2 (50 mL) followed by the addition of Et3N
(7.30 mL, 52.5 mmol) and dropwise addition of acetyl chloride
°
(2.75 mL, 38.5 mmol) at 0 C. After stirring for 16 hours at room
temperature 30 mL of H2O were added to the reaction. The organic
phase was separated and the aqueous layer was extracted with
CH2Cl2 (3×50 mL). The resulting organic layer was dried over
anhydrous Na2SO4 and concentrated. The crude product was
purified by silica gel flash chromatography using a mixture of
EtOAc/petroleum ether (5:95) as the eluent. Yield: 55%. GC-MS
1
(m/z): 99; Rt =7.812 min (Method A). H NMR (400 MHz, CDCl3): δ=
5.81 (ddt, J=17.0, 10.2, 5.8 Hz, 1H), 5.16 (q, J=17.0 Hz, 1H), 5.10 (q,
J=10.1 Hz, 1H), 3.84 (tt, J=5.7, 1.5 Hz, 2H), 1.99 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ=170.1, 134.3, 116.3, 42.2, 23.6. The spectral
data were identical to those reported in the literature.[57]
General method for the formation of benzoyl allylamides 9–
10and 12–13.
(Allyloxy)(tert-butyl)dimethylsilane
16.97 mmol) and TBDMSCl (2.56 g, 16.97 mmol) were added to a
solution of the alcohol (11.31 mmol) in dry CH2Cl2 (35 mL) at 0 C.
(15).
Imidazole
(1.16 g,
A mixture the appropriate carboxylic acid (16 mmol) in freshly
distilled SOCl2 (12 mL) was heated to reflux for 2 h, then cooled to
room temperature and evaporated under vacuum to dryness to
afford quantitatively corresponding acid chlorides. In a dried flask
under N2 atmosphere, a solution of allylamine (1.8 mL, 24 mmol)
and Et3N (3.3 mL, 24 mmol) in dry CH2Cl2 (25 mL) was cooled in an
°
Stirring was continued at room temperature for 4 h. H2O (20 mL)
was added and the organic layer was washed with NaClss (20 mL)
and concentrated after drying with anhydrous Na2SO4. The crude
was purified by column chromatography on silica gel (20% EtOAc
in petroleum ether) to afford the title compound as a colorless
liquid. Yield: 82%. GC-MS (m/z): 172; Rt=10.465 min (Method A).
1H NMR (400 MHz, CDCl3) δ 6.08–5.74 (m, 1H), 5.25 (d, J=17.0 Hz,
1H), 5.05 (d, J=9.0 Hz, 1H), 4.32–4.01 (m, 2H), 0.92 (s, 9H), 0.20 (s,
6H); 13C NMR (101 MHz, CDCl3) δ 137.5, 113.9, 64.1, 25.9, 18.4, À 5.3.
The spectral data were identical to those reported in the
literature.[56]
°
ice bath to 0 C. Then, the appropriate benzoyl chloride (16 mmol)
was added dropwise. The solution was allowed to warm to room
temperature and then stirred for 16 h. H2O (15 mL) was added and
the organic layer was separated. The aqueous layer was extracted
with CH2Cl2 (2×30 mL). The combined organic phases were washed
with NaClss (15 mL), dried over Na2SO4 and the solvent removed.
The crude product was purified by precipitation or column
chromatography on silica gel.
tert-Butyldimethyl(undec-10-en-1-yloxy)silane
(900 mg, 23.8 mmol) was added to a solution of 10-undecenal
(2.38 mL, 11.9 mmol) in dry MeOH (50 mL) at 0 C. After stirring for
(16).
NaBH4
N-Allyl-3,4,5-trimethoxybenzamide (9). The crude was solubilized
in the minimum amount of CH2Cl2 (10 mL) and petroleum ether
(50 mL) was added slowly in order to obtain a white precipitate
that was filtered on Büchner washing with cold petroleum ether.
°
°
1 h at 0 C, NH4Clss (25 mL) was added. The organic phase was
separated and evaporated after drying with anhydrous Na2SO4.
1
Yield: 70%. H NMR (600 MHz, CDCl3): δ 7.02 (s, 2H), 6.42 (bs, 1H),
1
Yield: 95%. GC-MS (m/z): 170; Rt=14.116 min (Method A). H NMR
5.96–5.55 (m, 1H), 5.20 (dd, J=45.4, 13.7 Hz, 2H), 4.04 (d, J=5.7 Hz,
2H), 3.87 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 167.1, 153.2, 140.9,
134.2, 129.9, 116.7, 104.4, 60.9, 56.4, 42.7. Elemental Analysis Calcd
for C13H17NO4: C, 62.14; H, 6.82; N, 5.57; O, 25.47. Found: C, 62.14; H,
6.82; N, 5.57; O, 25.47.
(400 MHz, CDCl3): δ 5.92–5.71 (m, 1H), 5.08–4.86 (m, 2H), 3.73–3.55
(m, 2H), 2.13–1.96 (m, 2H), 1.65–.49 (m, 2H), 1.47–1.18 (m, 13H). 13C
NMR (101 MHz, CDCl3): δ 139.3, 114.2, 63.2, 33.9, 32.9, 29.7, 29.5,
29.0, 25.9. The spectral data were identical to those reported in the
literature.[58] From the previous intermediate alcohol, the title
compound was obtained as a colorless liquid following the same
procedure reported for 15. Yield: 65%. GC-MS (m/z): 284; Rt=
N-Allyl-2,4-difluorobenzamide (10). The product was purified by
means of flash chromatography using EtOAc in petroleum ether
mixture as the eluent. Yield: 72%. 1H NMR (600 MHz, CDCl3): δ
8.23–7.99 (m, 1H), 6.98–6.95 (m, 1H), 6.86–6.82 (m, 1H), 6.76 (bs,
1H), 5.91 (ddq, J=15.2, 10.0, 5.0, 4.5 Hz, 1H), 5.21 (dd, J=47.2,
13.6 Hz, 2H), 4.08 (d, J=5.7 Hz, 2H). 13C NMR (151 MHz, CDCl3): δ
165.6, 162.3, 160.1, 133.9, 117.6, 116.5, 112.3, 104.4, 104.0, 42.4.
1
17.876 min (Method A). H NMR (600 MHz, CDCl3): δ 5.81 (ddt, J=
17.1, 10.2, 6.8 Hz, 1H), 5.03–4.98 (m, 1H), 4.95–4.91 (m, 1H), 3.59 (t,
J=6.7 Hz, 2H), 2.10–2.02 (m, 2H), 1.57–1.48 (m, 2H), 1.41–1.36 (m,
2H), 1.33–1.23 (m, 10H), 0. 09 (s, 9H), 0.05 (s, 6H). 13C NMR
(151 MHz, CDCl3): δ 139.2, 114.2, 63.3, 33.8, 32.8, 29.5, 29.4, 29.2,
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28.9, 26.0, 25.8, 18.4, À 5.3. The spectral data were identical to those
General methods for the hydroformylation reaction
reported in the literature.[59]
Method A (for liquid alkenes). A 80 mL MW tube was charged with a
solution of TPGS-750 M (2.5 wt% in H2O, 3 mL) and alkene
(2.25 mmol, 0.75 M solution). Then NaHSO3 (269 mg, 2.59 mmol),
Rh(CO)H(PPh3)3 (21 mg, 0.0225 mmol) and Xantphos (52 mg,
0.09 mmol) were added. The yellow suspension was stirred for 5
minutes under N2. The mixture was subjected to 3 cycles of
vacuum/syngas inside the microwave cavity. Syngas was added
Allyl benzoate (17). In a dry round bottom flask charged with
benzoic acid (1.5 g, 12.30 mmol) and dry CH2Cl2 (40 mL) allyl alcohol
(557 μL, 8.2 mmol) and DMAP (100 mg, 0.82 mmol) were added.
°
The solution was cooled to 0 C and stirred for 15 minutes before
the addition of DCC (3.4 g, 16.4 mmol). The reaction was stirred at
room temperature for 16 h under N2. The mixture was filtered,
concentrated in vacuo, and the crude was purified by flash
chromatography on silica gel (20% EtOAc in petroleum ether) to
afford a clear product as a colorless oil. Yield: 53%. GC-MS (m/z):
°
since 130 psi (8.8 bar) are detected, and irradiated at 70 C for 40
minutes cooling while heating with a fixed power of 300 Watt. After
irradiation the mixture was cooled-down to room temperature and
the internal gas released by opening the external pressure valve.
The mixture was filtered on Büchner washing with EtOAc (5 mL) to
afford the bisulfite adduct as a crystalline powder that was
solubilized in H2O. If no precipitation was observed, the mixture
was extracted with EtOAc (9 mL). Depending on the substrate,
NaOH 10 N or HCl 4 N was added to the aqueous phase since pH=
8 or pH=2, respectively. EtOAc (9 mL) was added and the mixture
stirred at r.t. for 15 minutes. The two phases were separated and
the organic phase was washed with NaClss (2×5 mL) and H2O
(5 mL), dried with dry Na2SO4, filtered, evaporated under reduced
1
163; Rt = 12.670 min (Method A). H NMR (400 MHz, CDCl3): δ 8.04
(d, J=8.0 Hz, 2H), 7.52 (t, J=7.3 Hz, 1H), 7.41 (t, J=7.2 Hz, 2H), 6.02
(ddt, J=16.3, 10.7, 5.4 Hz, 1H), 5.32 (dd, J=50.5, 14.1 Hz, 2H), 4.80
(d, J=5.4 Hz, 2H). 13C NMR (151 MHz, CDCl3): δ 166.3, 133.1, 132.2,
130.1, 129.7, 128.5, 118.3, 65.6. The spectral data were identical to
those reported in the literature.[58]
Synthesis of N-allyl-4-(benzyloxy)benzamide (11): Benzyl 4-(ben-
zyloxy)benzoate: Dry K2CO3 (15 g, 110.0 mmol) was added to a
solution of 4-hydroxybenzoic acid (1.5 g, 11.0 mmol) in dry acetone
(81 mL) at room temperature. After stirred for 30 minutes, benzyl
bromide (5.2 mL, 44.0 mmol) was added dropwise and the reaction
was stirred for another 30 minutes at room temperature. The
mixture was heated to reflux for 16 h. K2CO3 was filtered on
Büchner washing with acetone and the filtrate was evaporated
under reduced pressure. The product was precipitated with
petroleum ether (30 mL) and filtrated on Büchner washing the
white powder with cold petroleum ether. Yield: 92%. 1H NMR
(600 MHz, CDCl3) δ 8.07 (d, J=8.7 Hz, 2H), 7.51–7.32 (m, 8H), 7.02
(d, J=8.7 Hz, 2H), 5.37 (s, 2H), 5.13 (s, 2H). 13C NMR (151 MHz,
CDCl3) δ 166.2, 131.8, 128.7, 128.6, 128.3, 128.2, 128.1, 127.5, 114.5,
70.1, 66.5. The spectral data were identical to those reported in the
literature.[59]
1
pressure and analyzed by GC/MS or H-NMR, furnishing the desired
aldehyde (or the hemiacetal in a 1:1 diastereoisomeric mixture, see
Scheme 1).
Method B (for solid alkenes). A 80 mL MW tube was charged with a
solution of TPGS-750 M (2.5 wt% in H2O, 3 mL) and alkene
(2.25 mmol, 0.75 M). Then NaHSO3 (269 mg, 2.59 mmol ), Rh(CO)
H(PPh3)3 (42 mg, 0.045 mmol ) and Xantphos (104 mg, 0.18 mmol )
were added. The suspension was vigorously stirred for 15 minutes
under N2. The mixture was subjected to 3 cycles of vacuum/syngas
inside the microwave cavity. Syngas was added since 130 psi
°
(8.8 bar) are detected, and irradiated at 70 C for 60 minutes cooling
while heating with a fixed power of 300 Watt. After irradiation the
mixture was cooled-down to room temperature and the internal
gas released by opening the external pressure valve. The mixture
was worked up as for Method A.
4-(Benzyloxy)benzoic acid: 10 N NaOH (6 mL, 59.43 mmol) was
added to
a suspension of intermediate benzyl 4-(benzyloxy)
benzoate (2.7 g, 8.49 mmol) in MeOH (85 mL). The mixture was
heated at reflux for 1 h then concentrated under reduced pressure.
The residue was poured into H2O (50 mL) and washed with
petroleum ether (25 mL). The aqueous phase was acidified until
pH=2 with HCl 4 N until the formation of a white solid was
observed. This latter was filtered on Büchner, washed with cold H2O
When necessary, the crude was purified by chromatography on
silica gel using EtOAc in petroleum ether as the eluent (see single
methods for ratios). The yields are referred to the isolated linear
products. If not described, the branched products were not isolated
from the crude materials.
1
and dried in vacuo. Yield: 80%. H NMR (600 MHz, CD3OD) δ 7.93
4-Phenylbutanal (2a). The title compound was obtained following
general method A, starting from allylbenzene and using 10 N NaOH
during the work-up. Yield: 86%. GC/MS (m/z): 149; Rt =12.744 min
(Method A). 1H NMR (400 MHz, CDCl3): δ 9.73 (s, 1H), 7.28 (t, J=
7.3 Hz, 2H), 7.18 (q, J=7.5 Hz, 3H), 2.65 (t, J=7.2 Hz, 2H), 2.43 (t, J=
7.4 Hz, 2H), 1.95 (q, J=8 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 202.5,
141.3, 129.1, 128.9, 128.5, 128.3, 126.2, 43.2, 35.0, 23.7. The spectral
data were identical to those reported in the literature.[61]
(d, J=8.5 Hz, 2H), 7.45–7.27 (m, 5H), 6.98 (d, J=8.5 Hz, 2H), 5.12 (s,
2H). 13C NMR (151 MHz, CD3OD) δ 161.6, 131.2, 128.2, 127.7 (2 C),
127.2, 113.9, 69.7. The spectral data were identical to those
reported in the literature.[60]
N-Allyl-4-(benzyloxy)benzamide (11):
A mixture of allylamine
(539 μL, 7.18 mmol), 4-(benzyloxy)benzoic acid (1.8 g, 7.90 mmol),
EDCI (1.4 mL, 7.90 mmol) and HOBt (1.07 g, 7.90 mmol) in anhy-
drous DMF (20 mL) was stirred at room temperature for 16 h. H2O
(30 mL) was added and the mixture was extracted with Et2O (3×
30 mL). The organic layer was washed with NaClss (30 mL), dried
over dry Na2SO4, filtered and concentrated under reduced pressure.
The resulting residue was purified by flash chromatography (20%
EtOAc in petroleum ether) to give the desired product. Yield: 54%.
1H NMR (600 MHz, CD3OD): δ 7.76 (d, J=8.4 Hz, 2H), 7.43 (d, J=
7.5 Hz, 2H), 7.39 (t, J=7.5 Hz, 1H), 7.35 (d, J=7.2 Hz, 2H), 6.99 (d,
J=8.5 Hz, 2H), 6.29 (bs, 1H), 5.93 (ddt, J=16.2, 10.7, 5.6 Hz, 1H),
5.21 (dd, J=48.5, 13.6 Hz, 2H), 5.10 (s, 2H), 4.06 (d, J=5.8 Hz, 2H).
13C NMR (151 MHz, CD3OD): δ 166.9, 161.4, 136.4, 134.2, 129.0,
128.8, 128.7, 128.2, 127.5, 127.0, 125.3, 120.3, 116.5, 114.7, 109.4
70.1, 42.4.
Nonanal (21). The title compound was obtained following general
method A starting from 1-octene and using 10 N NaOH during the
work-up. Yield: 90%. GC/MS (m/z): 142; Rt =10.818 min (Method A).
1H NMR (400 MHz, CDCl3) δ 9.73 (t, J=1.8 Hz, 1H), 2.38 (td, J=7.3,
1.7 Hz, 2H), 1.61–1.57 (m, 2H), 1.26–1.23 (m, 10H), 0.84 (t, J=6.3 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 203.1, 44.0, 31.9, 29.4, 29.3, 29.2,
22.8, 22.2, 14.2. The spectral data were identical to those reported
in the literature.[62]
5-Oxopentanenitrile (22a), 3-methyl-4-oxobutanenitrile(22b)
(22a/22b 85:15). The compounds mixture was obtained following
general method A, starting from allyl cyanide and using 10 N NaOH
during the work-up. Purification: by means of chromatography on
silica gel, using an increasing gradient of EtAOc in petroleum ether,
it was not possible to isolate the linear aldehyde to the branched
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one. Yield: 41% (of the mixture). GC/MS (m/z): 98; Rt linear
aldehyde= 8.039 min; Rt branched aldehyde=8.139 min. H NMR
analysis allowed to establish the ratio between linear and branched
compound (85:15).
3,4,5-Trimethoxy-N-(2-methyl-3-oxopropyl)benzamide (27b). The
title compound was obtained following general method B, starting
from 9 and using 10 N NaOH during the work-up. Purification: 2%
MeOH in CH2Cl2. Yield: 9%. 1H NMR (600 MHz, CDCl3): δ 9.68 (s, 1H),
7.05 (s, 2H), 3.91 (s, 6H), 3.88 (s, 3H), 1.99 (ddt, J=169.1, 14.3, 7.6 Hz,
2H), 2.05–1.91 (m, 1H), 1.02 (d, J=7.4 Hz, 3H). 13C NMR (151 MHz,
CDCl3): δ 199.3, 167.1, 153.3, 141.3 129.2, 104.6, 60.9, 60.3, 56.4,
29.7, 14.1, 9.5. Elemental analysis calcd. for C14H19NO5: C, 59.78; H,
6.81; N, 4.98; O, 28.44. Found: C, 59.83; H, 6.84; N, 4.90.
1
11-(1,3-Dioxolan-2-yl)undecanal (23). The title compound was
obtained following general method A, starting from 5 and using
10 N NaOH during the work-up. Purification: 10% EtAOc in
petroleum ether. Yield: 72%. GC/MS (m/z): 242; Rt =20.425 min
(Method A). 1H NMR (600 MHz, CDCl3): δ 9.76 (s, 1H), 4.84 (t, J=
4.8 Hz, 1H), 3.96 (t, J=6.8 Hz, 2H), 3.84 (t, J=6.8 Hz, 2H), 2.41 (t, J=
7.2 Hz, 2H), 1.63 (dp, J=17.5, 7.0, 6.3 Hz, 2H), 1.41 (p, J=7.1 Hz, 2H),
1.35–1.23 (m, 14H). 13C NMR (151 MHz, CDCl3): δ 203.0, 104.7, 64.8,
43.9, 33.9, 29.5, 29.4 (2 C), 29.3 (2 C), 29.12, 24.1, 22.1. Elemental
analysis calcd. for C14H26O3: C, 69.38; H, 10.81; O, 19.80. Found: C,
69.44; H, 10.84.
2,4-Difluoro-N-(4-oxobutyl)benzamide (28). The title compound
was obtained following general method A, starting from 10 and
using 10 N NaOH during the work-up. Purification: 50% EtAOc in
1
petroleum ether. Yield: 65%. H NMR (600 MHz, CDCl3): δ 9.83 (s,
1H), 8.17–8.07 (m, 1H), 7.47 (q, J=7.5 Hz, 1H), 6.92–6.85 (m, 1H),
6.77 (bs, 1H), 3.52 (t, J=6.5 Hz, 2H), 2.60 (t, J=7.0 Hz, 2H), 1.98 (q,
J=7.1 Hz, 2H). 13C NMR (151 MHz, CDCl3): δ 202.0, 151.9, 133.8,
130.7 112.5, 112.0, 104.6, 104.1, 39.5, 23.4, 22.0. Elemental analysis
calcd. for C11H11F2NO2: C, 58.15; H, 4.88; F, 16.72; N, 6.16; O, 14.08.
Found: C, 58.20; H, 4.93; N, 6.17.
4-Oxobutyl acetate (24). The title compound was obtained
following general method A, starting from allyl benzoate and using
4 N HCl during the work-up. Yield: 81%. GC/MS (m/z): 130; Rt =
8.655 min (Method A). 1H NMR (600 MHz, CDCl3): δ 9.80 (s, 1H), 4.11
(t, J=6.2 Hz, 2H), 2.55 (t, J=6.9 Hz, 2H), 2.05 (s, 3H), 1.98 (q, J=
6.4 Hz, 2H). 3C NMR (151 MHz, CDCl3): δ 201.2, 171.0, 63.4, 40.5,
21.3, 20.9. The spectral data were identical to those reported in the
literature.[63]
4-(Benzyloxy)-N-(4-oxobutyl)benzamide (29). The title compound
was obtained following general method B, starting from 11 and
using 10 N NaOH during the work-up. Yield: 37%. 1H NMR
(600 MHz, CDCl3): δ 9.83 (s, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.58 (bs, 1H),
7.46–7.38 (m, 5H), 7.00 (d, J=7.9 Hz, 2H), 5.12 (s, 2H), 3.49 (t, J=
5.9 Hz, 2H), 2.63 (t, J=6.8 Hz, 2H), 1.98 (q, J=6.8 Hz, 2H). 13C NMR
(151 MHz, CDCl3): δ 202.3, 136.4, 129.6, 129.5, 129.4, 128.7, 128.2,
127.5, 126.9, 123.9, 114.7, 114.6, 114.5, 114.3, 70.1, 39.6, 29.7, 22.7.
Elemental analysis calcd. for C18H19NO3: C, 72.71; H, 6.44; N, 4.71; O,
16.14. Found: C, 72.66; H, 6.48; N, 4.78.
4-(1,3-Dioxoisoindolin-2-yl)butanal (25). The title compound was
obtained following general method B, starting from 7 and using
10 N NaOH during the work-up. Yield: 83%. GC/MS (m/z): 217; Rt =
21.046 min (Method A). 1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H),
7.87–7.83 (m, 2H), 7.74–7.71 (m, 2H), 3.74 (t, J=6.6 Hz, 2H), 2.54 (t,
J=6.8 Hz, 2H), 2.05–1.98 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 201.2,
168.7, 134.4, 132.3, 123.6, 41.4, 37.4, 21.5. The spectral data were
identical to those reported in the literature.[64]
N-(4-Oxobutyl)benzamide (30a). The title compound was obtained
following general procedure A, starting from 12 and using 10 N
NaOH during the work-up. Purification: 10% EtAOc in petroleum
ether. Yield: 62%. GC-MS (m/z): 191.2, Rt =15.050 min (Method A).
1H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.72
(d, J=8.4 Hz, 2H), 7.47 (dd, J=7.4, 7.4 Hz, 1H), 7.44 (dd, J=7.4,
7.4 Hz, 1H), 7.42 (dd, J=7.5, 7.4 Hz, 2H), 7.34 (dd, J=7.8, 7.7 Hz, 2H),
6.70 (bs, 1H), 6.64 (dd, J=7.5, 7.4 Hz, 1H), 6.44 (bs, 1H), 3.54 (dd, J=
6.5, 6.5 Hz, 2H), 3.53 (dd, J=6.4, 6.4 Hz, 2H), 2.65 (dd, J=6.0, 6.0 Hz,
2H), 2.59 (dd, J=7.5, 7.5 Hz, 1H), 2.58 (dd, J=7.0, 7.0 Hz, 1H), 1.92
(ddd, J=7.0, 7.0, 6.9 Hz, 2H), 1.44 (bs, 2H). 13C NMR (101 MHz,
CDCl3) δ 202.1, 170.9, 167.6, 135.7, 134.3, 131.2, 130.3, 128.4, 128.3,
127.1, 126.7, 82.3, 49.1, 41.4, 39.3, 32.1, 23.6, 21.7. The spectral data
were identical to those reported in the literature.[65]
4-(3,4-Dimethoxyphenyl)butanal (26a). The title compound was
obtained following general method A, starting from 4-allyl-1,2-
dimethoxybenzene and using 10 N NaOH during the work-up.
Purification: 10% EtAOc in petroleum ether. Yield: 65%. GC/MS
(m/z): 208; Rt =18.345 min (Method A). 1H NMR (600 MHz, CDCl3): δ
9.76 (s, 1H), 6.80 (d, J=7.9 Hz, 1H), 6.71 (d, J=9.1 Hz, 1H), 6.70 (s,
1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.61 (t, J=7.5 Hz, 2H), 2.61 (t, J=
7.5 Hz, 2H), 1.95 (p, J=7.3 Hz, 2H). 13C NMR (151 MHz, CDCl3): δ
202.4, 148.9, 147.4, 133.9, 120.3, 111.7, 111.3, 56.0, 43.1, 34.6, 23.8.
Elemental analysis calcd. for C12H16O3: C, 69.21; H, 7.74; O, 23.05.
Found: C, 69.17; H, 7.72.
3-(3,4-Dimethoxyphenyl)-2-methylpropanal (26b). The title com-
pound was obtained following general method A, starting from 4-
allyl-1,2-dimethoxybenzene and using 10 N NaOH during the work-
up. Purification: 10% EtAOc in petroleum ether. Yield: 11%. GC/MS
(m/z): 208; Rt =17.359 min (Method A). 1H NMR (600 MHz, CDCl3): δ
9.64 (s, 1H), 6.87 (d, J=6.5 Hz, 1H), 6.75 (d, J=9.9 Hz, 1H), 6.66 (s,
1H), 3.90 (s, 3H), 3.88 (s, 3H), 2.13–2.04 (m, 1H), 1.77–1.70 (m, 1H),
1.67 (q, J=8 Hz, 1 H), 0.91 (s, 3H). 13C NMR (151 MHz, CDCl3): δ
201.0 121.1, 119.7, 111.6, 111.1, 109.7, 60.4, 55.9, 22.8, 11.7, 10.3.
Elemental analysis calcd. for C12H16O3: C, 69.21; H, 7.74; O, 23.05.
Found: C, 69.19; H, 7.72.
N-(2-Methyl-3-oxopropyl)benzamide (30b). The title compound
was obtained following general procedure A, starting from 12 and
using 10 N NaOH during the work-up. Purification: 10% EtAOc in
petroleum ether. Yield: 14%. GC-MS (m/z): 191.3, Rt =16.716 min
1
(Method A). H NMR (400 MHz, CDCl3): δ 9.69 (s, 1H), 7.70 (d, J=
7.0 Hz, 2H), 7.45 (d, J=7.3 Hz, 1H), 7.41–7.36 (m, 2H), 3.78–3.43 (m,
2H), 2.77 (td, J=7.6, 4.3 Hz, 1H), 1.19 (d, J=7.5 Hz, 3H). 13C NMR
(101 MHz, CDCl3): δ 204.4, 167.6, 134.2, 131.6, 128.6, 126.9, 46.8,
39.8, 11.5.[66]
4-((tert-Butyldimethylsilyl)oxy)butanal (33). The title compound
was obtained following general method A, starting from 15 and
using 10 N NaOH during the work-up. Yield: 11%. GC/MS (m/z):
3,4,5-Trimethoxy-N-(4-oxobutyl)benzamide (27a). The title com-
pound was obtained following general method B, starting from 9
and using 10 N NaOH during the work-up. Purification: 2% MeOH
1
202; Rt =10.995 min (Method A). H NMR (400 MHz, CDCl3) δ: 5.82
(ddt, J=6.8, 10.5, 12.6 Hz, 1H), 5.05–4.92 (m, 2H), 3.61 (t, J=6.8 Hz,
2H), 2.12 (m, 2H), 1.63–1.58 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H); 13C
NMR (101 MHz, CDCl3) δ: 138.8, 114.6, 62.7, 32.1, 30.2, 26.1, 18.5,
À 5.1. The spectral data were identical to those reported in the
literature.[67]
1
in CH2Cl2. Yield: 60%. H NMR (400 MHz, CDCl3): δ 9.79 (s, 1H), 6.98
(s, 2H), 3.87 (s, 3H), 3.83 (s, 6H), 3.44 (t, J=6.3 Hz, 2H), 2.61 (t, J=
6.6 Hz, 2H), 1.94 (q, J=6.7 Hz, 2H). 13C NMR (151 MHz, CDCl3): δ
200.0, 167.1, 153.3, 141.4, 129.1, 104.6, 60.9, 60.3, 56.3, 39.9, 23.2,
22.2. Elemental analysis calcd. for C14H19NO5: C, 59.78; H, 6.81; N,
4.98; O, 28.44. Found: C, 59.80; H, 6.87; N, 4.93.
12-((tert-Butyldimethylsilyl)oxy)dodecanal (34). The title com-
pound was obtained following general method A, starting from 16
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and using 10 N NaOH during the work-up. Yield: 81%. GC/MS (m/z):
314; Rt=21.415 min (Method A). H NMR (400 MHz, CDCl3) δ=9.76
eoisomeric mixtures. The branched products, leading to the
substituted 5-membered hemiacetals, were not isolated from the
crude materials.
1
(t, J=1.9 Hz, 1H), 3.59 (t, J=6.6 Hz, 2H), 2.41 (td, J=7.4, 1.9 Hz, 2H),
1.67–1.58 (m, 2H), 1.52–1.47 (m, 2H), 1.35–1.24 (m, 14H), 0.89 (s,
9H), 0.05 (s, 6H). 13C NMR (101 MHz, CDCl3) δ=203.0, 63.4, 44.0,
33.0, 29.7, 29.6, 29.5 (3 C), 29.3, 26.1 (3 C), 25.9, 22.2, 18.5, À 5.1
(2 C). The spectral data were identical to those reported in the
literature.
6-(4-Bromophenyl)tetrahydro-2H-pyran-2-ol (40a). Prepared start-
ing from allylalcohol 39a. Yield: 40%. GC/MS (m/z): 256.8–258.2 (Br
1
isotopes), Rt = 20.251 min (Method A). H NMR (400 MHz, CDCl3) δ
7.43 (dd, J=8.4, 2.2 Hz, 4H), 7.22 (dd, J=8.6, 2.1 Hz, 4H), 5.42 (s,
1H), 4.95 (d, J=11.5 Hz, 1H), 4.88–4.78 (m, 1H), 4.43 (d, J=11.1 Hz,
1H), 2.90 (d, J=5.9 Hz, 1H), 2.51 (s, 1H), 2.06–1.99 (m, 1H), 1.93 (d,
J=11.4 Hz, 2H), 1.83–1.61 (m, 4H), 1.58–1.49 (m, 3H), 1.48–1.34 (m,
2H). 13C NMR (101 MHz, CDCl3) δ 142.1, 141.1, 131.4, 127.8, 127.7,
121.3, 121.1, 97.0, 92.4, 70.5, 33.7, 32.7, 32.4, 29.4, 22.4, 17.8.
Elemental analysis calcd. for C11H13BrO2: C, 51.38; H, 5.10; Br, 31.08;
O, 12.44. Found: C, 51.39; H, 5.10.
4-Oxobutyl benzoate (35). The title compound was obtained
following general method A, starting from 17 and using 4 N HCl
during the work-up. Yield: 61%. The reaction was analyzed through
1H NMR (600 MHz). 1H NMR (400 MHz, CDCl3): δ 9.81 (s, 1H), 8.08 (d,
J=7.5 Hz, 2H), 7.58 (t, J=7.5 Hz, 1H), 7.44 (t, J=7.7 Hz, 2H), 4.34 (t,
J=6.3 Hz, 2H), 2.61 (t, J=7.1 Hz, 2H), 2.09 (q, J=6.8 Hz, 2H). 13C
NMR (151 MHz, CDCl3): δ 194.5, 157.6, 133.7, 133.1, 130.2, 129.6,
128.5, 128.4, 63.9, 40.6, 29.7. The spectral data were identical to
those reported in the literature.[65]
4-(6-Hydroxytetrahydro-2H-pyran-2-yl)benzonitrile (40b). Pre-
pared starting from allylalcohol 39b. Yield: 57%. GC/MS (m/z):
1
203.6, Rt =20.845 min (Method A). H NMR (400 MHz, CDCl3) δ 7.56
2-Phenylpropanal (36a). The title compound was obtained follow-
ing general procedure A, starting from 12 and using 10 N NaOH
during the work-up. Purification: 10% EtAOc in petroleum ether.
Yield: 57%. GC-MS (m/z): 134.5, Rt =10.405 min (Method A). 1H
NMR (400 MHz, CDCl3) δ 9.72 (d, J=1.4 Hz, 1H), 7.44–7.37 (m, 2H),
7.30 (tt, J=7.4, 2.1 Hz, 1H), 7.24–7.18 (m, 2H), 3.65 (qd, J=7.2,
0.8 Hz, 1H), 1.41 (d, J=7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
201.2, 137.9, 129.2, 128.4, 127.7, 53.1, 14.7.
(dd, J=8.1, 3.0 Hz, 4H), 7.41 (dd, J=13.9, 8.1 Hz, 4H), 5.40 (s, 1H),
5.02 (d, J=11.6 Hz, 1H), 4.83 (d, J=9.2 Hz, 1H), 4.48 (d, J=11.1 Hz,
1H), 3.61 (bs, 1H), 3.17 (bs, 1H), 2.15–1.98 (m, 1H), 1.91 (t, J=
11.6 Hz, 2H), 1.86–1.56 (m, 5H), 1.56–1.30 (m, 4H). 13C NMR
(101 MHz, CDCl3) δ 148.5, 147.4, 132.2, 126.8, 126.6, 126.5, 126.2,
118.9, 111.1, 110.9, 96.9, 92.3, 70.3, 33.7, 32.7, 32.2, 29.4, 22.4, 17.7.
The spectral data were identical to those reported in the
literature.[68]
3-Phenylpropanal (36b). The title compound was obtained follow-
ing general procedure A, starting from 12 and using 10 N NaOH
during the work-up. Purification: 10% EtAOc in petroleum ether.
Yield: 19%. GC-MS (m/z): 134.4, Rt =11.527 min (Method A). 1H
NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 7.28–7.23 (m, 2H), 7.21–7.17 (t,
J=8.1 Hz, 3H), 2.88 (t, J=7.54 Hz, 2H), 2.75 (t, J=7.3 Hz, 2H). 13C
NMR (101 MHz, CDCl3) δ 201.6, 140.6, 128.7, 128.5, 126.3, 45.7, 28.2.
6-(4-(tert-Butyl)phenyl)tetrahydro-2H-pyran-2-ol (40c). Prepared
starting from allylalcohol 39c. Yield: 82%. GC-MS (m/z): 234.7, Rt =
20.368 min (Method B). 1H NMR (600 MHz, CDCl3) δ 7.38 (dd, J=8.3,
2.4 Hz, 4H), 7.35–7.28 (m, 4H), 5.44 (s, 1H), 5.01 (d, J=11.3 Hz, 1H),
4.86 (d, J=9.5 Hz, 1H), 4.46 (d, J=11.2 Hz, 1H), 3.33 (bs, 1H), 2.88
(bs, 1H), 2.11–2.01 (m, 1H), 1.94 (t, J=15.7 Hz, 2H), 1.85 (d, J=
13.0 Hz, 1H), 1.80–1.73 (m, 2H), 1.73–1.62 (m, 4H), 1.55 (qd, J=13.0,
3.7 Hz, 1H), 1.48–1.38 (m, 1H), 1.32 (s, 18H). 13C NMR (151 MHz,
CDCl3) δ 143.7, 141.4, 126.2, 125.9, 125.8, 125.3, 125.2, 125.0, 96.9,
94.4, 71.2, 34.5, 33.1, 32.7, 31.5, 29.6, 28.69, 22.4, 17.8. Elemental
analysis calcd. for C15H22O2: C, 76.88; H, 9.46; O, 13.65. Found: C,
76.89; H, 9.48.
(8R)-8-(6-Methoxyquinolin-4-yl)-7-oxa-1-azatricyclo[7.4.0.0[3,11]
]
tridecan-6-ol (37). The title compound was obtained following
general method B, starting from quinine 19 and using 10 N NaOH
1
during the work-up. Yield: 53%. H NMR (600 MHz, CD3OD): δ 8.63
(d, J=4.5 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.65 (d, J=4.4 Hz, 1H),
7.40 (s, 1H), 7.38 (d, J=7.5 Hz, 1H), 5.59 (d, J=7.4 Hz, 1H), 4.35 (t,
J=6.91 Hz, 1H), 3.94 (s, 3H), 3.10 (dq, J=13.0, 9.3, 7.0 Hz, 2H), 2.73–
2.62 (m, 1H), 2.45–2.35 (m, 2H), 1.86 (ddd, J=26.4, 12.6, 7.2 Hz, 2H),
1.59 (d, J=8.2 Hz, 1H), 1.53–1.37 (m, 4H), 1.27 (dt, J=11.0, 5.8 Hz,
3H). 13C NMR (151 MHz, CD3OD): δ 158.4, 149.1, 146.8, 143.4, 130.0,
126.7, 122.0, 118.7, 101.1, 98.4, 70.7, 59.5, 57.9, 55.1, 42.8, 35.0, 34.4,
29.3, 27.2, 25.8, 19.9.
6-(4-Ethylphenyl)tetrahydro-2H-pyran-2-ol (40d). Prepared start-
ing from allylalcohol 39d. Yield: 73%. GC-MS (m/z): 206.5, Rt =
18.824 min (Method B). 1H NMR (600 MHz, CDCl3) δ 1H NMR
(600 MHz, CDCl3) δ 7.28 (dd, J=12.8, 6.0 Hz, 4H), 7.22–7.14 (m, 4H),
5.47 (s, 1H), 4.93 (d, J=9.3 Hz, 1H), 4.81 (d, J=11.3 Hz, 1H), 4.44 (d,
J=11.0 Hz, 1H), 3.11–3.00 (m, 1H), 2.72 (dd, J=15.0, 7.4 Hz, 1H),
2.65 (q, J=6.8 Hz, 2H), 2.13–2.05 (m, 2H), 1.97 (d, J=10.1 Hz, 2H),
1.92–1.59 (m, 6H), 1.59–1.41 (m, 2H), 1.24 (t, J=7.7 Hz, 3H). 13C NMR
(151 MHz, CDCl3) δ 143.6, 141.3, 129.1, 128.2, 127.9 (2 C), 125.9,
125.3, 97.6, 93.1, 70.9, 33.7, 32.7, 29.4, 28.6, 22.4, 17.7. Elemental
analysis calcd. for C13H18O2: C, 75.69; H, 8.80; O, 15.51. Found: C,
75.68; H, 8.78.
5-Methyl-5-(4-methylpent-3-en-1-yl)tetrahydrofuran-2-ol (38). The
title compound was obtained following general method A, starting
from linalool 20 and using 10 N NaOH during the work-up. Yield:
78%. GC/MS (m/z): 184; Rt =13.887 min (Method A). 1H NMR
(600 MHz, CDCl3): δ 5.49 (bs, 1H), 5.40 (t, J=6.9 Hz, 1H), 5.11 (t, J=
7.0 Hz, 1H), 3.64 (s, 3H), 2.10–1.95 (m, 4H), 1.91 (dq, J=17.1, 7.2,
5.8 Hz, 2H), 1.68 (s, 3H), 1.61 (s, 3H), 1.46 (ddt, J=10.6, 7.2, 4.2 Hz,
2H). 13C NMR (151 MHz, CDCl3): δ 124.6, 99.9, 84.2, 70.6, 42.8, 41.9,
34.8, 28.2, 25.7, 23.6, 17.6. Elemental analysis calcd. for C11H20O2: C,
71.70; H, 10.94; O, 17.36. Found: C, 71.75; H, 10.89.
6-(4-Fluorophenyl)tetrahydro-2H-pyran-2-ol (40e). Prepared start-
ing from allylalcohol 39e. Yield: 85%. GC/MS (m/z): 196.3, Rt =
16.523 min (Method A). 1H NMR (400 MHz, CDCl3) δ 7.30 (dt, J=8.9,
8.0 Hz, 4H), 6.99 (t, J=7.8 Hz, 4H), 5.42 (s, 1H), 4.97 (d, J=11.6 Hz,
1H), 4.85 (dd, J=8.4, 6.9 Hz, 1H), 4.44 (d, J=11.3 Hz, 1H), 3.02 (d,
J=5.9 Hz, 1H), 2.62 (s, 1H), 2.01 (t, J=12.1 Hz, 1H), 1.98–1.85 (m,
2H), 1.84–1.62 (m, 6H), 1.51–1.31 (m, 3H). 13C NMR (151 MHz, CDCl3)
δ 162.9, 161.3, 138.8, 137.9, 127.8, 127.7, 127.6, 115.2, 115.1, 96.9,
92.4, 77.9, 70.5, 33.8, 32.8, 32.3, 29.4, 22.4, 17.8. Elemental analysis
calcd. for C11H13FO2: C, 67.33; H, 6.68; F, 9.68; O, 16.31. Found: C,
67.40; H, 6.73.
General methods for the synthesis of cyclic hemiacetals
The following hemiacetalic compounds were all synthesized
following general method A, using 10 N NaOH in the work-up. The
crude compounds were purified by means of chromatography on
silica gel eluting with a very slow 5–75% gradient of EtAOc in
petroleum ether, if not otherwise specified. The yields are referred
to the isolated 6-membered hemiacetals, obtained as 1:1 diaster-
6-(4-Nitrophenyl)tetrahydro-2H-pyran-2-ol (40f). Prepared starting
from allylalcohol 39f. Yield: 41% GC/MS (m/z): 223.6 Rt =
1
19.357 min (Method A). H NMR (400 MHz, CDCl3) δ 8.22–8.16 (m,
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4H), 7.60–7.45 (m, 4H), 5.50 (s, 1H), 5.13 (dd, J=12, 2.4 Hz, 1H),
4.95–4.90 (m, 1H), 4.61 (dd, J=11.4, 2.2 Hz, 1H), 3.02 (bs, 1H), 2.62
(bs, 1H), 1.38–1.62 (m, 2H), 1.66–2.20 (m, 4H), 2.12–1.92 (m, 2H),
1.91–1.72 (m, 6H), 1.58–1.41 (m, 4H). 13C NMR (101 MHz, CDCl3) δ
150.4, 149.2, 147.1, 147.0, 126.5, 123.5, 96.9, 92.2, 70.1, 33.8, 32.8,
32.1, 29.3, 22.3, 17.6. The spectral data were identical to those
reported in the literature.[69]
1-(3,4-Dichlorophenyl)tetrahydro-2H-pyran-2-ol (40l). Prepared
starting from allylalcohol 39l. Yield: 25%. GC/MS (m/z): 246.0
(246.9) À 247.6 (248.5) (Cl isotopes), Rt = 18.550 min (Method B). H
1
NMR (600 MHz, CDCl3) δ 7.47 (d, J=22.1 Hz, 2H), 7.42–7.36 (m, 2H),
7.17 (dd, J=16.8, 8.2 Hz, 2H), 5.43 (s, 1H), 4.97 (d, J=11.6 Hz, 1H),
4.85 (d, J=9.6 Hz, 1H), 4.44 (d, J=11.4 Hz, 1H), 2.77 (bs, 2H), 2.11–
2.01 (m, 2H), 1.95 (t, J=13.1 Hz, 2H), 1.87–1.63 (m, 4H), 1.55–1.48
(m, 2H), 1.46–1.38 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 143.4, 142.3,
132.4, 131.3, 131.1, 130.3, 128.1, 128.0, 125.4, 125.2, 96.9, 92.4, 69.9,
33.7, 32.7, 32.3, 29.4, 22.3, 17.7. Elemental analysis calcd. for
C11H12Cl2O2: C, 53.47; H, 4.89; Cl, 28.69; O, 12.95. Found: C, 53.40; H,
4.85.
6-Phenyltetrahydro-2H-pyran-2-ol (40g). Prepared starting from
allylalcohol 39g. Yield: 51%. GC/MS (m/z): 178.5, Rt =16.457 min
(Method B). 1H NMR (600 MHz, CDCl3): δ 7.38–7.26 (m, 10H), 5.44 (s,
1H), 5.02 (dd, J=12.0, 2.0 Hz, 1H), 4.88–4.85 (m, 1H), 4.48 (d, J=
11.5, 1H), 3.29 (s, 1H), 2.84 (bs, 1H), 2.08–1.39 (m, 12H); 13C NMR
(151 MHz, CDCl3): δ 142.9, 142.0, 128.3, 127.5, 127.4, 126.0, 125.9,
96.9, 92.4, 78.6, 71.1, 33.6, 32.7, 32.3, 29.4, 22.5, 17.9. The spectral
data were identical to those reported in the literature.[69]
Acknowledgements
6-(2-Fluorophenyl)tetrahydro-2H-pyran-2-ol (40h). Prepared start-
ing from allylalcohol 39h. Yield: 76%. GC/MS (m/z): 196.4, Rt =
16.242 min (Method A). 1H NMR (400 MHz, CDCl3) δ 7.48 (dt, J=
30.3, 7.5 Hz, 2H), 7.25–7.15 (m, 2H), 7.10 (td, J=6.9, 4.4 Hz, 2H),
7.03–6.93 (m, 2H), 5.41 (s, 1H), 5.35 (d, J=11.6 Hz, 1H), 4.87–4.80 (m,
1H), 4.77 (d, J=11.2 Hz, 1H), 3.57 (d, J=5.7 Hz, 1H), 3.07 (s, 1H),
2.08–2.02 (m, 1H), 1.94–1.84 (m, 3H), 1.65 (m, 4H), 1.55 (dd, J=11.8,
3.6 Hz, 1H), 1.48–1.35 (m, 3H). 13C NMR (151 MHz, CDCl3) δ 160.6,
158.5, 130.1, 129.8, 128.8, 128.7, 127.4, 124.3, 123.9, 115.2, 115.1,
102.0, 97.7, 97.1, 93.1, 92.5, 71.8, 64.8, 32.4, 32.4, 31.8, 31.7, 29.7,
29.6, 29.5, 29.3, 22.7, 22.5, 18.4, 17.8. Elemental analysis calcd. for
C11H13FO2: C, 67.33; H, 6.68; F, 9.68; O, 16.31. Found: C, 67.37; H,
6.70.
This work was supported in part by the Italian Ministero
dell’Istruzione, dell’Università e della Ricerca (MIUR) in the context
of the projects PRIN2015LZE994 and “Development and applica-
tion of QM/MM technologies for the design of light responsive
proteins or protein-mimics based on rhodopsin architecture”
within the program “Dipartimenti di Eccellenza – 2018–2022”. A
special thanks to Prof. Maurizio Taddei for discussions and
suggestions. Thanks to Elisabetta Monciatti and Dr. Andrea Bernini
for helping with NMR studies.
1-(3-Phenoxyphenyl)tetrahydro-2H-pyran-2-ol (40i). Prepared
starting from allylalcohol 39i. Yield: 78%. GC-MS (m/z): 270.0, Rt =
22.205 min (Method B). H NMR (600 MHz, CDCl3) δ 7.37–7.24 (m,
Conflict of Interest
1
6H), 7.16–6.98 (m, 10H), 6.98–6.85 (m, 2H), 5.46 (s, 1H), 4.94 (d, J=
9.4 Hz, 1H), 4.80 (d, J=10.4 Hz, 1H), 4.43 (d, J=11.1 Hz, 1H), 3.76 (s,
1H), 2.55 (bs, 1H), 2.12–2.00 (m, 2H), 1.96 (s, 2H), 1.91–1.55 (m, 6H),
1.55–1.38 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 145.4, 144.4, 129.7,
123.2, 123.1, 120.9, 119.0, 118.8, 117.8, 117.8, 117.7, 116.8, 97.6,
94.2, 71.1 33.3, 32.6, 31.0, 29.5, 22.7, 18.2. Elemental analysis calcd.
for C17H18O32: C, 75.53; H, 6.71; O, 17.76. Found: C, 75.52; H, 6.67.
The authors declare no conflict of interest.
Keywords: Hydroformylation · micellar catalysis · microwave ·
cyclic acetals
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4H), 7.39 (t, J=7.5 Hz, 4H), 7.34 (d, J=7.2 Hz, 2H), 7.28–7.24 (m, 2H),
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(dd, J=13.2, 3.5 Hz, 2H), 1.52 (dd, J=12.8, 3.4 Hz, 1H), 1.49–1.39 (m,
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pared starting from allylalcohol 39k. Yield: 40%. GC-MS (m/z):
1
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121.5, 121.3, 107.6, 107.5, 97.7, 93.2, 72.5, 65.2, 60.7, 56.0, 32.6, 31.2,
29.6, 25.9, 23.0, 18.7. Elemental analysis calcd. for C14H20O: C, 62.67;
H, 7.51; O, 29.81. Found: C, 62.66; H, 7.46.
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ChemCatChem
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Manuscript received: February 3, 2021
Revised manuscript received: March 16, 2021
Accepted manuscript online: March 24, 2021
Version of record online: ■■■, ■■■■
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FULL PAPERS
F. Migliorini, F. Dei, M. Calamante,
Dr. S. Maramai, Prof. E. Petricci*
1 – 14
Micellar Catalysis for Sustainable
Hydroformylation
Without purifications: A fully sustain-
able and generally applicable protocol
for the regioselective hydroformyla-
tion of terminal alkenes, using cheap
commercially available catalysts and
ligands, in mild reaction conditions
was developed. The process can take
advantages from both micellar
catalysis and microwave irradiation to
obtain the linear aldehydes as the
major or sole regioisomers in high
yields. The reaction is efficient even in
large scale the catalyst and micellar
water phase being reused at least 5
times without any impact in reaction
yields.