Continuous Endoperoxidation of Conjugated Dienes and Subsequent Rearrangements Leading to C-H Oxidized Synthons

Article abstract of DOI:10.1021/acs.joc.8b01307

We have investigated the continuous flow photooxidation of several conjugated dienes and subsequent rearrangement using a practical and safe continuous-flow homemade engineered setup. End-to-end approaches involving endoperoxidation, Kornblum-DeLaMare rearrangement, and additional rearrangements are comprehensively detailed with optimization, scope, and scale-up to obtain useful hydroxyenones, furans, and 1,4-dicarbonyl building blocks.

Full text of DOI:10.1021/acs.joc.8b01307

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Featured Article
Continuous endoperoxidation of conjugated dienes, and
subsequent rearrangements leading to C-H oxidized synthons
Juliana Maria de Souza, Timothy J Brocksom, D. Tyler McQuade, and Kleber Thiago de Oliveira
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01307 • Publication Date (Web): 02 Jun 2018
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Continuous endoperoxidation of conjugated dienes, and
subsequent rearrangements leading to C-H oxidized synthons
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Juliana M. de Souza, Timothy J. Brocksom, D.Tyler McQuade and Kleber T.
1
de Oliveira *
1.
Carlos, SP, 13565ꢀ905, Brazil.
Department of Chemical and Life Science Engineering, Virginia
Commonwealth University, Richmond, VA, 23284ꢀ3068, USA.
. Centro de Ciências Naturais e Humanas, Universidade Federal do ABC,
Departamento de Química, Universidade Federal de São Carlos, São
2.
3
Santo André, SP, 09210ꢀ580, Brazil.
*Eꢀmail: kleber.oliveira@ufscar.br
ABSTRACT
We have investigated the continuous flow photooxidation of several conjugated
dienes, and subsequent rearrangement using a practical and safe continuousꢀ
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flow homemade engineered setup. Endꢀtoꢀend approaches involving
endoperoxidation, KornblumꢀDeLaMare (KDM) rearrangement and additional
rearrangements are comprehensively detailed with optimization, scope and
scaleꢀup, to obtain useful hydroxyꢀenones, furans and 1,4ꢀdicarbonyl building
blocks.
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Keywords: photooxygenations, endoperoxides, endꢀtoꢀend continuous flow
setups, rearrangements, KornblumꢀDeLaMare (KDM) rearrangement
INTRODUCTION
Photocatalyzed reactions involving singlet oxygen (¹O ) have been
2
1
described for more than 70 years, although the nature of this transformation
was not well recognized at that time. It is noteworthy that studies on the excited
state of molecular oxygen were a landmark for better understanding of
2
photooxygenation reactions as well as their applications in the synthesis of
3
natural products and drugs.
This reaction is a powerful ally in the synthesis of oxygenated structures
(hydroperoxides, peroxides, dioxetanes, endoperoxides and sulfoxides),
promoting carbonꢀoxygen and heteroatomꢀoxygen bond formation, besides high
4
atomꢀeconomy and low cost. In this context, [4+2] and [2+2] cycloadditions,
5
ene reactions and heteroatom oxidations can be performed. Dyeꢀsensitized
3
photoexcitation of triplet oxygen ( O
2
) employing porphyrinoid compounds is
6
already well known, and is among the most efficient organic photocatalysts
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capable of generating singlet oxygen ( O
2
) in situ in photooxygenation
reactions.
Despite molecular oxygen being a sustainable, naturally occurring and
inexpensive reagent, there are some experimental limitations with regard to the
potential hazards of flammable solventꢀoxygen mixtures, and the same holds
true for reactions involving potentially explosive intermediates, such as
endoperoxides. In addition, photochemical batch reactions do not present
homogeneous irradiation despite the fact that dilute mediums are necessary to
avoid many side reactions. All these factors have made scaledꢀup
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photooxygenations and their industrial use not a simple task.
Continuous flow approaches have been applied with success to
transformations with ¹O , from the use of methodologies that involve higher
2
technological challenges, such as the use of supercritical carbon dioxide as the
reaction medium, to simpler and more accessible assemblies using “homeꢀ
8
engineered” reactors for improving the efficiency and safety. Many advantages
such as controlled mixing, fast heat transfer, residence time control, process
automation and intensification and easy scaleꢀup can be observed by using this
9
enabling technology.
Although the formation and rearrangement of endoperoxides have been
10
extensively studied, the use of continuous flow conditions has not been well
8
explored. For example, the KornblumꢀDeLaMare (KDM) rearrangement is a
very versatile transformation in organic synthesis which allows an umpolung
modification on the endoperoxide structure, but with serious restrictions of its
11,12
use due to safety issues and difficulties to scale up the reactions.
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Herein, we report a methodological study on endoperoxidation reactions
of variably substituted dienes followed by the KDM rearrangement and other
transformations in a continuous flow regime, stepꢀbyꢀstep or by endꢀtoꢀend
approaches. For this, a homemade photochemical reactor as well as a gasꢀ
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liquid flow reactor made with a semipermeable Teflon AFꢀ2400 membrane
(tubeꢀinꢀtube) were set up, making use of simple and accessible materials. The
latter has been successfully applied to several organic transformations under
continuous flow conditions with reactive gases, which facilitates their transfer
13
into liquid streams.
Variables such as different photocatalyst loading,
substrate concentrations, oxygen pressure, flow rates and temperatures of the
rearrangements were evaluated. Moreover, application of the developed
methodology is shown to achieve important synthetic intermediates.
RESULTS AND DISCUSSION
The studies were initiated by the evaluation of the endoperoxidation
conditions for cisꢀ1,3ꢀcyclooctadiene (1) (Scheme 1) using both homemade
batch and continuous flow photoreactors (see details in the supporting
information). Cyclooctadiene (1) was selected for the methodology development
due to its wellꢀknown endoperoxide stability, which would enable the evaluation
of a series of variables and reaction conditions. After some exploratory tests in
batch, continuous flow studies were started using the assembly shown in
Scheme 1. Pump A was used to inject the solution containing 1 and mesoꢀ
3 2 2
tetraphenylporphyrin (TPP) in CH CN:CH Cl (2:1) through the tubeꢀinꢀtube
reactor pressurized with O . Firstly, we decided to carry out the
2
photooxygenation (Step 1) under continuous flow conditions and study the KDM
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rearrangement (Step 2) in batch, in a simultaneous manner by reacting the
endoperoxide 2 after collection. To do so, a syringe pump (Pump B) was used
to slowly inject a DBU solution (1 eqv.) as an attempt to simulate future endꢀtoꢀ
end transformation experiments. In this setup, a 100 psi back pressure regulator
1
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(
BPR) was also adapted at the end of the photochemical reactor, thus enabling
the endoperoxidation to occur in a pressurized medium with high amounts of
dissolved oxygen (ca. 1:1 v/v).
Scheme 1. Diene 1 photooxygenation and KornblumꢀDeLaMare rearrangement
–
Flow/Batch setup for the initial studies.
ꢀ
Three flow rates (0.25, 0.50 and 1.0 mL.min ¹) were evaluated (Tables 1ꢀ3) in
order to find the best residence time for the endoperoxidation step. For the
ꢀ
1
batch KDM rearrangement (step 2), a 0.4 mol.L DBU solution at reduced flow
ꢀ1
o
(
0.025ꢀ0.05 mL.min ) was employed keeping the batch transformation at 40 C;
the DBU flow rate was maintained ten times lower in relation to the diene
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solution flow rate in order to avoid a very large dilution during the
rearrangement. After collecting the whole reaction content, the reaction was
maintained at 40°C for 45 min in all experiments until all the endoperoxide 2
had been consumed.
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The results obtained at 1.0 mL.min ¹ flow rate (Pump A) are depicted in Table 1
(residence time = 23 min). From 0.1 to 0.5 mol% of TPP no significant
differences in the yields were obtained (21ꢀ36%) with the best productivity (9.6
ꢀ
1
g.day ) and yield (36%) as shown in entry 4 (Table 1). However, given the low
residence time in the photochemical reactor, the diene 1 was partially recovered
in all the conditions.
ꢀ
1
Table 1. Checking of TPP loading at 1.0 mL.min (Pump A)
a,b,c
Entry
TPP
mol%)
Yield (3)
(%)
Throughput
(g⁄day)
(
1
2
3
4
5
0.1
0.2
0.3
0.4
0.5
21
29
34
5.5
7.5
9.1
d
d
36/35
9.6/9.3
33
8.6
a
b
c
d
ꢀ1
3
3 2 2
mmol of the substrate 1 in a mixture CH CN/CH Cl (2:1), 75 mL at 0.04 mol.L
1 equiv of DBU for the batch rearrangement step (step 2)
photoreactor residence time = 23 min
double checked experiment for reproducibility confirmation
ꢀ
We then tested a flow rate of 0.5 mL.min ¹ (residence time = 46 min ꢀ Table 2)
and obtained significant yield increases (37ꢀ62%) with a throughput of 7.7
ꢀ
1
g.day for TPP at 0.4mol% (entry 4), as the best result balancing yield,
productivity and the lower TPP loading.
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Table 2. Checking of TPP loading at 0.5 mL.min (Pump A)
a,b,c
Entry
TPP
mol%)
Yield (3)
(%)
Throughput
(g⁄day)
(
1
2
3
4
5
0.1
0.2
0.3
0.4
0.5
37
44
53
4.9
5.8
7.0
d
d
56/59
7.4/7.7
62
8.2
a
b
c
d
ꢀ1
3
1
mmol of the diene 1 in a mixture CH
3 2 2
CNꢁCH Cl (2:1), 75 mL at 0.04 mol.L
equiv of DBU for the batch rearrangement step (step 2)
photoreactor residence time = 46 min
double checked experiment for reproducibility confirmation
ꢀ
Finally, the flow rate was reduced to 0.25 mL.min ¹ and further improvements in
yields were observed (60ꢀ78%, residence time = 92 min ꢀ Table 3), however,
ꢀ
with lower productivity compared to the previous flow at 0.5 mL.min ¹. In view of
these results, we selected the conditions of entry 4, Table 2, as the optimized
condition.
ꢀ
1
Table 3. Checking of TPP loading at 0.25 mL.min (Pump A)
a,b,c
Entry
TPP
(mol%)
Yield (3) (%)
Throughput
(g⁄day)
1
2
3
4
5
0.1
0.2
0.3
0.4
0.5
60
67
72
4.0
4.4
4.8
d
d
74/77
4.9/5.0
78
5.1
a
b
ꢀ1
3 mmol of the diene 1 in a mixture CH CNꢁCH Cl (2:1), 75 mL at 0.04 mol.L
3
2
2
1
equiv of DBU for the batch rearrangement step (step 2)
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c
photoreactor residence time = 92 min
d
double checked experiment for reproducibility confirmation
Two additional variables were analyzed in order to check the influence of diene
1
concentration (Table 4, residence time = 46 min), as well as the influence of
2
pressure in the tubeꢀinꢀtube reactor. In the evaluated conditions, the
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O
increase of the diene 1 concentration decreases both the yields and throughput,
ꢀ
1
which lead us to select the concentration of 0.04 mol.L as the highest
acceptable charge of starting material. It is important to note that in entries 3ꢀ7
(
Table 4), precipitation of the photocatalyst TPP was observed. However, even
under conditions where TPP remained solubilized (entry 6, Table 4) the results
were not higher than those of entry 2, Table 4, which are identical to those of
entry 4, Table 2, as previously optimized. The influence of different oxygen
pressures was evaluated by using all the previous optimized conditions and
keeping the pressure into the tubeꢀinꢀtube membrane reactor at 4, 6 or 8 bar,
with no significant changes in yields (54ꢀ58%); we decided to keep 6 bar (56%)
2
as the normal pressure of O .
Table 4. Influence of different diene 1 concentration
a,b
c
Entry
[1]
Yield (3) (%)
Throughput
(g⁄day)
-
1
(
mol.L )
1
2
3
4
5
0.02
0.04
0.08
0.08
0.12
50
6.6
d
d
56/59
7.4/7.7
e
47
6.1
6.5
5.0
f
49
e,f
38
g
g
g
g
6
0.12
40
5.2
a
b
c
d
1
equiv of DBU for the batch rearrangement step (step 2)
photoreactor residence time = 46 min and flow rate at 0.5 mL.min (Pump A)
using CH CNꢁCH Cl (2:1) mixture as solvent and 0.4 mol% of TPP
ꢀ1
3
2
2
double checked experiment for reproducibility confirmation
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e
f
we observed partial TPP precipitation
1:1 CH CN
̸
CH Cl mixture was used to avoid TPP precipitation.
3
2
2
g
carried out in CH
2
Cl
2
.
The KornblumꢀDeLaMare rearrangement, is often performed with basic
catalysis and heating, but depends upon the endoperoxide preparation. It is
noteworthy that this rearrangement has been little explored, due to the relative
instability (may be explosive) of the endoperoxide substrate and, to date, there
are no reports on continuous flow studies or even scaled up protocols. In our
hands, the initial endoperoxidation of diene 1 in the presence of DBU (catalyst
for the second step) does not occur, probably due to the photochemical
quenching that DBU causes in TPP, thus preventing the formation of singlet
oxygen. Therefore, an integration of the separate steps is necessary for having
an endꢀtoꢀend protocol.
1
1
1
1
1
1
1
1
1
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These studies were initiated using a 250 ꢂL microchip for the rearrangement
step (Scheme 2A). For the optimization under continuous flow conditions, the
purified endoperoxide 2 was used to evaluate separately how it is processed,
without any losses caused by byproducts from the photooxygenation stage.
The flow rate of 2 and the temperature of the KDM rearrangement were the
ꢀ
1
o
same as previously optimized (0.5 mL.min and 40°C). However, at 40 C
(
residence time = 30 s) the endoperoxide 2 was not completely converted to 3.
o
Rearrangement temperatures were raised to 90ꢀ180 C (Scheme 2A), obtaining
o
the best result at 140 C (84% yield). Despite the success of this last result,
occasional clogging of the microchip reactor was observed. In order to solve
this problem, the KDM rearrangement was also performed using a 16 mL
tubular stainlessꢀsteel reactor (1/8 inch OD) (Scheme 2B) giving the product 3
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o
in 90% yield at 60 C (residence time = 32 min) in a more robust and
reproducible manner.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2. Continuous KDM rearrangement optimizations. A) using a 250ꢂL
microchip; B) using a 16 mL stainless steel coil reactor.
Telescoping of the two steps was performed (Scheme 3) with an additional loop
at the beginning of the setup in order to avoid direct contact of the reagents with
the pump (more details in the supporting information). The first endꢀtoꢀend
experiment using all the previously optimized steps (Scheme 3) yielded
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compound 3 in 55% (isolated yield). When compared to the yields of the
independent steps (59% and 90%) the overall yield was slightly better thus
confirming the efficiency of the endꢀtoꢀend setup.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Endꢀtoꢀend setup for photooxygenation followed by KDM
rearrangement.
We have also tested the process intensification of this endꢀtoꢀend protocol
carrying out a longꢀrunning experiment using the reactors for almost 9h in a
continuous steady state mode (setup – Scheme 3). The scaleꢀout from 3 mmol
to 10 mmol was accomplished giving the product 3 in 63% overall yield (ca 1.0
g). It is important to highlight that in very similar batch conditions (see details in
the supporting information) and using the same residence times of the flow
setup, compound 3 was obtained in only 16% yield, showing the significant
advantages of our continuous setup.
Reaction scope
1
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1
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1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The substrates were chosen to explore their different reactivities, the relative
instabilities of the endoperoxide intermediates, as well as the tolerance of
functional groups and possible applications of the rearranged products (Table
5).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
For the scope development, as expected, some modifications in the
methodology were needed for some substrates, as can be seen in Table 5.
These small changes, especially in the KDM rearrangement temperatures, were
carried out only when necessary. During the execution of the scope studies,
exploratory experiments of isolated steps under continuous conditions were
carried out in order to check the total consumption of the substrates,
endoperoxide formation and rearrangements.
Table 5. Scope for the developed protocol.
KDM
Overall
Base
Entry
Diene
Endoperoxide
reaction
Product
Yield
(1eqv)
o
a
T( C)
(%)
1
DBU
DBU
60
60
55
92
2
3
DBU
25
36
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DBU
or
4
5
Complex mixture
ꢀ
3
Et N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
b
DBU
DBU
60(80)
29(67)
O
O
c
6
25
10
14
14
O
O
d
7
8
9
Et
3
N
25(0)
13(29)
DBU
DBU
25
15
O
O
e
60
74
23
10
DBU
60
96
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1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
OH
OH
OH
OH
OH
11
DBU
80
+
38
2
9
30 (17%)
31 (21%)
0
1
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7
8
9
0
1
2
3
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
12
DBU
DBU
80
60
32
22
1
3
4
1
Complex mixture
Complex mixture
ꢀ
ꢀ
ꢀ
ꢀ
-
-
ꢀ
ꢀ
15
16
DBU
or
25
25
Complex mixture
Complex mixture
ꢀ
ꢀ
Et N
3
DBU
or
1
7
8
Et
3
N
1
Et
3
N
60
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Et N
3
and
60
after,
f
19
42
PTSA
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
Et N
and
after,
PTSA
g
20
0
0
29
3
Et N
and
after,
PTSA
f
21
58
42
80
22
Et
3
N
N
25
60
23
Et
3
a
b
c
d
isolated yield after purifications by chromatography.
o
º
2
9% yield with the rearrangement temperature at 60 C and 67% yield at 80 C.
in the presence of DBU only the dimer 28 is formed.
3
The KDM rearrangement performed in the presence of Et N yielded exclusively the hydroxyꢀ
º
enone 17 at 25 C (13% yield) and at 0ºC the yield was improved to 29%.
e
2 2 3
the reaction was performed in CH Cl due to the precipitation of anthraquinone (23) in CH CN,
which caused clogging.
f
in this case the reaction was performed starting from a solution of diene at 0.04 M and 0.4
ꢀ
1
ꢀ1
mL.min (PUMP A). Et
3
N solution (0.4 M) was pumped at 40ꢂL.min (PUMP B), and PTSA
ꢀ1
solution (0.05M) was pumped at 0.4 mL.min . It was necessary for a complete starting material
consumption in the photooxygenation step.
g
in this case the reaction was performed starting from a solution of diene at 0.04 M and 0.25
ꢀ1
ꢀ1
3
mL.min (PUMP A). Et N solution (0.4 M) was pumped at 0.025 mL.min (PUMP B), and PTSA
ꢀ
1
solution (0.05M) was pumped at 0.25 mL.min . It was necessary for a complete starting
material consumption in the photooxygenation step.
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In entry 2, it was possible to apply the standard optimized conditions and
convert cycloheptadiene 4 to the hydroxyenone 6 in 92% overall yield.
Cycloheptatriene (7) was efficiently photooxygenated, and the endoperoxide 8
was converted to the corresponding hydroxyenone (entry 3), and after water
elimination, tropone (9) was obtained in 36% overall yield. This result is quite
relevant due to the number of steps performed in a single process, as well as
the lack of more efficient methodologies in the literature for the production of
0
1
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8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
14
this important synthetic intermediate. The use of tropone (9) as the diene
(entry 4) did not yield any rearrangement product that could be isolated,
although we isolated the corresponding endoperoxide 10 (58%) in an
exploratory photooxygenation experiment. In entry 5, the product 13 was
obtained starting from 11 in 29% yield when the rearrangement step was
carried out at 60°C, however, when the rearrangement temperature was
adjusted to 80°C the compound 13 was obtained in 67% yield.
The photooxygenation of diene 14 was monitored in an experiment under
continuous flow conditions in which we wanted to evaluate only the occurrence
of endoperoxidation under the optimized parameters of the methodology, and
total consumption of the starting material was observed. By using DBU (entry 6)
for the rearrangement step only traces of the product 17 were observed, with
3
preferential formation of dimer 16 (10%). On the other hand, by using Et N
(entry 7), the dimer 16 was not detected, occurring preferential formation of 17
in 13% yield by keeping the rearrangement temperature at 25°C, or 29% yield
at 0°C; it is important to highlight that compound 17 is considered an important
15
intermediate in the synthesis of myoꢀinositol.
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The reaction of diene 18 produced catechol (20) in 15% overall yield (entry 8).
In this case, loss of the TMS protective group and aromatization were observed.
There are examples in the literature in which silicon protections can be removed
16
in the presence of DBU.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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9
0
1
2
3
4
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8
9
0
Reaction of substrates 21 and 24 (entries 9 and 10) efficiently yielded products
23 and 26 in 74 and 96% yields, respectively. It is noteworthy that in the case of
substrate 21 an additional oxidation of the hydroxyꢀketone intermediate was
observed since only anthraquinone 23 was isolated (74% yield).
Some derivatives with acyclic or with at least one exocyclic double bond such
27, 32, 37 and 41 were also tested and are shown in entries 11ꢀ14. In entries 11
and 12, two semiꢀsynthetic dienes 27 and 32 were tested. In both cases, there
was complete consumption of the dienes, and stable and isolable
endoperoxides were observed. However, attempts to isolate the KDM
rearrangement products 29 and 34 were not successful. Due to the possibility of
degradation of the possible aldehydes 29 and 34, it was decided to react the
crude reaction mixture with NaBH
corresponding 30 (17%) and 31 (21%) diols (entry 11), and 35 (15%) and 36
17%) (entry 12). Similarly, the reaction of the diene 37 yielded a stable
4
(2 eqv), thus allowing to isolate the
(
endoperoxide intermediate 38 (52%), and in an endꢀtoꢀend experiment gave the
compounds 39 + 40 (2:1) in 22 % yield (entry 13).
As somewhat expected, isoprene (41) (entry 14) and cyclopentadiene (42)
(
entry 15) yielded complex mixtures in the first step, probably due to the
occurrence of various organic peroxides and [2 + 2] cycloaddition products with
17
singlet oxygen or endoperoxide thermal rearrangements at room temperature.
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
3
4
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4
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5
5
5
5
5
6
Dienes 43 and 45 (entries 16 and 17) yielded the respective endoperoxides 44
and 46 during the exploratory experiments of the photooxygenation step,
however, in the endꢀtoꢀend processes only complex mixtures were obtained.
As shown in entry 17, endoperoxide 46 was efficiently prepared and isolated in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
57% yield in exploratory experiments, however, a very complex mixture
occurred in the rearrangement step. In an attempt to circumvent this problem,
we decided to protect the alcohol 45 with a benzyl group, yielding the diene 47.
The photooxygenation of 47 (entry 18) similarly yielded the corresponding
endoperoxide and attempts to perform the KDM rearrangement in the presence
3
of Et N or DBU (endꢀtoꢀend protocol) gave rise to a relatively polar major
product (possible ketoꢀalcohols 49 or 50). When we tried to characterize 49/50
1
by HꢀNMR in CDCl it was possible to confirm the formation of furan 51, and
3
TLC analyzes of the initial reaction product and sample after the NMR analysis
indicated that they were different substances. Therefore, the possibility that
furan 51 was formed in CDCl
confirm this, a sample of the reaction mixture (49/50) was treated with PTSA
1.2 equiv to neutralize the DBU and keep the medium slightly acid) in batch,
3
was considered (possibly acid catalysis). To
(
thus confirming the acid catalyzed formation of furan 51. Bearing in mind the
importance of this multistep transformation, we decided to adapt the flow setup
with an inꢀline workup containing PTSA (Scheme 4) and the diene 47 was
efficiently converted directly into the furan 51 in 42% overall yield (entry 19).
Dienes 52 and 55 were also submitted to the endꢀtoꢀend reaction conditions of
Scheme 4 and generated 54 (29%) and 57 (58%), respectively, demonstrating
the possibility of a continuous endꢀtoꢀend production of different substituted
furans (entries 20 and 21). Similar results involving furan chemistry have been
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reported in the literature, but never under continuous conditions or even in an
18, 19
endꢀtoꢀend protocol.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Continuous endꢀtoꢀend assembly for furan synthesis, and probable
mechanism of the furan formation.
Relevant results were observed starting from diene 52 and 55, in which the
respective furans 54 (29% yield) and 57 (58% yield) are obtained if the KDM
rearrangement is carried out at 0°C with further inꢀline treatment with PTSA
(entries 20 and 21), however, only the respective dicarbonyl compounds 58
o
(
42% yield) and 59 (80% yield) are isolated at 25 C and 60ºC (entries 22 and
23, respectively) even after further PTSA treatment at the same temperature.
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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3
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4
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4
4
4
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5
5
5
5
5
5
5
5
5
5
6
o
These results indicate that at 0 C the ketoꢀalcohol intermediates are produced
and easily converted into the furans under acid catalysis (Scheme 5), and at
higher temperatures there is an additional proton rearrangement yielding more
stable dicarbonyl products which are more resistant to inꢀline transformation into
the respective furans (Scheme 5).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Further rearrangements of KDM products at different temperatures.
CONCLUSIONS
In summary, these studies allowed us to explore a continuous approach to a
series of transformations on diene moieties involving a safe photooxygenation
step to obtain endoperoxides followed by rearrangements. Relevant results
demonstrate the ability of the developed setup to perform safe, reproducible
and scalable multiꢀstep transformations with CꢀH oxidations to yield
functionalized synthons. In particular, these studies open up possibilities for the
continuous scaled up production of important synthetic intermediates, as well as
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proof of concept for other methodological studies aiming at the synthesis of
hydroxyenones, substituted furans and 1,4ꢀdicarbonyl derivatives.
Experimental Section
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
0
1
2
3
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9
0
1
2
3
4
5
6
7
8
9
0
The starting materials were purchased from SigmaꢀAldrich and used without
20
21
22
23
further purification except the compounds 14 , 27 , 32 , 47 which were
prepared as described in the literature. For thin layer chromatography (TLC) we
used 60 F254 (0.25 mm) silica gel and for column chromatography silica gel
(pore size 60Å, 70–230 mesh, 63ꢀ200ꢂm).
1
13
H NMR and CꢀNMR spectra were recorded on a Bruker Avance 400
operating at 400.15 MHz and 100.62 MHz, respectively, at room temperature,
using CDCl or C D or acetoneꢀd , when necessary. Chemical shifts are
3
6
6
6
assigned in δ (ppm) relative to tetramethylsilane (TMS) or to the residual
solvent peak as a reference and the coupling constants (J) are given in Hertz
(Hz). The multiplicity is presented as follows: singlet (s), broad singlet (br. s.),
doublet (d), broad doublet (br. d), triplet (t), quadruplet (q), octet (oct), double
doublet (dd), double triplet (dt), double double doublet (ddd), triple doublet (td),
multiplet (m).
The melting points of the solids were determined on a Microquimica MQAPFꢀ
301 apparatus and are not corrected. HRMS analyses were recorded on a
Bruker micrOTOFꢀQ II mass spectrometer equipped with electron spray
ionization ꢀ time of flight (ESIꢀTOF), operating in positive mode. IR analyses
were recorded on an IRꢀPrestigeꢀ21 Fourier transform infrared
spectrophotometer ꢀ SHIMADZU, with the absorption frequencies expressed in
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5
5
6
ꢀ
1
cm . The solids samples were analyzed on KBr pellets and liquid samples as
liquid films on KBr cells.
NMR data were processed using the ACD Labs software and the names of all
compounds were generated using the PerkinElmer ChemDraw Ultra v.12.0.2
software package.
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Continuous flow experiments were carried out using Syrris equipment (Asia
modules): syringe pump (500ꢂL and 1000ꢂL), stainless steel coil (16 mL) and
microchip reactor (250 ꢂL). The backꢀpressure regulators (BPR – 100 psi) were
acquired from Upchurch Scientific Inc. KNAUER HPLC pumps (AZURA P 4.1S)
were also used. All capillary tubing and fittings were purchased from Swagelok
and materials for the photoreactor construction were purchased locally.
Batch Protocol with
Followed by KDM Rearrangement. To a round bottom flask was added 7.38
2
mg of TPP (0.4 mol%, 0.012 mmol) which was dissolved in 25 mL of CH Cl .
cis,cis-1,3-cyclooctadiene (1) Photooxygenation
2
Subsequently, cis,cisꢀ1,3ꢀcyclooctadiene (1) (381.1 ꢂL, 3 mmol) was added and
then 50 mL CH CN. The photochemical batch reactor (white LED ~ 100W, see
3
Supporting Information) was used, maintaining the irradiation and magnetic
stirring of this mixture for 46 min. Then, 457.8 ꢂl of DBU (3 mmol) was added,
submitting the reaction to heating at 60°C in a conventional oil bath for 32 min.
Compound 3 was obtained in 16% yield (0.48 mmol; 67.5 mg) after purification
by silica gel chromatography (CH Cl /MeOH (9:1)).
2
2
General Procedure for Diene Photooxygenation Followed by KDM
Rearrangement in Continuous End-to-end Experiments. The methodology
2
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ꢀ
was developed with 3 mmol of substrate in 75 mL of solvent (0.04 mol.L ¹), and
the scope with 1 mmol in 25 mL of solvent. TPP (2.46 mg; 0.004 mmol; 0.4
mol%) was dissolved in 8 mL of CH
2 2
Cl , and then 1 mmol of the diene in 17 mL
of CH CN were mixed giving a diene concentration of 0.04 mol.L¹. The resulting
3
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
2
2
2
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9
0
solution was then transferred to the PFA loop (25 mL), which was then
connected to the system and protected from light.
Operation 1. Before connecting the PFA loop to the system, valve 2 (Scheme
3 2 2
3) must be closed, and the flow of the solvent mixture (CH CN/CH Cl (2:1))
ꢀ
from pump A (Knauer) (0.5 mL.min ¹ flow rate) directed into the loop to
pressurize it up to 6 bar. After reaching this pressure, valve 1 was also closed to
the pressurized loop, and then opened in the reactors direction. The whole
setup is pressurized with oxygen (6 bar) until its stabilization (ca. v/v 1:1
gas/solvent using 100 psi BPR).
Operation 2. Simultaneously to operation 1, a solution of DBU or Et
3
N (1 eqv;
ꢀ
ꢀ
0.4 mol.L ¹) is injected with a syringe pump (pump B, Syrris) at 50 ꢂL.min ¹ into
the temperature controlled coil – stainless steel reactor, 16 mL, Syrris (25ꢀ80ºC
experiments) or PFA coil reactor, 16 mL, Syrris (0ºC experiments) ꢀ where the
3
DBU or Et N solution encounters the endoperoxide containing reaction mixture.
Operation 3. After setup stabilization, valve 2 is then opened and pump A
solvent flow is redirected to the loop, using valve 1, in order to allow the input of
diene + TPP into the reactors.
After collecting the whole reaction volume was concentrated under reduced
pressure at 30°C. The crude residue was then purified by column
chromatography with silica gel. Changes in the purification process are shown
for each case where it is necessary.
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6
General Procedure for Diene Photooxygenation Followed by KDM
Rearrangement to Obtain Furans in a Continuous End-to-end Approach.
Operations 1, 2 and 3 already described were performed for furan synthesis.
Additionally, a new pump (pump C) was inserted into the setup after the
0
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9
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stainless steel or PFA coil reactor output, where the KDM product mixture
ꢀ
encounters a PTSA solution in CH CN/CH Cl (2:1) (0.05 mol.L ¹; flow rates in
3
2
2
Table 5) in a TꢀMixer (Scheme 4).
,8ꢀdioxabicyclo[4.2.2]decꢀ9ꢀene (2). Obtained after purification by silica gel
24
7
chromatography using CH
2
Cl
2
as eluent (6ꢀ21% yield ꢀ degradation during
1
purification in silicaꢀgel). Endoperoxide 2 is a paleꢀyellow oil: H NMR (400 Hz,
CDCl ): δ 6.13ꢀ6.18 (m, 2H), 4.74ꢀ4.77 (m, 2H), 2.07ꢀ2.14 (m, 2H), 1.70ꢀ1.90
3
H
1
3
1
(
m, 4H), 1.56ꢀ1.63 (m, 2H); C{ H} NMR (100 Hz, CDCl
24.0.
9ꢀoxabicyclo[4.2.1]nonꢀ7ꢀenꢀ1ꢀol (3) . Obtained as a white solid after
3 C
): δ 128.1, 76.5, 33.1,
25
purification by chromatography with silica gel (CH
2
2
Cl /MeOH (9:1)) (yields
26
1
available in Tables 1ꢀ4): m.p. 93ꢀ95ºC (lit. 93ꢀ94ºC); H NMR (400 Hz, C D ):
6
6
δ
H
5.48 (dd, J = 5.7, J = 1.2 Hz, 1H), 5.43 (dd, J = 5.7, J = 1.9 Hz, 1H), 4.73ꢀ4.75
(m, 1H), 2.99 (s, 1H), 2.07ꢀ2.14 (m, 1H), 1.72ꢀ1.84 (m, 2H), 1.48ꢀ1.63 (m, 2H),
13
1
1.23ꢀ1.41 (m, 2H), 1.07ꢀ1.14 (m, 1H); C{ H} NMR (100 Hz, CDCl
3
C
): δ 134.4,
−
1
132.6, 111.4, 81.6, 39.0, 33.4, 23.7, 23.0. FTꢀIR (KBr pellet, cm ): 3400, 3302,
1618, 1438, 1419, 1203, 1180, 1130, 1097, 1062, 1043.
27
4
ꢀhydroxycycloheptꢀ2ꢀenone (6) . Obtained as a yellow oil after purification by
chromatography with silica gel (CH
2
Cl
2
/MeOH (9.5:0.5)) in 92% overall yield
): δ 6.27 (ddd, J = 12.6, J = 3.1, J
1
(
0.92 mmol; 116 mg): H NMR (400 Hz, C
6
D
6
H
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=
1.2 Hz, 1H), 5.86 (ddd, J = 12.6, J = 2.3, J = 1.0 Hz, 1H), 4.01ꢀ4.06 (m, 1H),
2.52 (br s, 1H), 2.25ꢀ2.32 (m, 1H), 2.10ꢀ2.17 (m, 1H), 1.67ꢀ1.75 (m, 1H), 1.41ꢀ
13
1
1
1
1
6 6 C
.50 (m, 1H), 1.15ꢀ1.37 (m, 2H); C{ H} NMR (100 Hz, C D ): δ 202.8, 150.0,
−1
30.1, 70.6, 43.4, 35.5, 18.7. FTꢀIR (KBr, thin film, cm ): 3412, 1652, 1286,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
4
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6
0
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6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
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4
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7
8
9
0
1
2
3
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8
9
0
1
2
3
4
5
6
7
8
9
0
049.
28
Cycloheptaꢀ2,4,6ꢀtrienone (9). Tropone (9) was obtained as a yellowꢀorange
oil after purification by chromatography with silica gel (AcOEt/hexane (7:3)) in
1
36% overall yield (0.36 mmol; 38.2 mg): H NMR (400 Hz, CDCl
3
): δ
H
7.07ꢀ7.15
13
1
3
(m, 2H), 7.00ꢀ7.05 (m, 2H), 6.96ꢀ6.99 (m, 2H); C{ H} NMR (100 Hz, CDCl ):
−1
δ
1
6
C
188.3, 142.2, 136.2, 134.8. FTꢀIR (KBr, thin film, cm ): 1631, 1541, 1517,
253.
,7ꢀdioxabicyclo[3.2.2]nonaꢀ3,8ꢀdienꢀ2ꢀone (10). Obtained as a yellow oil after
Cl as eluent.
29
purification by flash chromatography with silica gel employing CH
2
2
Starting from 0.5 mmol of 9 and using optimum photooxygenation conditions
ꢀ
(P
O
2
= 6 bar, 0.5 mL.min ¹ flow rate) endoperoxide 10 was isolated in 62% yield
1
(0.31 mmol; 43 mg): H NMR (400 Hz, CDCl
): δ
3 H
7.00ꢀ7.07 (m, 2H), 6.48ꢀ6.53
(m, 1H), 6.01 (ddd, J = 10.9, J = 2.2, J = 0.7 Hz, 1H), 5.08 (t, J = 7.4 Hz, 1H),
13
1
3 C
4.99 (br. d, J = 7.8 Hz, 1H); C{ H} NMR (100 Hz, CDCl ): δ 195.1, 144.8,
138.1, 131.4, 123.2, 85.6, 75.4.
30
4ꢀhydroxycyclohexꢀ2ꢀenone (13) . Obtained as a yellow oil after purification by
chromatography with silica gel (CH Cl /MeOH (9:1)) in 67% overall yield (0.67
2
2
mmol; 74.8 mg) at 80ºC and 29% (0.29 mmol; 32.6 mg) at 60ºC (see Table 5):
1
6 6 H
H NMR (400 Hz, C D ): δ 6.50 (ddd, J = 10.2, J = 2.3, J = 1.7 Hz, 1H), 5.78
(
ddd, J = 10.2, J = 2.0, J = 1.0 Hz, 1H), 3.87ꢀ3.99 (m, 1H), 2.64 (br. s, 1H), 2.27
dt, J = 16.7, J = 4.5 Hz, 1H), 1.83ꢀ1.92 (m, 1H), 1.72ꢀ1.79 (m, 1H), 1.54ꢀ1.64
(
2
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5
5
6
1
3
1
(
m, 1H); C{ H} NMR (100 Hz, C
6
D
6
): δ
FTꢀIR (KBr, thin film, cm ) ν: 3431, 2960, 2879, 1658, 1209, 1066, 972, 943,
66.
C
198.6, 153.7, 129.2, 66.4, 35.9, 32.9;
−
1
8
(
3aR,7aS)ꢀ2,2ꢀdimethylꢀ3a,4,7,7aꢀtetrahydroꢀ4,7ꢀepidioxybenzo[d][1,3]dioxole
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20
(
15) . The crude photooxygenated residue was concentrated under reduced
pressure (30ºC) and then dissolved in iceꢀcold hexane/AcOEt (8:2) mixture,
®
stirred with activated carbon and, finally, filtered through a Celite plug. The
endoperoxide appears as a solid slightly purple due to TPP contamination.
Purification on a chromatographic column leads to endoperoxide degradation
1
(
exploratory experiments): mp 115ꢀ118ºC (lit. not available); H NMR (400 Hz,
CDCl
3
): δ
H
6.55ꢀ6.56 (m, 2H), 4.87ꢀ4.90 (m, 2H), 4.56ꢀ4.57 (m, 2H), 1.33ꢀ1.34
13
1
(
m, 6H); C{ H} NMR (100 Hz, CDCl ): δ 130.5, 110.3, 71.8, 71.5, 25.6, 25.4.
3
C
−
1
FTꢀIR (KBr pellet, cm ): 2994, 2922, 1382,1262, 1205, 1160, 1070, 923, 881,
842, 791, 726.
20
Decahydrodibenzofurans 16. Obtained as a diastereoisomeric mixture (yellow
oil), after purification by chromatography with silica gel (Hexane/AcOEt (9:1)) in
1
0% overall yield (0.10 mmol; 36.8 mg): Complex NMR spectra (see Supporting
Information).
ꢀhydroxyꢀ2,2ꢀdimethylꢀ7,7aꢀdihydrobenzo[d][1,3]dioxolꢀ4(3aH)ꢀone
2
0
7
(17) .
Obtained as a slightly yellow oil, after purification by chromatography with silica
gel (Hexane/AcOEt (6:4), (1:1)), in 13% (0.13 mmol; 24.3 mg) at 25ºC and 29%
(
0.29 mmol; 52.8 mg) at 0ºC, overall yield, when Et N (1 equiv.) is used in the
3
KDM rearrangement step. Compound 17 is not stable at room temperature
1
(
hydroxyl group must be protected to avoid aromatization): H NMR (400 Hz,
3 H
CDCl ): δ 6.83 (ddd, J = 10.3, J = 3.4, J = 0.9 Hz, 1H), 6.05ꢀ6.09 (m, 1H), 4.52ꢀ
2
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,54 (m, 1H), 4.40ꢀ4.44 (m, 2H), 2.36 (br. s, 1H), 1.36ꢀ1.38 (m, 6H); C{ H}
NMR (100 Hz, CDCl ): δ 193.8, 147.7, 128.6, 110.6, 79.4, 74.2, 67.2, 27.3,
3
C
−
1
2
5.7; FTꢀIR (KBr, thin film, cm ) ν: 3435, 1734, 1679, 1637, 1382, 1224, 1080.
31
Pyrocatechol (20) . Obtained after purification by chromatography with silica
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
gel (CH
2 2
Cl /MeOH (9:1)) as a brown solid in 15% yield (0.15 mmol; 16.3 mg):
32
1
m.p. 97ꢀ100ºC (lit. 104ºC); H NMR (400 Hz, CDCl
3
): δ
H
6.82ꢀ6.89 (m, 4H),
13
1
5
.22 (s, 2H); C{ H} NMR (100 Hz, CDCl ): δ 143.5, 121.2, 115.5. FTꢀIR (KBr
3
C
−1
pellet, cm ) ν: 3437, 1616, 1514, 1466, 1361, 1253, 1094, 848, 746.
33
9
,10ꢀdihydroꢀ9,10ꢀepidioxyanthracene (22) . Obtained as a white solid. After
removing part of the solvent mixture containing the crude photoꢀoxygenated
compound, under reduced pressure (30ºC), endoperoxide 22 was precipitated
1
and filtered off (exploratory experiment): m.p. 155ꢀ158ºC (lit. 156ºC); H NMR
1
3
1
(
400 Hz, CDCl
NMR (100 Hz, CDCl
3023, 2345, 1460, 1172, 769, 621.
3 H
): δ 7.42ꢀ7.44 (m, 4H), 7.29ꢀ7.31 (m, 4H), 6.04 (s, 2H); C{ H}
−
1
3
C
): δ 138.0, 127.9, 123.6, 79.3; FTꢀIR (KBr pellet, cm ):
33
Anthraceneꢀ9,10ꢀdione (23) . Anthraquinone presents low solubility and
precipitates during the solvent concentration. The precipitate was filtered and
2 2
washed with a small amount of CH Cl to remove TPP traces and the remaining
solvent was then evaporated under reduced pressure (30ºC) and the recovered
product was purified by chromatography with silica gel (Hexane/AcOEt (7:3)).
Compound 23 was obtained as an offꢀwhite solid in 74% overall yield (0.74
1
mmol; 154.8 mg): m.p. 284ꢀ287ºC (decomposition) (lit. 284ꢀ286ºC); H NMR
13
1
(
400 Hz, CDCl
CDCl ): δ 183.2, 134.1, 133.5, 127.2; FTꢀIR (KBr pellet, cm ): 1676, 1573,
328, 1280, 935, 806, 692.
3 H
): δ 8.31ꢀ8.34 (m, 4H),7.80ꢀ7.84 (m, 4H); C{ H} NMR (100 Hz,
−1
3
C
1
2
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0ꢀhydroxyꢀ10ꢀmethylanthracenꢀ9(10H)ꢀone (26) . Obtained as a pale yellow
solid in 96 % yield (0.96 mmol; 214.4 mg) after purification by chromatography
35
1
with silica gel (CH
2
Cl
): δ
.62ꢀ7.68 (m, 2H), 7.41ꢀ7.46 (m, 2H), 2.75 (br s, 1H), 1.68 (s, 3H); C{ H} NMR
): δ 183.5, 148.7, 133.8, 129.6, 128.0, 127.0, 125.9, 70.0, 36.9;
2
/hexane (9:1)): m.p. 156ꢀ159ºC (lit. 159ꢀ161°C); H NMR
(400 Hz, CDCl
3
H
8.14 (dd, J = 7.90, J = 1.35 Hz, 2H), 7.90ꢀ7.94 (m, 2H),
1
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
7
(100 Hz, CDCl
3
C
−
1
FTꢀIR (KBr pellet, cm ): 3433, 1649, 1598, 1580, 1460, 1385, 1322, 1283,
1082, 1028, 929, 761, 687.
7
ꢀ(propꢀ1ꢀenꢀ2ꢀyl)ꢀ3,5,6,7,8,8aꢀhexahydrobenzo[c][1,2]dioxine
(28).
The
endoperoxide, a colorless oil, was obtained as a mixture of diastereoisomers
2 2
after purification by chromatography with silica gel (Hexane/CH Cl (7:3)) in
1
3
1% yield (0.31 mmol; 56.6 mg): H NMR (400 Hz, CDCl ): δ 5.56ꢀ5.65 (m,
3
H
1
H), 4.64ꢀ4.98 (m, 4H), 4.27ꢀ4.36 (m, 1H), 2.00ꢀ2.45 (m, 4H), 1.72ꢀ1.86 (m,
13
1
3H), 1.15ꢀ1.50 (m, 2H); C{ H} NMR (100 Hz, CDCl
3 C
): δ 148.3, 145.2, 138.4,
137.6, 116.1, 115.5, 111.4, 109.5, 78.9, 75.8, 70.4, 70.2, 42.7, 38.6, 34.6, 31.8,
3
1.4, 31.2, 28.3, 27.3, 22.5, 20.6 (diastereoisomeric mixture ꢀ duplicate signals).
−1
FTꢀIR (KBr, thin film, cm ): 1645, 1438, 1049, 894; HRMSꢀESIꢀTOF: m/z calcd
+
for C11
H
17
O
2
[M + H] 181.1223; found 181.1220.
(
Z)ꢀ2ꢀ((4S)ꢀ2ꢀhydroxyꢀ4ꢀ(propꢀ1ꢀenꢀ2ꢀyl)cyclohexylidene)acetaldehyde
(29).
Obtained as a mixture (0.25:1) of the diastereoisomeric aldehydes. Overall
yields are low (<10%) and not reproducible due to the aldehyde instability
during purification by chromatography (See Supporting Information for NMR
+
spectra). HRMSꢀESIꢀTOF: m/z calcd for C11
81.1218.
H
17
O
2
[M + H] 181.1223; found
1
2
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Page 29 of 42
The Journal of Organic Chemistry
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(
Z)ꢀ2ꢀ(2ꢀhydroxyethylidene)ꢀ5ꢀ(propꢀ1ꢀenꢀ2ꢀyl)cyclohexanol (30). Obtained after
reduction of the reaction mixture, containing the intermediate diastereoisomeric
aldehydes, by stirring the collected solution with NaBH (2 eqv) for 2h (batch
4
procedure) at room temperature and purifying the diol 30 by chromatography
with silica gel (AcOEt/hexane (7:3)). Compound 30, a pale yellow solid, was
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isolated in 17% overall yield (0.17 mmol; 30.2 mg): m.p. 69ꢀ72ºC; H NMR (400
Hz, CDCl ): δ 5.48 (t, J= 6.7 Hz, 1H), 4.64 (br s, 2H), 4.26 (dd, J = 11.6, J = 4.4
3
H
2
Hz, 1H), 4.17 (d, J= 6.7 Hz, 2H), 3.57 (br. s, 1H), 2.20 (dt, J = 13.5, J = 3.6 Hz,
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H), 1.96ꢀ2.15 (m, 3H), 1.69ꢀ1.76 (m, 1H), 1.65 (s, 3H), 1.41 (q, J= 11.9 Hz,
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1
H), 1.14ꢀ1.24 (m, 2H); C{ H} NMR (100 Hz, CDCl
): δ
3 C
148.5, 146.1, 120.6,
−1
1
09.1, 73.5, 58.3, 43.9, 42.3, 36.0, 32.6, 20.8. FTꢀIR (KBr pellet, cm ): 3329,
+
1
643, 1439, 1001. HRMSꢀESIꢀTOF: m/z calcd for C H O [M + H] 183.1379;
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2
found 183.1372.
2ꢀ(2ꢀhydroxyethyl)ꢀ5ꢀ(propꢀ1ꢀenꢀ2ꢀyl)cyclohexanol (31). Same experimental
procedure as described for 30 obtained as a complex mixture of
diastereoisomers from further reduction of reaction mixture, in 21% overall yield
(0.21 mmol; 39.5 mg), dark yellow oil: Complex NMR data (see Supporting
−
1
Information); FTꢀIR (KBr, thin film, cm ): 1643, 1438, 1087, 1001, 881. HRMSꢀ
+
ESIꢀTOF: m/z calcd for C11
H
21
O
2
[M + H] 185.1536; found 185.1531.
(Z)ꢀ2ꢀ(2ꢀhydroxyethylidene)ꢀ5ꢀisopropylcyclohexanol (35). Obtained after
reduction of the crude mixture containing the diastereoisomeric aldehydes, by
stirring the collected solution with NaBH (2 eqv) for 2h (batch procedure) at
4
room temperature. Diol 35, a pale yellow solid, was isolated in 15% overall yield
(0.15 mmol; 27.7 mg) after purification by chromatography with silica gel
1
(
AcOEt/hexane (7:3)): m.p. 59ꢀ63ºC; H NMR (400 Hz, CDCl
): δ
3 H
5.51 (t, J =
2
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