Studying the Morita-Baylis-Hillman Reaction in Continuous Flow Using Packed Bed Reactors

Article abstract of DOI:10.1021/acs.oprd.8b00298

Conditions for the Morita-Baylis-Hillman reaction were developed under continuous flow using a packed bed reactor carrying 4-(dimethylamino)pyridine immobilized on silica. High reaction rates were obtained, as the packed bed reactor mimics super-stoichiom

Full text of DOI:10.1021/acs.oprd.8b00298

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Full Paper
Studying the Morita-Baylis-Hillman Reaction in
Continuous Flow Using Packed Bed Reactors
Rasmus A. T. Verdier, Jesper Hyldal Mikkelsen, and Anders T. Lindhardt
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00298 • Publication Date (Web): 17 Oct 2018
Downloaded from http://pubs.acs.org on October 17, 2018
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Studying the Morita-Baylis-Hillman Reaction in
Continuous Flow Using Packed Bed Reactors
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Rasmus A. T. Verdier, Jesper H. Mikkelsen and Anders T. Lindhardt*
Department Of Engineering, Carbon Dioxide Activation Center (CADIAC),
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Hangøvej 2, 8200
Aarhus N, Denmark
Lindhardt@eng.au.dk
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Abstract
Conditions for the Morita-Baylis-Hillman reaction have been developed under
continuous flow using a packed bed reactor carrying DMAP immobilized on silica.
High reaction rates were obtained as the packed bed reactor mimics super-
stoichiometric catalyst loadings for the passing reaction mixture. Catalyst
deactivation was circumvented by avoiding acrylate esters as the reaction partners.
The developed flow protocol provided all desired Morita-Baylis-Hillman products in
yields attaining 95% with typical retention times between just 30-60 minutes.
Precise control of the retention time proved imperative for one example, in which
optimal yield was attained in just 10 minutes, while outpacing sideproduct
formation. Finally, a scale-out study was performed proving high stability of the
packed bed reactor setup and catalyst for more than 20 hours of operation.
Keywords
Morita-Baylis-Hillman, Continuous Flow, Packed Bed Reactor, DMAP Catalysis,
Scale-Out
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Introduction
The Morita-Baylis-Hillman (MBH) reaction is the coupling of an electron deficient
olefin with an aldehyde, ketone or imine, typically catalyzed by a tertiary amine.1,2
The transformation was initially named the Baylis-Hillman reaction by the group of
Roos et. al., based on a patent filed by Baylis and Hillman in 1972.3 However, the
reaction was originally reported by Morita et. al. in 1968 using tertiary phosphines
as catalysts.3a
MBH reactions are known for their mild reaction conditions, allowing the products
thereof, to be decorated with a vide variety of functional groups. A carbon-carbon
bond is formed during the MBH reaction and the transformation runs with complete
atom efficiency as shown with the generic example depicted in Scheme 1A.
Despite its simple appearance, an interesting feature to the MBH reaction is its fairly
complex reaction kinetics and multiple competitive reaction pathways.4 Reaction
times in the MBH reaction range from hours to days, and it has been shown that
electron-deficient aldehydes reacts at higher rates than their more electron rich
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counterparts. Reaction of methyl acrylate with p-nitrobenzaldehyde (1) affords 2 in
83% in just three hours. In comparison the similar reaction with the more electron
rich p-chlorobenzaldehyde (3) takes three days to yield 4 in 53% under identical
conditions. (Scheme 1 – B and C, respectively).5
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Tertiary amine
OH
O
EWG
or phosphine catalyst
EWG
A
Ar
Ar
H
H
O
OH
O
(1 equiv)
N
N
O
H
OMe
2 - 83%
OMe
OMe
Dioxane:water 1:1, rt.
1
B
C
O2N
3 hours
O2N
OH
O
O
O
OMe
As above
H
4 - 53%
3 days
3
Cl
Cl
Continuous Flow
OH
O
EWG
N
MeN
EWG
This work
Ar
Ar
H
H
33-95%
10 - 60 minutes
Dmap Immobilized on
Packed Bed Reactor
Scheme 1. A) General Morita-Baylis-Hillman reaction of an aromatic aldehyde with
an electron deficient olefin. B) MBH reaction with electron-deficient aldehyde. C)
MBH reaction with electron rich aldehyde.
The reaction kinetics of the MBH reaction are dependent on all reaction components
including, carbonyl derivative, olefin, catalyst, etc. and combined reaction orders of
up to 4 have been reported.6 Furthermore, alcohols and protic solvents have been
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shown to play the important role of facilitating proton transfer, resulting in an
increased reaction rate.7 Whereas long reaction times of multiple days clearly define
a drawback to the MBH reaction, another set of problems emerges with increasing
electrophilicity of the olefin.8 Examples of this are provided in Scheme 2, where the
olefin has reacted with the formed MBH product. Hence, both the desired product 5
and sideproduct 6 are formed in 50% and 27%, respectively, when methyl vinyl
ketone (MVK) is applied as the olefin (Scheme 2A). Turning to phenyl vinyl ketone
(PVK) only the product 7, from double olefin addition, is observed after 60 hours at
room temperature (Scheme 2B). In this example the authors also isolated the
product 8 derived from dimerization of PVK. When acrylates are used as the
reacting olefin the formation of 1,3-dioxan-4-ones, such as compound 9, are also
observed amongst the sideproducts of the Morita-Baylis-Hillman transformation
(Scheme 2C). It is important to note that the catalyst for the MBH reaction also
catalyzes the formation of the in Scheme 2 mentioned sideproducts. Hence, if the
reaction kinetics favor formation of the target MBH product, precise control of the
reaction time would lead to improve yields by inhibiting these secondary reaction
events.
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Scheme 2. Potential by-products formed during the MBH reaction with electrophilic
olefins.
As part of an ongoing project in our laboratory, access to a set of different MBH
substrates were needed, and furthermore, some of these substrates were required
in a +20 gram scale.9 Hence, focus was directed towards their preparation in
continuous flow, as scale-out would allow the MBH-products to be prepared in
practical any scale.10 Despite the numerous reports on the MBH reaction, a detailed
search through the literature only revealed few previous examples of the
transformation being performed in continuous flow. One report by Acke and
Stevens studies the MBH reaction between 4-nitrobenzaldehyde and methyl
acrylate in a plug-flow microreactor setup.11 Despite the improved mass transfer
and temperature control obtained by the microreactor setup, only a reduction of
30% in reaction time was observed. Prof. Baxendale reported on the MBH reaction
between isobutyraldehyde and acrylonitrile in continuous stirred tank reactors
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(CSTR). 12 The setup was devised by aligning 6 x 100 mL CSTR´s in series thereby
allowing an impressive +200 mmol/h of reactants to be processed when running all
reactors at 65 °C. Finally, Ishitani et. al. devised a packed bed reactor (PBR) loaded
with DMAP immobilized on silica for the reaction between β-styrene with ethyl
glyoxalate in toluene at room temperature.13,14 This setup initially provided Ishitani
with a high 1H-NMR yield, however, catalyst degradation led to depletion in
conversion rates to approx. 50% within 48 hours of operation.
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As discussed above, it has been shown that the loading of nucleophilic catalyst
affects the overall reaction rate of the MBH reaction by an order of one.6 Hence,
addition of an organo-catalyst, such as DABCO or DMAP, in super-stoichiometric
loadings should reduce the total reaction time of the MBH transformation. However,
the same high loading of catalyst also catalyzes the formation of undesired by-
products (Scheme 2). From these observations, we concluded that a similar
approach to that of Ishitani and co-workers would provide a setup with a two-fold
benefit. Firstly, a PBR carrying an immobilized amine catalyst would increase the
MBH reaction rate, as the on-reactor reaction mixture experiences super-
stoichiometric catalyst loadings. Secondly, precise control of the reaction time
becomes possible as the catalyst is retained in the PBR upon reaction mixture exit.
The latter being relevant for combinations of highly reactive substrates, where the
secondary reaction events described in Scheme 2, quickly leads to deterioration of
the overall reaction yield. Finally, work by Lin and co-workers indicates that
application of immobilized catalysts inhibits sideproduct formation in MBH
reactions.15
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In this manuscript we wish to report on the development of the Morita-Baylis-
Hillman reaction in continuous flow using dimethylaminopyridine, immobilized on
silica particles, as the catalyst in a packed bed reactor (Scheme 1 – This work). In
particular, the combination of methyl vinyl ketone as the vinylic reaction partner in
1-butanol, as the solvent, led to fast reaction rates and improved catalyst stability.
Furthermore, precise control of the reaction time for highly reactive combinations
of MBH reagents led to significantly improved isolated yields of the desired
products. Finally, a scale-out experiment proved the stability of both the reactor and
catalyst with no loss of reactivity during 20 hours of operation.
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Results and Discussion
Initially, the MBH reaction between 4-chlorobenzaldehyde (3) and methyl acrylate
was chosen as the test reaction. A small screening of reaction conditions in batch
revealed commercially available polymer bound 4-(dimethylamino)pyridine
(polyDMAP, 3 mmol/g) as the catalyst combined with 1-butanol as the solvent to be
an efficient system (results not shown).7,16 Next, a packed bed reactor (PBR) was
constructed by loading polyDMAP into an empty HPLC column (ID = 5.0 mm, L =
130 mm) which was placed in an oil bath heated to 50 °C (See Experimental Section
for details). A stock solution of 3 (0.3 M) and methyl acrylate (0.9 M) dissolved in 1-
butanol was loaded onto a sample loop (10 mL) and pumped through the reactor
using 1-butanol as the background solvent (See Scheme 3 - a). Combined with a
retention time of 20 minutes this setup provided the desired MBH product 4 in a
good 76% isolated yield after column chromatography.
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O
O
5
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OMe
Cl
OH
O
3 (0.3 M)
(0.9 M)
50 C
OMe
9
69 bar
BPR
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Sample loop
HPLC-pump
Cl
4 - 76%
Poly-dmap
Packed bed reactor
O
O
N
O
N
OMe
N
O
OMe
N
OH
N
N
Betaine
derivative - 10
Scheme 3. Continuous flow MBH reaction using a polyDMAP packed bed reactor.
Below: Catalyst deactivation with formation of 10.
Although polyDMAP provided good results for the MBH reaction the catalytic
activity dropped rapidly in sequential runs. This deactivation of the catalyst was
ascribed to a similar observation made by Hu and Stevens, who both reported the
formation of an inactive betaine species 10 upon mixing of acrylates with DABCO
(Scheme 3 – bottom).11, 5a Speculating that the same reaction could occur for DMAP
in the presence of methyl acrylates, it was decided to substitute methyl acrylate for
methyl vinyl ketone (MVK) for further optimization (Table 1).
Table 1. Optimization of the MBH-Reaction using poly-DMAP as catalyst in
Continuous Flow.a
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O
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MVK
Cl
OH
O
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Temp, Rt
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69 bar
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BPR
Cl
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HPLC-pump
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[a] A stock solution of 4-chlorobenzaldehyde (3) and MVK in 1-butanol (2 mL) was
loaded onto the sample-loop. The reaction mixture was then pumped through the
PBR at the temperature and retention time given in the table, using 1-butanol as the
background solvent. Sample collection was continued for 2,5 times the retention
time. The crude reaction mixture was concentrated under reduced pressure and the
1
yield determined by H-NMR analysis using dimethyl terephthalate as the internal
[b]
standard. Reactor 1 contained 0.5 g polymer bound DMAP (6 mmol/g), reactor 2
[c]
contained 1.0 g polymer bound DMAP (6 mmol/g). Yield in brackets is isolated
yield after column chromatography.
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A stock solution of 3 (0.2 M) and MVK (0.3 M) was prepared using 1-butanol as the
solvent. The stock solution (2 mL) was loaded onto a sample loop and passed
through the packed bed reactor at 60 °C with a retention time of 30 min. This
resulted in a disappointing 1H-NMR yield of only 12% of 11, the remaining material
being unreacted 3 and MVK (Table 1, entry 1). Increasing the concentrations of 3 to
0.4 M and MVK to 1.2 M at 50 °C afforded an improved yield of 32% (Entry 2).
Further increases in the concentration of MVK to 2.4 M and 3.6 M provided 11 in 43
% and 45 %, respectively (entries 3 and 4). Performing the reaction at 60 °C and
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prolonging the retention time to 45 minutes resulted in an increase in the H-NMR
yield to 56% (entries 5 and 6). Importantly, loss of catalytic activity was no longer
observed when applying MVK as the olefinic reaction partner. At this stage it was
decided to double the polyDMAP loading of the packed bed reactor from 3 mmol to
6 mmol. Gratifyingly, the presence of additional catalyst afforded 11 in a good 59%
yield after only 30 minutes on the reactor at 60 °C (entry 7). Higher temperatures or
increased MVK concentrations did not lead to any improvements in yield (entries 8
and 9). Finally, doubling the retention time from 30 to 60 minutes led to a
1
satisfactory H-NMR yield of 72% with a 61% isolated yield of 11 after column
chromatography (Entry 10).
Satisfied with the developed conditions, the scope of the reaction was next
investigated, a few results of which are depicted in Scheme 4.
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O
O
5
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R
2.4 M
0.4 M
7
8
OH
O
60 C, Rt = 60 min
9
R
69 bar
BPR
Sample loop
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HPLC-pump
0.4 M
Poly-dmap
Packed Bed Reactor
OH
O
OH
O
NO2 OH
O
F
OH
Cl
O
Br
O2N
62 % - 12
83 % - 5
83 % - 14
82 % - 13
Scheme 4. MBH Reactions using poly-DMAP in Continuous Flow. See supporting
information for reaction details.
Substitution of chlorine for bromine provided 12 in 62% isolated yield. The electron
poor aldehydes 4- and 2-nitrobenzaldehyde afforded 5 and 13 in 83% and 82%
isolated yields, respectively. Finally, when 2-chloro-6-fluorobenzaldehyde was
tested 14 was obtained in an excellent 83% isolated yield after only 60 minutes on
the PBR.
Although the devised reactor setup initially provided promising results, the
pressure drop over the PBR steadily increased as a function of time. The
commercially available polyDMAP beads used in this study are crosslinked using 2
w/w% divinyl benzene. The observed increase in pressure drop is most likely
related to the swelling of the polyDMAP beads, inside the reactor, leading to
clogging. Examination of the packed bed reactor content after several runs also
indicated the column material to have become tightly packed. The group of Steven
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Ley has previously reported that application of beads with higher degrees of
crosslinking leads to decreased swelling, and hence, increased packed bed reactor
stability.17 Following this concept, it was decided to change the solid reactor
material to DMAP bound on silica particles (Si-DMAP).13,15,18 The Si-DMAP
particles sizes range between 40-63 μm and has a DMAP loading of 0.53 mmol/g.
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The new continuous flow setup was constructed by serial connection of two HPLC-
columns (ID = 4,6 mm, L = 250 mm) loaded with Si-DMAP (See Scheme 5 for
schematic diagram).19 The applied silica-DMAP PBRs had average combined DMAP
loadings of 4.25 mmol and average void volumes of 3.92 mL (see Experimental
Section for details). The Si-DMAP reactor setup carries a reduced average catalyst
loading of 4.25 mmol, compared to the poly-DMAP system, with 6 mmol
DMAP/reactor. This effect of this resulted in a decreased yield of 20% of 11 when
tested under the conditions developed in Table 1 – entry 10 (results not shown).
However, the silica matrix provided a packed bed reactor performing with a
completely stabilized pressure drop. Hence, no further optimization studies were
performed at this stage and the scope of the MBH reacted was investigated using Si-
DMAP as the matrix-bound catalyst (Scheme 5). Some of the reactions required the
addition of CH2Cl2 as a co-solvent in order to fully solubilize the starting aldehyde in
the stock solution.20,21 The retention time was optimized for each entry with an
upper limit of 60 minutes. Halogenated aldehydes afforded the 15 and 14 in 59%
and 56% isolated yields. Interestingly, the normally highly reactive nitrated
aromatic aldehydes only afforded compounds 5 and 13 in 62% and 47% isolated
yields, respectively. The presence of a p-cyano substituent provided 17 in a good
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64% isolated yield after only 30 minutes on the reactor, whereas the presence of a
methyl ester deteriorated the yield to 33% of compound 16. Next, the 2,3 and 4-
pyridinecarboxaldehydes were tested.
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O
O
R
MVK
Si-DMAP Packed Bed Reactors
OH
O
69 bar
BPR
R
Sample loop
HPLC-pump
60 °C, rt = 30 or 60 min
OH
O
F
OH
O
OH
O
OH
O
NO2
OH
O
MeO
Cl
Cl
O2N
15 - 59%
rt = 60 min
14 - 56%
rt = 60 min
5 - 62%
rt = 60 min
16 - 33%
rt = 60 min
13 - 47%
rt = 60 min
Cl
O
OH
O
OH
O
OH
O
OH
O
OH
O
EtO
O
N
N
NC
N
21 - 73%
rt = 60 min
17 - 64%
rt = 30 min
18 - 90%
rt = 30 min
19 - 57%
rt = 30 min
20 - 95%
rt = 30 min
F
OH
O
OH
O
OH
O
Not isolated
NH2
NH2
O
N
Cl
23 - 77%
rt = 60 min
24 - 71%
rt = 30 min
22 - 27%
rt = 60 min
Scheme 5. Morita-Baylis-Hillman reaction in Continuous Flow using a Si-DMAP
Catalyst.
All proved highly reactive and afforded compounds 18, 19, 20 in yields attaining
95% with a retention time of only 30 minutes. When ethyl glyoxalate was used the
desired MBH-product 21 was obtained in a good 73% isolated yield, again with only
30 minutes on the reactor. Finally, the less reactive acrylamide was tested instead of
1
MVK. However, H-NMR analysis of the crude reaction mixtures showed formation
of several sideproducts. These impurities severely hampered isolation by column
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chromatography and only a mere 27% of 22 was secured in its pure form. Despite
these isolation problems both acrylamide and 2-cyclobutenone proved reactive
under the developed conditions affording the MBH products 23 and 24 in 77% and
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71% H-NMR yields. Importantly, opposed to the observations made by Ishitani et.
al. the Si-DMAP catalyst seemed to operate without loss of activity under the
developed conditions.13
Attention was next turned towards terephthalaldehyde as substrate.
Terephthalaldehyde was chosen to test if the reaction of the second aldehyde
functionality could be prevented, thereby leading to the desymmetrized MBH-
product. However, significant overreactions of the MBH adduct with MVK occurred
during the reaction (Figure 1). The formation of sideproducts is clearly visible from
1
the presence of several additional aldehyde peaks in the H-NMR of the crude
reaction mixture (see SI for full spectrum).22 Hence, when performing this reaction
1
with a retention time of 60 minutes only a meager H-NMR yield of 24% of 25 was
obtained. Interestingly, reducing the retention time to 30 minutes provided a lower
conversion of terephthalaldehyde, however, this was counterbalanced by small
1
increase in product selectivity and 25 was present in a H-NMR yield of 39%.
Finally, application of a retention time of only 10 minutes nearly outpaced the
formation of overacted sideproducts, and 25 was secured in a good 71% isolated
yield after column chromatography. Notably, the majority of remaining material was
unreacted terephthalaldehyde and the side reaction of MVK with butanol was also
suppressed (See the Experimental Section). Further reductions in retention time did
not lead to any further improvements. The reaction of terephthalaldehyde with
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MVK exemplifies the importance of precision reaction time control obtained when
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Figure 1. Elimination of sideproduct formation in the MBH reaction by precise time
control.
As the final part of this study, it was decided to test the PBR catalyst stability by a
scale-out experiment (Scheme 6). Towards this purpose the MBH reaction between
4-pyridinecarboxaldehyde and MVK, using a retention time of 30 minutes, was
chosen (See Scheme 5, compound 20). The flow setup was allowed to run for 45
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minutes before sample collection was initiated, in order to secure steady state
operation in the packed bed reactor. Samples were collected every 30 or 60 minutes
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for the first ten hours and analyzed by H-NMR using dimethyl terephthalate as
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internal standard. The setup continuously afforded 20 in a >90% yield. The setup
was then allowed to run overnight, and before termination of the experiment, one
final 30-minute sample was collected.
Scheme 6. 20 hour Scale-out experiment affording 20.
1
Both the overnight run and the final sample contained 20 in 93% H-NMR yield,
thereby proving the high stability of the catalyst in the PBR. All samples were
combined and 20 was isolated in an excellent 93% yield (10.5 grams, 59.3 mmol).
With a total PBR loading of 4.19 mmol of Si-DMAP this corresponds to a TON of
more than 14 without loss of activity.
Conclusions
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In conclusion, reaction conditions for the Morita-Baylis-Hillman reaction have been
developed in continuous flow using DMAP immobilized on silica in a packed bed
reactor setup. DMAP catalyst deactivation was overcome by avoiding methyl
acrylate as the olefin. This setup allowed for the repeated use of the same PBR-
catalyst to generate a library of MBH adducts using retention times of 30 or 60
minutes for all entries. The conditions provided all desired MBH products in yields
ranging from 33% to 95%. The ability to control the reaction time with great
precision was exemplified by the reaction between terephthalaldehyde and MVK.
Here sideproduct formation was suppressed by only subjecting the reaction mixture
to the catalyst for 10 minutes while affording the target product in 71% isolated
yield. Finally, a scale-out experiment was performed to investigate the catalyst and
reactor stability. Gratifyingly, running the continuous flow system for 20.5 hours
afforded the desired product in an excellent 93% isolated yield. Importantly, no sign
of catalyst deactivation was observed throughout the entire scale-out experiment.
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Experimental section
General
All solvents were HPLC-graded quality and were used without further treatment
unless otherwise stated. All chemicals were used as received. DMAP-MS was
obtained from silicycle (product nr: R75630B, lot: 104492, 0.98 mol/g). Physical
properties of DMAP-MS (particle size = 40 - 63 μm, surface area = 480-550 m2/g,
pore diameter = 60 Å). Concentration in vacuo was conducted using a rotary
o
o
evaporator with a water bath set to 40 C - 55 C . Flash column chromatography
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was conducted with silica gel (230-400 mesh particle sizes, 60 Å pore size) as the
stationary phase. TLC was conducted using silica coated alumina plates (Kieselgel
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60 F254). The TLC plates were visualized using UV light. H-NMR spectra were
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recorded at 400 MHz, 13C-NMR were recorded at 101 MHz spectroscopy and 19F
1
NMR were carried out at 376 MHz on a 400 MHz spectrometer. H NMR and 13C
NMR spectra are reported in ppm and correlated to their respective solvent residual
peak23. High-resolution mass spectra were conducted on a LC TOF (ES) apparatus,
with positive electrospray ionization. Masses were calibrated using internal
standards from sodium formate clusters. Melting points (mp) were obtained on a
capillary melting point apparatus and are uncorrected. Quantitative NMR was
conducted with dimethyl terephthalate as the internal standard.
General Methods
General Continuous Flow Reactor Setup
A HPLC pump was used to pump the stock solution through the flow setup. A back-
pressure regulator (69 bar) was connected to prevent boiling of solvents and
reagents. All stainless steel tubing (1/16’’ OD x 0.75 mm ID) and reactors were
connected using HPLC fittings (T-pieces, unions etc. all with 0.75 mm ID). The
packed bed reactors were heated in an oil bath (scheme-1, fig.1). Important: All
parts of the continuous flow setup, i.e. tubing, columns, fittings, connectors, back-
pressure regulator, etc, are constructed using HPLC-components. This is done to
ensure a high level of security during operation at high pressures.
Determination of Internal Volume:
The void volume of the PBR was determined by weighing the newly prepared PBR’s
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(m1). Then 1-butanol was pumped through the reactor to fill the reactor void with
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solvent and the PBR was weighed again (m2). The total reactor void volume, Vvoid
,
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was determined by:
Eq(1)
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MBH Reactions Using Poly-DMAP in Continuous Flow
The aldehyde (0.4 M, 1 equiv.) and the activated alkene (2.4 M, 6 equiv.) were
dissolved in n-butanol in a measuring flask (10 mL). 2.0 mL of the stock-solution
was loaded into the sample loop and pumped through the packed bed reactor
containing DMAP (1.0 g, 6 mmol/g, 200-400 mesh, 2 % cross-linked) and silica gel
with a flow rate of 0.019 mL/min corresponding to a residence time of 60 min at 60
°C. The product was collected for 5.5 hours, concentrated under reduced pressure
and purified by flash column chromatography.
Packed bed reactor
An empty HPLC column (13 cm length, 0.5 cm ID) was filled with a mixture of
polystyrene-bound DMAP (1 g, 6 mmol/g, 200-400 mesh, 2% cross-linked) and
silica gel. Both ends of the column were fitted with a small piece of cotton (∼20 mg).
4-Hydroxy-4-(4-chlorophenyl)-3-methylenebutan-2-one (4): The crude product
was obtained using the general method for MBH reaction in continuous flow. The
title compound was purified using flash column chromatography eluting with
EtOAc/pentane (1/7) and obtained as a colorless oil (103 mg, 0.49 mmol, 61 %
1
yield). H NMR (400 MHz, CDCl3): δ 7.28 (s, 4H), 6.19 (s, 1H), 5.98 (s, 1H), 5.56 (s,
1H), 3.27 (bs, 1H), 2.32 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 200.4, 149.8, 140.2,
133.5, 128.6, 128.0, 127.0, 72.2, 26.6. The title product (11) was also produced in a
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one pot fashion. The reaction was conducted in a one chamber reaction flask in 24
hours at 60 degree celcius (table 1).
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4-Hydroxy-4-(4-bromophenyl)-3-methylenebutan-2-one
(12):ꢀThe
crude
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product was obtained using the general method for MBH reaction in continuous
flow. The title compound was purified using flash column chromatography eluting
with EtOAc/pentane (1/5) and obtained as a colorless oil (127 mg, 0.50 mmol, 62 %
yield). 1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 8.40 Hz, 2H), 7.22 (d, J = 8.40 Hz, 2H),
6.19 (s, 1H), 5.97 (s, 1H), 5.55 (s, 1H), 3.22 (s, 1H), 2.33 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 200.3, 149.6, 140.6, 131.5, 128.3, 127.0, 121.6, 72.3, 26.5. HRMS (m/z):
Calculated C11H12BrO2 [M+H]+ 255.0015 found 255.0000.
4-Hydroxy-4-(4-nitrophenyl)-3-methylenebutan-2-one (5):24 The crude product
was obtained using the general method for MBH reaction in continuous flow. The
reagents were dissolved in DCM (2 mL) and the measuring flask was filled with n-
butanol). The title compound was purified using flash column chromatography
eluting with EtOAc/pentane (2/3) and obtained as a white solid (147 mg, 0.66
1
mmol, 83 % yield). Mp: 74.5 - 76.1 °C. H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 8.0
Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 6.26 (s, 1H), 6.03 (s, 1H), 5.67 (d, J = 5.60 Hz, 1H),
3.32 (d, J = 5.60 Hz, 1H), 2.35 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 200.2, 149.1,
149.0, 147.5, 127.9, 127.4, 123.7, 72.4, 26.5. HRMS (m/z): Calculated C11H11NO4
[M+H]+ 222.0761 found 222.0745.
4-hydroxy-4-(2-nitrophenyl)-3-methylenebutan-2-one (13):25 The crude
product was obtained using the general method for MBH reaction in continuous
flow. The title compound was purified using flash column chromatography eluting
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with EtOAc/pentane (1/3) and obtained as a white solid (145 mg, 0.65 mmol, 82 %
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yield). Mp: 71.4 - 74.3 °C. H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.0 Hz, 1H), 7.77
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(d, J = 8.0 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 6.22 (d, J = 3.80 Hz,
1H) 6.17 (s, 1H), 5.79 (s, 1H), 3.52 (d, J = 3.80, 1H), 2.37 (s, 1H). 13C NMR (101 MHz,
CDCl3): δ 200.0, 149.0, 148.2, 136.6, 133.6, 129.0, 128.6, 126.7, 124.8, 67.7, 26.2.
HRMS (m/z): Calculated C11H11NO4 [M+H]+ 222.0761 found 222.0741.
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4-Hydroxy-4-(2-chloro-6-fluoro-phenyl)-3-methylenebutan-2-one (14): The
crude product was obtained using the general method for MBH reaction in
continuous flow. The title compound was purified using flash column
chromatography eluting with EtOAc/pentane (1/5) and obtained as a yellow oil
(152 mg, 0.66 mmol, 83 % yield). 1H NMR (400 MHz, CDCl3): δ 7.20 (m, 2H), 6.97 (m,
1H), 6.24 (s, 1H), 6.13 (d, J = 6.20 Hz, 1H), 6.01 (s, 1H), 3.23 (d, J = 6.20 Hz, 1H), 2.37
(s, 3H). 13C NMR (101 MHz, CDCl3): δ 199.8, 163.0, 160.5, 147.8, 134.7 (d, J = 6.2 Hz),
129.8 (d, J = 10 Hz), 126.9 (d, J = 14.4 Hz), 126.0 (d, J = 26.2 Hz), 126.0 (d, J = 22.4
Hz) 115.3 (d, J = 23.0 Hz), 67.6, 26.5. 19F NMR (376 MHz, CDCl3): δ -111.24 - -111.28
(m).
HRMS (m/z): Calculated C11H10ClFO2 [M+H]+ 229.0426 found 229.0431.
Morita-Baylis-Hillman reaction in Continuous Flow using a Si-DMAP Catalyst
General continuous flow procedure A: The packed bed reactor setup was flushed
with 1-butanol:CH2Cl2 (3:1) prior to the reaction. The aldehyde (10 mmol, 1 equiv.)
and MVK (60mmol, 6 equiv.) were mixed in a measuring flask (25 mL) filed with 1-
butanol:CH2Cl2 (3:1). Prior to sample collection the reaction was run for two times
the residence times to reach steady state (se individual entries for flow rates). The
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crude reaction mixture was collected for one residence time in a round-bottomed
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flask. Conversion was determined by quantitative H-NMR analysis using dimethyl
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terephthalate as internal standard.
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General continuous flow procedure B: The packed bed reactors setup were
flushed with MeOH:H2O (2:1) prior to the reaction. The aldehyde (2.4 mmol, 1
equiv.) and Acrylamide (60mmol, 6 equiv.) were mixed in a measuring flask (25 mL)
filed with MeOH:H2O (2:1). Prior to sample collection the reaction was run for two
times the residence times to reach steady state (se individual entries for flow rates).
The crude reaction mixture was collected for one residence time in a round-
bottomed flask. 1 mL internal standard (see individual entry for concentrations)
1
was added to the crude reaction and the yield was determined by quantitative H-
NMR analysis.
Packed Bed Reactor
Two empty HPLC columns (25 cm length, 0.46 cm ID) were fitted with a small ball of
cotton in one of the ends which was compressed with a metal rod. The columns
were each filled with DMAP-MS (0.98 mmol/g). Four reactor setups were used in
total for this study, and in the following reactor(letter) refers to the specific dual-
PBR setup with total silica-DMAP loading and void volume. ReactorA: Loading of
4.45 mmol DMAP, void volume = 4.09 mL. ReactorB: Loading of 4.17 mmol DMAP,
void volume = 3.98 mL. ReactorC: Loading of 4.15 mmol DMAP, void volume = 3.69
mL. ReactorD: Loading of 4.19 mmol DMAP, void volume = 3.90 mL.
Extraction method A: The crude mixture was suspended in H2O (50 mL) and
poured into a separation funnel. The aqueous phase was extracted with Et2O (30
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mL). The organic phase was re-extracted with H2O (50 mL). The aqueous phases
were combined and evaporated in vacuo.
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3-(Hydroxy(4-nitrophenyl)methyl)but-3-en-2-one (5):24 The reaction was
performed using general method A on reactorB with 4-nitrobenzaldehyde (10
mmol, 0.4 M, 1 equiv.), MVK (60 mmol, 2.4 M, 6 equiv.). Flowrate = 0.068 mL·min-1
giving a residence time tR = 60 min. The crude mixture was concentrated in vacuo
and conversion was determined using dimethyl terephthalate as internal standard.
The title compound was purified using flash chromatography eluting with
toluene:MeOH (99.5:0.5), and was obtained as an yellow oil (0.216 mg, 0.98 mmol,
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62 %). H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H),
6.26 (s, 1H), 6.03 (s, 1H), 5.68 (d, J = 5.6 Hz, 1H), 3.33 (d, J = 5.7 Hz, 1H), 2.35 (s, 3H).
13C NMR (101 MHz, CDCl3): δ 200.2, 149.1, 149.1, 147.5, 127.9, 127.4 (2C), 123.7
(2C), 72.4, 26.5. HRMS (m/z): Calculated C11H12NO4 [M+H]+ 222.0761 found
222.0756
3-(Hydroxy(2-nitrophenyl)methyl)but-3-en-2-one (13):25 The reaction was
performed using general method A on reactorA with 2-nitrobenzaldehyde ((10
mmol, 0.4 M, 1 equiv.), MVK (60 mmol, 2.4 M, 6 equiv.). Flowrate = 0.068 mL·min-1
giving a residence time tR = 60 min. The crude mixture was concentrated in vacuo
and conversion was determined using dimethyl terephthalate as internal standard.
The title compound was purified using flash chromatography eluting with CH2Cl2,
and was obtained as a brown solid (0.170 mg, 0.77 mmol, 47 %). Mp: 72.5 oC - 75.0
oC , lit 75 oC .27 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 8.0
Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 8.2 Hz, 1H), 6.23 (d, J = 4.3 Hz, 1H), 6.17 (s,
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1H), 5.79 (s, 1H), 3.47 (s, 1H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 200.0,
149.0, 141.0, 136.5, 133.7, 129.0, 128.7, 126.7, 124.8, 67.8, 26.2. HRMS (m/z):
Calculated C11H12NO4 [M+H]+ 222.0761 found 222.0756.
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3-((2-Chloro-6-fluorophenyl)(hydroxy)methyl)but-3-en-2-one
(14):
The
reaction was performed using general method A on reactorB with 2-chloro-6-
fluoro-benzaldehyde (10 mmol, 0.4 M, 1 equiv.), MVK (60 mmol, 2.4 M, 6 equiv.).
Flowrate = 0.066 mL·min-1 giving a residence time tR = 60 min. The crude mixture
was concentrated in vacuo and conversion was determined using dimethyl
terephthalate as internal standard. The title compound was purified using flash
chromatography eluting with pentane:CH2Cl2 (1:4), and was obtained as an yellow
oil (0.204 mg, 0.89 mmol, 56 %). 1H NMR (400 MHz, CDCl3): δ 7.18 (m, 2H), 6.97 (m,
1H), 6.24 (s, 1H), 6.14 (d, J = 6.6 Hz, 1H), 6.01 (s, 1H), 3.21 (s, 1H), 2.37 (s, 1H). 13C
NMR (101 MHz, CDCl3): δ 199.8, 163.1 (d, J = 251.7 Hz), 147.8, 134.8 (d, J = 6.5 Hz),
129.9 (d, J = 10.1 Hz), 126.9 (d, J = 14.3 Hz), 126.3 (d, J = 2.1 Hz), 126.0 (d, J = 3.4 Hz),
115.3 (d, J = 23.2 Hz), 67.7, 26.6. 19F NMR (376 MHz, CDCl3): δ -111.24 - -111.28 (m)
HRMS (m/z): Calculated C11H11ClFO2 [M+H]+ 229.0426 found 229.0424.
3-((3,4-Dichlorophenyl)(hydroxy)methyl)but-3-en-2-one (15): The reaction
was performed using general method A on reactorA with 3,4-dichlorobenzaldehyde
(10 mmol, 0.4 M, 1 equiv.), MVK (60 mmol, 2.4 M, 6 equiv.). Flowrate = 0.068
mL·min-1 giving a residence time tR = 60 min. The crude mixture was concentrated in
vacuo and conversion was determined using dimethyl terephthalate as internal
standard. The title compound was purified using flash chromatography eluting with
pentane:CH2Cl2 (1:4), and was obtained as an yellow oil (0.235 mg, 0.96 mmol, 59
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%). 1H NMR (400 MHz, CDCl3): δ 7.44 (s, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 8.3
Hz, 1H), 6.22 (s, 1H), 6.01 (s, 1H), 5.53 (d, J = 5.4 Hz, 1H), 3.30 (s, 1H), 2.33 (s, 3H).
13C NMR (101 MHz, CDCl3): δ 200.2, 149.2, 142.1, 132.6, 131.7, 130.4, 128.6, 127.5,
126.0, 71.9, 26.5. HRMS (m/z): Calculated C11H11Cl2O2 [M+H]+ 266.9950 found
266.9947.
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Methyl 4-(1-hydroxy-2-methylene-3-oxobutyl)benzoate (16): The crude
mixture was obtained using general method A on reactorC with methyl 4-
formylbenzoate (10 mmol, 0.4 M, 1 equiv.), MVK (60 mmol, 2.4 M, 6 equiv.).
Flowrate = 0.061 mL·min-1 giving a residence time tR = 60 min. The crude mixture
was concentrated in vacuo and conversion was determined using dimethyl
terephthalate as internal standard. The title compound was purified using flash
chromatography eluting with pentane:EtOAc (6:1), and was obtained as a colorless
1
oil (0.114 mg, 0.49 mmol, 33 %). H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 8.1 Hz,
2H), 7.45 (d, J = 8.1 Hz, 2H), 6.22 (s, 1H), 5.96 (s, 1H), 5.66 (d, J = 5.6 Hz, 1H), 3.91(s,
3H), 3.23 (d, J = 5.6 Hz, 1H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 200.4, 167.0,
149.6, 146.7, 129.9, 129.6, 127.5, 126.6, 72.8, 52.3, 26.6. HRMS (m/z): Calculated
C13H15O4 [M+H]+ 235.0965 found 235.0962.
4-(1-Hydroxy-2-methylene-3-oxobutyl)benzonitrile (17):26 The reaction was
performed using general method A on reactorC with 4-cyanobenzaldehyde (7.5
mmol, 0.3 M, 1 equiv.), MVK (45 mmol, 1.8 M, 6 equiv.). Flowrate = 0.123 mL·min-1
giving a residence time tR = 30 min. The crude mixture was concentrated in vacuo
and conversion was determined using dimethyl terephthalate as internal standard.
The title compound was purified using flash chromatography eluting with CH2Cl2,
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and was obtained as a light red oil (0.182 mg, 0.71 mmol, 64 %). H NMR (400 MHz,
CDCl3): δ 7.62 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 6.25 (s, 1H), 6.01 (s, 1H),
5.63 (d, J = 5.6,1H), 3.24 (d, J = 5.7, 1H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3): δ
200.2, 149.2, 147.1, 132.4 (2C), 127.8, 127.3 (2C), 118.9, 111.6, 72.6, 26.5. HRMS
(m/z): Calculated C12H12NO2 [M+H]+ 202.0863 found 202.0860.
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3-(Hydroxy(pyridin-2-yl)methyl)but-3-en-2-one (18):27 The reaction was
performed using general method A on reactorB with 2-pyridinecarboxaldehyde (10
mmol, 0.4 M, 1 equiv.), MVK (60 mmol, 2.4 M, 6 equiv.). Flowrate = 0.123 mL·min-1
giving a residence time tR = 30 min. The crude mixture was concentrated in vacuo
and conversion was determined using dimethyl terephthalate as internal standard.
The title product was purified by extraction method A, and was obtained as an
yellow oil (0.235 mg, 1.33 mmol, 90 %). 1H NMR (400 MHz, CDCl3): δ 8.51 (d, J = 4.0
Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 5 Hz, 1H), 6.21 (s,
1H), 6.15 (s, 1H), 5.70 (s, 1H), 4.78 (s, 1H), 2.34 (s, 3H). 13C NMR (101 MHz, CDCl3): δ
199.9, 160.0, 149.9, 148.3, 137.0, 127.2, 122.7, 121.6, 71.3, 26.6. HRMS (m/z):
Calculated C10H12NO2 [M+H]+ 178.0863 found 178.0863.
3-(Hydroxy(pyridin-3-yl)methyl)but-3-en-2-one (19):24 The reaction was
performed using general method A on reactorA with 3-pyridinecarboxaldehyde (10
mmol, 0.4 M, 1 equiv.), MVK (60 mmol, 2.4 M, 6 equiv.). Flowrate = 0.068 mL·min-1
giving a residence time tR = 60 min. The crude mixture was concentrated in vacuo
and conversion was determined using dimethyl terephthalate as internal standard.
The title product was purified by extraction method A, and was obtained as an
yellow solid (0.161 mg, 0.91 mmol, 57 %). Mp: 69.0 C - 71.1 C , lit: 85 C .24 1H
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NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 8.52 (d, J = 5.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H),
7.28 (t, J = 5.0 Hz, 1H), 6.25 (s, 1H), 6.03 (s, 1H), 5.64 (s, 1H), 3.26 (d, 1H), 2.36 (s,
3H). 13C NMR (101 MHz, CDCl3): δ 200.2, 149.4, 149.2, 148.5, 137.2, 134.4, 127.4,
123.5, 71.2, 26.5. HRMS (m/z): Calculated C10H12NO2 [M+H]+ 178.0863 found
178.0867.
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3-(Hydroxy(pyridin-4-yl)methyl)but-3-en-2-one (20):28 The reaction was
performed using general method B on reactorA with 4-pyridinecarboxaldehyde (10
mmol, 0.4 M, 1 equiv.), MVK (60 mmol, 2.4 M, 6 equiv.). Flowrate = 0.133 mL·min-1
giving a residence time tR = 30 min. The crude mixture was concentrated in vacuo
and conversion was determined using dimethyl terephthalate as internal standard.
The title product was purified by extraction method A, and was obtained as a red
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solid. (0.268 mg, 1.51 mmol, 95 %). Mp: 93.1 C - 97.1 C , lit 103 C .26 1H NMR
(400 MHz, CDCl3): δ 8.56 (d, J = 6.0 Hz, 2H), 7.30 (d, J = 6.0 Hz, 2H,), 6.25 (s, 1H), 6.02
(s, 1H), 5.56 (s, 1H), 2.36 (s, 3H), 1.25 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 200.3
150.8, 150.0 (2C), 149.0, 127.9, 121.4 (2C), 72.1, 26.5. HRMS (m/z): Calculated
C10H12NO2 [M+H]+ 178.0863 found 178.0864.
Ethyl 2-hydroxy-3-methylene-4-oxopentanoate (21):29 The crude mixture was
obtained using general method A on reactorD with ethyl glyoxalate ((10 mmol, 0.4
M, 1 equiv.), MVK (60 mmol, 2.4 M, 6 equiv.). Flowrate = 0.065 mL·min-1 giving a
residence time tR = 60 min. The crude mixture was concentrated in vacuo and
conversion was determined using dimethyl terephthalate as internal standard. The
title compound was purified using flash chromatography eluting with
pentane:EtOAc (2:1), and was obtained as a colorless oil (0.1951 mg, 1.13 mmol, 73
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