Microwave-assisted Cannizzaro reaction—Optimisation of reaction conditions

Article abstract of DOI:10.1080/00397911.2019.1657459

The microwave-assisted Cannizzaro reaction was studied in order to develop fully reproducible synthetic protocols for transformation of aldehydes to carboxylic acid and alcohols. Optimised were the following process parameters: power, temperature, and time. Aromatic, heteroaromatic and aliphatic aldehydes were used in the studies. It was found that furfural, thiophene-2-carbaldehyde, pyridinecarboxaldehyde and aromatic aldehydes react under mild conditions, while 1-methyl-pyrrole-2-carboxaldehyde derivatives and aliphatic aldehydes require more drastic reaction conditions and a longer exposure time to microwave radiation.

Full text of DOI:10.1080/00397911.2019.1657459

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Microwave-assisted Cannizzaro
reaction—Optimisation of reaction conditions
Łukasz Janczewski, Małgorzata Walczak, Justyna Frączyk, Zbigniew J.
Kamiński & Beata Kolesińska
To cite this article: Łukasz Janczewski, Małgorzata Walczak, Justyna Frączyk, Zbigniew J.
Kamiński & Beata Kolesińska (2019): Microwave-assisted Cannizzaro reaction—Optimisation of
reaction conditions, Synthetic Communications, DOI: 10.1080/00397911.2019.1657459
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https://doi.org/10.1080/00397911.2019.1657459
Microwave-assisted Cannizzaro reaction—Optimisation of
reaction conditions
ꢀ
Łukasz Janczewski, Małgorzata Walczak, Justyna Fra˛czyk, Zbigniew J. Kaminski,
ꢀ
and Beata Kolesinska
Institute of Organic Chemistry, Lodz University of Technology, Lodz, Poland
ABSTRACT
ARTICLE HISTORY
Received 21 May 2019
The microwave-assisted Cannizzaro reaction was studied in order to
develop fully reproducible synthetic protocols for transformation of
aldehydes to carboxylic acid and alcohols. Optimised were the fol-
lowing process parameters: power, temperature, and time. Aromatic,
heteroaromatic and aliphatic aldehydes were used in the studies. It
was found that furfural, thiophene-2-carbaldehyde, pyridinecarboxal-
dehyde and aromatic aldehydes react under mild conditions, while
1-methyl-pyrrole-2-carboxaldehyde derivatives and aliphatic alde-
hydes require more drastic reaction conditions and a longer expos-
ure time to microwave radiation.
KEYWORDS
Aromatic and aliphatic
aldehydes; crossed
Cannizzaro reaction;
microwave irradiation;
optimal conditions;
reproducibility; syn-
thetic protocols
GRAPHICAL ABSTRACT
Introduction
Cannizzaro reaction is a disproportionation of an aldehyde to an equimolar mixture of
primary alcohol and carboxylic salt with a maximum yield 50% of both products. The
reaction occurs with aldehydes without a–hydrogens in the presence of strong bases,[1–3]
although there are also reports indicating that the reaction can be efficiently catalysed by
Lewis Acids.[4] The Cannizzaro reaction is used in the synthesis of structurally differenti-
ated intermediates that are substrates for a variety of biologically active compounds.[5–9]
The hydride transfer was found to take place directly between substrates without par-
ticipation of reaction medium, which gives the possibility of carrying out the reaction
under solvent free conditions.[10] The reaction in which the oxidant aldehyde differs
from the reductant aldehyde are also known as the cross (or crossed) Cannizzaro reac-
tion. Depends on reactants used, this approach was found useful for synthesis focussed
on either alcohol or carboxylic acid with increased yield.
ꢀ
CONTACT Beata Kolesinska
beata.kolesinska@p.lodz.pl
Faculty of Chemistry, Institute of Organic Chemistry, Lodz
University of Technology, Lodz, Poland.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
Ł. JANCZEWSKI ET AL.
Figure 1. Aldehydes used in microwave-assisted Cannizzaro reaction.
Currently, for a significant reduction of reaction time, increase of selectivity and spe-
cificity of transformations,[11] many chemical processes are conducted under microwave
irradiation conditions. The Cannizzaro reaction is not an exception and can also be car-
ried out under microwave irradiation.[12–14]
The aim of the research was to apply microwave radiation in the Cannizzaro reaction
to perform systematic studies on optimisation of the process conditions allowing the
reproducible preparation of the target alcohol and carboxylic acid.
This research goal was promoted by encouraging results of the preliminary studies
described by Sharifi et al.,[15] where the results of experiments involving a wide range of
aromatic aldehydes in the Cannizaro reaction were presented. However, reported pro-
cess conditions were not precise (commercial microwave oven was used), what made
the reproducibility difficult and sometimes even impossible. Therefore, to eliminate this
limitation, attempts have been made to develop a fully reproducible synthetic protocol
under standard and optimised Cannizzaro reaction assisted by microwave radiation.
Results and discussion
Eleven aldehydes 1a–k (Figure 1) were selected to experiment with microwave-assisted
Cannizzaro reaction.
The search for reproduce reaction conditions in microwave assisted Cannizzaro reac-
tion started with furfural (1a) (Table 1). The choice of this substrate was dictated by the
fact that furfural is one of the key-compounds formed in biorefinery processes and it is
often transformed into other valuable compounds.[16–18]
The use of Cannizzaro’s reaction allows the simultaneous synthesis of both furfuryl
alcohol (2a) and furan-2-carboxylic acid (3a).
It was found that careful grinding all reagents in the mortar resulted in the increase
1
of conversion from 35% (based on H NMR) (Table 1, entry 1) to 100% (Table 1, entry
2–4, and entry 7). The yield of isolated alcohol 2a and carboxylic acid 3a was increased
from 40% to 49% when microwave radiation was prolonged from 1 min to 2 min
(Table 1, entry 2 and 3). In the next stage, the influence of regents on the course of the
reaction was checked. Performing the reaction without catalytic amount of water
resulted in decreasing yield of products 2a and 3a to 35% (Table 1, entry 4). In the
absence of both H2O and Al2O3 the conversion was 83% (Table 1, entry 5) while in the
case of reaction without NaOH, decrease the conversion to 12% (Table 1, entry 6) was
observed. For comparison, in the absence of Al2O3 the conversion of furfural reached
100% and products 2a and 3a were isolated in 45% of yield, each (Table 1, entry 7).
In the next stage, attempts were made to check whether amount of furfuryl alcohol
(2a) can be increased in a mixture of products by using paraformaldehyde (1k) as
reducing agent. In the studies, 1–3 equivalents of 1k were used and it was found that it

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Table 1. Optimisation of process condition for furfural aldehyde (1a).a
MW conditionsb
Products (%)c
Conversion of 1a (%)
Entry
Temp (ꢀC)
Time (min)
according to 1H NMR
2a
3a
1d
2
100
100
100
100
100
100
100
1
1
2
2
2
2
2
35
100
100
100
83
12
100
–
40
49
35
–
–
45
–
40
49
35
–
–
45
3
4e
5f
6g
7h
aConditions: 1a (0.16 mL, 2 mmol), NaOH (0.5 g, 12.5 mmol), Al2O3 base (2 g, 19.6 mmol), H2O (400 lL), all substrates
grinded in a mortar.
bStandard mode – 200 W.
cYields without purification.
dSubstrates not mixed in a mortar.
eReaction without H2O.
fReaction without H2O and Al2O3.
gReaction without NaOH.
hReaction without Al2O3.
Table 2. The effect of paraformaldehyde (1k) addition to Cannizzaro reaction of furfural
aldehyde (1a).a
Entry
Ratio of substrates 1a:1k (eq)
Conversion of 1a (%)b
Ratio of products 2a/3ac
1
1:1
1:1
1:3
100
100
100
1.00/0.50
1.00/0.70
1.00/0.50
2d
3d
aConditions: 1a (0.16 mL, 2 mmol), 1k (for details see Table 2), NaOH (0.5 g, 12.5 mmol), Al2O3
H2O (400 lL).
(2 g, 19.6 mmol),
base
1
bConversion based on H NMR.
1
cRation of products 2a/3a based on H NMR.
dReaction without Al2O3.
is possible to increase the amount of alcohol 2a in the mixture with acid 3a to ratio 2:1
1
according to H NMR (Table 2).
The optimal conditions found for furfural aldehyde (1a) (Table 1, entry 3) have been
applied for thiophene-2-carbaldehyde (1b), aromatic aldehydes 1c–e (Table 3), and het-
eroaromatic analogues of pyridinecarboxaldehyde 1f–g (Figure 2). In the presence of 2 g
of Al2O3, 0.5 g of NaOH and 400 lL of H2O in reaction proceeding at 100 ꢀC after
2 min microwave radiation (standard mode) 100% of conversion of 1b to 2-thiophene-
methanol (2b) and 2-thiophenylcarboxylic acid (3b) isolated both in 47% yield (Table 3,

4
Ł. JANCZEWSKI ET AL.
Table 3. Synthesis of alcohols 2b–e and carboxylic acids 3b–e.
Entry
1
Substrate
R
Yield of product 2 (%)
Yield of product 3 (%)
1b
47
47
2
3
4
1c
1d
1e
45
45
47
45
45
47
NaOH (0.5 g, 12.5 mmol),
Al2O3 (2 g, 19.6 mmol),
4
OH
O
3
H2O (400 µL)
COH
+
MW: standard mode, 100
°C, 2 min.
2
N
N
N
H
O
1f-1g (2 mmol)
2f-2g
3f-3g
1f= COH in positin 4
2f (47%)
2g (47%)
3f (47%)
1g= COH in position 2
3g (47%)
Figure 2. MW assisted Cannizzaro reaction of 4-pyridinecarboxaldehyde (1f) and 2-pyridinecarboxalde-
hyde (1g).
entry 1). The use of the described above conditions for aromatic aldehydes 1c–e also
resulted in 100% conversion and high yields. Benzyl alcohol (2c) and benzoic acid (3c)
were obtained both in 45% yield when benzaldehyde (1c) was uses as a substrate
(Table 3, entry 2). The presence of the methyl group in the para position in 4-methyl-
benzaldehyde (1d) did not affect the yield of both products. Both 4-methylbenzyl alco-
hol (2d) and 4-methylbenzoic acid (3d) were obtained with 45% yield (Table 3,
entry 3). Replacement the methyl group with a chlorine atom in 4-chlorobenzaldehyde
(1e) resulted the slightly increase the yields of 4-chlorobenzyl alcohol (2e) and 4-chloro-
benzoic acid (3e) to 47% (Table 3, entry 4).
Application the optimal conditions for 4-pyridinecarboxaldehyde (1f) and 2-pyridinecar-
boxaldehyde (1g) resulted 100% conversion (Figure 2). In both cases, corresponding alco-
hols pyridin-4-ylmethanol (2f) and pyridin-2-ylmethanol (2g) were obtained with high
yields (47%), and the position of nitrogen atom in the ring was not important. However,

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Table 4. Optimisation of Cannizzaro reaction condition for of N-methyl-pyrrole-2-carboxaldehyde
(1 h) and compounds 4–6.
1
Entry
Substrate; R
Conversion (%) according to H NMR
Result
Substrate 4
Substrate 4
1a
2a
3a
4a
5b
H (4)
Boc (5)
Ts (6)
Me (1h)
Me (1h)
0
0
0
6
90
Substrate 4
6% conversion
2h (39%)c and 3h (39%)
aAldehyde 4, 5, 6 or 1 h (2 mmol), Al2O3 (19.6 mmol), NaOH (12.5 mmol), H2O (400 lL), all reagents grinded in a mortar;
MW conditions: standard mode, 100 ꢀC, 2 min.
bAldehyde 1 h (2 mmol), NaOH (12.5 mmol), (CH2O)n (4 mmol), H2O (400 lL); MW conditions: standard mode,
120 ꢀC, 30 min.
cYield after flash chromatography.
attempts to isolated target acids—isonicotinic acid and picolinic acid—were failed. Due to
the presence of the carboxyl group and the nitrogen atom in the pyridine ring, the stand-
ard procedure for the isolation by acidification and extraction has not a positive effect. For
this reason, the mixture was acidified to an isoelectric point (pH 5.5)[19] and the products
were isolated as zwitter ions (3f and 3g) with 47% of yields (Figure 2).
Encouraged by the results of studies using 1a and 1b, we have attempted to apply the
optimal conditions of microwave-assisted Cannizzaro reaction for conversion of pyr-
role-2-carboxaldehyde (4) (Table 4). However, in this case, all attempts were unsuccess-
ful and only unreacted substrate 4 was recovered (Table 4, entry 1). Increasing the
temperature (up to 140 ꢀC) and extending the reaction time (up to 10 min) resulted also
in the recovery of the substrate. Experiments with replacement of NaOH by KOH or
Ba(OH)2 ꢁ 8 H2O also were fruitless. Performing the reaction under optimised condi-
tions with N-Boc protected aldehyde 5 resulted deprotection of Boc group and isolation
of aldehyde 4 (Table 4, entry 2). The same result was obtained for N-Ts protected alde-
hyde 6 (Table 4, entry 3). Under standard conditions, Ts group has been removed and
the only reaction product was an aldehyde 4. To our knowledge, the observed deprotec-
tion of both Boc and Ts groups from 2-pyrrole aldehyde derivatives under the
Cannizzaro reaction conditions is the first noted example. Therefore, attempts have
been made to apply N-methyl-pyrrole-2-carboxaldehyde (1h). Under standard mode
1
condition (100 ꢀC, 2 min) 6% conversion to the product 2h based by H NMR (Table 4,
entry 4) was observed. Elongation time of reaction to 30 min and increase the tempera-
ture to 150 ꢀC did not improve conversion. However, in the absence of Al2O3, at tem-
perature raised to 160 ꢀC, after 30 min reaction conversion of substrate increased to
88%. However, due to drastic conditions, the reaction was unrepeatable because under
mentioned conditions the vials were breaking in MW reactor. Lowering the temperature
to 120 ꢀC and performing the irradiation for 30 min in the presence of paraformaldehy-
dem (2 eq) and without Al2O3 allowed to obtain a conversion of 90% and to isolate

6
Ł. JANCZEWSKI ET AL.
Table 5. Optimisation of condition of Cannizzaro reaction assisted MW irradiation for aldehyde 1i.
MW conditions
Entry
Temp (ꢀC)
Time (min)
Conversion (%)a
1b
2d
3d
4d
5d
6e
100
100
100
100
120
100
2
2
15
30
15
30
–
6
31
63
13
44
c
1
aConversion based on H NMR.
bAldehyde 1i (2 mmol), Al2O3 (19.6 mmol), NaOH (12.5 mmol), H2O (400 lL), all reagents grinded in a mortar.
cNo product and substrate.
dAldehyde 1i (2 mmol), Al2O3 (19.6 mmol), H2O (400 lL), all reagents grinded in a mortar.
eAldehyde 1i (2 mmol), Al2O3 (19.6 mmol), H2O (400 lL), (CH2O)n (4 mmol) all reagents grinded in a mortar.
pure (1-methyl-1H-pyrrole-2-yl)-methanol (2h) after flash chromatography with 39% of
yields and pure 1-methyl-2-pyrrolecarboxylic acid (3h) also with 39% (Table 4, entry 5),
respectively.
The reaction of the aldehyde 4 in the presence of the paraformaldehyde resulted in
the recovery of unreacted starting material 4.
In the next stage, attempts were made to adapt the optimal reaction conditions to the
transformation of aliphatic aldehydes 1i–k. Performing the reaction of trichloroacetalde-
hyde (1i) under condition optimised for furfural, resulted in the consumption of sub-
strate 1i but no expected product 2i (Table 5, entry 1) were isolated. After removing
NaOH from reacting mixture and repeating the process under the standard conditions
6% conversion of substrate to 2i (Table 5, entry 2) was obtained. Extending the reaction
time to 15 and then to 30 min (Table 5, entries 3 and 4) increased the conversion to 31
and 63%, respectively. However, further extension of time did not improve the conver-
sion. Rising the temperature to 120 ꢀC for 15 min resulted in decreasing of conversion
to 13% (Table 5, entry 5). Addition of formaldehyde (2 eq) increased the conversion to
44% (Table 5, entry 6), however an attempts to isolate pure alcohol 2i from the mixture
of substrate 1i and alcohol 2i were unsuccessful. The use of optimal conditions (100 ꢀC,
30 min) for trimethylacetaldehde (1j) was unsuccessful. It was not possible to obtained
the target 2,2-dimethylpropan-1-ol and pivalic acid, or even recover an unreacted sub-
strate 1j.
Transformation of formaldehyde (1k) to methanol (2k) under the conditions optimal
for 1a, as the expected target alcohol proceeded with 22% of yield (Table 6, entry 1).
Increasing the reaction temperature to 120 ꢀC, or to 140 ꢀC resulted in increase of yield
to 27 and 39%, respectively (Table 6, entries 2 and 3). However, further elevating tem-
perature to 160 ꢀC resulted in a slight decrease of the methanol yield to 36% (Table 6,
entry 4). Extending the reaction time to 30 min at the 140 ꢀC allowed to obtain product
2e with 39% (Table 6, entry 5).

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Table 6. Condition of Cannizzaro reaction assisted MW irradiation for paraformaldehyde (1k).a
MW conditions
Entry
Temp (ꢀC)
Time (min)
Yield (%)b
Area under peakc
1
2
3
4
5
100
120
140
160
140
2
2
2
2
30
22
27
39
36
39
2436
3741
5158
4741
5217
aAldehyde 1k (2 mmol), Al2O3 (19.6 mmol), NaOH (12.5 mmol), H2O (400 lL), all reagents mixed in a mortar.
bYield based on GC.
cBased on GC.
In all cases, the yield of the Cannizzaro reaction of paraformaldehyde (1k) was deter-
mined using used gas chromatography method after calibration of GC peak (see
Supplementary Material, Section 8, Fig. S31).
Conclusions
Optimisation of the Cannizzaro reaction conditions assisted by microwave radiation
allowed the development of fully reproducible synthetic protocols. Aromatic, hetero-
aromatic and aliphatic aldehydes were used in the studies, and the mixture of Al2O3
and NaOH was used as a catalyst. It has been found that the optimal for the aro-
matic and heteroaromatic aldehydes is to conduct the reaction at temperature
100–120 ꢀC for 1–2 min using standard mode – 200 W. Under these conditions, the
conversion was 100%, and alcohols 2a–e and carboxylic acids 3a–e were isolated with
almost quantitative yields. For analogues of pyridinecarboxaldehyde 1f–g conversion
was also 100% and both alcohols 2f–g were isolated with high yields, and acids were
isolated as zwitter ions 3f–g. In case of pyrrole-2-carboxaldehyde (4) and Boc- and
Ts-N-protected derivatives, 5 and 6 the expected products were not obtained. For
both protected pyrrole-2-carboxaldehyde derivatives under Cannizzaro reaction condi-
tions deprotection and formation pyrrole-2-carboxaldehyde (4) was observed, which
was not disproportionate to the expected carboxylic acid and alcohol. However, it
turned out that the application N-methyl-pyrrole-2-carboxaldehyde (1h) as substrate
allowed 90% conversion and obtaining (1-methyl-1H-pyrrole-2-yl)-methanol (2h) iso-
lated with 39% yield and 1-methyl-2-pyrrolecarboxylic acid (3h) also with 39% yield.
The transformation in the presence of 2 equivalents of paraformaldehyde required
30 min microwave radiation at 120 ꢀC.
Optimisation of reaction conditions also allowed for efficient transformation of tri-
chloroacetaldehyde (1i). The conversion rate of 63% was obtained in the reaction car-
ried out at 100 ꢀC for 30 min under standard mode—200 W. In the case of aldehyde
1i, the addition of paraformaldehyde did not increase the conversion. Despite

8
Ł. JANCZEWSKI ET AL.
attempts, it was not possible to obtain the target alcohol and acid from trimethylace-
taldehyde (1j).
It was also found that paraformaldehyde (1k) disproportionate to methanol and for-
mic acid. The optimal transformation conditions: temperature 120–140 ꢀC, time 2 min,
standard mode 200 W.
Experimental part
1
NMR spectra were measured on a Bruker Avance II Plus spectrometer (700 MHz for H
NMR and 176 MHz for 13C NMR) and a Bruker Avance DPX spectrometer
1
1
(250.13 MHz for H NMR) in CDCl3 solution. H and 13C NMR spectra are referenced
according to the residual peak of the solvent based on literature data. Chemical shifts
(d) are reported in ppm and coupling constants (J) in Hz. 13C NMR spectra were pro-
ton-decoupled. Flash chromatography was performed with a glass column packed with
Baker silica gel (30–60 lm). For TLC, silica gel on aluminum-backed TLC plates
(Sigma-Aldrich) with indicator 254 mm were used. A monomode microwave reactor
(CEM Discover) equipped with an IntelliVent pressure control system was used. The
standard method was applied, and the maximum pressure was set to 250 psi. Melting
points were obtained using a Bu€chi SMP-20 apparatus. Reactions were monitored by
gas chromatograph Hewlett Packard Series II 5890, gc column Zebron ZB-5MS. Gas
chromatography conditions: temperature 35 ꢀC, 5 min, 35–65 ꢀC, 1 ꢀC/min, 65 ꢀC, 5 min.
ESI/MS: micrOTOF-Q III spectrometer Bruker Daltonics equipped with electrospray
source and time of flight detector. N-Boc protected aldehyde 5 was prepared according
to the procedure described by Waser et al.[20] N-Ts protected aldehyde 6 was prepared
according to the procedure given by Abell et al.[21] N-methyl-pyrrole-2-carboxaldehyde
(1c) was obtained according to the procedure described by Li et al.[22]
General procedure for compounds 1a–e
NaOH (0.5 g, 12.5 mmol), Al2O3 (2.0 g, 19.6 mmol), aldehyde 1a–e (2 mmol) and H2O
(400 lL) were grinded in a mortar. Next, the paste was placed in a glass pressure vials
(10 mL) and reaction was carried out in microwave reactor: standard mode (200 W),
100 ꢀC, 2 min. After that, reaction mixture was extracted with DCM (2 ꢁ 20 mL).
Organic layer was evaporated under reduce pressure yielding 2a–e. Solid residue was
washed by water (2 ꢁ 15 mL). Aqueous phase was diluted and acidify with 1 N HCl
(30 mL), and extracted by DCM (2 ꢁ 80 mL). Organic layer was dried under anhydrous
MgSO4 and evaporated under reduce pressure to give pure 3a–e.
Furfuryl alcohol (2a)
1
Colorless oil. Yield 49% (0.096 g). H NMR (CDCl3, 700 MHz): d 7.39 (dd, 1 H, JHH
¼
1.8 Hz, JHH ¼ 0.8 Hz, CHAr), 6.34 (dd, 1 H, JHH ¼ 3.2 Hz, JHH ¼ 1.8 Hz, CHAr), 6.28
(dd, 1 H, JHH ¼ 3.2 Hz, JHH ¼ 0.6 Hz, CHAr), 4.60 (s, 2 H, CH2), 2.00 (bs, 1 H, OH). 13C
NMR (CDCl3, 176 MHz): d 154.14 (s, 1 C, CAr), 142.69 (s, 1 C, CAr), 110.48 (s, 1 C,

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SYNTHETIC COMMUNICATIONSV
9
CAr), 107.86 (s, 1 C, CAr), 57.58 (s, 1 C, CH2). The analytical data are in agreement with
those reported previously in the literature.[23]
Furan-2-carboxylic acid (3a)
1
Brown solid, mp 129–130 ꢀC (lit.[24] 130–132 ꢀC). Yield 49% (0.110 g). H NMR (CDCl3,
700 MHz): d 11.6 (bs, 1 H, OH), 7.64 (s, 1 H, CHAr), 7.33 (d, 1 H, JHH ¼ 3.4 Hz, CHAr),
6.56 (d, 1 H, JHH ¼ 2.3 Hz, CHAr). 13C NMR (CDCl3, 176 MHz): d 163.8 (s, 1 C, CO),
147.6 (s, 1 C, CArH), 143.9 (s, 1 C, CAr), 120.3 (s, 1 C, CArH), 112.4 (s, 1 C, CArH). The
analytical data are in agreement with those reported previously in the literature.[25]
General procedure for compounds 1f–g
NaOH (0.5 g, 12.5 mmol), Al2O3 (2.0 g, 19.6 mmol), aldehyde 1f–g (2 mmol) and H2O
(400 lL) were grinded in a mortar. Next, the paste was placed in a glass pressure vials
(10 mL) and reaction was carried out in microwave reactor: standard mode (200 W),
100 ꢀC, 2 min. After that, reaction mixture was extracted with DCM (2 ꢁ 20 mL).
Organic layer was evaporated under reduce pressure yielding 2f–g. Solid residue was
washed by water (2 ꢁ 15 mL). Aqueous phase was acidified with 1 N HCl to pH 5.5 and
centrifuged. After that aqueous layer was pour down and precipitate was lyophilized.
Products 3f–g were obtained as white solids.
Procedure for compound 1h
NaOH (0.50 g, 12.5 mmol), formaldehyde 1k (0.12 g, 4 mmol), aldehyde 1h (2 mmol)
and water (400 lL) were placed in a glass pressure vials (10 mL) and mixed. Reaction
was carried out in microwave conditions: standard mode, 120 ꢀC, 30 min. After that,
reaction mixture was diluted by water (15 mL) and extracted with DCM (2 ꢁ 25 mL).
Organic layer was dried under anhydrous MgSO4 and evaporated under reduce pres-
sure. Alcohol 2h was isolated and purified by flash chromatography on silica gel in
hexane:EtOAc 5:1. Water layer was diluted and acidify by 1 N HCl (30 mL), and
extracted by DCM (2 ꢁ 50 mL). Organic layer was dried under anhydrous MgSO4 and
evaporated under reduce pressure to give pure acid 3h.
General procedure for compound 1i
Al2O3 (2.0 g, 19.6 mmol), aldehyde 1i (2 mmol) and H2O (400 lL) were grinded in a
mortar. Next, the paste was placed in a glass pressure vials (10 mL) and reaction was
carried out in microwave reactor: standard mode, 100 ꢀC, 30 min. After that, reaction
mixture was extracted with DCM (2 ꢁ 20 mL). Organic layer was evaporated under
reduce pressure to give mixture of substrate 1i and product 2i in rate 0.60:1.00
(1H NMR).

10
Ł. JANCZEWSKI ET AL.
General procedure for compound 1k
NaOH (0.50 g, 12.5 mmol), Al2O3 (2.0 g, 19.6 mmol), aldehyde 1k (2 mmol) and H2O
(400 lL) were grinded in a mortar. Next, the paste was placed in a glass pressure vials
(10 mL) and reaction was carried out in microwave reactor: standard mode, 140 ꢀC,
2 min. After that, reaction mixture was extracted with DCM (2 ꢁ 20 mL). The yield of
alcohol 2k was determined by GC, tR ¼ 2.765 min. Yield of reaction is 39%.
The exact experimental procedures and full characteristics of the obtained compounds are
included in the Supplementary Information.
Funding
This research was funded by the National Center for Research and Development under Project
BIOSTRATEG2/296369/5/NCBR/2016.
References
[1] March, J. Advanced Organic Chemistry, 4th ed.; Wiley & Sons: New York, 1992; pp. 1234.
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