Preparation of acetals from aldehydes and alcohols under basic conditions

Article abstract of DOI:10.1039/c8ob00017d

A new, simple protocol for the synthesis of acetals under basic conditions from non-enolizable aldehydes and alcohols has been reported. Such reactivity is facilitated by a sodium alkoxide along with a corresponding trifluoroacetate ester, utilizing formation of sodium trifluoroacetate as a driving force for acetal formation. The usefulness of this protocol is demonstrated by its orthogonality with various acid-sensitive protecting groups and by good compatibility with functional groups, delivering synthetically useful acetals complementarily to the synthesis under acidic conditions from aldehydes and alcohols.

Full text of DOI:10.1039/c8ob00017d

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COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C8OB00017D
Preparation of acetals from aldehydes and alcohols under basic
conditions
Jakub Grabowski, Jarosław M. Granda, and Janusz Jurczak*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
ABSTRACT: A new, simple protocol for synthesis of acetals under basic conditions from non-
enolizable aldehydes and alcohols is reported. Such reactivity is facilitated by a sodium
alkoxide along with a corresponding trifluoroacetate ester, utilizing formation of sodium
trifluoroacetate as a driving force for acetal formation. The usefulness of this protocol is
demonstrated by its orthogonality with various acid-sensitive protecting groups and by good
compatibility with functional groups, delivering synthetically useful acetals complementarily
to the synthesis under acidic conditions from aldehydes and alcohols.
The carbonyl group is, arguably, one of the most important functional groups in
contemporary organic synthesis.1-5 The diverse reactivity of the carbonyl group allows for its
facile transformation into a variety of other functional groups, including imines, alcohols,
olefins, etc. Carbonyl compounds are also commonly encountered as key-building blocks in
the synthesis of complex pharmaceutical drugs and biologically active molecules.6, 7 However,
this highly reactive functional group requires protection/deprotection during multistep
organic transformations.8, 9 One of the most common protecting group used for protection of
carbonyl compounds is the acetal functionality. Its formation is usually straightforward and
entails the reaction of the carbonyl compound with an alcohol in the presence of either a
Brønsted or a Lewis acid. However, as in acid catalyzed acetalizations acetals are at
equilibrium with aldehydes, they require water scavenger, e.g. trimethyl orthoformate. For
example, Thurkauf and colleagues have described a procedure in which diaryl ketones are
1

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protected using trimethyl orthoformate, methanol and a catalytic amount of triflic acid in
nitromethane.10 Also, Gemal and Luche have published a letter where they describe
acetalization of aldehydes in the presence of various lanthanide chlorides.11 One of the
interesting recent reports is the work by Yi and coworkers,12 in which acetal formation is
facilitated by green light and a catalytic amount of Eosin Y. For a thorough review of the
protection of carbonyl compounds, we refer to Greene’s Protective Groups in Organic
Chemistry.13 Despite these considerable advantages, acetalization under acidic conditions can
become challenging when acid-sensitive functional groups are present in the molecule. To
address these limitations, several complementary methods for acetalization under non-acidic
conditions have been developed. These notably include the method for acetalization
described by Basu and coworkers, using a catalytic amount of iodine in methanol.14 Similarly,
Karimi and Golshani have prepared cyclic 1,3-dioxanes using 1,3-bistrimethylsiloxypropane
(BTSP) in dichloromethane, also in the presence of catalytic amounts of iodine.15 Additionally,
Kumamoto and coworkers have reported that dimethyl acetals are formed at high pressure
(0.8 GPa) in methanol in the presence of trialkyl orthoformates.16 Barbasiewicz and Mąkosza
described acetalization of the carbonyl group in the presence of halohydrins.17 Their method
utilizes the formation of the chlorohydrin anion, which is trapped by a carbonyl compound,
forming an appropriate hemiacetal, which then forms a cyclic acetal by elimination of the
chloride. As the favored reaction for chlorohydrin anions is the formation of oxirane, the
process is conducted at -60 ºC. Nevertheless, most of the above-mentioned methods only
enable access to the specific group of acetals.
In this communication, we present a general method for synthesis of acetals under mild,
basic conditions from non-enolizable aldehydes and alcohols. Recently, we have been
investigating an anion receptor containing triptycene.18 One of the steps in its synthesis
required the reaction of trialdehyde 1 with methyl azidoacetate in the presence of sodium
methoxide (Scheme 1). However, the outcome of this reaction was different from that
1
expected. Analysis of the H, 13C NMR and MS spectra showed that triacetal product 2 was
formed instead of the expected Knoevenagel reaction product 3.19 On the grounds of this
serendipitous observation we hypothesized that methyl azidoacetate might have methylated
the hemiacetal formed from aldehyde 1 and sodium methoxide, due to the electron
withdrawing nature of azide group, enabling access to acetal formation.
2

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Scheme 1. The serendipitous observation of aldehyde 1 acetalization under basic conditions.
To test this hypothesis, we decided to use methyl trifluoroacetate as a methylating agent. To
our delight, when benzaldehyde (4) was treated with sodium methoxide and then methyl
trifluoroacetate in methanol at room temperature we observed complete conversion of the
aldehyde to (dimethoxymethyl)benzene (5a) in a good yield of 85%.
We commenced our studies on acetalization of aldehydes under basic conditions by
testing the applicability of this protocol to several alcohols (Table 1). We screened methanol,
ethanol, isopropanol as a source of alkoxide. Similarly, to (dimethoxymethyl)benzene (5a),
(diethoxymethyl)benzene (5b) was synthesized with an excellent yield of 96%. Diisopropyl
acetal 5c, on the other hand, were synthesized in a lower yield of 23%, probably due to
increased steric hindrance of the alcohol.
Table 1. Reaction yields for various alcohol partners a
R
RONa, CF3CO2R
ROH, RT, 1-24h
O
PhCHO
R
Ph
O
4
5a-f
OiPr
MeO
OMe
OBn
EtO
OEt
iPrO
5a, 85%
5b, 96%
AllO OAll
5c, 23%b
D3CO OCD3
BnO
5d, 82%
5e, 64%b
5f, 76%
3

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a Reaction conditions: benzaldehyde (10 mmol), alcohol (15 mL), sodium alkoxide (20 mmol), alcohol
b
trifluoroacetate (20 mmol). All yields refer to isolated products. Product purified by column
chromatography.
Additionally, we also obtained dibenzyl and diallyl acetals 5d and 5e with good yields of 64%
and 82%, respectively. Moreover, we synthesized a deuterated acetal 5f with a good yield of
76%.
After examining the compatibility of our method with various alcohols, we examined a
broad spectrum of aromatic carbonyl partners possessing a wide range of functionalities
(Table 2a). In most cases, the aldehydes (6a-u) were cleanly converted into their dimethyl
acetals (7a-u) with yields in the 80-90% range, and the presence of either electron-donating
groups or mildly electron withdrawing-groups had little effect on the overall yield of the
reaction. However, strong electron-withdrawing groups like -CF3, -NO2 or – B(OR)2, by
contrast, have a detrimental effect on the purity of the products and the overall yield (7g, 7l,
7h), with the notable exception of the nitrile acetal 7m, which was obtained with an
excellent yield of 99%. Moreover, when the -NO2 substituent was present at the ortho
position towards the carbonyl group, an appropriate acetal could not be isolated, probably
due to the strong hydrogen bonding between the -NO2 and -CHO groups, resulting in the
increased stability of the carbonyl group against a nucleophilic attack.
In our scope of substrates, we included several aldehydes containing groups which could
potentially react under the acetalization reaction conditions, such as ethynyl aldehyde 6i, and
azo aldehyde 6j. Those substances, however, have proved resistant to the basic reaction
conditions and furnished their appropriate acetals 7i and 7j in yields of 88% and 99%,
respectively. Additionally, the phosphine aldehyde 6k undergoes acetalization with a yield of
78%, with the only impurities being those resulting from oxidation due to the air exposure
during work-up. Although we have successfully isolated the acetal of salicylaldehyde (7c)
with a yield of 81%, we have not been able to isolate the acetal of 3-formylbenzoic acid in
pure form. Also, the naphthalene and anthracene-based acetals (7n, 7o) were obtained in
high yields of 96% and 97%, respectively.
Table 2a. Reaction yields for various carbonyl partners a
4

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a Reaction conditions: aldehyde (10 mmol), methanol (15 mL), sodium methoxide (20 mmol), methyl
b
c
trifluoroacetate (20 mmol). All yields refer to isolated products 72 h reaction time Yield after
recrystallization d Product purified by column chromatography.
Next, we turned our attention towards aldehydes containing acid-sensitive protective
groups. N-protected acetal 7s, as well as O-protected acetals 7p and 7r, were isolated with
yields of 97%, 87%, and 78%, respectively. However, acetal 7t containing NH-Cbz protective
group was obtained in a moderate yield of 48%, as a result of the protective group’s
susceptibility to the nucleophilic attack of the methoxide. Also, the phthalimide-containing
acetal 7u was obtained with a slightly lower yield of 42%.
Knowing that our method proved compatible with various substituted benzaldehydes,
naphthaldehyde and anthraldehyde (Table 2a), we turned our attention to heteroaromatic
aldehydes (Table 2b). Thiophene acetal 9a and pyrrole acetal 9b were obtained with high
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yields of 90% and 96%, respectively. The furaldehyde acetal 9c was obtained with a
diminished yield of 62%, because of furaldehyde’s sensitivity towards basic conditions. The
pyridine-based acetal 9d was obtained with a moderate yield of 39%, probably due to the
carbonyl group being situated at a very electron-deficient 2-position. Moreover, we have
synthesized in considerable yield of 89 % the ferrocene acetal 9e. This fact suggests that our
acetalization method could be successfully applied to other, more complex organometallic
compounds. Next, we turned our attention to other carbonyl-containing compounds, such as
ketones and non-aromatic aldehydes. Reaction with benzophenone did not result in
conversion of starting material to the desired product and the attempted acetalization of
acetophenone yielded only the aldol reaction products. Aliphatic aldehydes, such as
butyraldehyde yield mostly aldol reaction products, and in effect we were not able to isolate
its corresponding acetal in pure. Similarly, α,β-unsaturated aldehydes, such as
crotonaldehyde and 3-methylcrotonaldehyde give an intractable mixture of products
resulting from both aldol and Michael reactions.
Table 2b. Reaction yields for various carbonyl partners a
a
Reaction conditions: aldehyde (10 mmol), methanol (15 mL), sodium (20 mmol), methyl
b
trifluoroacetate (20 mmol). All yields refer to isolated products Product unstable at room
temperature c Product purified by vacuum distillation d Product purified by column chromatography
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However, cinnamaldehyde cleanly converts into an appropriate dimethyl acetal 9f, as the
double bond is stabilized by the presence of the aromatic ring. Similarly, the myrtenal acetal
(9g) can be obtained in a yield of 91%, due to the strained nature of the substituted
cyclohexyl ring, resulting in an unfavorable geometry for the conjugated addition of
methoxide
ion.
Furthermore,
the
non-aromatic
and
weakly
enolizable
cyclohexylformaldehyde gave the dimethyl acetal 9h in a good yield of 68%. Next, we have
explored the possibility of forming cyclic acetals by employing ω-bromo-substituted aliphatic
aldehydes, however the reaction of 4-bromobutyraldehyde and 5-bromovaleraldehyde did
not yield neither the expected 2-methoxytetrahydrofuran, nor 2-methoxytetrahydropyran,
respectively.
Having established the scope and limitations of our protocol, we decided to gain
further insight into the reaction mechanism. We envisioned two plausible reaction pathways
for our acetalization reaction (Scheme 2). The first step is identical for both pathways, and
involves the nucleophilic addition of methoxide to the carbonyl group, reversibly creating a
alkoxide anion 10. In path A, the alkoxide anion 10 is acylated, forming a trifluoroacetate
ester 11, which in turn is attacked by a methoxide anion, resulting in formation of the
desired acetal and a trifluoroacetate anion. In path B the alkoxide is directly methylated by
the trifluoroacetate ester, also yielding the final acetal product and a trifluoroacetate anion.
The formation of sodium trifluoroacetate drives the formation of the product which makes
our method not an equilibrium one, as in case of acid catalyzed acetalizations. Both these
mechanisms seem to explain the fact that electron-poor aldehydes are less efficiently
converted to their acetals, as their intermediate hemiacetal is a weaker nucleophile
compared with electron-rich hemiacetals. An interesting and seemingly contradictory
observation is that a very electron-rich aldehyde 6d requires very long reaction times for a
total conversion. This can be explained by the diminished aldehyde electrophilicity, resulting
in a lower equilibrium concentration of the hemiacetal.
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Scheme 2. Possible reaction mechanisms for acetalization of benzaldehyde 4.
Seeking further evidence in support of the proposed mechanism, we decided to study
the kinetic isotope effect for conversion of benzaldehyde (4a) to dimethoxy acetal (5a) under
1H NMR control. As our reaction conditions involve methanol and a trifluoroacetic acid
methyl ester under basic conditions, we were forced to conduct the reaction using
methanol-d4 or and methyl-d3 trifluoroacetate for its deuterated variant. We studied the
reaction kinetics by intermittingly quenching a portion of the reaction mixture by adding it to
a known volume of water, extracting the resulting mixture with chloroform-d and, after
1
separation, recording the chloroform solution’s H NMR spectrum. The data fitted to a
second order reaction kinetics (Figure 1) revealed a moderate value of kinetic isotope effect
(KIE = 2.148), which proves that the intermediate hemiacetal 10 does attack the methyl
group of the ester. When we studied the reaction kinetics in methanol-d3, however, we have
found a smaller value of kinetic isotope effect (KIE=1.813), which suggests that the alcohol -
OH group plays an important role in stabilizing some of the reaction’s transition states.
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Figure 1. Benzaldehyde (4) conversion at 25 °C fitted to second order kinetic.
In summary, we have developed an efficient yet simple method for acetalization of
aldehydes under basic conditions using readily available starting materials. The method's
general applicability and good functional group compatibility has been demonstrated in 35
structurally diverse examples (yields up to 99%). Furthermore, we have also determined
structural factors necessary for successful acetalization, namely the absence of easily
enolizable protons in α position to the carbonyl group or strongly electron-withdrawing
functional groups in the aromatic ring. We believe that this methodology will expand the
existing methods of acetalization and may find broad application in organic synthesis.
EXPERIMENTAL SECTION
General information All solvents were of reagent grade quality. All reagents were obtained
commercially and used without further purification, unless otherwise specified. All reactions
were performed under argon atmosphere. Column chromatography was carried out using
Merck Kieselgel 60 (230-400 mesh), TLC was carried out on Merck Kieselgel F254 plates.
Melting points were determined using a Stanford Research Systems EZ-Melt apparatus. The
1H and 13C NMR spectra were recorded on Bruker Avance 400 MHz. Mass spectral analyses
were performed with on magnetic sector mass spectrometer AutoSpec Premier (Waters,
USA), equipped with an electron impact (EI) ion source and the EBE double focusing
geometry mass analyzer and on Synapt G2-S HDMS (Waters Inc) mass spectrometer
equipped with an electrospray ion source and q-TOF type mass analyzer. The instruments
were controlled and recorded data were processed using MassLynx V4.1 software package
(Waters Inc).
2,7,15-tributoxy-3,6,14-tris(dimethoxymethyl)-9,10-dihydro-9,10-[1,2]benzenoanthracene 2
A solution of trialdehyde 1 (56 mg, 0.1 mmol) in 1 mL of THF and 1 mL of methanol was
cooled to 0 °C. Then, methyl azidoacetate was added (173 mg, 1.5 mmol, 15 eq) along with a
solution of sodium methoxide (81 mg, 1.5 mmol, 15 eq) in 1 mL of methanol. The solution
was stirred for 24 hours in 0 °C and for the next 24 hours at room temperature. The reaction
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mixture was quenched with a saturated solution of NH4Cl (5 mL) and extracted with AcOEt (2
x 10 mL). The combined organic phases were dried over Na2SO4 and evaporated. The crude
product was purified using column chromatography (SiO2/hexanes:AcOEt, 4:1, v:v) yielding
triacetal 2 (20 mg, 0.03 mmol, 30%) as an off-white solid, mp 170-175 ℃; 1H NMR (400 MHz,
DMSO-d6) δ 7.35 (s, 3H), 7.14 (s, 3H), 5.54 (s, 2H), 5.39 (s, 3H), 3.94 (t, J = 6.3 Hz, 6H), 3.20 (s,
18H), 1.72 – 1.61 (m, 6H), 1.48 – 1.35 (m, 6H), 0.91 (t, J = 7.4 Hz, 9H).13C NMR (101 MHz,
DMSO-d6) δ 153.3, 146.4, 138.0, 122.4, 121.3, 109.0, 99.2, 67.9, 53.7, 53.1, 50.2, 30.9, 18.7,
13.6.
HRMS (ESI) calcd for [C41H59O9+Na]+ 715.3822, found 715.3810. IR (KBr) νmax: 2956, 2933, 2872,
2827.
A General Procedure for the synthesis of acetals: A solution of alkoxide was prepared by
dissolving Na (0.46 g, 20 mmol, 2 eq) in anhydrous alcohol (15 mL). To this mixture aldehyde
(10 mmol) was added, followed immediately by an appropriate trifluoroacetate ester (20
mmol, 2 eq). The reaction mixture was stirred overnight at room temperature. After
confirming the complete conversion of the aldehyde with TLC, alcohol was removed under
reduced pressure and to the solid remainings H2O (50 mL) was added. The aqueous phase
was extracted with DCM (2 x 50 mL). The combined organic phases were washed with brine
(50 mL), dried over anhydrous Na2SO4, and evaporated, yielding an appropriate acetal. The
product was not further purified, unless otherwise stated.
1
Benzaldehyde dimethyl acetal (5a) Colorless oil (1.29 g, 8.5 mmol, 85%). H NMR (400 MHz,
DMSO-d6) δ 7.46 – 7.26 (m, 5H), 5.37 (s, 1H), 3.24 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ
138.2, 128.3, 128.0, 126.5, 102.7, 52.5. Anal. Calcd. for C9H12O2: C, 71.03; H, 7.95. Found: C,
71.09; H, 8.08.
Benzaldehyde diethyl acetal (5b) Colorless oil (1.74 g, 9.6 mmol, 96%).1H NMR (400 MHz,
DMSO-d6) δ 7.63 – 7.05 (m, 5H), 5.47 (s, 1H), 3.75 – 3.37 (m, 4H), 1.14 (t, J = 7.1 Hz, 3H). 13C
NMR (101 MHz, DMSO-d6) δ 139.2, 128.1, 128.0, 126.3, 100.9, 60.7, 15.1 Anal. Calcd for
C11H16O2: C, 73.30; H, 8.95. Found: C, 73.22; H, 9.10.
Benzaldehyde diisopropyl acetal (5c) Purified using column chromatography
(SiO2/hexanes:AcOEt, 9:1, v:v). Colorless oil (0.10 g, 2.9 mmol, 29%).1H NMR (400 MHz,
DMSO-d6) δ 7.44 – 7.26 (m, 5H), 5.54 (s, 1H), 3.83 (sept, J = 6.1 Hz, 2H), 1.12 (d, J = 6.2 Hz,
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6H), 1.09 (d, J = 6.1 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ 140.7, 128.0, 127.9, 126.4, 98.6,
67.4, 22.9, 22.3.
1
Benzaldehyde dibenzyl acetal (5d) Colorless oil (2.5 g, 8.2 mmol, 82%). H NMR (400 MHz,
DMSO-d6) δ 7.53 – 7.48 (m, 2H), 7.45 – 7.23 (m, 13H), 5.77 (s, 1H), 4.59 (s, 4H). 13C NMR (101
MHz, DMSO-d6) δ 138.4, 138.0, 128.5, 128.24, 128.22, 127.5, 127.4, 126.5, 100.7, 67.1. Anal.
Calcd for C21H20O2: C, 82.86; H, 6.62. Found: C, 83.04; H, 6.59.
Benzaldehyde diallyl acetal (5e) Purified using column chromatography (SiO2/hexanes:AcOEt,
1
9:1, v:v). Colorless oil (1.33 g, 6.5 mmol, 65%). H NMR (400 MHz, DMSO-d6) δ 7.45 – 7.32
(m, 5H), 5.99 – 5.86 (m, 2H), 5.59 (s, 1H), 5.28 (dq, J = 17.2, 1.8 Hz, 2H), 5.14 (dq, J = 10.4, 1.4
Hz, 2H), 4.03 (dt, J = 5.2, 1.3 Hz, 4H). 13C NMR (101 MHz, DMSO-d6) 138.6, 134.8, 128.4,
128.1, 126.4, 116.3, 100.4, 66.1 Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.50;
H, 7.89.
1
Benzaldehyde dimethyl acetal-d6 (5f) Colorless oil (1.14 g, 7.2mmol, 72%). H NMR (400
MHz, DMSO-d6) δ 7.44 – 7.30 (m, 5H), 5.37 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 138.2,
128.2, 128.0, 126.4, 102.5, 51.5 (sep, J = 21.7 Hz). HRMS(ESI/Q-TOF) m/z [M]+ Calcd for
C9H6D6O2 158.1214; Found 158.1216.
1
2-Chlorobenzaldehyde dimethyl acetal (7a) Colorless oil (1.73 g, 9.3 mmol, 93%). H NMR
(400 MHz, DMSO-d6) δ 7.59 – 7.52 (m, 1H), 7.49 – 7.43 (m, J = 5.5, 3.1 Hz, 1H), 7.42 – 7.34
(m, 2H), 5.55 (s, 1H), 3.29 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 135.2, 132.1, 130.2, 129.4,
128.0, 126.9, 100.5, 53.5. Anal. Calcd for C9H11ClO2: C, 57.92; H, 5.94; Cl, 18.99. Found: C,
57.69; H, 6.02; Cl, 18.91.
1
2-Methoxybenzaldehyde dimethyl acetal (7b) Colorless oil (1.71 g, 9.4 mmol, 94%). H NMR
(400 MHz, DMSO-d6) δ 7.38 (dd, J = 7.5, 1.8 Hz, 1H), 7.32 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H), 7.01
(dd, J = 8.3, 0.8 Hz, 1H), 6.95 (td, J = 7.4, 0.7 Hz, 1H), 5.54 (s, 1H), 3.79 (s, 3H), 3.24 (s, 6H). 13
C
NMR (101 MHz, DMSO-d6) δ 156.7, 129.5, 126.8, 125.9, 119.8, 111.1, 98.6, 55.4, 53.2. Anal.
Calcd for C10H14O3: C, 65.92; H, 7.74. Found: C, 65.94; H, 7.68.
2-Hydroxybenzaldehyde dimethyl acetal (7c) Purified by dissolving in DCM and filtering
through a layer of silica gel. Yellow, deliquescent solid (1.37 g, 8.1 mmol, 81%).
1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.29 (dd, J = 7.6, 1.5 Hz, 1H), 7.23 – 7.00 (m, 1H),
6.93 – 6.63 (m, 2H), 5.53 (s, 1H), 3.25 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 154.9, 129.2,
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127.0, 124.1, 118.4, 115.4, 99.2, 53.2. Anal. Calcd for C9H12O3: C, 64.27; H 7.19. Found: C,
64.54; H, 7.17.
N,N-diethyl-4-aminobenzaldehyde dimethyl acetal (7d) Yellow oil (1.95 g, 8.7 mmol, 87%).1H
NMR (400 MHz, DMSO-d6) δ 7.14 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.9 Hz, 2H), 5.22 (s, 1H), 3.32
(q, J = 7.0 Hz, 4H), 3.19 (s, 6H), 1.08 (t, J = 7.0 Hz, 6H).13C NMR (101 MHz, DMSO-d6) δ 147.3,
127.5, 124.4, 110.7, 103.1, 52.1, 43.6, 12.4. HRMS(ESI/Q-TOF) m/z [M+H]+ Calcd for
C13H22NO2 224.1651; Found 224.1646. Anal. Calcd for C13H21NO2: C, 69.92; H, 9.48; N, 6.27.
Found: C, 70.03; H, 9.48; N, 6.22. IR (CH2Cl2, thin film) νmax: 2971, 2933, 2896, 2826,
1
4-Methoxybenzaldehyde dimethyl acetal (7e) Colorless oil (1.79 g, 9.8 mmol, 98%). H NMR
(400 MHz, DMSO-d6) δ 7.33 – 7.25 (m, 2H), 6.95 – 6.89 (m, 2H), 5.31 (s, 1H), 3.75 (s, 3H), 3.21
(s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 159.2, 130.3, 127.7, 113.4, 102.5, 55.0, 52.3.
Anal. Calcd for C10H14O3: C, 65.92; H, 7.74. Found: C, 65.74; H, 7.68.
Terepthalaldehyde bis-dimethyl acetal (7f) Recrystallization from methanol. Colorless
1
needles (1.76 g, 7.8 mmol, 78%), mp 53-54 ℃; H NMR (400 MHz, DMSO-d6) δ 7.39 (s, 4H),
5.39 (s, 2H), 3.24 (s, 12H).13C NMR (101 MHz, DMSO-d6) δ 138.3, 126.3, 102.4, 52.5. Anal.
Calcd for C12H18O4: C, 63.70; H, 8.02. Found: C, 63.72; H, 8.11.
4-(Trifluoromethyl)benzaldehyde dimethyl acetal (7g) Purified by column chromatography
1
(hexanes:AcOEt, 9:1, v:v). Colorless oil. (0.47 g, 2.2 mmol, 22%). H NMR (400 MHz, DMSO-
d6) δ 7.74 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 5.48 (s, 1H), 3.27 (s, 6H).13C NMR (101
MHz, DMSO-d6) δ 142.7 (d, J = 1.1 Hz), 128.9 (q, J = 31.8 Hz), 127.4, 125.0 (q, J = 3.9 Hz),
124.1 (q, J = 272.1 Hz), 101.7, 52.7. Anal. Calcd for C10H11F3O2: C, 54.55; H, 5.04; F, 25.88.
Found: C, 54.32; H, 5.09; F, 25.83.
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzaldehyde dimethyl acetal (7h) Off-white
1
solid (1.15 g, 4.1 mmol, 41%), mp 63-65 ℃; H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 7.9
Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 5.40 (s, 1H), 3.23 (s, 6H), 1.29 (s, 12H).13C NMR (101 MHz,
DMSO-d6) δ 141.2, 134.2, 125.9, 102.3, 83.6, 52.4, 24.6. HRMS(ESI/Q-TOF) m/z [M+Na]+
Calcd for C15H24BO4Na 301.1587; Found 359.1581.
1
3-Ethynylbenzaldehyde dimethyl acetal (7i) Yellow oil (1.55 g, 8.8 mmol, 88%). H NMR (400
MHz, DMSO-d6) 7.53 – 7.47 (m, 2H), 7.43 (td, J = 7.5, 1.3 Hz, 1H), 7.37 (td, J = 7.5, 1.4 Hz, 1H),
5.59 (s, 1H), 4.40 (s, 1H), 3.29 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 139.9, 132.5, 128.62,
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128.55, 126.1, 120.6, 101.71, 85.1, 80.8, 53.7. Anal. Calcd for C11H12O2: C, 74.98; H, 6.86.
Found: C, 74.76; H, 6.80.
3-Diazophenylbenzaldehyde dimethyl acetal (7j) Red oil (2.55 g, 9.9 mmol, 99%) 1H NMR (400
MHz, DMSO-d6) δ 7.96 – 7.86 (m, 4H), 7.66 – 7.54 (m, 5H), 5.52 (s, 1H), 3.30 (s, 6H).
13C NMR (101 MHz, DMSO-d6) δ 151.9, 151.8, 139.8, 131.6, 129.5, 129.44, 129.36, 123.3,
122.5, 119.7, 102.1, 52.7. Anal. Calcd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C,
70.10; H, 6.31; N, 10.96. IR (CH2Cl2, thin film) νmax: 3062, 2991, 2935, 2829.
3-(Diphenylphosphine)benzaldehyde dimethyl acetal (7k) Purified by dissolving in DCM and
1
filtering through a layer of silica gel. Yellow solid (2.62 g, 7.8mmol, 78%), mp 82-85 ℃; H
NMR (400 MHz, DMSO-d6) δ 7.64 – 7.56 (m, 1H), 7.45 – 7.27 (m, 8H), 7.24 – 7.14 (m, 4H),
6.95 – 6.88 (m, 1H), 5.89 (d, J = 5.3 Hz, 1H), 3.06 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ
142.6 (d, J = 22.6 Hz), 136.5 (d, J = 10.3 Hz), 135.1 (d, J = 18.7 Hz), 133.6, 133.3 (d, J = 19.8
Hz), 128.8, 128.7, 128.57, 128.55, 128.48, 126.18 (d, J = 5.9 Hz), 101.32 (d, J = 22.4 Hz), 53.02
HRMS(ESI/Q-TOF) m/z [M+Na]+ Calcd for C21H21O2PNa 359.1177; Found 359.1164. IR (CH2Cl2,
thin film) νmax: 3054, 2987, 2930, 2826.
3-Cyanobenzaldehyde dimethyl acetal (7l) Yellow oil (1.76 g, 9.9 mmol, 99%).1H NMR (400
MHz, DMSO-d6) δ 7.83 (d, J = 8.5 Hz, 1H), 7.78 (s, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 7.8
Hz, 1H), 5.45 (s, 1H), 3.27 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 139.8, 132.2, 131.4, 130.1,
129.5, 118.6, 111.3, 101.5, 52.8. Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found:
C, 67.43; H, 6.26; N, 7.87.
3-Nitrobenzaldehyde dimethyl acetal (7m) Purified by column chromatography (hexanes:
1
AcOEt, 4:1, v:v). Yellow oil (1.17 g, 5.9 mmol, 59%). H NMR (400 MHz, DMSO-d6) δ 8.25 –
8.20 (m, 1H), 8.20 – 8.17 (m, 1H), 7.86 – 7.80 (m, 1H), 7.70 (t, J = 7.9 Hz, 1H), 5.55 (s, 1H),
3.30 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 147.7, 140.4, 133.2, 129.9, 123.3, 121.1, 101.3,
52.9. Anal. Calcd for C9H11NO4: C, 54.82; H, 5.62; N, 7.10. Found C, 54.72; H, 5.54; N, 6.96.
1
1-Naphthaldehyde dimethyl acetal (7n) Colorless oil (1.93 g, 9.6 mmol, 96%). H NMR (400
MHz, DMSO-d6) δ 8.28 – 8.17 (m, 1H), 8.03 – 7.82 (m, 2H), 7.65 (d, J = 6.7 Hz, 1H), 7.61 – 7.44
(m, 3H), 5.91 (s, 1H), 3.31 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 133.4, 133.2, 130.2, 128.9,
128.3, 126.0, 125.7, 124.8, 124.6, 124.3, 102.3, 53.2. Anal. Calcd for C13H14O2: C, 77.20; H,
6.98. Found: C, 76.98; H, 6.90.
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9-Anthracenecarboxyaldehyde dimethyl acetal (7o) Recrystallization from methanol.
1
Colorless needles (1.76 g, 7.0 mmol, 70%), mp 136-139 ℃; H NMR (400 MHz, DMSO-d6) δ
8.79 – 8.69 (m, 2H), 8.62 (s, 1H), 8.14 – 8.02 (m, 2H), 7.59 – 7.43 (m, 4H), 6.63 (s, 1H), 3.46 (s,
6H). 13C NMR (101 MHz, DMSO-d6) δ 130.9, 129.5, 129.2, 128.7, 128.5, 125.7, 125.2, 125.0,
103.3, 55.5. Anal. Calcd for C17H16O2: C, 80.93; H, 6.39. Found: C, 80.77; H, 6.33.
2-Benzyloxybenzaldehyde dimethyl acetal (7p) Colorless oil (2.24 g, 8.7 mmol, 87%).1H NMR
(400 MHz, DMSO-d6) δ 7.50 – 7.44 (m, 2H), 7.43 – 7.37 (m, 3H), 7.35 – 7.26 (m, 2H), 7.10 (d, J
= 7.6 Hz, 1H), 7.00 – 6.92 (m, 1H), 5.61 (s, 1H), 5.15 (s, 2H), 3.25 (s, 6H). 13C NMR (101 MHz,
DMSO-d6) δ 155.7, 137.2, 129.6, 128.4, 127.7, 127.2, 126.9, 126.4, 120.1, 112.6, 98.8, 69.3,
53.3. HRMS(ESI/Q-TOF) m/z [M+Na]+ Calcd for C16H18O3Na 281.1154; Found 281.1153. Anal.
Calcd for C16H18O3: C, 74.40; H, 7.02. Found: C, 74.36; H, 7.12. IR (CH2Cl2, thin film) νmax
:
3064, 3034, 2987, 2933, 2906, 2827.
2-(Methoxymethoxy)-benzaldehyde dimethyl acetal (7r) Yellow oil (1.66 g, 7.8 mmol, 78%).
1H NMR (400 MHz, DMSO-d6) δ 7.41 (dd, J = 7.6, 1.7 Hz, 1H), 7.29 (ddd, J = 8.5, 7.4, 1.8 Hz,
1H), 7.12 – 7.07 (m, 1H), 7.00 (td, J = 7.4, 0.6 Hz, 1H), 5.58 (s, 1H), 5.22 (s, 2H), 3.39 (s, 3H),
3.26 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 154.1, 129.5, 127.0, 127.0, 121.0, 114.4, 98.7,
93.9, 55.6 53.3. HRMS(ESI/Q-TOF) m/z [M+Na]+ Calcd for C11H16O4Na 235.0946; Found
235.0944 Anal. Calcd for C11H16O4: C, 62.34; H, 7.60. Found: C, 62.34; H, 7.63. IR (CH2Cl2, thin
film) νmax: 2988, 2934, 2905, 2828.
NH-Boc-3-aminobenzaldehyde dimethyl acetal (7s) Yellow solid (2.60 g, 9.7 mmol, 97%) mp
70-73℃ 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.58 (s, 1H), 7.41 – 7.31 (m, 1H), 7.23 (t,
J = 7.8 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 5.30 (s, 1H), 3.23 (s, 6H), 1.47 (s, 9H). 13C NMR (101
MHz, DMSO-d6) δ 152.7, 139.4, 138.7, 128.2, 120.2, 118.1, 116.3, 102.7, 79.0, 52.4, 28.1.
HRMS(ESI/Q-TOF) m/z [M+Na]+ Calcd for C14H21NO4Na 290.1368; Found 290.1365 Anal. Calcd
for C14H21NO4: C, 62.90; H, 7.92; N, 5.24. Found C, 63.12; H, 8.00; N, 5.11. IR (CH2Cl2, thin
film) νmax: 3324, 2978, 2934, 2830, 1730, 1705.
NH-Cbz-3-aminobenzaldehyde dimethyl acetal (7t) Purified by column chromatography
1
(SiO2/DCM). Colorless oil (1.43g, 4.8 mmol, 48%). H NMR (400 MHz, DMSO-d6) δ 9.81 (s,
1H), 7.57 (s, 1H), 7.46 – 7.18 (m, 7H), 7.01 (d, J = 7.6 Hz, 1H), 5.32 (s, 1H), 5.15 (s, 2H), 3.22 (s,
6H). 13C NMR (101 MHz, DMSO-d6) δ 153.4, 139.0, 138.9, 136.7, 128.52, 128.47 (2C), 128.08,
128.05, 126.4, 120.7, 102.5, 65.7, 52.5. HRMS(ESI/Q-TOF) m/z [M+Na]+ Calcd for
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C17H19NO4Na 324.1212; Found 324.1208. IR (KBr) νmax: 3313, 3064, 3033, 2939, 2830, 1735,
1710.
N-Phth-3-aminobenzaldehyde dimethyl acetal (7u) Light yellow solid (1.24 g, 4.2mmol, 42%)
mp 70-74 ℃ 1H NMR (400 MHz, DMSO-d6) δ 8.00 – 7.93 (m, 2H), 7.93 – 7.87 (m, 2H), 7.55 (t,
J = 7.7 Hz, 1H), 7.49 (s, 1H), 7.48 – 7.40 (m, 2H), 5.46 (s, 1H), 3.29 (s, 6H). 13C NMR (101 MHz,
DMSO-d6) δ 166.9, 139.1, 134.6, 131.8, 131.5, 128.6, 127.2, 126.1, 125.4, 123.3, 102.1, 52.6.
Anal. Calcd for C17H15NO4: C, 62.90; H, 5.09; N, 4.71. Found: C, 68.63; H, 4.98; N, 4.66. IR
(CH2Cl2, thin film) νmax: 3063, 2991, 2938, 2905, 2831, 1726.
1
Thiophene-2-carboxyaldehyde dimethyl acetal (9a) Yellow oil (1.42 g, 9.0 mmol, 90%). H
NMR (400 MHz, DMSO-d6) δ 7.52 (dd, J = 5.0, 1.3 Hz, 1H), 7.11 – 7.05 (m, 1H), 7.05 – 7.01 (m,
J = 5.0, 3.5 Hz, 1H), 5.63 (s, 1H), 3.27 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 141.5, 126.7,
126.1, 125.5, 99.6, 52.4. Anal. Calcd for C7H10O2S: C, 53.14; H, 6.37; S, 20.26. Found C, 53.24;
H, 6.17; S, 20.04.
Pyrrole-2-carboxyaldehyde dimethyl acetal (9b)20 Yellow oil (1.35g, 9.6 mmol, 96%). Product
1
unstable at room temperature and sensitive to moisture. H NMR (400 MHz, DMSO-d6) δ
10.77 (s, 1H), 6.72 – 6.60 (m, 1H), 6.02 – 5.98 (m, 1H), 5.98 – 5.93 (m, 1H), 5.38 (s, 1H), 3.21
(s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 128.3, 117.7, 107.0, 106.3, 98.7, 52.1. HRMS(ESI/Q-
TOF) m/z [M+Na]+ Calcd for C7H11NO2Na 164.0687; Found 164.0685.
2-Furaldehyde dimethyl acetal (9c)21 Purified by vacuum distillation. Colorless oil (0.88 g, 6.2
mmol, 62%). 1H NMR (400 MHz, DMSO-d6) δ 7.65 (dd, J = 1.7, 0.9 Hz, 1H), 6.47 – 6.44 (m, J =
3.2, 1.8 Hz, 1H), 6.44 – 6.41 (m, J = 3.3, 0.8 Hz, 1H), 5.43 (s, 1H), 3.24 (s, 6H). 13C NMR (101
MHz, DMSO-d6) δ 150.8, 142.8, 110.1, 108.3, 97.4, 52.5. Anal. Calcd for C7H10O3: C, 59.15; H,
7.09. Found C, 58.98; H, 6.88.
Pyridine-2-carboxyaldehyde dimethyl acetal (9d) Purified by column chromatography
1
(SiO2/DCM: MeOH, 98:2, v:v) Yellow oil (0.60 g, 3.9 mmol, 39%). H NMR (400 MHz, DMSO-
d6) δ 8.55 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 7.83 (td, J = 7.7, 1.8 Hz, 1H), 7.48 (dt, J = 7.9, 0.9 Hz,
1H), 7.37 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 5.27 (s, 1H), 3.30 (s, 6H). 13C NMR (101 MHz, DMSO-
d6) δ 157.0, 148.7, 136.7, 123.7, 120.7, 104.0, 53.4. HRMS(ESI/Q-TOF) m/z [M+Na]+ Calcd for
C8H11NO2Na 176.0687, found 176.0686
Ferrocene 2-carboxyaldehyde dimethyl acetal (9e) Dark brown solid (2.32 g, 8.9 mmol, 89%)
1
mp 115-118 ℃ (decomposition) H NMR (400 MHz, DMSO-d6) δ 5.38 (s, 1H), 4.26 (t, J = 1.8
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Hz, 2H), 4.16 (d, J = 3.6 Hz, 5H), 4.15 – 4.14 (m, 2H), 3.20 (s, 6H). 13C NMR (101 MHz, DMSO-
d6) δ 101.6, 85.0, 68.6, 67.5, 66.8, 51.9.
E-Cinnamaldehyde dimethyl acetal (9f) Yellow oil (1.74 g, 9.8 mmol, 98%). 1H NMR (400 MHz,
DMSO-d6) δ 7.54 – 7.45 (m, 2H), 7.38 – 7.31 (m, 2H), 7.30 – 7.25 (m, 1H), 6.70 (d, J = 16.2 Hz,
1H), 6.23 (dd, J = 16.2, 5.1 Hz, 1H), 4.94 (dd, J = 5.2, 1.1 Hz, 1H), 3.28 (s, 6H). 13C NMR (101
MHz, DMSO-d6) δ 135.8, 132.6, 128.6, 128.0, 126.6, 126.1, 102.5, 52.3. Anal. Calcd for
C11H14O2: C, 74.13; H, 7.92. Found C, 74.16; H, 7.91.
(1R)-(−)-Myrtenal dimethyl acetal (9g) Yellow oil (1.79 g, 9.1 mmol, 91%). 1H NMR (400 MHz,
DMSO-d6) δ 5.59 (d, J = 1.1 Hz, 1H), 4.49 (d, J = 0.5 Hz, 1H), 3.19 (s, 3H), 3.17 (s, 3H), 2.40 –
2.16 (m, 4H), 2.12 – 2.01 (m, 1H), 1.26 (s, 3H), 1.07 (t, J = 11.2 Hz, 1H), 0.79 (s, 3H).13C NMR
(101 MHz, DMSO-d6) δ 144.8, 120.9, 104.4, 53.2, 52.7, 40.9, 40.3, 37.2, 31.1, 30.7, 25.9, 21.1.
Anal. Calcd for C12H20O2: C: 73.43; H: 10.27. Found C: 73.33; H: 10.46.
Cyclohexanecarboxyaldehyde dimethyl acetal (9h) Yellow oil (1.07 g, 6.8 mmol, 68%) 1H NMR
(400 MHz, DMSO-d6) δ 3.97 (d, J = 6.9 Hz, 1H), 3.23 (s, 6H), 1.72 – 1.62 (m, 4H), 1.63 – 1.55
(m, 1H), 1.55 – 1.39 (m, 1H), 1.25 – 1.01 (m, 3H), 1.01 – 0.84 (m, 2H). 13C NMR (101 MHz,
DMSO-d6) 107.7, 53.2, 39.6, 27.4, 25.9, 25.2.
AUTHOR INFORMATION
Corresponding Author
jurczak_group@icho.edu.pl
Notes
The authors declare no competing financial interests.
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20.
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This compound is sensitive to moisture and unstable at room temperature
The commercially available furfural (Sigma-Aldrich) was purified by distilling it from
K2CO3 (10% w:w), under reduced pressure, yielding a clear, colorless liquid, which
was stored in a brown glass bottle under argon.
17