α-Chymotrypsin-Induced Acetalization of Aldehydes and Ketones with Alcohols

Article abstract of DOI:10.1055/s-0039-1690883

This is the first report of a simple and general method for acetalization of aldehydes via an α-chymotrypsin-induced reaction under mild conditions. A broad range of aromatic and heteroaromatic aldehydes have been acetalized under neutral conditions in good yields using a catalytic amount of chymotrypsin.

Full text of DOI:10.1055/s-0039-1690883

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–F
paper
A
en
J. Lan et al.
Paper
Synthesis
-Chymotrypsin-Induced Acetalization of Aldehydes and Ketones
with Alcohols
Jin Lan
R3 R3
O
Guofang Jiang
Jiangnan Yang
Haibo Zhu
α-Chymotrypsin
R3OH
+
O
O
R1 R2
R1 R2
60 °C
Broad substrate scopes
16 examples
Mild reaction conditions
Up to 98% yield
Zhanggao Le*
Zongbo Xie*
C–O bond formation
Biocatalysis-promoted
Department of Applied Chemistry, East China University of
Technology, Nanchang 330013, Jiangxi, P. R. of China
zhgle@ecut.edu.cn
zbxie@ecut.edu.cn
Received: 04.02.2020
Accepted after revision: 23.03.2020
Published online: 06.04.2020
ical catalysis.14 Additionally, it is the advantages of these
enzymes that are frequently reported in organic reactions
catalyzed by enzymes.15–20 Due to the aforementioned
properties possessed by enzymes, researchers are currently
focusing on the combination of enzymes and conventional
catalysts to develop organic reactions that cannot be
achieved by a single catalyst, such as photoenzymatic
ones.21–23 As a well-studied hydrolase, -chymotrypsin has
been demonstrated that it can keep its activity in organic
solvents.24 Herein, we report a general and direct acetaliza-
tion method for aldehydes with alcohols using a biocatalyt-
ic process under neutral conditions.
DOI: 10.1055/s-0039-1690883; Art ID: ss-2020-g0067-op
Abstract This is the first report of a simple and general method for
acetalization of aldehydes via an -chymotrypsin-induced reaction un-
der mild conditions. A broad range of aromatic and heteroaromatic al-
dehydes have been acetalized under neutral conditions in good yields
using a catalytic amount of chymotrypsin.
Key words -chymotrypsin, acetalization, biocatalysis, green chemis-
try
The carbonyl group is one of the most important func-
tional groups in contemporary organic synthesis.1,2 The di-
verse reactivity of the carbonyl group allows for its facile
transformation into various other functional groups, in-
cluding imines, alcohols, and olefins. Protection of carbonyl
compounds like aldehydes and ketones via acetal or ketal
formation has been a common and powerful tool in multi-
step synthesis.3 In addition, the acetal functional group can
also be used as a reaction intermediate.4 The traditional
way to synthesize acetal or ketal compounds is the use of
acids, metals, or ionic solvents,5 for example, CF3CO2Na,6
CuBF4,7 Rh2(CO)4Cl2,8 Rh,9 and Pd(II).10 Recently, research ef-
forts have been devoted to developing synthetic strategies
involving metal-organic frameworks,11 electrochemistry,12
and photocatalysis.13 However, these procedures have limit-
ed scope for acetals, like extended reaction times, or can
cause potential metal and chemical pollution.
Biocatalysis offers an alternative approach to functional
compounds with high efficiency and is environmentally
friendly. As a biodegradable green biocatalyst in organic
synthesis, enzymes have many fascinating features, such as
excellent regio-, chemo-, and stereoselectivity, high catalyt-
ic efficiency, mild reaction conditions, fewer by-products,
and fewer synthetic steps, compared to conventional chem-
A model reaction was investigated using readily avail-
able and reasonably priced 4-nitrobenzaldehyde (1a) and
methanol (2a) by varying enzyme sources, the amount of
enzyme, and temperatures to obtain the optimum reaction
conditions, the results of which are summarized in Table 1.
Initially, the reaction was performed using excess methanol
as a solvent without any catalyst at 60 °C (Table 1, entry 1).
However, these reaction conditions were ineffective. Differ-
ent enzyme sources were chosen when the reaction was
performed under specific conditions for 28 hours. When
other enzymes were selected as catalysts, such as amano li-
pase A from Aspergillus niger, pepsin from porcine gastric
mucosa, lipase from porcine pancreas, amano lipase M from
Mucor javanicus, and papain from papayalatex, no products
were obtained (entries 2–6). Nevertheless, bovine trypsin
showed low activity toward this reaction (entry 7). Surpris-
ingly, -chymotrypsin possessed excellent catalytic activity
(entry 8).
These results indicate the necessity of a catalyst for this
reaction. Furthermore, the effect of the amount of -chy-
motrypsin was also investigated. In this study, we per-
formed numerous experiments with the catalyst amount
varying in the range from 0 to 16000 U under similar condi-
tions (Table 1, entry 1, entries 8–12). When the amount of
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. Lan et al.
Paper
Synthesis
Table 1 Optimization of the Reaction Conditionsa
O
O
CHO
OH
NO2
NO2
1a
2a
3a
Entry
Catalyst (U)
blank
Temp (°C)
Time (h)
Added H2O (L)
Yield (%)b
1
2c
60
60
60
60
60
60
60
60
60
60
60
60
25
40
50
70
60
60
60
60
60
60
60
60
60
60
28
28
28
28
28
28
28
28
28
28
28
28
28
28
28
28
28
28
28
28
12
24
28
30
36
48
0
0
no reaction
amano lipase A from Aspergillus niger (300000 U/g)
pepsin from porcine gastric mucosa (601 U/mg)
lipase from porcine pancreas (30-90 U/mg)
amano lipase M from Mucor javanicus (> =10000 U/g)
papain from papayalatex (1.5–10 U/mg)
bovine trypsin (> =2500 U/mg)
-chymotrypsin (800 U/mg)
-chymotrypsin (1600 U)
no reaction
3c
0
no reaction
4c
0
no reaction
5c
0
no reaction
6c
0
no reaction
20
7c
0
8c
0
88
9
0
78
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
-chymotrypsin (4000 U)
0
88
-chymotrypsin (8000 U)
0
89
-chymotrypsin (16000 U)
0
90
-chymotrypsin (4000 U)
0
28
-chymotrypsin (4000 U)
0
45
-chymotrypsin (4000 U)
0
56
-chymotrypsin (4000 U)
0
70
-chymotrypsin (4000 U)
20
50
100
200
0
83
-chymotrypsin (4000 U)
74
-chymotrypsin (4000 U)
61
-chymotrypsin (4000 U)
48
-chymotrypsin (4000 U)
60
-chymotrypsin (4000 U)
0
77
-chymotrypsin (4000 U)
0
88
-chymotrypsin (4000 U)
0
93
-chymotrypsin (4000 U)
0
93
-chymotrypsin (4000 U)
0
93
a Reaction conditions: 1a (0.2 mmol), 2 mL of 2a for a specific time.
b Yields refer to isolated products.
c Enzyme (15 mg).
catalyst was 4000 U, the yield of the reaction was 88% (en-
try 10). An increase in the amount of catalyst resulted in the
yield remaining nearly constant (entries 11, 12). Therefore,
4000 U was selected as the optimal amount for the reaction.
Thereafter, the model reaction was screened using -chy-
motrypsin as the catalyst and excess methanol as the sol-
vent at different temperatures (entry 10, entries 13–16).
Product 3a was obtained in excellent yield at 60 °C. -chy-
motrypsin showed low activity toward this reaction when
the temperature was too high or too low. When the tem-
perature was too low, the enzyme could not fully exert its
catalytic activity. When the temperature was too high, the
enzyme became deactivated. The aforementioned results
indicate that the optimal temperature was 60 °C for this re-
action.
Water content strongly affects the catalytic behavior of
an enzyme in non-aqueous media. Thus, the effect of water
content on the reaction yield was investigated. The yield
was found to decrease with increasing water content. Since
the formation and hydrolysis of acetal are in equilibrium,
addition of water inhibits the progress of the reaction. Fi-
nally, the duration of the reaction between 4-nitrobenz-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F

C
J. Lan et al.
Paper
Synthesis
crease in yield; thus, 30 hours was selected as the optimal
reaction time. In summary, the optimal conditions were as
follows: 0.2 mmol of aldehyde was reacted with excess
methanol, catalyzed by 4000 U of -chymotrypsin at 60 °C
for 30 hours.
O
O
O
O
O
O
O
O
O
O
S
NO2
Br
3c, 30 h, 78% 3d, 30 h, 66% 3e, 12 h, 98%
CN
The substrate scope was further investigated as shown
in Figures 1 and 2. Aromatic aldehydes containing electron-
donating and electron-withdrawing substituents were
studied; the reaction worked well with electron-withdraw-
ing substituents (Figure 1, 3a–d). For electron-donating
substituents, the pure products could not be obtained be-
cause the formation and hydrolysis of acetal are in equilib-
rium and the product decomposed into raw materials
during post-treatment. Moreover, benzothiophene-3-car-
baldehyde and cinnamaldehyde were chosen to investigate
the reaction scope of heterocyclic and aliphatic aldehydes.
Both substrates produced the target products in high yields
(Figure 1, 3e, 3f). Furthermore, carbonyl-containing sub-
strates, such as acetoacetanilide and isatin were acetalized
in moderate yields (Figure 1, 3g, 3h). Finally, 2-naphthalde-
hyde was selected to investigate whether the reaction was
also applicable to naphthalene rings; the 68% yield suggest-
ed successful reaction (Figure 1, 3i).
3a, 30 h, 93% 3b, 30 h, 95%
O
O
O
O
O
O
O
O
O
N
H
O
N
H
3f, 30 h, 65%
3g, 30 h, 58%
3h, 30 h, 30%
3i, 30 h, 68%
Figure 1 The range of aldehydes and ketones
aldehyde and methanol catalyzed by -chymotrypsin was
investigated. Under the optimal conditions, the yield of the
product was 93% after 30 hours (Table 1, entry 24). As the
reaction time was prolonged, there was no significant in-
O
O
O
O
O
O
O
O
CN
3k, 30 h, 88%
The reaction was also compatible with ethanol, which
could react with several aldehydes to form the target ac-
etals in high yields (Figure 2, 3j, 3k, 3l). However, when pro-
panol was used as a protecting group, the yield was reduced
(Figure 2, 3m). Moreover, this reaction was not limited to
methanol or ethanol as a protecting group, because eth-
ylene glycol also delivered acetals in medium yield (Figure
2, 3n). To further assess the usefulness of our protocol, we
considered the effect of space. The steric hindrance of alde-
hyde protection usually causes lower yields, and therefore,
Br
3l, 30 h, 68%
NO2
NO2
3j, 48 h, 89%
3m, 48 h, 22%
O
O
O
O
O
O
O2N
O2N
3o, 30 h, 93%
NO2
3n, 48 h, 46%
3p, 30 h, 80%
Figure 2 The range of alcohols and the effects of space
O
O
H
N
N
O
H
O
O
OH
OH2
O
OH
Me
Me
Me
O
H
N
O
H
O
H
N
H2O
O
H
H
Me
O
Me
Me
O
O
Me
O
Me
H
O
O
H
N
O
N
O
H
Scheme 1 Possible reaction mechanisms for acetalization
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F

D
J. Lan et al.
Paper
Synthesis
more drastic reaction conditions are required. However,
ortho- and meta-substituted aldehydes could smoothly af-
ford the target acetal products in high yield under standard
conditions (Figure 2, 3o, 3p). Thus, these results revealed
that the present -chymoprotein catalyzed acetalization
strategy is feasible.
1H NMR (500 MHz, CDCl3):  = 7.44 (d, J = 7.0 Hz, 2 H), 7.36 (dd, J =
11.4, 4.5 Hz, 2 H), 7.30 (s, 1 H), 5.38 (s, 1 H), 3.31 (s, 6 H).
13C NMR (126 MHz, CDCl3):  = 138.1, 128.5, 128.2, 126.7, 103.2, 52.7.
3-(Dimethoxymethyl)benzo[b]thiophene (3e)37
Yellow liquid; yield: 40.7 mg (98%).
Based on our experiments and literature data,24–33
a
1H NMR (500 MHz, CDCl3):  = 7.98 (dd, J = 7.3, 1.2 Hz, 1 H), 7.83 (d, J =
8.0 Hz, 1 H), 7.55 (s, 1 H), 7.35 (m, J = 16.3, 7.2, 1.2 Hz, 2 H), 5.70 (d, J =
0.9 Hz, 1 H), 3.33 (s, 6 H).
13C NMR (126 MHz, CDCl3):  = 140.7, 137.1, 133.5, 125.6, 124.5,
124.3, 122.9, 122.7, 99.9, 52.4.
possible reaction mechanism is proposed for the formation
of the acetal compounds, as depicted in Scheme 1. Initially,
the carbonyl group is effectively activated by Ser-195 resi-
due of the enzyme. Thereafter, the alcohol attacks the car-
bonyl group of aldehyde. Afterwards, intermediates are
formed by dehydration. Finally, the alcohol attacks the in-
termediate to produce the target product.
In conclusion, herein, a convenient -chymotrypsin-
induced method for the acetalization of aldehydes and
ketones with alcohols was developed. A series of acetal
compounds were synthesized in good yields. The method
has the advantages readily available materials and catalysts,
low process cost, low toxicity, simple operation and post-
treatment, and mild reaction conditions.
(E)-(3,3-Dimethoxyprop-1-en-1-yl)benzene (3f)34
Yellow liquid; yield: 23.1 mg (65%).
1H NMR (500 MHz, CDCl3):  = 7.41 (d, J = 8.5 Hz, 2 H), 7.32 (t, J = 7.5
Hz, 2 H), 7.26 (d, J = 8.3 Hz, 1 H), 6.72 (d, J = 16.1 Hz, 1 H), 6.15 (dd, J =
16.2, 4.9 Hz, 1 H), 4.96 (d, J = 5.9 Hz, 1 H), 3.38 (s, 6 H).
13C NMR (126 MHz, CDCl3):  = 136.1, 133.6, 128.6, 128.2, 126.8,
125.758, 103.0, 52.8.
3,3-Dimethoxy-N-phenylbutanamide (3g)38
White solid; yield: 26.1 mg (58%); mp 79.2–81.9 °C.
1H NMR (500 MHz, CDCl3):  = 8.45 (s, 1 H), 7.50 (d, J = 7.6 Hz, 2 H),
7.30 (dd, J = 21.9, 13.5 Hz, 2 H), 7.15–7.02 (m, 1 H), 3.29 (s, 6 H), 2.74
(s, 2 H), 1.45 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 167.9, 138.0, 129.0, 124.1, 119.7,
100.1, 48.6, 46.0, 21.3.
-Chymotrypsin-Induced Acetalization of Aldehydes and Ketones
with Alcohols; General Procedure
The respective aldehyde or ketone (0.2 mmol) and -chymotrypsin
(4000 U) were added to the corresponding alcohol (2.0 mL) and
stirred at 60 °C for the specified reaction time and monitored by TLC.
The excess alcohol was evaporated under reduced pressure and the
residue was purified by column chromatography. The eluent used for
column chromatography was EtOAc and PE in a volume ratio of 1:4;
column chromatography was generally performed on silica gel (200–
300 mesh).
3,3-Dimethoxyindolin-2-one (3h)39
Yellow solid; yield: 11.8 mg (30%); mp 75.0–76.1 °C.
1H NMR (500 MHz, CDCl3):  = 8.61 (s, 1 H), 7.40 (dd, J = 7.5, 1.2 Hz, 1
H), 7.30 (dd, J = 7.8, 1.2 Hz, 1 H), 7.08 (dt, J = 8.5, 4.3 Hz, 1 H), 6.90 (dd,
J = 7.8, 0.8 Hz, 1 H), 3.58 (s, 6 H).
13C NMR (126 MHz, CDCl3):  = 173.0, 140.5, 130.8, 125.2, 122.8,
110.9, 97.3, 50.9.
1-(Dimethoxymethyl)-4-nitrobenzene (3a)34
Yellow liquid; yield: 36.6 mg (93%).
1H NMR (500 MHz, CDCl3):  = 8.23 (d, J = 8.8 Hz, 2 H), 7.65 (d, J = 8.8
Hz, 2 H), 5.49 (s, 1 H), 3.35 (s, 6 H).
13C NMR (126 MHz, CDCl3):  = 148.0, 145.1, 127.8, 123.4, 101.6, 52.7.
2-(Dimethoxymethyl)naphthalene (3i)36
Yellow liquid; yield: 26.4 mg (68%).
1H NMR (500 MHz, CDCl3):  = 7.93 (s, 1 H), 7.88–7.77 (m, 3 H), 7.55
(d, J = 8.8 Hz, 1 H), 7.47 (dd, J = 6.2, 3.2 Hz, 2 H), 5.54 (s, 1 H), 3.36 (s, 6
H).
4-(Dimethoxymethyl)benzonitrile (3b)35
13C NMR (126 MHz, CDCl3):  = 135.5, 133.5, 133.1, 128.4, 128.1,
127.7, 126.3, 126.2, 126.1, 124.4, 52.8.
Yellow liquid; yield: 33.4 mg (95%).
1H NMR (500 MHz, CDCl3):  = 7.69–7.65 (m, 2 H), 7.58 (d, J = 8.1 Hz, 2
1-(Diethoxymethyl)-4-nitrobenzene (3j)34
H), 5.43 (s, 1 H), 3.33 (s, 6 H).
13C NMR (126 MHz, CDCl3):  = 143.2, 132.1, 127.6, 118.7, 112.3,
Yellow liquid; yield: 40 mg (89%).
101.8, 52.7.
1H NMR (500 MHz, CDCl3):  = 8.22 (d, J = 5.1 Hz, 2 H), 7.67 (d, J = 8.7
Hz, 2 H), 5.58 (s, 1 H), 3.84–3.31 (m, 4 H), 1.26 (t, J = 7.1 Hz, 6 H).
13C NMR (126 MHz, CDCl3):  = 147.9, 146.1, 127.7, 123.4, 100.1, 61.3,
1-Bromo-4-(dimethoxymethyl)benzene (3c)36
Yellow liquid; yield: 35.7 mg (78%).
1H NMR (500 MHz, CDCl3):  = 7.49 (d, J = 8.5 Hz, 2 H), 7.32 (d, J = 8.4
15.1.
4-(Diethoxymethyl)benzonitrile (3k)40
Hz, 2 H), 5.35 (s, 1 H), 3.31 (s, 6 H).
13C NMR (126 MHz, CDCl3):  = 137.1, 131.3, 128.5, 122.5, 102.3, 52.6.
Yellow liquid; yield: 35.8 mg (88%).
1H NMR (500 MHz, CDCl3):  = 7.66 (d, J = 8.4 Hz, 2 H), 7.60 (d, J = 8.2
Hz, 2 H), 5.53 (s, 1 H), 3.70–3.44 (m, 4 H), 1.25 (t, J = 7.0 Hz, 6 H).
(Dimethoxymethyl)benzene (3d)34
Yellow liquid; yield: 20 mg (66%).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F

E
J. Lan et al.
Paper
Synthesis
13C NMR (126 MHz, CDCl3):  = 144.3, 132.1, 127.5, 118.8, 112.1,
100.3, 61.3, 15.1.
References
(1) Malins, L. R.; deGruyter, J. N.; Robbins, K. J.; Scola, P. M.;
Eastgate, M. D.; Ghadiri, M. R.; Baran, P. S. J. Am. Chem. Soc.
2017, 139, 5233.
(2) Ye, R.; Zhao, J.; Yuan, B.; Liu, W. C.; Somorjai, G. A. Nano Lett.
2016, 17, 584.
(3) Yu, M.; Pagenkopf, B. L. Tetrahedron 2003, 59, 2765.
(4) Tian, Y. P.; Gong, Y.; Hu, X. S.; Yu, J. S.; Zhou, Y.; Zhou, J. Org.
Biomol. Chem. 2019, 17, 9430.
1-Bromo-4-(diethoxymethyl)benzene (3l)41
Yellow liquid; yield: 34.5 mg (68%).
1H NMR (500 MHz, CDCl3):  = 7.48 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4
Hz, 2 H), 5.46 (s, 1 H), 3.70–3.40 (m, 4 H), 1.23 (t, J = 7.1 Hz, 6 H).
13C NMR (126 MHz, CDCl3):  = 138.2, 131.3, 128.5, 122.3, 100.8, 61.0,
15.2.
(5) Myles, L.; Gore, R. G.; Gathergood, N.; Connon, S. J. Green Chem.
2013, 15, 2740.
(6) Grabowski, J.; Granda, J. M.; Jurczak, J. Org. Biomol. Chem. 2018,
16, 3114.
(7) Kumar, R.; Chakraborti, A. K. Tetrahedron Lett. 2006, 46, 8319.
(8) Hoffman, R. V. Tetrahedron Lett. 1974, 2415.
(9) Diebolt, O.; Cruzeuil, C.; Müller, C.; Vogt, D. Adv. Synth. Catal.
2012, 354, 670.
1-(Dipropoxymethyl)-4-nitrobenzene (3m)42
Yellow liquid; yield: 11.1 mg (22%).
1H NMR (500 MHz, CDCl3):  = 8.22 (d, J = 10.9 Hz, 2 H), 7.66 (d, J = 8.7
Hz, 2 H), 5.58 (s, 1 H), 3.47 (qt, J = 9.3, 6.6 Hz, 4 H), 1.73–1.52 (m, 4 H),
0.96 (t, J = 7.4 Hz, 6 H).
13C NMR (126 MHz, CDCl3):  = 147.9, 146.2, 127.8, 123.4, 100.2, 67.3,
(10) Lipshutz, B. H.; Pollart, D.; Monforte, J.; Kotsuki, H. Tetrahedron
Lett. 1985, 26, 705.
22.9, 10.7.
(11) Cao, C. C.; Chen, C. X.; Wei, Z. W.; Qiu, Q. F.; Zhu, N. X.; Xiong, Y.
Y.; Jiang, J. J.; Wang, D.; Su, C. Y. J. Am. Chem. Soc. 2019, 141,
2589.
(12) Liu, C.; Shen, Y.; Xiao, Z.; Yang, H.; Han, X.; Yuan, K.; Ding, Y.
Green Chem. 2019, 21, 4030.
2-(4-Nitrophenyl)-1,3-dioxolane (3n)34
Yellow liquid; yield: 18 mg (46%).
1H NMR (500 MHz, CDCl3):  = 8.24 (d, J = 8.7 Hz, 2 H), 7.66 (d, J = 8.7
Hz, 2 H), 5.90 (s, 1 H), 4.18–4.01 (m, 4 H).
13C NMR (126 MHz, CDCl3):  = 148.5, 145.0, 127.4, 123.6, 102.3, 65.5.
(13) Zhou, Q.; Jia, T.; Li, X.-X.; Zhou, L.; Li, C.-J.; Feng, Y.-S. Synth.
Commun. 2018, 48, 1068.
(14) Schmid, A.; Dordick, J. S.; Hauer, B.; Kiener, A.; Wubbolts, M.;
Witholt, B. Nature 2001, 409, 6817, 258.
(15) Le, Z. G.; Liang, M.; Chen, Z. S.; Zhang, S. H.; Xie, Z. B. Molecules
2017, 22, 762.
(16) Zhang, S. G.; Xie, Z. B.; Liu, L. S.; Liang, M.; Le, Z. G. Chin. Chem.
Lett. 2017, 28, 101.
1-(Dimethoxymethyl)-3-nitrobenzene (3o)43
Yellow liquid; yield: 36.6 mg (93%).
1H NMR (500 MHz, CDCl3):  = 8.34 (s, 1 H), 8.19 (dd, J = 8.2, 2.2 Hz, 1
H), 7.80 (d, J = 7.7 Hz, 1 H), 7.56 (t, J = 7.9 Hz, 1 H), 5.49 (s, 1 H), 3.36 (s,
6 H).
13C NMR (126 MHz, CDCl3):  = 148.3, 140.4, 132.9, 129.3, 123.4,
122.0, 101.5, 52.7.
(17) Xie, Z. B.; Li, H. X.; Liu, L. S.; Lan, J.; Hu, Z. Y.; Le, Z. G. Chin. J. Org.
Chem. 2019, 39, 2632.
(18) Lu, Y.; Jiang, G. F.; Xie, Z. B.; Chen, G. Q.; Le, Z. G. Chin. J. Org.
Chem. 2018, 38, 1837.
(19) Xie, Z. B.; Zhang, S. G.; Jiang, G. F.; Liang, M.; Le, Z. G. Chin. J. Org.
Chem. 2017, 37, 514.
(20) Sun, D. Z.; Jiang, G. F.; Xie, Z. B.; Le, Z. G. Chin. J. Org. Chem. 2015,
33, 409.
(21) He, Y. H.; Xiang, Y.; Yang, D. C.; Guan, Z. Green Chem. 2016, 18,
5325.
1-(Dimethoxymethyl)-2-nitrobenzene (3p)44
Yellow liquid; yield: 31.5 mg (80%).
1H NMR (500 MHz, CDCl3):  = 7.81 (ddd, J = 13.5, 7.9, 1.1 Hz, 2 H),
7.61 (td, J = 7.7, 1.2 Hz, 1 H), 7.48 (td, J = 7.8, 1.4 Hz, 1 H), 5.93 (s, 1 H),
3.41 (s, 6 H).
13C NMR (126 MHz, CDCl3):  = 149.0, 132.7, 132.5, 129.4, 128.1,
(22) Sandoval, B. A.; Kurtoic, S. I.; Chung, M. M.; Biegasiewicz, K. F.;
Hyster, T. K. Angew. Chem. Int. Ed. 2019, 58, 8714.
(23) Schmermund, L.; Jurkaš, V.; Özgen, F. F.; Barone, G. D.;
Büchsenschütz, H. C.; Winkler, C. K.; Schmidt, S.; Kourist, R.;
Kroutil, W. ACS Catal. 2019, 9, 4115.
124.2, 99.5, 54.6.
Funding Information
(24) Kumar, A.; Venkatesu, P. Chem. Rev. 2012, 112, 4283.
(25) Thurkauf, A.; Jacobson, A. E.; Riee, K. C. Synthesis 1988, 233.
(26) Martichonok, V.; Jones, J. B. J. Am. Chem. Soc. 1996, 118, 950.
(27) Xie, Z. B.; Sun, D. Z.; Jiang, G. F.; Le, Z. G. Molecules 2014, 19,
19665.
National Natural Science Foundation of China (No. 21462001 and
11765002) and the Projects of Jiangxi Provincial Department of Sci-
ence and Technology (No. 20181BBH80007 and 20192BBH80012).
N
ati
o
n
a
l
N
atura
l
S
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
ofC
h
i
n
a(1
1
7
6
5
0
0
2)Nati
o
n
a
l
N
atura
l
S
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
ofC
h
i
n
a(2
1
4
6
2
0
0
1)
(28) Svedendahl, M.; Hult, K.; Berglund, P. J. Am. Chem. Soc. 2005,
127, 17988.
Supporting Information
Supporting information for this article is available online at
(29) Blow, D. M.; Birktoft, J. J.; Hartley, B. S. Nature 1969, 221, 5178,
337.
https://doi.org/10.1055/s-0039-1690883.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
(30) Liu, Y.; Liu, R. Food Chem. Toxicol. 2012, 50, 3298.
(31) Gemal, A. L.; Luche, J. L. J. Org. Chem. 1979, 44, 4187.
(32) Azzena, U.; Carraro, M.; Mamuye, A. D.; Murgia, I.; Pisano, L.;
Zedde, G. Green Chem. 2015, 17, 3281.
(33) Mallesham, B.; Sudarsanam, P.; Raju, G.; Reddy, B. M. Green
Chem. 2013, 15, 478.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F

F
J. Lan et al.
Paper
Synthesis
(34) Lyons, D. J. M.; Crocker, R. D.; Enders, D.; Nguyen, T. V. Green
Chem. 2017, 19, 3993.
(35) Casi, G.; Huguenin-Dezot, N.; Zuberbühler, K.; Scheuermann, J.;
Neri, D. J. Am. Chem. Soc. 2012, 134, 5887.
(36) Wiles, C.; Watts, P.; Haswell, S. J. Tetrahedron 2005, 61, 5209.
(37) Qin, B.; Schneider, U. J. Am. Chem. Soc. 2016, 138, 13119.
(38) Perronnet, J.; Girault, P.; Demoute, J. P. J. Heterocycl. Chem. 1980,
17, 727.
(40) Liu, S. T.; Chen, H. P.; Li, Y. T.; Liao, B. S. Synthesis 2011, 2639.
(41) Yi, H.; Niu, L.; Wang, S.; Liu, T.; Singh, A. K.; Lei, A. Org. Lett.
2016, 19, 122.
(42) Liu, T.; Fu, W.; Zheng, X.; Jiang, J.; Hu, M.; Tang, T. RSC Adv. 2014,
4, 18217.
(43) Sainz-Díaz, C. I. Monatsh. Chem. 2002, 133, 9.
(44) Subaramanian, M.; Landge, V. G.; Mondal, A.; Gupta, V.;
Balaraman, E. Chem. Asian J. 2019, 14, 4557.
(39) Dou, X.; Yao, W.; Jiang, C.; Lu, Y. Chem. Commun. 2014, 50,
11354.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F