One-pot two-step conversion of aromatic carboxylic acids and esters to aromatic aldehydes via indium-catalyzed reductive thioacetalization and desulfurization

Article abstract of DOI:10.1016/j.tetlet.2017.10.050

Described herein is that a new approach to a one-pot two-step conversion of aromatic carboxylic acids/esters to aromatic aldehydes, in which indium(III) iodide effectively catalyzes both the first reductive thioacetalization of carboxylic acids and a subsequent desulfurization of the in-situ formed thioacetal intermediates leading to aldehydes.

Full text of DOI:10.1016/j.tetlet.2017.10.050

Tetrahedron Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot two-step conversion of aromatic carboxylic acids and esters to
aromatic aldehydes via indium-catalyzed reductive thioacetalization
and desulfurization
⇑
Norio Sakai , Kohei Minato, Yohei Ogiwara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Described herein is that a new approach to a one-pot two-step conversion of aromatic carboxylic acids/
esters to aromatic aldehydes, in which indium(III) iodide effectively catalyzes both the first reductive
thioacetalization of carboxylic acids and a subsequent desulfurization of the in-situ formed thioacetal
intermediates leading to aldehydes.
Received 22 September 2017
Revised 16 October 2017
Accepted 20 October 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Indium
Carboxylic acid
Aldehyde
Thioacetalization
Desulfurization
Introduction
then directly isolated the corresponding aldehydes using only a
common work-up (Eq. 1 in Scheme 1). Moreover, a two-step prepa-
Aldehydes have constituted a central and an important position
in a variety of organic compounds, because they possess high elec-
trophilicity and are easily converted to other highly valuable com-
pounds, such as carboxylic acids and primary alcohols, via typical
oxidation and reduction. There are numerous synthetic routes to
prepare aldehydes.1 The synthesis of aldehydes via directly reduc-
tive conversion of carboxylic acids, however, has yet to gain wide
acceptance because the formed aldehydes are readily reduced to
primary alcohols by the remaining reducing reagents in a series
of transformations and because carboxylic acids generally show a
relatively high tolerance to a mild reducing agent.
Thus, to solve these problematic issues, various transformations
from carboxylic acids to aldehydes have been developed.2 As a typ-
ical approach involves the reduction of carboxylic acids with
lithium aluminum hydride to once produce alcohols, which is fol-
lowed by re-oxidation to produce aldehydes.3 A simple approach
involves the hydrogenation of carboxylic acids in the presence of
a metal catalyst.4 Also, several groups have treated carboxylic acids
with reducing reagents involving a methylamine solution with
lithium,5 thexylborane,6 aminoaluminium hydride,7 and a mixture
of isobutylmagnesium bromide and titanocene dichloride,8 and
ration involves converting carboxylic acids to activated intermedi-
ates, such as activated esters,9 acid anhydrides,10 thioesters,11 and
amides,12 which is then followed by the reduction of those inter-
mediates to obtain aldehydes (Eq. 2 in Scheme 1). After the initial
work on a reductive conversion of carboxylic acids using a diaryl-
hydrosilane tethered with an amino group by Corriu and co-work-
ers,13
Nagashima,14
Darcel,15
and
Brookhart16
groups
independently found that a combination of a metal or metalloid
catalyst, such as ruthenium, iron, and boron, and a hydrosilane
effectively reduced carboxylic acids to aldehydes, respectively.
Also, several reductive conversions of carboxylic acid derivatives,
such as esters,3,17 acid chlorides,18 and amides,19 to aldehydes in
the presence of reducing reagents involving an aluminum hydride,
tributyltin hydride and a hydrosilane, have been also developed.
We previously found that InI3 effectively catalyzed the reduc-
tive thioacetalization of a variety of carboxylic acids in the pres-
ence of a mild reducing agent, such as a hydrosilane.20,21 On the
basis of the results, we expected an indium catalyst to catalyze
the subsequent desulfurization step, and that it would be a novel
approach to the one-pot preparation of aromatic aldehydes from
aromatic carboxylic acids (Eq. 3 in Scheme 1). Practically, when
p-toluic acid was treated with the combination of a reducing sys-
tem composed of InI3 and tetramethyldisiloxane (TMDS) and a
subsequent desulfurization step using H2O2 aqueous solution, p-
⇑
Corresponding author.
E-mail address: sakachem@rs.noda.tus.ac.jp (N. Sakai).
https://doi.org/10.1016/j.tetlet.2017.10.050
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sakai N., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.10.050

2
N. Sakai et al. / Tetrahedron Letters xxx (2017) xxx–xxx
mal conditions for the transformation, and to extend its scope.
Herein, we report the results. We also disclose how the present
method could be applied to the one-pot conversion of aromatic
esters to aromatic aldehydes.
Results and discussion
Initially, on the basis of our previous work20 and similar works
found in the literature22,23 the optimization of an indium(III) com-
pound to promote a more effective desulfurization of a thioacetal
to p-tolualdehyde (1) was investigated (Table 1). As a model reac-
tion, prepared thioacetal was treated with several indium com-
pounds (10 mol%) in the presence of KI (10 mol%) and H2O2 (4
equiv) as an oxidizing agent in a mixture of ethyl acetate and
H2O.24 Consequently, regardless of a sort of a counter anion, all
Scheme 1. Divergent approaches to aldehydes from carboxylic acids.
tolualdehyde was successfully obtained in one-pot. In this case,
however, the conversion examined was limited to only one exam-
ple. Based on that situation, we intended to re-examine the opti-
indium compounds examined led to
a clean desulfurization
(entries 1–3). Also, with decreases in the amount of InI3 to 5 mol
%, the desired desulfurization took place quantitatively (entry 4),
but the use of only 1 mol% of the catalyst slightly reduced the pro-
duct yield (entry 5). On the other hand, even though the desulfur-
ization cleanly proceeded without the indium catalyst (entry 6),
the monitoring of a series of desulfurization reactions showed that
an additive effect of the indium compound remarkably accelerated
the conversion (see Scheme S1 in SI). In particular, with the addi-
tion of 10 mol% of InI3, the desired desulfurization was completed
within 2 h. Moreover, it was noteworthy that the desulfurization
proceeded smoothly and effectively without potassium iodide to
produce the corresponding aldehyde 1 (entries 7 and 8).
Table 1
a
Optimization of desulfurization with an indium(III) compound
.
Next, in order to effectively undertake a series of thioacetaliza-
tion and desulfurization reactions in one-pot, we sought a mutual
solvent by monitoring the model reaction via GC (Table 2). As
expected, ethyl acetate examined in Table 1 hardly occurred in
the first thioacetalization (entry 1). After several trials, with the
exception of acetonitrile,25 typical solvent, such as a halogenated
solvent, benzene and toluene, successfully undertook the second
desulfurization process in a relatively good yield. Therefore, it
seemed that a successful key to the entire conversion was the pro-
portion of the yield of the first thioacetalization step. Although the
use of chloroform and benzene showed good results, from the
viewpoint of an environmentally friendly solvent, we decided that
Entry
InX3
(mol%)
GC yield (%)
1
2
3
4
InCl3
InBr3
InI3
InI3
InI3
–
10
10
10
5
1
–
93
95
98
99
76
85
81
89
5
6
7a
8a
InI3
InI3
10
5
a
Without KI.
Table 2
Solvent effects of a series of thioacetalization and desulfurization.
Entry
Solv
Temp
GC yield (%)
(°C)
Step 1
Step 2a
Overall
1
2
3
4
5
6
7
AcOEt
1,2-DCE
CHCl3
CH3CN
Benzene
Toluene
Toluene
60
60
60
60
60
60
80
5
ND
91
94
–
81
85
87c
ND
23
83
–
71
25
89
ND
88
92
67
79 (69)b
58
a
b
c
Conversion yield based on formed 1a in the first step.
Isolated yield.
Reaction time at step 2 = 24 h.
Please cite this article in press as: Sakai N., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.10.050

N. Sakai et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
toluene at 60 °C, as shown in entry 6, would provide the best
results for a series of conversions.
Then, we examined the one-pot two-step protocol for the con-
version of various aromatic carboxylic acids to aromatic aldehydes
under the optimal conditions (Table 3).26 Because the use of TMDS
(2 equiv) was enough to consume a carboxylic acid in the first
thioacetalization step, subsequent examinations used 2 equiv of
TMDS. Benzoic acids without a substituent and with a methyl
group were converted to the corresponding aromatic aldehydes
2–5 in relatively good yields, regardless of either the location or
Table 3
Substrate scope of aromatic carboxylic acids.
Entry
1
Carboxylic acid
Aldehyde
Yield
(%)
2
3
4
5
41a
68
71
79
2
3
4
5
6
81
6
7
7
8
64
64
8
9
68
9
10
11
26a
69
10
11
12
12
13
55
33a
Please cite this article in press as: Sakai N., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.10.050

4
N. Sakai et al. / Tetrahedron Letters xxx (2017) xxx–xxx
we assume that the iodine cation species (I+) is a key promoter.
In this context, Kirihara and co-workers suggested that activation
of the thioacetal intermediate by the I+ equivalent that was gener-
ated from IÀ and H2O2 in the presence of a metal catalyst, such as
iron(III), niobium(V) and tantalum(V), and the subsequent hydrol-
ysis led to the preparation of aldehydes.23 We assume that the
desulfurization in the present study proceeded via a similar reac-
tion pathway.
Conclusions
Scheme 2. Applications to the one-pot conversion of aromatic esters to aromatic
aldehydes.
We demonstrated an indium(III)-catalyzed one-pot two-step
conversion of aromatic carboxylic acids to aromatic aldehydes.
The primary finding of the present study was that InI3 skillfully
promoted both reaction steps, which involved an initial reductive
thioacetalization and a subsequent desulfurization. We also found
that the present protocol could be applied to a similar transforma-
tion of aromatic esters to aromatic aldehydes. Further investigation
to determine the mechanistic details are now in progress.
the number of the group (entries 1–4). Because the isolation of
benzaldehyde itself was difficult, we attempted to isolate 2 as a
hydrazone derivative,16 which had caused a decrease in the pro-
duct yield. Also, benzoic acid derivatives with an electron-donating
group, such as a methoxy and phenoxy group, were readily
reduced to afford aromatic aldehydes 6 and 7 in practical yields
(entries 5 and 6). Moreover, the electron-withdrawing effect of a
halogenated groups had no influence on the reactivity of a series
of reductive thioacetalization and desulfurization, and the corre-
sponding benzaldehyde derivatives 8 and 9 were obtained in 64
and 68% yields (entries 7 and 8). On the other hand, an aromatic
carboxylic acid with a m-trifluoromethyl group was not effectively
converted to the expected aldehyde 10 (entry 9). In particular, the
desulfurization step hardly proceeded, and most thioacetal inter-
mediates remained. Aldehyde 10 was isolated as a corresponding
hydrazone derivative in a rather low yield. There was no clear rea-
son for the result. Also, 1- or 2-naphthoic acids were converted to
1- or 2-naphthaldehydes 11 and 12, respectively, in moderate to
good yields (entries 10 and 11). The conversion of a heterocyclic
carboxylic acid 2-fruoic acid produced the corresponding furfural
13 in a 33% isolated yield as a hydrazone derivative (entry 12).
When applying aliphatic carboxylic acids, the first thioacetaliza-
tion effectively proceeded to form the corresponding thioacetal
intermediates, but the second desulfurization of the intermediate
finally led to the formation of a complicated mixture. Also, the
use of either a conjugate carboxylic acid cinnamic acid or picolinic
acid with a pyridine ring did not produce the corresponding
aldehyde.
Acknowledgement
This work was partially supported by JSPS KAKENHI Grant
Number JP25410120. The authors deeply thank Shin-Etsu Chemi-
cal Co., Ltd., for the gift of hydrosilanes.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2017.10.050.
References
1. 2nd ed.For example, Larock RC. Comprehensive organic transformations. 2nd
ed. New York: John Wiley & Sons; 1999.
2. For example, Larson GL. Ionic and organometallic-catalyzed organosilane
reductions. New Jersey: John Wiley & Sons; 2010.
3. Zakharkin LI, Khorlina IM. Tetrahedron Lett. 1962;3:619–620.
4. Yokoyama T, Yamagata N. Appl Catal A. 2001;221:227–239.
5. Bedenbaugh AO, Bedenbaugh JH, Bergin WA, Adkins JD.
1970;92:5774–5775.
J Am Chem Soc.
6. Brown HC, Heim P, Yoon NM. J Org Chem. 1972;37:2942–2950.
7. (a) Muraki M, Mukaiyama T. Chem Lett. 1974;3:1447–1450;
(b) Hubert TD, Eyman DP, Wiemer DF. J Org Chem. 1984;49:2279–2281.
8. Sato F, Jinbo T, Sato M. Synthesis. 1981;871.
9. (a) Fujisawa T, Mori T, Tsuge S, Sato T. Tetrahedron Lett. 1983;24:1543–1546;
(b) Chandrasekhar S, Kumar MS, Muralidhar B. Tetrahedron Lett.
1998;39:909–910. See Ref. [18b].
10. (a) Nagayama K, Kawataka F, Sakamoto M, Shimizu I, Yamamoto A. Chem Lett.
1995;24:367–368;
The present method was then applied to the one-pot conversion
of an aromatic ester to an aromatic aldehyde (Scheme 2). Initially,
the treatment of a benzoic acid ester with the conditions that are
optimal for former carboxylic acids led to a decrease in the forma-
tion of the corresponding thioacetal intermediate. Thus, slight
adjustments were made to the first step, and the use of 10 mol%
of InI3 and a rise in temperature (120 °C) were effective. When
methyl p-toluate was treated with the conditions shown in
Scheme 2, p-tolualdehyde (1) was obtained in a 67% yield via the
formation of a corresponding thioacetal intermediate. Also, the
use of ethyl 4-iodobenzoate having an electron-withdrawing group
produced aldehyde 9 in a 63% yield. In contrast to alkyl benzoate
derivatives, the reaction with phenyl 4-methylbenzoate produced
an unidentified by-product in addition to the desired thioacetal
intermediate during the first thioacetalization step, which led to
a decrease in the entire yield. As yet, there is no clear reason for
this result.
(b) Nagayama K, Shimizu I, Yamamoto A. Bull Chem Soc Jpn.
2001;74:1803–1815;
(c) Gooßen LJ, Ghosh K. Chem Commun. 2002;836–837;
(d) Gooßen LJ, Khan BA, Fett T, Treu M. Adv Synth Catal. 2010;352:2166–2170.
11. Miyazaki T, Han-ya Y, Tokuyama H, Fukuyama T. Synlett. 2004;477–480.
12. Kangani CO, Kelley DE, Day BW. Tetrahedron Lett. 2006;47:6289–6292.
13. Corriu RJP, Lanneau GF, Perrot M. Tetrahedron Lett. 1987;28:3941–3944.
14. Miyamoto K, Motoyama Y, Nagashima H. Chem Lett. 2012;41:229–231.
15. Misal Castro LC, Li H, Sortais J-B, Darcel C. Chem Commun.
2012;48:10514–10516.
16. Bézier D, Park S, Brookhart M. Org Lett. 2013;15:496–499.
17. Song JI, An DK. Chem Lett. 2007;36:886–887.
18. (a) Four P, Guibe F. J Org Chem. 1981;46:4439–4445;
(b) Corriu RJP, Lanneau GF, Perrot M. Tetrahedron Lett. 1988;29:1271–1274;
(c) Fujihara T, Cong C, Iwai T, Terao J, Tsuji Y. Synlett. 2012;23:2389–2392.
19. Laval S, Dayoub W, Favre-Reguillon A, Demonchaux P, Mignani G, Lemaire M.
Tetrahedron Lett. 2010;51:2092–2094.
20. Nishino K, Minato K, Miyazaki T, Ogiwara Y, Sakai N.
2017;82:3659–3665.
J Org Chem.
Although we presented a plausible reaction pathway for the
reductive thioacetalization of carboxylic acids in the first step in
our previous work, at this point, we can offer no reasonable reac-
tion mechanism on the desulfurization of the intermediate in the
second step. However, because the addition of KI and the use of
InI3 as a catalyst effectively promote the latter desulfurization,
21. (a) For selected papers of indium(III)-catalyzed reductive transformation of
carbonyl compounds using a hydrosilane, see: Miura K, Yamada Y, Tomita M,
Hosomi A. Synlett. 2004;1985–1989;
(b) Shibata I, Kato H, Ishida T, Yasuda M, Baba A. Angew Chem Int Ed.
2004;43:711–714;
(c) Sakai N, Moriya T, Konakahara T. J Org Chem. 2007;72:5920–5922;
Please cite this article in press as: Sakai N., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.10.050

N. Sakai et al. / Tetrahedron Letters xxx (2017) xxx–xxx
5
(d) Tsuchimoto T, Igarashi M, Aoki K. Chem Eur J. 2010;16:8975–8979;
1997;858–860;
(e) Pehlivan L, Métay E, Delbrayelle D, Mignani G, Lemaire M. Eur J Org Chem.
2012;4689–4693;
(f) Moriya T, Yoneda S, Kawana K, Ikeda R, Konakahara T, Sakai N. J Org Chem.
2013;78:10642–10650;
(g) Inamoto Y, Kaga Y, Nishimoto Y, Yasuda M, Baba A. Org Lett.
2013;15:3452–3455;
(m) Curini M, Marcotullio MC, Pisani E, Rosati O. Synlett. 1997;769–770;
(n) Kamitori Y, Hojo M, Masuda R, Kimura T, Yoshida T.
1986;51:1427–1431;
J Org Chem.
(o) Balogh M, Cornelis A, Laszlo P. Tetrahedron Lett. 1984;25:3313–3316;
(p) Vedejs E, Fuchs PL. J Org Chem. 1971;36:366–367.
23. (a) Kirihara M, Suzuki S, Ishizuka Y, et al. Tetrahedron Lett. 2013;54:5477–5480;
(b) Kirihara M, Noguchi T, Okajima N, et al. Tetrahedron. 2012;68:1515–1520;
(c) Kirihara M, Harano A, Tsukiji H, Takizawa R, Uchiyama T, Hatano A.
Tetrahedron Lett. 2005;46:6377–6380.
24. When the same reaction (entry 4, Table 1) was performed with a mixture of
AcOEt and H2O2 (2 mL), the thioacetalization proceeded in a nearly quantitative
yield.
(h) Ogiwara Y, Uchiyama T, Sakai N. Angew Chem Int Ed. 2016;55:1864–1867;
(i) Nomiyama S, Hondo T, Tsuchimoto T. Adv Synth Catal. 2016;358:1136–1149.
22. (a) For selected papers for deprotetion of 1,3-dithiolanes, see: Myles L,
Gathergood N, Connon SJ. Eur J Org Chem. 2015;188–194;
(b) Oksdath-Mansilla G, Hajj V, Andrada DM, et al.
2015;80:2733–2739;
J Org Chem.
(c) Veisi H, Sedrpoushan A, Zolfigol MA, Mohanazadeh F, Hemmati S.
Heterocycl Chem. 2013;50:E204–E206;
J
25. The use of an oxygen-containing solvent, such as tetrahydrofuran and 2-
methyltetrahydrofuran, were ineffective for the conversion.
(d) Bahrami K, Khodaei MM, Tajik M, Shakibaian V. Chin Chem Lett.
2012;23:81–85;
(e) Veisi H, Amiri M, Hamidian AH, et al. Phosphorus, Sulfur Silicon Relat Elem.
2010;185:689–696;
(f) Hajipour AR, Khazdooz L, Ruoho AE. J Sulfur Chem. 2009;30:46–52;
(g) Oksdath-Mansilla G, Penenory AB. Tetrahedron Lett. 2007;48:6150–6154;
(h) Desai UV, Pore DM, Tamhankar BV, Jadhav SA, Wadgaonkar PP. Tetrahedron
Lett. 2006;47:8559–8561;
(i) Hajipour AR, Zarei A, Khazdooz L, Ruoho AE. Synthesis. 2006;1480–1484;
(j) Iranpoor N, Firouzabadi H, Shaterian HR. Tetrahedron Lett.
2003;44:4769–4773;
26. General procedure for the one-pot conversion of an aromatic carboxylic
acid (or ester) to an aromatic aldehyde: To a freshly distilled toluene solution
(2.0 mL) in a screw-capped test tube under a N2 atmosphere were successively
added a magnetic stirrer bar, an aromatic carboxylic acid (or ester) (1.0 mmol),
1,2-ethanedithiol (1.20 mmol, 108 mg), InI3 (0.050 mmol, 46 mg), and TMDS
(2.0 mmol, 2.6 Â 102
lL). The test tube was sealed with a cap that contained a
PTFE septum, and was heated to 60 (or 120) °C for 2 (or 4) h. After the reaction
time, H2O2 (30% aqueous solution, 4 mmol, 0.5 mL) was added and stirred at
room temperature for 15 h.27 The resultant mixture was directly subjected to a
column tube filled with a silica gel (hexane as an eluent) to isolate the
aldehyde. If necessary, the aldehyde was treated with 2,4-dinitrophenyl-
hydrazine to isolate the corresponding hydrazone derivative.
(k) Firouzabadi H, Iranpoor N, Hazarkhani H, Karimi B.
2002;67:2572–2576;
J Org Chem.
27. After the conversion, the pH value of the resultant solution was neutral.
(l) Hirano M, Ukawa K, Yakabe S, Clark JH, Morimoto T. Synthesis.
Please cite this article in press as: Sakai N., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.10.050