Boronic Acid Accelerated Three-Component Reaction for the Synthesis of α-Sulfanyl-Substituted Indole-3-acetic Acids

Article abstract of DOI:10.1021/acs.orglett.7b02727

Boronic acid was used to accelerate a three-component reaction of indoles, thiols, and glyoxylic acids for the synthesis of α-sulfanyl-substituted indole-3-acetic acids. Boronic acid catalysis to activate the α-hydroxy group in α-hydroxycarboxylic acid in

Full text of DOI:10.1021/acs.orglett.7b02727

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Boronic Acid Accelerated Three-Component Reaction for the
Synthesis of α‑Sulfanyl-Substituted Indole-3-acetic Acids
Amrita Das, Kenji Watanabe,* Hiroyuki Morimoto, and Takashi Ohshima*
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
S
* Supporting Information
ABSTRACT: Boronic acid was used to accelerate a three-component
reaction of indoles, thiols, and glyoxylic acids for the synthesis of α-
sulfanyl-substituted indole-3-acetic acids. Boronic acid catalysis to
activate the α-hydroxy group in α-hydroxycarboxylic acid intermediates
and intramolecular assistance by free carboxylic acid were the keys to
accelerating the product formation.
2).3 A different activation mode was recently introduced, in
oronic and boric acid catalyzed transformations of
which nucleophilic activation of carboxylic acids was achieved
Bcarboxylic acids are frequently applied in the field of
using BH3·SMe2 as a borane catalyst in the presence of DBU as
the base (Scheme 1, eq 3).4 Boronic acid is also useful to
activate α-hydroxycarboxylic acid in the formation of amides5
and esters6 (Scheme 1, eq 4).
organic synthesis. The most widely investigated transformation
is the direct activation of carboxylic acids to afford amides and
esters (Scheme 1, eq 1).1,2 Diels−Alder and [3 + 2]
cycloaddition reactions of carboxylic acids are also accelerated
by boronic and boric acid catalysts, as exemplified by
chemoselective electrophilic activation of carboxylic acid in
the presence of ester in a Diels−Alder reaction (Scheme 1, eq
Although activation of carboxylic acids by boronic and boric
acid derivatives is well developed, activation of an α-hydroxy
group of carboxylic acids with boron-based catalysts is rarely
described.7 To this end, we were interested in Petasis-type
borono-Mannich reactions,8 in which stoichiometric amounts
of boronic acids act as nucleophiles to form α-arylated acetic
acids (Scheme 1, eq 5). Because electron-deficient boronic
acids are less prone to act as nucleophiles,9 we envisioned that
electron-deficient boronic acids would promote the activation
of α-hydroxy groups without the concomitant formation of
Petasis-type products (Scheme 1, eq 6).8b In conjunction with
our recent interests in the activation of unactivated hydroxy
groups,10 including modification of thiols with α-hydroxycar-
boxylic acids,11 here we present boronic acid accelerated
substitution of the α-hydroxy group of carboxylic acids in a
three-component reaction of indoles, glyoxylic acids, and thiols.
We further demonstrated chemoselective activation of the
carboxylic acid over the corresponding ester.
Scheme 1. Activation Modes of Carboxylic Acids with
Boronic and Boric Acids
To evaluate the feasibility of this mode of activating an α-
hydroxy group with boronic acids, we selected a three-
component reaction of indoles, thiols, and glyoxylic acids
because this combination yields α-sulfanyl-substituted indole-
acetic acids, a core structure of many bioactive compounds.12
Although the synthesis of related sulfur-containing indole
derivatives using metal or acid catalysts has been reported,13
multicomponent reactions to generate compounds containing
Received: September 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02727
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
free carboxylic acids have not yet been described. We began
screening various catalysts using N-benzylindole 1a, glyoxylic
acid monohydrate 2a, and 2-mercaptopyridine 3a as model
substrates to facilitate monitoring of the reaction progress
(Table 1). The desired reaction did not proceed without a
Scheme 2. Substrate Scope
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
yield (%)
1
none
n.d.
n.d.
3
2
AcOH
H3PO4
3
4
CF3CO2H
7
5
p-TsOH·H2O
CF3SO3H
40
8
6
7
B(OH)3
18
20
15
16
68
82
8
8
EtB(OH)2
9
PhB(OH)2
10
11
12
13
4-MeOC6H4B(OH)2
3,5-(CF3)2C6H3B(OH)2
C6F5B(OH)2
(C6F5)3B
a
Reaction conditions: at 0.20 mmol scale, 1/2/3 (1:1.5:1.2) in 1,4-
dioxane (0.20 M) at 40 °C for 24 h using C6F5B(OH)2 (15 mol %) as
c
14
C6F5B(OH)2
C6F5B(OH)2
90
b
cd
,
e
catalyst. At 1.0 mmol scale, 1a/2a/3b (1.3:1.5:1.0) in 1,4-dioxane
15
92 (73)
c
a
(0.20 M) at 60 °C for 24 h using 5 mol % of catalyst. Determined by
Reaction conditions: 1a/2a/3a (1:1:1) and catalyst (15 mol %) in
1,4-dioxane (0.20 M) at 30 °C for 24 h. Determined by H NMR
analysis of the crude mixture. At 40 °C. 1a/2a/3a (1:1.5:1.2).
b
1H NMR analysis of the crude mixture.
1
c
d
e
mildness of the current reaction conditions compared with
conventional strongly acidic conditions used for related α-
substitution reactions.13a−c
Next, transformation of the product 4 was performed
(Scheme 3). N-TIPS-protected indole was deprotected to
Isolated yield. n.d. = not detected.
catalyst (entry 1), and even the use of stronger acids did not
promote the reaction well (entries 2−6). On the other hand,
boric acid (pKa = 9.2) as well as ethyl- and phenylboronic acids
afforded the desired product 4a, albeit in low yields (entries 7−
9). To improve the reactivity, we evaluated several arylboronic
acids and found that electron-deficient arylboronic acids
promoted the reaction in high yield (entries 10−12), whereas
strongly Lewis acidic tris(pentafluorophenyl)borane provided
4a in low yield (entry 13), suggesting that the formation of
boronate ester was important for promoting the desired
reaction. Further optimization of the temperature (entry 14)
and substrate ratio gave 4a in 92% yield (entry 15).14,16
Scheme 3. Transformation of the Products
Having determined the optimized conditions, we next
examined the substrate scope (Scheme 2). We selected benzyl
mercaptan 3b to study the scope of indole 1 with glyoxylic
acids 2. Product 4b was obtained in good yield, even at 1.0
mmol scale and 5 mol % catalyst loading, with slightly modified
reaction conditions.15 Various substituted indoles 1c−f gave the
products 4c−f in good yields. Indoles having several N-
protecting groups 1g−1i were tolerated, and even unprotected
indole 1j gave the product 4j, albeit in moderate yield. Pyruvic
acid 2b and phenylglyoxylic acid 2c were also suitable to
generate products 4k and 4l containing quaternary carbon
centers in good yields. The substrate scope of thiol 3 was
studied with 4-substituted benzenethiols and 2-mercapto-
pyridine; electron-rich thiols afforded a better yield of the
desired product 4. Notably, acid-sensitive N-Boc protective
groups were tolerated to give 4p in good yield, suggesting the
give N-unprotected product 4j. Amide bond formation of 4f
was achieved with glycine methyl ester hydrochloride to give
the desired product 6f in 91% yield.
To clarify the accelerating effects of boronic acids, we
monitored the reaction progress. In the absence of the catalyst,
α-hydroxycarboxylic acid intermediate 7a formed slowly
(Scheme 4), and the structure of 7a was confirmed after in
situ transformation to the corresponding ester.15 Product 4a
also formed very slowly and only after the formation of 7a
B
DOI: 10.1021/acs.orglett.7b02727
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Monitoring the Reaction Progress
Figure 2. Comparison of transition state energies.
Table 2. Chemoselective Reaction between Glyoxylic Acid
a
and Its Ethyl Ester
(Figure 1a), suggesting that the formation of 4a (the second
step) was slower than that of 7a (the first step) without a
b
b
entry
catalyst
4a (%)
5a′ (%)
4a/5a′
1
2
3
C6F5B(OH)2
84
37
14
2
17
2
42:1
2.2:1
7:1
p-TsOH·H2O
H3PO4 (1 equiv)
a
Reaction conditions: 1a/2a/2a′/3a (1:1:1:1) in 1,4-dioxane (0.20 M)
b
1
at 30 °C for 24 h. Determined by H NMR analysis of the crude
reaction mixture.
maintained the chemoselectivity in favor of carboxylic acid.
These results support the proposed reaction mechanism by
which the carboxylic acid moiety functions to facilitate
elimination of the α-hydroxy group.17
In summary, we developed a novel boronic acid accelerated
three-component reaction of indoles, thiols, and glyoxylic acids,
providing a unique class of α-sulfanyl-substituted indole
derivatives containing free carboxylic acids via the formation
of α-hydroxycarboxylic acids. We also demonstrated that
simultaneous activation of the α-hydroxy group with a boronic
acid catalyst and internal carboxylic acid is key to promoting
the reaction. Although the scope is currently limited to indole
derivatives, this strategy could be further extended in principle
to other substitution reactions of α-hydroxy carboxylic acids.
The exploration of such reactions is ongoing in our laboratory.
Figure 1. Reaction progress (a) without catalyst and (b) with catalyst.
catalyst. On the other hand, addition of the boronic acid
catalyst significantly accelerated the formation of 4a, and only a
trace amount of the intermediate 7a was observed during the
reaction (Figure 1b). These results indicate that the second
step was faster than the first step in the presence of the catalyst
and suggest that the boronic acid catalyst accelerated the
second step.
To elucidate how the boronic acid catalyst accelerated the
second step, we explored plausible reaction mechanisms in the
presence of the catalyst using DFT calculations (Figure 2).15
The calculated activation energies suggest that the reaction via
acyclic boronate TS1 was favored over that via cyclic boronate
TS2, most probably because the carboxylic acid moiety assists
in eliminating the α-hydroxy group during the transition state
of acyclic boronate.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02727.
Detailed experimental procedures and characterization
data of compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
To obtain experimental evidence for the carboxylic acid
assisted activation of the intermediate, we examined the
chemoselective reaction with glyoxylic acid in the presence of
the corresponding ester (Table 2). The boronic acid catalyst
produced high chemoselectivity with carboxylic acid 4a over
ester 5a′, whereas rather strong acids (p-toluenesulfonic acid
and phosphoric acid) promoted the reaction more slowly but
■
*E-mail: kwatanabe@phar.kyushu-u.ac.jp.
*E-mail: ohshima@phar.kyushu-u.ac.jp.
ORCID
Hiroyuki Morimoto: 0000-0003-4172-2598
C
DOI: 10.1021/acs.orglett.7b02727
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) For a review, see: (a) Lennox, A. J. J.; Lloyd-Jones, G. C. Chem.
Soc. Rev. 2014, 43, 412. For selected references, see: (b) Billingsley, K.
L.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 4695. (c) Takeda,
Y.; Ikeda, Y.; Kuroda, A.; Tanaka, S.; Minakata, S. J. Am. Chem. Soc.
2014, 136, 8544.
Takashi Ohshima: 0000-0001-9817-6984
Notes
The authors declare no competing financial interest.
(10) For our recent contributions on the activation of unactivated
hydroxy groups, see: (a) Ohshima, T.; Miyamoto, Y.; Ipposhi, J.;
Nakahara, Y.; Utsunomiya, M.; Mashima, K. J. Am. Chem. Soc. 2009,
131, 14317. (b) Ohshima, T.; Nakahara, Y.; Ipposhi, J.; Miyamoto, Y.;
Mashima, K. Chem. Commun. 2011, 47, 8322. (c) Das, K.; Shibuya, R.;
Nakahara, Y.; Germain, N.; Ohshima, T.; Mashima, K. Angew. Chem.,
Int. Ed. 2012, 51, 150. (d) Shibuya, R.; Lin, L.; Nakahara, Y.; Mashima,
K.; Ohshima, T. Angew. Chem., Int. Ed. 2014, 53, 4377. (e) Zhang, M.;
Watanabe, K.; Tsukamoto, M.; Shibuya, R.; Morimoto, H.; Ohshima,
T. Chem. - Eur. J. 2015, 21, 3937.
ACKNOWLEDGMENTS
■
This work was supported by Grant-in-Aid for Scientific
Research on Innovative Areas (JSPS KAKENHI Grant No.
JP15H05846 in Middle Molecular Strategy for T.O.) and
Grant-in-Aid for Encouragement of Young Scientists (B) (JSPS
KAKENHI Grant No. JP16K17902 for K.W.) from JSPS, and
Platform for Drug Discovery, Informatics, and Structural Life
Science from AMED. A.D. thanks Japan International
Cooperation Agency (JICA) for a research fellowship (D-
1490347). We thank Drs. R. Yazaki, Y. Taniguchi, and Y. Fuchi
for assistance in analytical measurement.
(11) Watanabe, K.; Ohshima, T. Submitted.
(12) Song, Y.; Zhan, P.; Liu, X. Curr. Pharm. Des. 2013, 19, 7141.
(13) (a) Wu, X.-S.; Tian, S.-K. Chem. Commun. 2012, 48, 898.
(b) Dar, A. A.; Ali, S.; Khan, A. T. Tetrahedron Lett. 2014, 55, 486.
(c) Khorshidi, A.; Shariati, S. RSC Adv. 2014, 4, 41469. (d) Chen, P.;
Lu, S. M.; Guo, W.; Liu, Y.; Li, C. Chem. Commun. 2016, 52, 96.
(14) Isolated yield of 4a was reduced due to the instability of 4a upon
isolation. However, we were able to isolate the corresponding methyl
ester 5a in 89% yield after in situ transformation of 4a.15
(15) See Supporting Information for details.
(16) We also examined effects of water on reactivity under the
catalytic conditions, and complete removal of water from the reaction
mixture was found unnecessary but excess amounts of water could
reduce the reactivity, possibly because of the inhibition of formation of
boronate esters with hydroxycarboxylic acid intermediate as well as
formation of glyoxylic acid from its hydrate.15
REFERENCES
■
(1) For a review on boron-reagent-promoted transformations of
carboxylic acids into amides, see: (a) Charville, H.; Jackson, D.;
Hodges, G.; Whiting, A. Chem. Commun. 2010, 46, 1813. Some earlier
reports: (b) Nelson, P.; Pelter, A. J. Chem. Soc. 1965, 5142. (c) Pelter,
A.; Levitt, T. E.; Nelsoni, P. Tetrahedron 1970, 26, 1539. (d) Furuta,
K.; Miwa, Y.; Iwanaga, K.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110,
6254.
(2) For reviews on catalysis with boronic and boric acid derivatives,
see: (a) Dimitrijevic, E.; Taylor, M. S. ACS Catal. 2013, 3, 945.
́
(b) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Chem. Soc.
Rev. 2014, 43, 2714. (c) Georgiou, I.; Ilyashenko, G.; Whiting, A. Acc.
Chem. Res. 2009, 42, 756. For selected references, see: (d) Ishihara,
K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61, 4196. (e) Maki,
T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7, 5043. (f) Arnold, K.;
Davies, B.; Giles, R. L.; Grosjean, C.; Smith, G. E.; Whiting, A. Adv.
Synth. Catal. 2006, 348, 813. (g) Maki, T.; Ishihara, K.; Yamamoto, H.
(17) Comparison of transition state energies of α-hydroxycarboxylic
acid intermediate and its ester with boronic acid catalyst revealed that
activation of ester was more energetically unfavorable than that of
carboxylic acid.15 In addition, addition of 1 equiv of iPr2NEt
diminished the reactivity, suggesting that acidic condition is important
for promoting the reaction.15
̌ ̌
Tetrahedron 2007, 63, 8645. (h) Maras, N.; Kocevar, M. Helv. Chim.
Acta 2011, 94, 1860. (i) Liu, S.; Yang, Y.; Liu, X.; Batsanov, A. S.;
Whiting, A. Eur. J. Org. Chem. 2013, 2013, 5692. (j) Noda, H.;
Furutachi, M.; Asada, Y.; Shibasaki, M.; Kumagai, N. Nat. Chem. 2017,
9, 571.
(3) (a) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int.
Ed. 2008, 47, 2876. (b) Zheng, H.; McDonald, R.; Hall, D. G. Chem. -
Eur. J. 2010, 16, 5454. (c) Zheng, H.; Lejkowski, M.; Hall, D. G.
Tetrahedron Lett. 2013, 54, 91.
(4) (a) Morita, Y.; Yamamoto, T.; Nagai, H.; Shimizu, Y.; Kanai, M. J.
Am. Chem. Soc. 2015, 137, 7075. (b) Nagai, H.; Morita, Y.; Shimizu,
Y.; Kanai, M. Org. Lett. 2016, 18, 2276.
(5) (a) Yamashita, R.; Sakakura, A.; Ishihara, K. Org. Lett. 2013, 15,
3654. (b) Lu, Y.; Ishihara, K. Chem. Sci. 2016, 7, 1276.
(6) (a) Lawrence, W. W., Jr. Tetrahedron Lett. 1971, 12, 3453.
(b) Houston, T. A.; Wilkinson, B. L.; Blanchfield, J. T. Org. Lett. 2004,
6, 679. (c) Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7,
5047. (d) Levonis, S. M.; Bornaghi, L. F.; Houston, T. A. Aust. J. Chem.
2007, 60, 821.
(7) For a review of direct activation of hydroxy groups using boronic
acids, see ref 2a. For selected examples, see: (a) McCubbin, J. A.;
Hosseini, H.; Krokhin, O. V. J. Org. Chem. 2010, 75, 959.
(b) McCubbin, J. A.; Krokhin, O. V. Tetrahedron Lett. 2010, 51,
2447. (c) McCubbin, J. A.; Nassar, C.; Krokhin, O. V. Synthesis 2011,
2011, 3152. (d) Zheng, H.; Lejkowski, M.; Hall, D. G. Chem. Sci. 2011,
2, 1305. (e) Zheng, H.; Ghanbari, S.; Nakamura, S.; Hall, D. G. Angew.
Chem., Int. Ed. 2012, 51, 6187.
(8) For a review, see: (a) Candeias, N. R.; Montalbano, F.; Cal, P. M.
S. D.; Gois, P. M. P. Chem. Rev. 2010, 110, 6169. For selected
́
references, see: (b) Naskar, D.; Neogi, S.; Roy, A.; Mandal, A. B.
Tetrahedron Lett. 2008, 49, 6762. (c) Candeias, N. R.; Paterna, R.; Cal;
́
Pedro, M. S. D.; Gois, P. M. P. J. Chem. Educ. 2012, 89, 799.
D
DOI: 10.1021/acs.orglett.7b02727
Org. Lett. XXXX, XXX, XXX−XXX