Catalyst- And Substituent-Controlled Regio- And Stereoselective Synthesis of Indolyl Acrylates by Lewis-Acid-Catalyzed Direct Functionalization of 3-Formylindoles with Diazo Esters

Article abstract of DOI:10.1021/acs.orglett.1c00277

A facile and efficient In(OTf)3- and BF3·OEt2-catalyzed direct transformation of 3-formylindoles with diazo esters has been developed for synthesizing diverse and functionalized indolyl acrylates. This one-pot protocol furnishes various (Z)-α-hydroxy-β-indolyl acrylates, (E)-β-(2-alkoxy-2-oxoethoxy)-α-indolyl acrylates, and (Z)-3-hydroxy-2-indolyl acrylates by a catalyst- and substituent-controlled, regio- and stereoselective cascade reaction. The protocol has several advantages, including low loading of the catalyst, mild reaction conditions, broad scope, and high functional group tolerance. The synthesized compounds can be further converted into diversely functionalized materials.

Full text of DOI:10.1021/acs.orglett.1c00277

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Letter
Catalyst- and Substituent-Controlled Regio- and Stereoselective
Synthesis of Indolyl Acrylates by Lewis-Acid-Catalyzed Direct
Functionalization of 3‑Formylindoles with Diazo Esters
Sana Jamshaid, Shreedhar Devkota, and Yong Rok Lee*
Cite This: Org. Lett. 2021, 23, 2140−2146
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ABSTRACT: A facile and efficient In(OTf)3- and BF3·OEt2-
catalyzed direct transformation of 3-formylindoles with diazo esters
has been developed for synthesizing diverse and functionalized
indolyl acrylates. This one-pot protocol furnishes various (Z)-α-
hydroxy-β-indolyl acrylates, (E)-β-(2-alkoxy-2-oxoethoxy)-α-indol-
yl acrylates, and (Z)-3-hydroxy-2-indolyl acrylates by a catalyst-
and substituent-controlled, regio- and stereoselective cascade
reaction. The protocol has several advantages, including low
loading of the catalyst, mild reaction conditions, broad scope, and
high functional group tolerance. The synthesized compounds can
be further converted into diversely functionalized materials.
iazo compounds are one of the most valuable starting
materials and versatile intermediates in organic syn-
TrBF4-catalyzed reaction of 3-formylcarbonyl with α-diazo
acetates to yield the corresponding β-keto esters was also
reported by the Lv group (Scheme 1B).17 However, the Lewis-
acid-catalyzed reaction of 3-formylindoles with diazo acetates
to afford conjugated esters bearing α-hydroxy or β-alkoxyester
groups is yet to be studied. Thus we envisioned the
development of a novel protocol for introducing new moieties
at the three-position on the indole nuclei, starting from 3-
formyl indoles and diazo esters.
We have previously developed new methodologies to
synthesize biologically interesting heterocycles18 and diverse
organic molecules starting from diazo compounds.19 Extending
the study of diazo-compound-based synthetic new protocols,
herein we report a novel and efficient strategy to synthesize
biologically important (Z)-α-hydroxy-β-indolyl acrylates via
oxygen atom transfer (Scheme 1C), (E)-β-(2-alkoxy-2-
oxoethoxy)-α-indolyl acrylates via indolyl migration (Scheme
1D), and (Z)-3-hydroxy-2-indolyl acrylates via indolyl
migration (Scheme 1E) by In(OTf)3- and BF3·OEt2-catalyzed
reactions of 3-formylindoles and diazo esters.
D
thesis.1,2 They have been extensively used to synthesize
bioactive natural products,3 pharmaceuticals,4 and many
heterocycles.5 The transition-metal-catalyzed, thermal, and
photoreactions of diazo compounds have been well explored
for the synthesis of diverse molecules.6 In this regard, several
synthetic methodologies based on the use of arylaldehydes and
diazo acetates have been reported, including transition-metal-
catalyzed olefination,7 racemic or asymmetric aldol-type
addition for β-hydroxy-α-ketoesters,8,9 Lewis-acid- and metal-
catalyzed formation of β-ketoesters,10 and transition-metal-
catalyzed epoxidation.11 Although the capabilities of diazo
compounds for olefination, β-hydroxy-α-ketoester formation,
and β-ketoester epoxidation are well established, their ability to
afford unsaturated α-hydroxy esters has not yet been
elucidated.
Indoles are the principal scaffolds in several bioactive natural
and synthetic products and are also present in many
pharmaceuticals.12 The indole moiety of indolic compounds
is currently present in 24 commercialized pharmaceuticals.13 In
particular, the formyl group of indoles is an important
synthetic building block in organic synthesis as well in the
chemical industry.14 Among them, 3-formylindoles and their
derivatives are key starting materials and intermediates in the
preparation of biologically active molecules through organic
reaction transformation.15 A few methods using diazo esters
have been reported for the transformation of 3-formylindoles.
For example, the Lebel group has demonstrated the copper-
catalyzed olefination of 3-formylindole with diazo acetate for
the preparation of conjugated esters (Scheme 1A).16 The
The reaction of 1-methylindole-3-carboxaldehyde (1a) with
ethyl diazoacetate (2a) was investigated using different
solvents and catalysts (Table 1). In initial attempts with
Received: January 26, 2021
Published: March 2, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00277
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2140−2146
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(entries 6−8). Importantly, the expected olefination and β-
keto formation products were not isolated at all. A better yield
(76%) was obtained with 5 mol % In(OTf)3 on refluxing in
1,2-dichloroethane for 6 h in an open atmosphere (entry 9) as
compared with the same reaction in an inert N2 atmosphere
(entry 10). Notably, the reaction in other solvents, including
THF, DMF, and CH3CN, in 5 mol % In(OTf)3 did not afford
3a (entries 11−13). Decreasing or increasing the quantity of
In(OTf)3 to 2 or 10 mol %, respectively, did not improve the
yield (entries 14 and 15). The (Z)-stereochemistry of 3a was
confirmed by X-ray crystallography of 4m.
Scheme 1. Synthesis of Three-Functionalized Indoles by the
Reaction of 3-Formylindoles with Diazoacetates
The reaction generality was further explored using
substituted 3-formylindoles 1a−1x with various diazoacetates
2a−2g (Scheme 2). The combination of 1a with diazoacetates
2b−2d bearing i-propyl, n-butyl, and allyl groups afforded the
products 3b−3d in 71, 63, and 73% yields, respectively. Other
diazo compounds 2e−2g bearing benzyl, ethylphenyl, and
propylphenyl groups resulted in the desired products 3e−3g in
60−87% yields. When 2a was treated with N-alkyl-substituted
indole-3-carboxaldehydes 1b−1f such as ethyl, n-propyl, n-
Scheme 2. Substrate Scope of Substituted 3-Formylindoles
1a−1x and Various Diazoacetates 2a−2g
a
Table 1. Reaction Optimization for the Synthesis of 3a
b
entry
cat. (mol %)
solvent
temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
9
Rh2(OAc)4 (2)
Cu(OAc)2 (5)
Cu(OTf)2 (5)
InCl3 (5)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1,2-DCE
1,2-DCE
THF
80
80
80
80
80
80
80
80
reflux
reflux
reflux
80
reflux
reflux
reflux
24
24
12
12
12
12
8
8
6
6
24
12
12
12
12
0
0
0
0
0
10
54
68
76
63
0
InBr3 (5)
Yb(OTf)3 (5)
Sc(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (2)
In(OTf)3 (10)
c
10
11
12
13
14
15
DMF
0
0
44
57
CH3CN
1,2-DCE
1,2-DCE
a
Reaction conditions: 1a (0.5 mmol), 2a (1.1 mmol), and solvent (3
b
c
mL). Isolated yield. Reaction under N2.
Rh2(OAc)4, Cu(OAc)2, Cu(OTf)2, InCl3, and InBr3 in toluene
at 80 °C for 12−24 h, no product 3a was formed at all (entries
1−5). Thus other catalysts such as Yb(OTf)3, Sc(OTf)3, and
In(OTf)3 were next screened. Interestingly, treating 1a with 2a
using Yb(OTf)3, Sc(OTf)3, and In(OTf)3 in toluene at 80 °C
for 8−12 h led to 3a in 10, 54, and 68% yields, respectively
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Letter
butyl, n-pentyl, and 3-chloropropyl, the desired products 3h−
3l were obtained in 55−67% yields. Additional reactions of N-
benzyl-, N-allyl-, N-phenyl-, and N-acyl-substituted indole-3-
carboxaldehydes 1g−1k with diazoesters 2a and 2b provided
3m−3q in 44−77% yields. Furthermore, the combination of
indole-3-carboxaldehydes 1l and 1m bearing electron-donating
groups at the four-position on the aromatic ring (such as 4-
OBn and 4-Ph) with 2a or 2c readily generated the
corresponding products 4a−4c in 50−56% yields. Similarly,
reactions of indole-3-carboxaldehydes 1n−1q bearing sub-
stituents at the five-position on the aromatic ring, such as 5-
methyl, 5-methoxy, 5-phenyl, and 5-(naphthalene-2-yl), with
2a provided 52−63% yields of products 4d−4g. Moreover,
treatment of indole-3-carboxaldehydes 1r−1u bearing sub-
stituents of electron-withdrawing and electron-withdonating
groups at the six-position on the aromatic ring, such as 6-Me,
6-Br, 6-Cl, and 6-F, afforded the corresponding products 4h−
4k in 60−72% yields. The combination of 1v, bearing a methyl
substituent at the seven-position, with 2a provided a 63% yield
of product 4l. Notably, the reaction of 2a with 1-methyl-
1,6,7,8-tetrahydrocyclopenta[g]indole-3-carbaldehyde (1w)
and 1-methyl-1H-benzo[g]indole-3-carbaldehyde (1x), having
a cyclic or aromatic ring on the indole nuclei, provided the
corresponding products 4m and 4n in 71 and 65% yields,
respectively. However, with indole-3-carboxaldehyde, the
desired product was not isolated; instead, 3,4,5-triethoxycar-
bonyl-2-pyrazoline (2a′) was formed (57%) due to trimeriza-
tion of the diazo compound.20 (See the Supporting
Information.)
β-(2-alkoxy-2-oxoethoxy)-α-indolyl acrylates as compared with
the previous reactions, shown in Scheme 2. For example, the
combination of 1,2-dimethyl 1H-indole-3-carboxyaldehyde
(5a) or 1-benzyl-2-methyl 1H-indole-3-carboxyaldehyde (5b)
with 2.2 equiv of 2a or 2b provided the unexpected products
6a−6c in 56, 61, and 58% yields, respectively. In these
reactions, any other product containing one unit of diazo
compound was not formed, despite the use of 1 equiv of
diazoester. Similarly, reactions of 2b with 5c or 5d bearing 2-
ethyl and 2-phenyl groups led to products 6d and 6e in 52 and
66% yields, respectively. However, with 5f bearing the
electron-withdrawing group (2-Cl), no products were isolated.
The (E)-stereochemistry was determined by the X-ray
crystallography of 6e.
Next, the efficacy of the protocol was explored using BF3·
OEt2 as a metal-free and stronger Lewis acid (Scheme 4).
Scheme 4. BF3·OEt2-Catalyzed Reactions of 3-
Formylindoles 1a, 1g, 1s, 1w, and 5e with Diazoesters 2a,
2b, and 2h
We depict the exploration of the substrate scope of our
protocol and the investigation of other reactions of C-2-
substituted 3-formylindoles 5a−5f in Scheme 3. Surprisingly,
the reactions of 3-formylindoles 5a−5e, having electronic-
donating groups such as methyl, ethyl, and phenyl at the two-
position on the indole ring, furnished different products of (E)-
Scheme 3. Substrate Scope of 3-Formylindoles 5a−5f
Bearing C-2 Substituents and Diazoesters 2a and 2b
Interestingly, the reaction of 1a with 2a (2.2 equiv) using BF3·
OEt2 generated the product 7a in a 72% yield (Scheme 4).
Surprisingly, the reaction of the C-2 substituted 3-formylindole
5e with 2a yielded 67% of the desired product 7b.
Combinations of 1a, 1g, 1s, and 1w with 2a, 2b, or 2h
provided a 43−67% yield of products 7c−7g. X-ray crystallo-
graphic analysis confirmed the (Z)-stereochemistry of
compound 7c. Importantly, in these cases, the products that
were formed using the In(OTf)3 catalyst were not isolated.
To elucidate the reaction mechanism, control experiments
were carried out as shown in Scheme 5. Treatment of the
deuterated compound 1aD with 2a under standard conditions
provided the product 3aD with a 50:50 percentage of
hydrogen and deuterium at the β-position on the acrylate
moiety. This result suggested the possibility of keto/enol
tautomerization for the formation of 3aD (Scheme 5a).
Treatment of 1aD with 2a in the presence of BF3·OEt2
provided deuterated product 7aD in 70% yield (Scheme 5b).
However, the reaction of 7a and 2a in the presence of
In(OTf)3 in ambient air did not provide compound 8, possibly
due to strong intramolecular hydrogen bonding (Scheme 5c).
In addition, Lewis-acid-catalyzed reactions of benzaldehyde
(5g) with 2a were already reported to afford products A and
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Scheme 5. Control Experiments
Scheme 6. Plausible Mechanisms for the Formation of 3a,
6a, and 7a
B.21,22 In the presence of BF3·OEt2, products A (21%) and B
(18%) were produced,21 and under an iron Lewis acid catalyst,
product A (70%) was obtained as a major component.22 When
we tried this reaction in the presence of 5 mol % of In(OTf)3,
major product B (58%) was produced with 7% of product A
(Scheme 5d).
On the basis of the observed results, we propose plausible
mechanisms for 3a, 6a, and 7a in Scheme 6. In the presence of
In(OTf)3, 3-formyl indole (1a) produces complex 1a′, which
reacts with 2a to afford intermediate 9 via nucleophilic
addition. The intramolecular SN2-type reaction of 9 gives
epoxide intermediate 10 that undergoes a ring opening by
electron movement from the nitrogen atom to furnish
intermediate 11. The 1,2-hydrogen shift by the movement of
the anion on the oxygen atom followed by double-bond
migration leads to intermediate 12, which undergoes
tautomerization to provide product 3a. The possibility of
keto−enol tautomerization was already proved in the control
experiment using deuterated compound 1aD. In the case of the
C-2-substituted indole-3-carboxaldehydes, complex 5a′ reacts
with 2a to afford intermediate 13. Subsequently, the indole
moiety whose electron density is increased by electron-
donating groups such as Me, Et, and Ph at the C-2 position
undergoes 1,2-indolyl migration through the movement of
electrons on the oxygen atom followed by the liberation of N2
to yield intermediate 14. This increase in electron density is
expected to provide a product different from that of 3a.
Intermediate 14 gives intermediate 15 by enol formation,
which undergoes proton and catalyst transfer to afford
intermediate 16. An SN2-type reaction proceeds to give the
final product 6a. In the presence of a BF3·OEt2 catalyst,
complex 1a′′ reacts with 2a to form a complex intermediate
17. In this case, the intramolecular SN2-type reaction does not
proceed; instead, the indolyl moiety rearranges to generate the
intermediate 18, which gives intermediate 19 by enol
formation. Regeneration of the catalyst affords the final
product 7a. The position of deuterium in 7aD confirmed the
mechanism of this reaction. Intermediate 19 does not react
further with 2a to form any O-alkylated products due to strong
intramolecular hydrogen bonding, as shown in Scheme 5c.
Furthermore, as an application of this protocol, synthesized
compound 3a was converted into different functionalized
products (Scheme 7). The treatment of 3a with benzoyl
a
Scheme 7. Further Transformations of 3a
a
Reaction conditions: (a) BzCl, K2CO3, toluene, rt, 12 h. (b) Allyl
bromide, K2CO3, toluene, rt, 12 h.
chloride and allyl bromide using a mild base K2CO3 at room
temperature in toluene for 12 h provided products 20 and 21
in 94 and 89% yields, respectively.
In conclusion, an efficient and facile methodology has been
developed to construct diverse indolyl acrylates, starting from
the readily available 3-formyl indoles and diazo esters via
In(OTf)3- and BF3·OEt2-catalyzed cascade reactions. This
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biologically important (Z)-α-hydroxy-β-indolyl acrylates, (E)-
β-(2-alkoxy-2-oxoethoxy)-α-indolyl acrylates, and (Z)-3-hy-
droxy-2-indolyl acrylates by the catalyst- and substituent-
controlled regio- and stereoselective method. Various func-
tional groups are tolerated, and the synthetic compound is
further transformed into functionalized materials.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00277.
Detailed experimental procedures, characterization, and
1H NMR and 13C NMR spectra of the final products
(PDF)
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FAIR data, including the primary NMR FID files, for
compounds 1h, 1q, 2a′, 3aD, 3a-3q, 4a−4n, 5c, 6a−6e,
7a−7g, 7aD, A, B, 20, and 21 (ZIP)
Accession Codes
CCDC 2057963−2057965 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Yong Rok Lee − School of Chemical Engineering, Yeungnam
University, Gyeongsan 38541, Republic of Korea;
orcid.org/0000-0002-4048-8341; Phone: +82-53-810-
2529; Email: yrlee@yu.ac.kr; Fax: +82-53-810-4631
Authors
Sana Jamshaid − School of Chemical Engineering, Yeungnam
University, Gyeongsan 38541, Republic of Korea
Shreedhar Devkota − School of Chemical Engineering,
Yeungnam University, Gyeongsan 38541, Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00277
(5) (a) Yada, A.; Fujita, S.; Murakami, M. Enantioselective Insertion
of a Carbenoid Carbon into a C-C Bond to Expand Cyclobutanols to
Cyclopentanols. J. Am. Chem. Soc. 2014, 136, 7217−7220. (b) Liu, Z.;
Tan, H.; Wang, L.; Fu, T.; Xia, Y.; Zhang, Y.; Wang, J. Transition-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Metal-Free Intramolecular Carbene Aromatic Substitution/Buchner
̈
■
Reaction: Synthesis of Fluorenes and [6,5,7]Benzo-fused Rings.
Angew. Chem. 2015, 127, 3099−3103. (c) Jing, C.; Xing, D.; Gao, L.;
Li, J.; Hu, W. Divergent Synthesis of Multisubstituted Tetrahydrofur-
ans and Pyrrolidines via Intramolecular Aldol-type Trapping of
Onium Ylide Intermediates. Chem. - Eur. J. 2015, 21, 19202−19207.
(d) Nicolle, S. M.; Lewis, W.; Hayes, C. J.; Moody, C. J.
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Copper-Catalyzed Coupling of 2-Siloxy-1-alkenes and Diazocarbonyl
This work was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korean
government (MSIT) (2018R1A2B2004432 and
2021R1A2B5B02002436) and by the Korean Ministry of
Education, Science, and Technology (2012M3A7B4049677).
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