Copper-catalyzed hydroboration of alkenyl oxindoles

Article abstract of DOI:10.1016/j.tetlet.2018.06.009

Herein we describe the NHC-Cu(I)-catalyzed hydroboration of alkenyl oxindoles. The corresponding boronates were obtained in good yields, under operationally simple and environmentally friendly conditions, using ethanol as the solvent. Our studies revealed that water-based systems were not very effective. Furthermore, the obtained products are amenable to further elaboration and can be useful to the synthesis of a broader range of oxindole-containing molecules with biological relevance.

Full text of DOI:10.1016/j.tetlet.2018.06.009

Accepted Manuscript
Copper-catalyzed hydroboration of alkenyl oxindoles
Maria Eduarda Contreira, Diogo S. Lüdtke, Angélica V. Moro
PII:
S0040-4039(18)30738-X
https://doi.org/10.1016/j.tetlet.2018.06.009
TETL 50047
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 May 2018
1 June 2018
3 June 2018
Please cite this article as: Contreira, M.E., Lüdtke, D.S., Moro, A.V., Copper-catalyzed hydroboration of alkenyl
oxindoles, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.06.009
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Copper-catalyzed hydroboration of alkenyl
oxindoles
Maria Eduarda Contreira, Diogo S. Lüdtke*, Angélica V. Moro
Leave this area blank for abstract info.

1
Tetrahedron Letters
Copper-catalyzed hydroboration of alkenyl oxindoles
Maria Eduarda Contreira, Diogo S. Lüdtke*, Angélica V. Moro
a Instituto de Química, Universidade Federal do Rio Grande do Sul, UFRGS, Av. Bento Gonçalves 9500, 91501-970, Porto Alegre, RS, Brazil.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we describe the NHC-Cu(I)-catalyzed hydroboration of alkenyl oxindoles. The
corresponding boronates were obtained in good yields, under operationally simple and
environmentally friendly conditions, using ethanol as the solvent. Our studies revealed that
water-based systems were not very effective. Furthermore, the obtained products are amenable
to further elaboration and can be useful to the synthesis of a broader range of oxindole-
containing molecules with biological relevance.
Available online
Keywords:
boron compounds
borylation
2009 Elsevier Ltd. All rights reserved.
copper catalysis
isatin
green solvents
The oxindole heterocyclic system has attracted the attention
from the synthetic1 and medicinal chemistry2 communities with a
number of biologically relevant molecules bearing this
substructural unit reported in the literature. Examples of natural
products include the convolutamidines,3 horsifiline,4 and
dioxibrassanin.5 In addition, the synthetic tyrosine-kinase
inhibitors SU-9516, semaxanib (SU-5416) and sunitinib (SU-
11248), displaying antiangiogenic properties, have also been
reported.6
Scheme 1. Literature precedents for the borylation of isatins and this
work
Recently, we have been interested in developing efficient and
environmentally friendly synthetic methods using organoboron
chemistry and we have developed a copper-catalyzed borylation
of propargyl-functionalized alkynes that enabled the synthesis of
vinylboronates in water, in the presence of a surfactant (Scheme
1B).9 Furthermore we have further expanded the concept and
developed the one-pot, dual metal catalytic synthesis of
arylallylamines in water, through a Cu-catalyzed borylation,
followed by a Pd-catalyzed Suzuki coupling.10
Figure 1. Representative examples of oxindoles
Reports regarding strategies for the synthesis of oxindole
systems bearing a boronate moiety are scarce in the literature. To
the best of our knowledge, the only reported approach was
independently described by Van der Eycken7 and Ma/Xu,8 both
using the Pd-catalyzed intramolecular Heck reaction, followed
Miyaura borylation with B2pin2 to assemble the desired
Considering the growing interest on the synthesis of
organoboron compounds with potential biological activities11 and
the pressing need for the replacement of hazardous solvents by
compounds (Scheme 1A).
———
Corresponding author. Tel.: +55 51 3308 9637; e-mail: dsludtke@iq.ufrgs.br (D. S. Lüdtke); angelica.venturini@ufrgs.br (A. V. Moro)

2
Tetrahedron Letters
greener alternatives,12 herein we report our studies for the
Table 1. Optimization of the reaction conditions for the Cu-
copper-catalyzed borylation of alkenyl oxindoles in ethanol and
water, that are solvents with excellent EHS (Environmental,
Health and Safety) properties (Scheme 1C).
catalyzed hydroboration
We started our investigation by the synthesis of the required
unsaturated starting materials, by the cyclization/decarboxylation
method reported by Xu and Wang (Scheme 2).13 The method
consists is reaction of the N-alkylated isatin 1 with acyl chlorides,
in the presence of DMAP, Et3N and MgSO4. Under these
conditions the desired alkenyl oxindoles have been obtained in
45-88% yield.
Entry [Cu] cat. (mol%)
solvent
time (h) Yield (%)a
1b
Cu(OAc)2 (8)
dppe (10)
SPGS-550M/H2O
18
37
2b
3b,c
4b
[CuCl(IMes)] (5)
[CuCl(IMes)] (5)
[CuCl(IMes)] (5)
[CuCl(IMes)] (5)
[CuCl(IMes)] (5)
[CuCl(IMes)] (5)
[CuCl(IPr)] (5)
SPGS-550M/H2O
SPGS-550M/H2O
SPGS-550M/H2O
SPGS-550M/H2O
SPGS-550M/H2O
SPGS-550M/H2O
SPGS-550M/H2O
TPGS-550M/H2O
H2O
18
18
4
54
65
55
83
83
81
41
80
87
85
97
5d
4
6e
4
7e
2
8e
4
9e
[CuCl(IMes)] (5)
[CuCl(IMes)] (5)
[CuCl(IMes)] (5)
[CuCl(IMes)] (5)
4
10d
11e
12
4
H2O
4
EtOH
4
aIsolated yield; experiments performed on a 0.3 mmol scale. work-up by the
addition of anhydrous MgSO4 and washing with EtOAc (3 x 1 mL). c1.5
equiv B2pin2. dconventional work-up using brine and EtOAc (3 x 5 mL).
edirect filtration of the reaction mixture through sodium polyacrylate (from a
baby´s diaper) at the top of a silica gel column. Note: SPGS-550M and
TPGS-750M are commercially available as 2 wt% in water.
b
Scheme 2. Preparation of the starting materials
With the required starting material in hand, we started to
investigate the conditions for the hydroboration of the conjugated
double bond present at the alkenyl oxindole system.14 Compound
2a with R1 and R2 as methyl groups was chosen as the model
substrate for the optimization studies, and the results are depicted
in Table 1.
First, we have submitted 2a to the catalytic conditions that
have been previously used with success in our work for the
hydroboration of propargyl-functionalized alkynes, using
micellar conditions.9 Reaction using Cu(OAc)2 as the copper
source and diphenylphosphinoethane (dppe) as the ligand in
SPGS-550M/water15 as the solvent resulted in the desired product
in only low yield (Table 1, entry 1). Slight increase in the yield
was achieved with the use of the N-heterocyclic carbene-based
catalyst [CuCl(IMes)] and the product was obtained in 54% yield
(entry 2). An attempt to further increase the yield by increasing
the amount of B2pin2 from 1.1 equiv to 1.5 equiv didn´t result in
any significant improvement (entry 3). Gratifyingly, we observed
that the reaction time could be shortened to only 4 h without
compromising the yield of the isolated product. Importantly, the
work-up method has a significant impact on the isolated yield
and when the product was extracted from the reaction mixture
using a conventional extraction procedure, the isolated yield
increased from 55 to 83% (compare entries 4 and 5). Despite this
significant improve in the product recovery, we still sought to
find a greener alternative. Pleasingly, we found out that simply
filtering the reaction mixture directly through sodium
polyacrylate (readily found in baby´s diapers15c) placed at the top
of a silica gel column easily retained the water present in the
reaction mixture, allowing the easy recovery of the pure product
from the chromatographic procedure in the same yield as
obtained in conventional extraction with EtOAc (entry 6).
Additional decrease in the reaction time to 2 h resulted in a
decrease yield (entry 4-6). Using a different NHC-Cu complex
also led to lower reaction yield of the desired product (entry 8).
Our next study involved evaluation of the role of the reaction
solvent. Changing the surfactant from SPGS-550M to TPGS-
550M didn´t result in any change in the reaction (entry 9). On the
other hand, using pure water resulted in a slight increase in the
yield to 87% (entries 10-11). Gratifyingly, when the water-based
systems were replaced by ethanol, full conversion was achieved
and the desired product 3 was isolated in 97% yield (entry 12).
Importantly, the reaction is performed in an open vessel, without
any precautions to exclude air and moisture, and using undried
95% ethanol as the solvent.
With the optimized conditions, we have studied the reaction
using different substituent both at R1 and R2 in order to examine
the scope of this Cu-catalyzed hydroboration reaction (Scheme
3).
Examining the scope of the reaction reveals that our protocol
is tolerant to the presence of common protecting groups at the
nitrogen such the N-Bn and N-Boc derivatives 4 and 5. The
reaction also works efficiently for different alkyl chains at the R2
position and it tolerates branched (8-9), longer linear (11), and
cyclic chains (7). Additionally, the presence of a phenyl group
was also possible and the corresponding product 6 was obtained
in 75% yield. It´s worth pointing out that ethanol is a more robust
solvent for the reactions, while in water (with or without

3
surfactant) did not result in efficient formation of the desired
products.
Scheme 4. Borylation/protodeboronation of alkenyl oxindole 12
To highlight the utility of the obtained boronates, we have
reacted boronate 3 with oxone in an acetone/water solution
resulted in the oxidation of the Bpin moiety to deliver the
corresponding alcohol 17 in 95% yield (Scheme 5). Additionally,
the boronate was also converted to corresponding 1,2,3-triazole
18, through a two-step, one-pot, copper-catalyzed azidation-
[3+2]-cycloaddition reaction. The azide was generated in situ by
a azidation of the boronate with NaN3. After the consumption of
the boronate, phenylacetylene and sodium ascorbate were added
to the reaction mixture and the 1,2,3-triazole was obtained as the
final product in 30% yield (two steps).
Scheme 3. Scope of the Cu-catalyzed borylation
Interestingly, when an alkenyl oxindoles 12a-b bearing two
electron-withdrawing group at the double bond was tested as
substrates for the hydroboration reaction,16 the borylated products
were not isolated. Instead, the products of the reduction of the
double bond 13, were isolated in excellent yields, presumably
through a hydroboration/protodeboronation sequence either using
aqueous micellar conditions or ethanol as the solvent (Scheme 4).
In this system, the borylation reaction would have occurred with
reverse regioselectivity, yielding boronate 14. This compound
underwent fast transmetallation with the catalyst to form a Cu(I)-
enolate 16, that can be protonated delivering the observed
product 13.17
Scheme 5. Utility of the product
In summary, we have described the copper-catalyzed
hydroboration of alkenyl oxindoles. The corresponding boronates
were obtained in good yields, under operationally simple and
environmentally friendly conditions, using ethanol as the solvent.
Water-based systems were not very effective. Furthermore, the
obtained products are amenable to further elaboration and can be
useful to the synthesis of a broader range of oxindole-containing
molecules with biological relevance.

4
Tetrahedron Letters
17. Bergman, J. Oxindoles. In Advances in Heterocyclic Chemistry
Acknowledgments
Vol. 117; Scriven, E. F. V.; Ramsden, C. A., Eds.;
Elsevier:Amsterdam, 2015; pp 1-81.
We are grateful to the CNPq, CAPES, and INCT-Catálise for
financial support.
References and notes
Supplementary Material
1. (a) da Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem.
Soc. 2001, 12, 273-324. (b) Millemaggi, A.; Taylor, R. J. K.
Liu, Y.; Wang, H.; Wan, J.
Supplementary material available: Detailed experimental
procedures and analytical data. Copies of NMR spectra.
Asian J. Org. Chem. 2013, 2, 374-386. (d) Singh, G. S.; Desta, Z.
Y. Chem. Rev. 2012, 112, 6104-6155. (e) Xia, M.; Ma, R. Z. J.
Heter. Chem. 2014, 51, 539-554. (f) Santos, M. M. M.
Tetrahedron 2014, 70, 9735-9757. (g) Mahammadi, S.; Heiran,
R.; Herrera, R. P.; Marqués-Lopes, E. ChemCatChem 2013, 5,
2131–2148.
2. (a) Kaur, M.; Singh, M.; Chadha, M.; Silakari, O. Eur. J. Med.
Chem. 2016, 123, 858-894. (b) Rane, R. A.; Karunanidhi, S.; Jain,
K.; Shaikh, M.; Hampannavar, G.; Karpoormath, R. Curr. Top.
Med. Chem. 2016, 16, 1262-1289. (c) Palovska, T. L.; Redkin, R.
G.; Lipson, V. V.; Atamanuk, D. V. Mol. Divers. 2016, 20, 299-
344. (d) Xia, M.; Ma, R. -Z. J. Hetererocyclic Chem. 2014, 51,
539-554. (e) Yu, B.; Yu, D. -Q.; Liu, H. -M. Eur. J. Med. Chem.
2015, 97, 673-698.
3. convolutamydines: (a) Kamano, Y.; Zhang, H.-P.; Ichihara, Y.;
Kizu, H.; Komiyama, K.; Pettit, G. R. Tetrahedron Lett. 1995, 36,
2783-2784. (b) Miah, S.; Moody, C. J.; Richards, I. C.; Slawin, A.
M. Z. J. Chem. Soc. Perkin Trans. 1 1997, 2405-2412.
4. horsfiline: Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.;
Bodo, B. J. Org. Chem. 1991, 56, 6527-6530.
5. dioxibrassinin: (a) Monde, K.; Sasaki, K.; Shirata, A.; Takasugi,
M. Phytochemistry 1991, 30, 2915-2917. (b) Suchý, M.; Kutschy,
P.; Monde, K.; Goto, H.; Harada, N.; Takasugi, M.; Dzurilla, M.;
Balentova, E. J. Org. Chem. 2001, 66, 3940-3947.
6. semaxanib: Solomon, V. R.; Hu, C.; Lee, H. Bioorg. Med. Chem.
2009, 17, 7585-7592.
7. Vachhani, D. D.; Butani, H. H.; Sharma, N.; Bhoya, U. C.; Shah,
A. K.; Van der Eycken, E. V. Chem. Commun. 2015, 51, 14862-
14865.
8. Wei, F.; Wei, L.; Zhou, L.; Tung, C. -H.; Ma, Y.; Xu, Z. Asian J.
Org. Chem. 2016, 5, 971-975
9. Costa, J. S.; Braun, R. K.; Horn, P. A.; Lüdtke, D. S.; Moro, A. V.
RSC Adv. 2016, 6, 59935-59938.
10. Horn, P. A.; Braun, R. K.; Isoppo, V. G.; Costa, J. S.; Lüdtke, D.
S.; Moro, A. V. Adv. Synth. Catal. 2017, 359, 2322-2328.
11. (a) See for example: Li, C.; Wang, J.; Barton, L. M.; Yu, S.; Tian,
M.; Peters, D. S.; Kumar, M.; Yu, A. W.; Johnson, K. A.;
Chatterjee, A. K.; Yan, M.; Baran, P. S. Science 2017, 356,
eaam7355 and references therein. (b) Trippier, P. C.; McGuigan,
C. MedChemComm 2010, 1, 183-198. (c) Smoum, R.; Rubinstein,
A.; Dembitsky, V. M.; Srebnik, M. Chem. Rev. 2012, 112, 4156–
4220. (d) Ballatore, C.; Huryn, D. M.; Smith 3rd, A. B.
ChemMedChem 2013, 8, 385–395.
12. (a) Capello, C.; Fischer, U.; Hungerbühler, K. Green Chem. 2007,
9, 927-934. (b) Byrne, F. P.; Jin, S.; Paggiola, G.; Petchey, T. H.
M.; Clark, J. H.; Farmer, T. J.; Hunt, A. J.; McElroy, R.;
Sherwood, J. Sustain Chem. Process 2016, 4, 7. (c) Lipshutz, B.
H.; Gallou, F.; Handa, S. ACS Sustainable Chem. Eng. 2016, 4,
5838-5849.
13. Chen, L.; Wu, Z.; Wang, Q.; Xu, X.; Wang, L. Chin. J. Chem.
2014, 32, 844-852.
14. For representative examples on the hydroboration of conjugated
alkenes: (a) Chea, H.; Sim, H. -S.; Yun, J. Bull. Korean Chem.
Soc. 2010, 31, 551-552. (b) Chea, H.; Sim, H. -S.; Yun, J. Adv.
Synth. Catal. 2009, 351, 855-858. (c) Gao, M.; Thorpe, S. B.;
Santos, W. L. Org. Lett. 2009, 11, 3478-3481. (d) Thorpe, S. B.;
Calderone, J. A.; Santos, W. L. Org. Lett., 2012, 14, 1918-1921.
(e) Lee, K.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 7253-7255.
15. (a) Lipshutz, B. H.; Ghorai, S.; Abela, A. R.; Moser, R.; Nishikata,
T.; Duplaisand, C.; Krasovskiy, A. J. Org. Chem. 2011, 76, 4379-
4391. (b) Klumphu, P.; Lipshutz, B. H. J. Org. Chem. 2014, 79,
888-900. (c) Lipshutz, B. H.; Gorai, S. Green Chem. 2014, 16,
3645–4018. (d) Sorella, G. L.; Strukul, G.; Scarso, A. Green
Chem. 2015, 17, 644-683.
16. Prepared according to the literature: Lian, Z.; Shi, M. Tetrahedron
2012, 68, 2401-2408.

5
Highlights:
Synthesis of organoboron compounds
with potential biological activities
Pressing need for the replacement of
hazardous
alternative
solvents
by
greener
Cu-catalyzed borylation of alkenyl
oxindoles in ethanol and water
Boronates obtained in good yields,
under
environmentally
friendly
conditions