Directing-group-assisted manganese-catalyzed cyclopropanation of indoles

Article abstract of DOI:10.1021/acs.orglett.9b00150

The first manganese-catalyzed cyclopropanation of indoles is reported in moderate to excellent yield with methyl-2-diazo-2-arylacetates. This new strategy involved acetyl (COCH₃) as the directing group and exhibited exceptional functional group tolerance. In the absence of stereodirecting groups the desired products were obtained as a mixture of diastereomers (7:3 → 8:2). Control experiments and DFT studies elucidated the probable pathway for the formation of cyclopropane-fused indole product. Deacetylation of the final products afforded both C3-substituted NH-indoles.

Full text of DOI:10.1021/acs.orglett.9b00150

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Directing-Group-Assisted Manganese-Catalyzed Cyclopropanation
of Indoles
†
†
‡
,†,‡
Pratip K. Dutta, Jyoti Chauhan, Mahesh Kumar Ravva, and Subhabrata Sen*
†Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Dadri, Chithera, Gautam Budh Nagar, UP 201314,
India
‡
Department of Chemistry, SRM University-AP, Amaravati, 522502, India
*
S Supporting Information
ABSTRACT: The first manganese-catalyzed cyclopropanation of indoles
is reported in moderate to excellent yield with methyl-2-diazo-2-
arylacetates. This new strategy involved acetyl (COCH ) as the directing
3
group and exhibited exceptional functional group tolerance. In the
absence of stereodirecting groups the desired products were obtained as a
mixture of diastereomers (7:3 → 8:2). Control experiments and DFT
studies elucidated the probable pathway for the formation of cyclo-
propane-fused indole product. Deacetylation of the final products afforded both C3-substituted NH-indoles.
y virtue of their ubiquitous presence in natural products
substrate or reagent is used to demonstrate the feasibility of the
B
and drug intermediates, indole derivatives hold a niche
protocol) and, apart from the first report, utilize a directing
group that is not easy to remove. Consequently there is a
window of opportunity to develop a novel methodology for the
cyclopropanation of indoles with a new catalyst. Additionally
we came across two reports by Wang et al. and Chang et al.
1
position in synthetic and medicinal chemistry. Among various
indole derivatives, cyclopropane-fused indoles are found widely
among natural products and pharmaceuticals and as synthons
for the synthesis of indole alkaloids. For example, Lundurine
A−D isolated from Kopsia tenuis are a group of alkaloids with
unique polycyclic scaffold with cyclopropane-fused indole as
the central unit. Lundurine A and C ameliorate the multidrug
involving C functionalization of N-pyrimidyl and NH indoles
2
catalyzed by Mn(CO) Br and [RuCl (p-cymene)] with α-
5
2
2
keto and α-aryldiazoesters, respectively, to afford C -
2
7
resistance in vincristine-resistant K cells. Lundurine B and D
B
substituted indoles (Scheme 1a). Even though Mn(CO) Br-
5
inhibit the proliferation of B16 melanoma cells. Additionally
cyclopropane-fused indoles form key intermediates for the
synthesis of indole alkaloids such as (−)-desoxyeseroline,
catalyzed reaction on N-pyrimidyl indole occurred through CH
activation, the Ru-catalyzed transformation of NH-indole was a
carbenoid functionalization that putatively involved the
cyclopropyl-fused indole as an intermediate, which the authors
2
communisin, minfiensine, and aspidofractinine.
To date, there are four strategies used to access cyclo-
7a
could not isolate. Accordingly, this prompted us to ponder
3
−6
propane-fused indoles (Scheme 1S, SI).
Three of them
about manganese-based catalysts with a new directing group at
the indole nitrogen which could enable us to isolate the
cyclopropyl-fused indole derivatives. Manganese is the third
most abundant transition metal after iron and titanium. It is
found in the crux of diverse enzymes required for various
include diazo compounds or tosyl hydrazone-mediated,
transition-metal (such as copper, iron, and cobalt) catalyzed
3
−5
reactions of indole derivatives.
The first report about
cyclopropanation of indoles was made in 2012, which involved
an enantioselective strategy using copper triflate (CuOTf) and
8
3
metabolizing reactions in the human body. It has been utilized
carbohydrate-based bis(oxazoline) ligands (Scheme S1).
in a gamut of radical-based reactions inspired from biological
Interestingly only two analogues were synthesized, and one
of them was extended to the synthesis of the natural product
9
systems. In the recent years manganese catalysts have also
1
0
evolved as a robust tool in organometallic C−H activation.
(
−)-deoxyeseroline. In 2016, after about five years, Reddy and
In general they work through chelation and afford atom-
economical access to architecturally diverse scaffolds. Herein
co-workers demonstrated a chemoselective protocol involving
cobalt(II) porphyrin-catalyzed intramolecular cyclopropana-
11
4
we report a bromopentacarbonylmanganese(I) [(Mn-
tion of N-alkyl indoles/pyrroles with alkylcarbenes. In another
(
CO) Br]-catalyzed cyclopropanation of N-acetyl indoles
5
example Xu et al. reported a highly enantioselective copper-
and iron-catalyzed intramolecular cyclopropanation of indoles
with appropriate diazo reagent in good to excellent yield
(Scheme 1b). Scale-up reaction demonstrated the robustness
of the protocol. This is a unique example of manganese-
5
with chiral ligands. Very recently Chen and co-workers
demonstrated a nondiazo approach involving a novel zinc
6
carbene source to generate these compounds. A close scrutiny
of these procedures revealed that in general they are either
Received: January 14, 2019
substrate or reagent specific (i.e., only one particular type of
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00150
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Reactions That Inspired Our Cyclopropanation
of Indoles
Table 1. Optimization of the Reaction Conditions for
Cyclopropanation of N-Acetyl Indoles
cat.
(mol %)
base
(equiv)
entry
R
solvent t (°C) yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Me
″
″
″
″
″
″
″
″
″
″
″
″
″
″
″
A (5)
B (5)
C (5)
″
″
″
″
″
″
″
″
″
″
″
C (10)
C (20)
″
-
C (5)
″
″
B1 (0.5)
″
″
″
″
″
″
B1 (1.0)
B1 (2.0)
B2 (2.0)
B3 (2.0)
B4 (2.0)
B5 (2.0)
B6 (2.0)
B1 (2.0)
″
dioxane
″
″
DCE
THF
50
″
″
″
″
″
80
″
″
″
″
″
″
″
″
″
0
16
20
25
20
15
45
60
70
65
30
0
<10
20
70
50
∼70
0
Et O
2
DCE
″
″
″
″
″
″
″
″
″
″
″
″
″
″
1
1
1
1
1
1
1
1
1
1
2
2
catalyzed, simple, efficient, and facile functionalization of
indoles from readily available catalysts and reagents.
In a bid to explore a suitable condition to facilitate the
cyclopropanation of indoles with manganese catalyst we chose
N-acetyl indole 2a and methyl 2-diazo-2-phenylacetate 3a as
appropriate reaction partners. To begin, 5 mol % of a variety of
manganese catalysts such as manganese acetoacetate (Mn-
″
″
″
″
″
-
100
80
″
″
″
0
0
35
t-BuO
Ph
B1 (2.0)
″
(
acac) ), manganese carbonyl (Mn(CO) ), and manganese
a
3
10
Isolated yield (scale of reactions 50 mg). A: Mn(acac), B:
Mn (CO) , C: MnBr(CO) , B : NaOAc, B : KOAc, B : Diisopropyl
pentacarbonyl bromide (Mn(CO) Br) was used in the
presence of 0.5 equiv of sodium acetate (NaOAc) as the
base with 1,4-dioxane as the solvent at 50 °C (Table 1, entries
5
2
10
5
1
2
3
Amine, B : triethyl amine, B : K PO , B : K CO , DCE: Dichloro-
4
5
3
4
6
2
3
ethane, THF: Tetrahydrofuran, Et O: Diethyl ether
2
1
−3). Among the manganese catalysts screened, Mn(CO) Br
5
worked the best, though with meagre yield of the desired
product 4a (Table 1, entry 3). In comparison, the other two
catalysts rendered no products (Table 1, entries 1 and 2). With
With the optimized procedure in hand we reacted diversely
substituted indoles 2b−k with a variety of methyl 2-diazo-2-
arylacetates 3a−h. The reaction provided the desired
compounds 4b−z′ in moderate to excellent yield (Scheme
2). The reaction was equally amenable toward electron-
donating (2b−f, n, and q) and electron-withdrawing (2g and
z) substituted indoles. It was also well tolerant toward the
reaction of 7-azaindole (2j) with 2-diazo-2-phenylacetate 3a,
to afford the desired product 4z′ in a moderate yield of 69%
(Scheme 2). The reactions took around 18−24 h for
completion, and the products were purified through column
chromatography. Due to the absence of a stereodirecting group
the desired compounds were obtained as a mixture of
diastereomers (Scheme 2).
The structures were confirmed by single X-ray crystallog-
raphy of representative analogues 4e and u. In order to
demonstrate the robustness of our reaction, it was conducted
in a scale of 2 g with 2a (12.45 mmol, 1.98 g) and 3a (12.45
mmol, 2.19 g). The desired product 4a was isolated in 82%
yield.
Mn(CO) Br as the better catalyst, we explored several reaction
5
conditions to optimize the procedure. Consequently, screening
several solvents, viz., tetrahydrofuran (THF), dichloroethane
(
7
DCE), and diethyl ether, at 50 and 80 °C (Table 1, entry 4−
) revealed that DCE at 80 °C was by far the best protocol to
generate 4a in 45% yield (Table 1, entry 7). Next, gradual
increase of NaOAc from 0.5 to 2 equiv improved the yield
from 45 to 70% (Table 1, entries 7−9). Screening the reaction
with various bases such as potassium acetate (KOAc),
diisopropylamine (DIPA), triethyl amine (TEA), potassium
phosphate (K PO ), and potassium carbonate (K CO )
3
4
2
3
(
Table 1, entries 10−14) could not improve the yield. Even
increasing the catalyst content from 5 to 20% or the
temperature to 100 °C could not improve the yield (Table
1
, entries 15−17). Reaction in the absence of a catalyst or base
afforded no products (Table 1, entries 18−19). This indicated
the relevance of both of these in our reaction. Exploring few
other directing groups on indole NH such as benzoyl and tert-
butyloxycarbonyl (t-Boc) (Table 1, entries 20−21) proved
futile. Hence the optimized procedure involved an equivalent
of N-acetyl indole 2a with an equivalent of 3a in the presence
Interestingly, when 4a was stirred with 5 N hydrochloric
acid in ethanol at 80 °C, not only did it undergo deacylation
but also the cyclopropane ring opened up to provide a mixture
of C3- and C2-substituted indoles 5a and 6a in 95:5 ratio,
of 5 mol % of Mn(CO) Br and 2 equiv of NaOAc in
5
dichloroethane at 80 °C, to afford the desired cyclopropane-
fused N-acetyl indole 4a (refer to SI).
which enabled us to isolate only the C -substituted product
(Scheme 3). This provides a facile route to access C3-
3
B
DOI: 10.1021/acs.orglett.9b00150
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Library of Cyclopropane-Fused N-Acetyl Indoles
benzoyl and tert-Boc-substituted indole derivatives also did not
provide the desired product. These results and the fact that
only N-acetyl indole facilitated the formation of the cyclo-
propane-fused products emphasized the importance of the
sterics and directing group effect of the functionalities that
substituted the indole nitrogen. The reaction of 2a and 3a in
the presence of radical scavenger butylated hydroxy toluene
4a−z′
(
BHT) had no effect on the yield of the reaction, thereby
indicating an ionic pathway for this transformation (Scheme
b).
Followed by the control experiments, DFT calculation were
4
14
performed to understand the potential reaction pathway. All
calculations were carried out using the Gaussian 16 program.
Geometries of all reactants and products were optimized using
the B3LYP functional employing the TZVP basis set for Mn
and Br and the SVP basis set for the other atoms (C, H, N, and
O). Vibrational analysis was carried out at the optimized
geometries to confirm the stationary points as local minima.
Furthermore, to get better energies, solvent environment is
implicitly included by a self-consistent reaction field (SCRF)
approach using the continuum solvation model (PCM) at the
M06/TZVP level using the geometries obtained at B3LYP/
TZVP(Br,Mn) and SVP(H,C,O,N) level.
Preliminary calculations revealed that the first step of the
reaction is the transformation of Mn(CO) Br to A in the
5
1
presence of NaOAc, a thermoneutral process (∼0.4 kcal/mol).
Later A is converted into A by losing one CO ligand with a
1
free energy penalty of ∼13 kcal/mol. This was also supported
7b
Scheme 3. Synthesis of C3-Substituted N−H Indoles
by the literature evidence. Reaction of 3a with A facilitates
the formation of the manganese carbenoid intermediate B, of
high energy (ΔG = ∼36 kcal/mol). Dissociation of a carbonyl
moiety from B enables it to coordinate with 1a to afford C in a
step associated with an energy change of ∼6 kcal/mol. Next,
cyclization of C provided the complex D (ΔG = −15.44 kcal/
mol) via two transition states (TS1 and TS2) (refer to Figure
S2 of the Supporting Information), and subsequent manganese
release from D afforded the desired product 4a which is
endergonic by 29.71 kcal/mol (Scheme 5).
substituted NH-indoles. They are acclaimed compounds
12
demonstrating a gamut of biological activities. To date,
transition-metal-catalyzed (other than palladium) C3-subsitu-
tion of indoles by C3−H activation had been achieved by N-
pyrimidyl, pyridylsulfonyl, or amidyl directing groups, where
Hence, to conclude, we have devised a highly efficient
directing-group-assisted cyclopropanation of N-acetyl indoles
13
removal of these groups has always been tedious.
Scheme 5. Putative Reaction Mechanism and Calculated
Free Energies in Solution (Dichloroethane) (All Values in
kcal/mol)
To understand the reaction mechanism, several control
reactions were conducted. For example, reaction of unpro-
tected indole under the optimized reaction condition with 3a
provided a trace amount of product (∼5%) (Scheme 4a).
During the optimization reaction as depicted in Table 1, the
Scheme 4. Control Experiments to Understand the
Mechanism
C
DOI: 10.1021/acs.orglett.9b00150
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
using α-aryldiazoacetates as reagents and Mn(CO) Br as the
Echavarren, A. M. Chem. - Eur. J. 2007, 13, 1358. (d) Ferrer, C.;
Escribano-Cuesta, A.; Echavarren, A. M. Tetrahedron 2009, 65, 9015.
5
catalyst. The acetyl moiety enacts a crucial role in facilitating
the formation of intermediate C. It also promotes the
cyclopropanation as the double bond character of the C2−
C3 bond of the substrate is retained compared to similar N-
pyrimidyl, pyridylsulfonyl, or amidyl indole substrates. Because
of a readily accessible directing group (−Ac), high yield, facile
scale-up option, and usage of an economical, easy to handle
catalyst, we presume that this Mn-catalyzed reaction will find a
niche position in the existing repertoire of indole functional-
ization. We have also demonstrated that the acetyl
functionality could be removed under mild conditions,
resulting in the formation of C3-substituted NH-indoles,
which are biologically extremely relevant.
(e) Donets, P. A.; Van Hecke, K.; Van Meervelt, L.; Van der Eycken,
E. V. Org. Lett. 2009, 11, 3618. (f) Schultz, E. E.; Pujanauski, B. G.;
Sarpong, R. Org. Lett. 2012, 14, 648. (g) Pearson, W. H.; Lee, I. Y.;
Mi, Y.; Stoy, P. J. Org. Chem. 2004, 69, 9109.
̈
̈
duru, G.; Schubach, T.; Boysen, M. M. K. Org. Lett. 2012,
(
1
(
3) Ozu
4, 4990.
4) Reddy, A. R.; Hao, F.; Wu, K.; Zhou, C.-Y.; Che, C.-M. Angew.
Chem., Int. Ed. 2016, 55, 1810.
(5) Xu, H.; Li, Y.-P.; Cai, Y.; Wang, G.-P.; Zhu, S.-F.; Zhou, Q.-L. J.
Am. Chem. Soc. 2017, 139, 7697.
(
2
(
6) Chen, W.; Ji, D.; Luo, Y.; Wang, Z.; Xu, P. Org. Chem. Front.
018, 5, 1768.
7) (a) Chan, W.-W.; Yeung, S.-H.; Zhou, Z.; Chan, A. S. C.; Yu, W.-
Y. Org. Lett. 2010, 12, 604. (b) Wang, C.; Maity, B.; Cavallo, L.;
Rueping, M. Org. Lett. 2018, 20, 3105.
(8) (a) Emsley, J. Nature’s Building Blocks: An A−Z. Guide to the
Elements - Manganese; Oxford University Press: Oxford, 2001; p 249.
ASSOCIATED CONTENT
Supporting Information
■
*
S
(
b) Law, N. A.; Caudle, M. T.; Pecoraro, V. L. Adv. Inorg. Chem.;
Sykes, A. G., Ed.; Academic Press: New York, 1998; Vol. 46, p 305.
9) (a) Paradine, S. M.; Griffin, J. R.; Zhao, J.; Petronico, A. L.;
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00150.
(
Miller, S. M.; White, M. C. Nat. Chem. 2015, 7, 987. (b) Huang, X.;
Bergsten, T. M.; Groves, J. T. J. Am. Chem. Soc. 2015, 137, 5300.
(c) Liang, J.-L.; Huang, J.-S.; Yu, X.-Q.; Zhu, N.; Che, C.-M. Chem. -
Eur. J. 2002, 8, 1563. (d) Yu, X.-Q.; Huang, J.-S.; Zhou, X.-G.; Che,
C.-M. Org. Lett. 2000, 2, 2233 and references cited therein . (e) Kim,
J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew. Chem., Int. Ed. 2010, 49,
Experimental procedures and additional results obtained
from DFT calculations (PDF)
Cartesian coordinates along with energies of all
stationary points, NMR spectra, and X-ray crystallo-
graphic data for new compounds (PDF)
9899. (f) Liu, W.; Groves, J. T. Acc. Chem. Res. 2015, 48, 1727.
Accession Codes
(g) Huang, X.; Liu, W.; Ren, H.; Neelamegam, R.; Hooker, J. M.;
Groves, J. T. J. Am. Chem. Soc. 2014, 136, 6842. (h) Liu, W.; Huang,
X.; Groves, J. T. Nat. Protoc. 2013, 8, 2348. (i) Liu, W.; Groves, J. T.
Angew. Chem., Int. Ed. 2013, 52, 6024. (j) Liu, W.; Huang, X.; Cheng,
M.-J.; Nielsen, R. J.; Goddard, W. A.; Groves, J. T. Science 2012, 337,
CCDC 1885102 and 1885198 contain the supplementary
crystallographic 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.
1
322. (k) Liu, W.; Groves, J. T. J. Am. Chem. Soc. 2010, 132, 12847.
10) (a) Dyker, G. Handbook of C-H Transformations: Applications in
Organic Synthesis; Wiley-VCH Verlag GmbH: Weinheim, 2008.
(
(b) Bergman, R. G. Nature 2007, 446, 391.
AUTHOR INFORMATION
Corresponding Author
(11) Liu, W.; Ackermann, L. ACS Catal. 2016, 6, 3743.
■
*
(12) (a) Sundberg, R. J. Indoles; Academic Press: New York, 1996.
(
(
b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
c) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010,
E-mail: subhabrata.s@srmap.edu.in.
ORCID
110, 4489. (d) Nuth, M.; Guan, H.-C.; Zhukovskaya, N.; Saw, Y. L.;
Ricciardi, R. P. J. Med. Chem. 2013, 56, 3235.
Subhabrata Sen: 0000-0002-4608-5498
Notes
(13) (a) Li, B.; Ma, J.-F.; Xie, W.-J.; Song, H.-B.; Xu, S.-S.; Wang, B.-
Q. J. Org. Chem. 2013, 78, 9345. (b) Lygnin, A. V.; Ackermann, L.
Org. Lett. 2011, 13, 3332. (c) John, A.; Nicholas, K. M.
Organometallics 2012, 31, 7914. (d) Ryu, J.; Shin, K.; Park, S. H.;
Kim, J. Y.; Chang, S. Angew. Chem., Int. Ed. 2012, 51, 9904. (e) Shi, J.-
J.; Zhou, B.; Yang, Y.-X.; Li, Y.-C. Org. Biomol. Chem. 2012, 10, 8953.
(f) Shi, J.; Zhao, G.; Wang, X.; Xu, H. E.; Yi, W. Org. Biomol. Chem.
2014, 12, 6831. (g) Zhu, X.; Su, J.-H.; Du, C.; Wang, Z.-L.; Ren, C.-
L.; Niu, J.-J.; Song, M.-P. Org. Lett. 2017, 19, 596. (h) Ding, Z.;
Yoshikai, N. Angew. Chem., Int. Ed. 2012, 51, 4698. (i) Sakata, K.; Eda,
M.; Kitaoka, Y.; Yoshino, T.; Matsunaga, S. J. Org. Chem. 2017, 82,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge Shiv Nadar University for financial support
and SRM Supercomputer Center, SRM Institute of Science
and Technology, for providing the computational facility to
conduct the DFT calculations.
7
2
(
379. (j) Zhang, Z.-Z.; Liu, Z. B.; Wang, C.-Y.; Shi, B.-F. Org. Lett.
015, 17, 4094.
14) Wang, H.; Choi, I.; Rogge, T.; Kaplaneris, N.; Ackermann, L.
REFERENCES
■
(
1) (a) Poulsen, T. B.; Jørgensen, K. A. Chem. Rev. 2008, 108, 2903.
b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (d) Bandini,
(
(
Nat. Catal. 2018, 1, 993.
M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett 2005, 2005,
199. (e) Sundberg, R. J. Indoles; Academic Press: London, UK, 1996.
f) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New
York, 1970. (g) Singh, T. P.; Singh, O. M. Mini-Rev. Med. Chem. 2017,
8, 9. (h) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.
H.; Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620.
2) (a) Kam, T. S.; Yoganathan, K.; Chuah, C. H. Tetrahedron Lett.
995, 36, 759. (b) Kam, T. S.; Lim, K. H.; Yoganathan, K.; Hayashi,
1
(
1
(
1
M.; Komiyama, K. Tetrahedron 2004, 60, 10739. Recent synthetic
studies toward related alkaloids: (c) Ferrer, C.; Amijs, C. H. M.;
D
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