[Copper(I)(Pyridine-Containing Ligand)] Catalyzed Regio- and Steroselective Synthesis of 2-Vinylcyclopropa[b]indolines from 2-Vinylindoles

Article abstract of DOI:10.1021/acs.orglett.7b03704

A [copper(I)pyridine-containing ligand]-catalyzed reaction between 2-vinylindoles and diazo esters is described. The reaction allows for the synthesis of a series of 2-vinylcyclopropa[b]indolines with excellent levels of regio- and sterocontrol under mild

Full text of DOI:10.1021/acs.orglett.7b03704

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
[
Copper(I)(Pyridine-Containing Ligand)] Catalyzed Regio- and
Steroselective Synthesis of 2‑Vinylcyclopropa[b]indolines from
‑Vinylindoles
2
,‡
‡
§
Valentina Pirovano,* Elisa Brambilla, and Giorgio Tseberlidis
‡Dipartimento di Scienze Farmaceutiche-Sezione di Chimica Generale e Organica “A. Marchesini”, Universita
̀
degli Studi di Milano,
Via Venezian 21, 20133 Milano, Italy
§Dipartimento di Chimica, Universita
̀
degli Studi di Milano, Via Golgi 19, 20133, Milano, Italy
*
S Supporting Information
ABSTRACT: A [copper(I)pyridine-containing ligand]-catalyzed reac-
tion between 2-vinylindoles and diazo esters is described. The reaction
allows for the synthesis of a series of 2-vinylcyclopropa[b]indolines with
excellent levels of regio- and sterocontrol under mild conditions.
he introduction of a cyclopropane unit into a carbo- or
Scheme 1. Reactions of Vinylindoles with EDA
T
heteroaromatic scaffold certainly represents an attractive
1
challenge in synthetic organic chemistry. While on the one
hand, the cyclopropane ring itself is an important motif in
2
medicinal chemistry, on the other side, its manipulation gives
access to other functionalities via ring opening and/or ring
3
expansion. Among the synthetic possibilities for generating a
cyclopropane ring, intermolecular cyclopropanation by metal-
catalyzed reactions with diazo compounds have been described4
for different electron-rich heterocycles including furans,
5
6
pyrroles, and indoles. Besides indoles, vinylindoles could
also represent an interesting substrate for cyclopropanation.
Thus, cyclopropanation at the C2−C3 bond of the indole
nucleus could give rise to a new class of dearomatized indoles
containing a vinyl-cyclopropyl moiety able to undergo further
7
transformations. However, vinylindoles have been seldom
involved in cyclopropanation reactions with diazo esters and
cyclopropanation regioselectively occurs at the exocyclic double
bond. For example, in 1998, Raj and co-workers proposed the
synthesis of 3-cyclopropylindoles by reacting N-sulfonylated 3-
vinylindoles with ethyl diazoacetate (EDA) in the presence of a
8
bisoxazoline copper(II) catalyst (Scheme 1a), while more
recently Marcin and co-workers proposed an asymmetric
version of the same reaction using a chiral pyBox-ruthenium(II)
9
complex (Scheme 1b). In both these reports, cyclopropanation
occurred at the external double bond of 3-vinylindole and, in
addition, only 3-vinylindoles were tested under the optimized
reaction conditions. Therefore, considering our interest in
metal catalyzed synthesis and functionalization of indoles and
indole derivatives, we decided to verify the reactivity of 2-
vinylindoles with EDA under metal catalysis (Scheme 1c). In
particular, we wanted to selectively address the synthesis of a
new class of dearomatized indoles, which could represent a
useful intermediate in the synthesis of more complex
11
molecules, by cyclopropanation at C2−C3 indole.
Thus, 2-vinylindole 1a and ethyl diazoacetate 2a were
reacted in a model reaction under various catalytic conditions.
1
0
Received: November 29, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03704
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Some selected results are summarized in Table 1 (see SI for
complete optimization report).
Scheme 2. Scope of the Reaction between 1 and 2
Table 1. Optimization of reaction conditions
a
b
entry
[M]/ligand
time, h ± 3a, (%)
1
2
3
4
5
6
[Cu(OTf)] ·Tol (2.5 mol %)
3
10
2
[Rh(OAc) ] (2.5 mol %)
3
<10
43
2
4
[Cu(OTf)] ·Tol (2.5 mol %) L (5 mol %)
3
2
1
[Cu(OTf)] ·Tol (2.5 mol %) L (5 mol %)
3
19
2
2
IPrCuCl (5 mol %), NaBAr (5 mol %)
3
n.r.
F
c
[Cu(OTf)] ·Tol (5 mol %) L (10 mol %)
12
68
2
1
a
Unless otherwise mentioned, all reactions were carried out using 1a
0.2 mmol) and 2a (0.3 mmol) in DCE (0.1 M). EDA was added with
(
b
c
a syringe pump at 0.5 or 0.17 mL/h. Isolated yield. 2a (0.5 mmol),
DCE (0.07 M) and 200 mg of 4 Å MS were added. IPr = 1,3-bis(2,6-
diisopropylphenyl)imidazole-2-ylidene.
a
Reaction conditions: 1 (0.2 mmol), 2 (0.5 mmol) in DCE (0.07 M)
c
and with 4 Å MS. Isolated yields. Reaction performed on 2 mmol
scale.
At the outset, we selected copper(I) triflate and rhodium(II)
acetate as best possible catalysts for our reaction. In fact, the
corresponding carbene complexes have been widely used in this
methyl, as well as secondary cyclic alkyl groups, products
± 3b−d were formed in good and reproducible yields. In
addition, the synthesis of ± 3a could also be performed on
higher scale without any substantial difference in the reaction
yield. Then, a 2-vinylindole having an endocyclic vinyl moiety
was employed, affording indoline ± 3e, even if in lower yield,
probably because of the steric hindrance at the side chain. We
could use as starting material also indoles substituted on 5-
position with electron-donating or electron-withdrawing
groups, obtaining ± 3f and ± 3g in 60% and 61% yield,
respectively. Then, we tested β-aryl substituted 2-vinylindoles
and we verified that the presence of an aromatic ring did not
influence the reaction outcome, and products ± 3h−j were
prepared efficiently. Besides EDA, other diazo compounds were
tested under standard reaction conditions. The use of t-butyl
diazoacetate (2b) afforded the desired product ± 3k in 51%
yield, while when we employed the α-disubstituted diazo
compound 2c, indoline ± 3l was obtained in high yield as a
single isomer.
12
kind of transformations. However, very poor yield of ± 3a was
observed with copper(I), while rhodium(II) afforded only
traces of the desired product. In both cases, unreacted 1a was
recovered besides other products arising from the dimerization
of 2a. We moved next to other Cu(I) species, in particular we
tested some complexes having a pyridine-containing macro-
13
cycle as ligand (L −L ) and showing enhanced solubility and
1
2
stability compared to simple CuOTf. Moreover, these
complexes were successfully applied as ligands in copper-
catalyzed cyclopropanation reactions and Si−H carbene
1
4
insertions. Therefore, when the reaction between 1a and
EDA (2a) was conducted in the presence of [Cu(I)L ]OTf,
1
generated in situ from [Cu(OTf)] ·Tol and the corresponding
2
ligand L , the yield was significantly increased up to 43% (entry
1
3
). 2-Vinylcyclopropa[b]indoline ± 3a was formed as single
regio- and diasteroisomer and its structure, as well as the
relative position of the substituents around the cyclopropane
ring, was completely elucidated by mono and bidimensional
NMR analyses (see SI). Similarly, we verified the activity of
Considering these results we decided to explore the
possibility of developing an enantioselective synthesis of
another complex, namely the [Cu(I)L ] complex, but the yield
2
13b
of ± 3a was strongly reduced (entry 4), while another copper(I)
cyclopropanindolines 3 by using chiral ligands.
To this
complex such as IPrCuCl/NaBAr failed to give the desired
scope, chiral pyridine-containing macrocycles L −L , as well as
F
3
5
product (entry 5). Finally, we found that doubling the catalyst
loading to 10% and working with an excess of 2a in the
presence of 4 Å MS led to ± 3a in 68% yield (entry 6). Having
the best conditions, we next explored the scope of our
transformation (Scheme 2).
a chiral bisoxazoline, were employed in some preliminary test
reactions (Scheme 3, see SI for further details).
First, we performed a brief screening of ligands for the
synthesis of 3a. In general, excellent results in terms of
enantioselectivity were obtained by using L and L , bearing
3
4
The copper-catalyzed reaction between various 2-vinyl-
indoles 1a−j and diazoesters 2a−c tolerated a wide substituent
pattern and the formation of products ± 3a-l was successful in
all tested reactions. In particular, when we reacted β-alkyl
substituted 2-vinylindoles bearing alkyl chain longer than
two isopropyl groups on the macrocycle. However, in both
cases, the yields resulted to be lower compared to the one
achieved with L . Other ligands, such as monosubstituted
1
macrocycle L and chiral bisoxazoline ligands gave worse er.
5
The activity of L was evaluated with other vinylindoles as well
3
B
DOI: 10.1021/acs.orglett.7b03704
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Enantioselective Synthesis of 3
iminium derivative I is highly electrophilic and can be quickly
trapped by the nucleophilic carbene carbon atom leading to the
stereoselective formation of the cyclopropyl ring (Scheme 4,
path a). Formation of the cyclopropane ring is faster than the
rearomatization process, which could give rise to C-3 alkylated
15
indoles (Scheme 4, path b).
To achieve some insights on our mechanistic hypothesis, we
performed additional experiments modifying the nature and the
position of the substituents at the starting indole. At first, we
decided to investigate the role of the substituent on the indole
nitrogen by introducing an electron-donating group in this
position. Nevertheless, the reaction of N-methyl-2-vinylindole 4
with EDA yielded the hydroarylated indole 5 as single product
(
Scheme 5a). This compound arises from intermediate II,
Scheme 5. Additional Performed Experiments
a
Reaction conditions: 1 (0.2 mmol), 2 (0.5 mmol) in DCE (0.07 M)
and with 4 Å MS. Isolated yields. HPLC was measured on pure
isolated product.
and, similarly to before, it afforded from good to excellent levels
of enantioselection despite the moderate yields of the resulting
indolines. On the other hand, when we employed α-phenyl
diazoacetate 2c instead than EDA (2a), we were able to isolate
3
l in 70% yield but we completely lost the enantioselectivity of
the process. A further optimization, in order to improve general
yields and enantioselectivity in the case of α-substituted
diazoester, is now on going in our laboratory.
analogous but relatively more stable than intermediate I in
16
Scheme 4. Thermodynamically favored indole 5 is thus
formed instead of cyclopropa[b]indoline ± 3. Moreover, 3-
vinylindole 6, tested under optimal reaction conditions,
afforded an E/Z mixture of 3-cyclopropylindolines ± 7 in
quite low yield (Scheme 5b). Thus, when the nucleophilicity of
C3 diminishes, for inductive or resonance substituent effects,
the cyclopropanation at C2−C3 of the indole is inhibited and
the exocyclic double bond is involved in the cyclopropanation
The mechanism we propose for the synthesis of 2-
vinylcyclopropa[b]indoline ± 3a is illustrated in Scheme 4.
After formation of the copper carbene complex from EDA and
[
Cu(I)L]OTf, nucleophilic attack of indole via C3 position
leads to iminium cation I as intermediate. Because of the
presence of an electron-withdrawing group on indole nitrogen,
8
,9
reaction. Finally, we decided to test 2-methyl- and 3-methyl-
N-ethoxycarbonylindoles 8 and 9 under optimal reaction
conditions (Scheme 5c). The behavior of these derivatives
parallels what observed with the corresponding vinylindoles 1
and 6, yielding the C2−C3 cyclopropanation adduct using 8 as
substrate; whereas 9 was recovered unaltered at the end of the
reaction.
Scheme 4. Proposed Reaction Mechanism
In conclusion, we report the first diastero- and enantiose-
lective synthesis of 2-vinylcyclopropa[b]indolines by reaction of
2
-vinylindoles with metal copper−carbene complexes having
pyridine-containing macrocycles as ligands. The proposed
method tolerated a broad range of substituents on the indole
moiety and the use of various diazoacetates. Further develop-
C
DOI: 10.1021/acs.orglett.7b03704
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ments of this work will be directed toward the improvement of
the reaction yield and of the expansion of the reaction scope
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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.7b03704.
(9) Marcin, L. R.; Denhart, D. J.; Mattson, R. J. Org. Lett. 2005, 7,
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651−2654.
Experimental procedures, characterization data and
(10) For a review on [4 + 2] cycloaddition reactions, see: (a) Rossi,
1
13
copies of H and C NMR spectra for all compounds
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E.; Pirovano, V.; Abbiati, G. Eur. J. Org. Chem. 2017, 2017, 4512−
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529. Then see: (b) Pirovano, V.; Negrato, M.; Abbiati, G.;
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Dell’Acqua, M.; Rossi, E. Org. Lett. 2016, 18, 4798−4801. (c) Pirovano,
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AUTHOR INFORMATION
Corresponding Author
■
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Lett. 2014, 16, 768−771.
*E-mail: valentina.pirovano@unimi.it.
(
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ORCID
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(
Valentina Pirovano: 0000-0003-3113-6579
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ACKNOWLEDGMENTS
■
We thank MIUR-Italy (postdoctoral fellowship to V.P., Ph.D.
fellowships to E.B and G. T.) for financial support. D. Nava and
G. Celentano (University of Milan) are acknowledged for some
NMR, mass, and HPLC analyses. We are grateful to Prof. E.
Rossi, Prof. A. Caselli (University of Milan) and to Prof. R.
Vicente (University of Oviedo) for helpful discussions.
(
P.; Sisti, M.; Caselli, A. Dalton Trans. 2013, 42, 2451−2462.
(d) Castano, B.; Zardi, P.; Honemann, Y. C.; Galarneau, A.; Gallo,
E.; Psaro, R.; Caselli, A.; Dal Santo, V. RSC Adv. 2013, 3, 22199−
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Org. Lett. XXXX, XXX, XXX−XXX