Palladium(0)-Catalyzed Dearomative [3 + 2] Cycloaddition of 3-Nitroindoles with Vinylcyclopropanes: An Entry to Stereodefined 2,3-Fused Cyclopentannulated Indoline Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b00784

The palladium(0)-catalyzed diastereoselective dearomative cyclopentannulation of 3-nitroindoles with vinylcyclopropanes is described. This straightforward and highly atom-economical method leads to a wide range of functionalized indolines in good yields a

Full text of DOI:10.1021/acs.orglett.7b00784

Letter
pubs.acs.org/OrgLett
Palladium(0)-Catalyzed Dearomative [3 + 2] Cycloaddition of
3‑Nitroindoles with Vinylcyclopropanes: An Entry to Stereodefined
2,3-Fused Cyclopentannulated Indoline Derivatives
Maxime Laugeois, Johanne Ling, Charlene Ferard, Veronique Michelet, Virginie Ratovelomanana-Vidal,
̀
́
́
and Maxime R. Vitale*
PSL Research University, Chimie ParisTech, CNRS, Institut de Recherche de Chimie Paris, Paris 75005, France
S
* Supporting Information
ABSTRACT: The palladium(0)-catalyzed diastereoselective dear-
omative cyclopentannulation of 3-nitroindoles with vinylcyclopro-
panes is described. This straightforward and highly atom-
economical method leads to a wide range of functionalized
indolines in good yields and diastereoselectivities and represents
an unprecedented entry toward the valuable 2,3-fused cyclo-
pentannulated indoline scaffold.
he indoline motif is prevalent in nature and can be found
evidenced once by Trost et al. in a study dedicated to the
Tin a wide variety of synthetic or natural products palladium(0)-catalyzed cycloaddition of trimethylenemethane
with nitroarenes [Scheme 1, eq (a)].9 Therefore, we questioned
encompassing a broad range of biological activities.1 In this
family, a great deal of interest has long been devoted to the 2,3-
fused pyrrolo derivatives (pyrroloindolines), for which
abundant synthetic methods have been developed.2 In sharp
contrast, despite also being important structural cores of
various natural products (Figure 1),3 the construction of 2,3-
fused cyclopentannulated analogues has been comparatively
less investigated.4−6
Scheme 1. Dearomative Cyclopentannulation of 3-
Nitroindoles
Figure 1. Relevant natural products containing a 2,3-fused cyclo-
pentannulated indoline core.
Following Kerr’s seminal studies,4 the main strategy allowing
the access to such skeletons has so far capitalized on the
nucleophilic character of indole substrates in 1,3-dipolar
cycloaddition reactions.5 However, this synthetic manifold is
still inadequate for the use of electron-deficient indole partners,
for which novel approaches remain highly desirable.
Recently, 3-nitroindoles, a particular class of electron-poor
indole derivatives, have demonstrated their interesting synthetic
potential in a variety of dearomative [3 + 2] heteroannulation
processes.7,8 Although successfully coupled with heteroatom-
based dipolar intermediates including azomethine ylides and
azomethine imines,7 their use in cycloaddition reactions
employing all-carbon 1,3-dipoles remains scarce. Actually, to
the best of our knowledge, this reactivity profile has only been
whether vinylcyclopropanes (VCPs), which we and others have
previously exploited as sources of all-carbon 1,3-dipoles,10
could promote the dearomatization of 3-nitroindole acceptors
[Scheme 1, eq (b)]. We wish to report herein that this original
dearomative [3 + 2] cycloaddition strategy gives access to a
wide variety of valuable 2,3-fused cyclopentannulated indolines
in a diastereoselective manner.
At the onset of our study, the validity of our approach was
evaluated by submitting N-benzoyl-3-nitroindole 1a and
dicyano vinylcyclopropane 2 to catalytic quantities of
Pd2(dba)3·CHCl3 in various reaction conditions (Table 1).
Received: March 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00784
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Organic Letters
Letter
a
a
Table 1. Optimization Studies
Scheme 2. Influence of the Indole N-Substitution Pattern
b
c
entry
ligand (%)
solvent
dr
yield (%)
1
2
3
4
5
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (5)
THF
6:1
52
46
82
95
99
toluene
DMF
11:1
11:1
10:1
9:1
EtOAc
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
d
e
6
10:1
95 (95)
d
7
f
d
8
d
L2 (10)
L3 (10)
L4 (5)
L5 (5)
2:1
86
85
39
f
9
5:1
d
10
13:1
d
11
a
Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), Pd2(dba)3·CHCl3
(5 mol %), ligand (x mol %) in 1 mL of solvent (0.2 M) at room
b
temperature for 45 min. Diastereoisomeric ratio was determined by
c
1H NMR analysis of the crude material. 1H NMR yields determined
d
using ethylene carbonate as internal standard. Reaction run with 2.5
mol % Pd2(dba)3·CHCl3. Isolated yield. No reaction.
e
f
a
Reaction conditions: 1a−i (0.2 mmol), 2 (0.2 mmol), Pd2(dba)3·
CHCl3 (2.5 mol %), dppe (5 mol %) in 1 mL of MeCN (0.2 M) at
room temperature. Diastereoisomeric ratios were determined by H
1
When the reaction was initially realized in THF in the
presence of 10 mol % dppe (L1) at room temperature, the
desired cycloaddition took place and the diastereoisomeric 2,3-
fused cyclopentannulated indolines 3a/3a′ (6:1 dr) were
obtained in encouraging 52% yield (Table 1, entry 1).11
Switching to toluene improved the diastereoselectivity of the
cycloaddition process, although at the expense of the reaction
yield (Table 1, entry 2). After a wider solvent screening,12
dimethylformamide, ethyl acetate, and acetonitrile showed their
superiority (Table 1, entries 3−5) with the best compromise
between yield and diastereoselectivity being obtained with the
latter (Table 1, entry 5). Interestingly, without substantial
detrimental effect, the catalyst loading could be reduced to 2.5
mol % of Pd2(dba)3·CHCl3 and 5 mol % of L1 (Table 1, entry
6). Although this reaction did not proceed in the absence of
dppe (Table 1, entry 7), other mono- or bidentate ligands L2−
L5 led to a drop in either diastereoselectivity or yield (Table 1,
entry 8−11).
With these optimized reaction conditions in hand, we then
investigated the influence of the indole N-substitution pattern
on the efficiency of this diastereoselective [3 + 2] cycloaddition
reaction (Scheme 2). Increasing the steric bulk on the benzoyl
aromatic ring did not severely impact the reaction such that the
2,3-fused cyclopentannulated indoline 3b could be obtained in
89% yield and 10:1 dr. When employing substrates 1c−1e
possessing acetyl, ethoxycarbonyl, and tert-butyloxycarbonyl
groups, the cycloaddition was equally operative, although a
diminution of the diastereoselectivity was typically observed. In
the same vein, a lower diastereocontrol was observed with both
the N-tosyl- and N-(2-nosyl)- substrates 1f and 1g. Never-
theless, switching to more sterically demanding 2,4,6-
trisubstituted arylsulfonyl moieties allowed a return to
satisfactory levels of stereocontrol (dr > 10:1) while retaining
NMR analysis of the crude material.
good reaction efficiency (3h and 3i). However, N-benzyl and
N-methyl 3-nitroindoles 1j and 1k did not undergo the desired
cycloaddition process, the polymerization of the starting VCP 2
being predominant in each of these cases.13,14
Next, a wider variety of N-benzoyl 3-nitroindoles was
prepared and evaluated (Scheme 3). Apart from 4g, which
proved to be inert in our reaction conditions,14 this palladium-
catalyzed cycloaddition operated efficiently with a nice range of
5-substituted substrates. Accordingly, the 5-methyl cyclo-
pentannulated indoline 5a was obtained in 84% yield and
13:1 dr and the 5-F, 5-Cl, 5-Br, and 5-I nitroindoles 4b−e
straightforwardly afforded the desired cycloadducts 5b−e.
Interestingly, in the latter case, the potential competitive
oxidative addition of the carbon−iodine bond to the
palladium(0) complex did not hamper the reaction, showing
that the [3 + 2] cycloaddition pathway is kinetically preferred.
On its side, the 5-CN indoline 5f was obtained in 65% yield and
lower 5:1 dr. Gratifyingly, this palladium-catalyzed reaction was
also amenable to the use of 6- and 7-functionalized 3-
nitroindoles without noticeable setbacks (5h−l), but the steric
hindrance in position 4 typically induced a slower cycloaddition
process encouraging the competitive polymerization of the
starting VCP. Nonetheless, performing the reaction in DMF
with 2.0 equiv of 2 allowed access to the cyclopentannulation
products 5m and 5n with good yields and remarkable
diastereocontrols (>50:1 dr).
Probing the scope of this [3 + 2] cycloaddition reaction
further, we demonstrated that other VCPs such as diesters 6
and 7 could be employed, although in these cases poorer
diastereoselectivities were observed [Scheme 4, eq (a)].
B
DOI: 10.1021/acs.orglett.7b00784
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Organic Letters
Letter
a
Scheme 3. Scope of Variously Functionalized 3-
Nitroindoles
Scheme 5. Scale-up Experiments and Post-
Functionalization Reactions
a
b
a
Experiments run on a 3 mmol scale (1a, in MeCN) or 2 mmol scale
b
(5e, in DMF). Reaction conditions: (a) 5e (1.0 equiv), PhB(OH)2
(1.5 equiv), Pd(PPh3)4 (5 mol %), NaHCO3 (2.2 equiv), toluene/
water (20/1), reflux, 16 h; (b) 5e (1.0 equiv), phenylacetylene (2.0
equiv), PdCl2(PPh3)2 (1 mol %), CuI (2 mol %), THF/Et3N (1/1), rt,
2 h.
From a mechanistic point of view (Scheme 6), we propose
that, upon oxidative addition of the starting VCP to the
a
Reaction conditions: 4a−n (0.2 mmol), 2 (0.2 mmol), Pd2(dba)3·
CHCl3 (2.5 mol %), dppe (5 mol %) in 1 mL of MeCN at room
temperature (isolated yields; diastereoisomeric ratios were determined
by H NMR of the crude material). DMF instead of MeCN. 1.5
Scheme 6. Mechanistic Proposal
b
c
1
d
equiv of 2. 2.0 equiv of 2.
a
Scheme 4. Evaluation of other VCPs and 2-Nitroindole
palladium(0) complex, the zwitterionic 1,3-dipole A would
initially be engaged in a Michael addition process with the
electrophilic 3-nitroindole partner. The irreversible intra-
molecular attack of the nitronate anion onto the π-allyl
palladium(II) moiety would then follow according to chairlike
transition states B or C.16,17 Although both would compete, B
would be favored because it allows the minimization of 1,3-
diaxial interactions with the pseudoequatorial π-allylpalladium
residue. Thus, diastereromer 3a would preferentially be formed.
However, transition state C, which notably entails steric
interactions between the pseudoaxial π-allylpalladium moiety
and the indole core, would lead to 3a′, a competitive cyclization
pathway, which could be suppressed when using more sterically
demanding 3-nitroindoles possessing a substituent in position
4.
In conclusion, we have developed a palladium-catalyzed
dearomative [3 + 2] cycloaddition of 3-nitroindoles and
vinylcyclopropanes. This efficient and atom-economical
method generates highly substituted 2,3-fused cyclopentannu-
lated indoline derivatives in a diastereoselective fashion. The
study of other 2-nitroindole derivatives, the use of a larger
range of alkenyl cyclopropanes, and the development of an
enantioselective version of this reaction are currently underway
and will be reported in due course.
a
Reaction conditions: 1a or 10 (0.2 mmol), 2, 6, or 7 (0.2 mmol),
Pd2(dba)3·CHCl3 (2.5 mol %), dppe (5 mol %) in 1 mL of MeCN at
room temperature (isolated yields; diastereoisomeric ratios were
determined by H NMR of the crude material). DMF instead of
MeCN.
b
1
Interestingly, when using the N-benzoyl-2-nitroindole 10, the
preparation of the isomeric cyclopentannulated indoline 11 was
also achievable, in quantitative yield and with perfect
diastereocontrol [Scheme 4, eq (b)].15
The usefulness of this method could be also established by
performing scale-up experiments and post-functionalization
reactions (Scheme 5). When starting from 1a (3.0 mmol), the
gram-scale preparation of 3a could be performed without major
impact on either reaction yield or diastereoselectivity.
Alternatively, starting from 4e (2.0 mmol) and after careful
column chromatography, the 5-iodo cycloadduct 5e was
isolated in diastereomerically pure form in 54% yield.
Interestingly, we could demonstrate that 5e may serve as a
valuable platform for the preparation of other 5-substituted
cyclopentannulated indolines through palladium-catalyzed
cross-coupling reactions. Indeed, the corresponding Suzuki−
Miyaura and Sonogashira cross-coupling products 12 and 13
were obtained in 92% yields.
C
DOI: 10.1021/acs.orglett.7b00784
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
6900−6903. (f) Li, H.; Hughes, R. P.; Wu, J. J. Am. Chem. Soc. 2014,
136, 6288−6296.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00784.
■
S
(6) (a) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314−
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R. Green Chem. 2017, 19, 82−87.
Experimental procedures, analytical data, and NMR
spectra for all compounds (PDF)
X-ray data for compound 3a (CIF)
X-ray data for compound 11 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: maxime.vitale@chimie-paristech.fr
ORCID
(8) For [4 + 2] processes, see: (a) Victoria Gom
Moreno, A.; Cossío, F. P.; de Coz
́
ez, M.; Aranda, A. I.;
ar, A.; Díaz-Ortiz, A.; de la Hoz, A.;
́
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Prieto, P. Tetrahedron 2009, 65, 5328−5336. (b) Andreini, M.; De
Paolis, M.; Chataigner, I. Catal. Commun. 2015, 63, 15−20. (c) Li, Y.;
Tur, F.; Nielsen, R. P.; Jiang, H.; Jensen, F.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2016, 55, 1020−1024.
Maxime R. Vitale: 0000-0002-6740-2472
Notes
(9) Trost, B. M.; Ehmke, V.; Michael O’Keefe, B.; Bringley, D. A. J.
Am. Chem. Soc. 2014, 136, 8213−8216.
The authors declare no competing financial interest.
(10) For recent reviews, see: (a) Meazza, M.; Guo, H.; Rios, R. Org.
Biomol. Chem. 2017, 15, 2479−2490. (b) Ganesh, V.; Chandrasekaran,
S. Synthesis 2016, 48, 4347−4380. For selected examples, see:
(c) Shimizu, I.; Ohashi, Y.; Tsuji, J. Tetrahedron Lett. 1985, 26, 3825−
3828. (d) Goldberg, A. F. G.; Stoltz, B. M. Org. Lett. 2011, 13, 4474−
4476. (e) Trost, B. M.; Morris, P. J. Angew. Chem., Int. Ed. 2011, 50,
6167−6170. (f) Trost, B. M.; Morris, P. J.; Sprague, S. J. J. Am. Chem.
Soc. 2012, 134, 17823−17831. (g) Wei, F.; Ren, C.-L.; Wang, D.; Liu,
L. Chem. - Eur. J. 2015, 21, 2335−2338. (h) Yuan, Z.; Wei, W.; Lin, A.;
Yao, H. Org. Lett. 2016, 18, 3370−3373. (i) Laugeois, M.; Ponra, S.;
Ratovelomanana-Vidal, V.; Michelet, V.; Vitale, M. R. Chem. Commun.
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ACKNOWLEDGMENTS
This work was supported by the Minister
Nationale, de l’Enseignement Super
the Centre National de la Recherche Scientifique. The authors
■
̀
e de l’Education
ieur et de la Recherche, and
́
warmly thank L.-M. Chamoreau and G. Gontard (IPCM,
Universite
́
Pierre et Marie Curie, Paris) for X-ray analyses.
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DOI: 10.1021/acs.orglett.7b00784
Org. Lett. XXXX, XXX, XXX−XXX