3-Alkenyl-2-silyloxyindoles in vinylogous mannich reactions: Synthesis of aminated indole-based scaffolds and products

Article abstract of DOI:10.1021/ol4036598

The first Lewis acid catalyzed vinylogous Mukaiyama-type Mannich addition of 3-alkenyl-2-silyloxyindoles to in situ generated N-Boc imines has been established, which affords chiral α-alkylidene-δ-amino-2-oxindole products with good efficiency and complet

Full text of DOI:10.1021/ol4036598

Letter
pubs.acs.org/OrgLett
3‑Alkenyl-2-silyloxyindoles in Vinylogous Mannich Reactions:
Synthesis of Aminated Indole-Based Scaffolds and Products
Beatrice Ranieri,†,⊥ Andrea Sartori,*,† Claudio Curti,† Lucia Battistini,† Gloria Rassu,‡ Giorgio Pelosi,§
Giovanni Casiraghi,† and Franca Zanardi*,†
†Dipartimento di Farmacia, Universita
̀
degli Studi di Parma, Parco Area delle Scienze 27A, I-43124 Parma, Italy
‡Istituto di Chimica Biomolecolare del CNR, Traversa La Crucca 3, I-07100 Li Punti Sassari, Italy
§Dipartimento di Chimica, Universita
̀
degli Studi di Parma, Parco Area delle Scienze 17A, I-43124 Parma, Italy
S
* Supporting Information
ABSTRACT: The first Lewis acid catalyzed vinylogous
Mukaiyama-type Mannich addition of 3-alkenyl-2-silyloxyin-
doles to in situ generated N-Boc imines has been established,
which affords chiral α-alkylidene-δ-amino-2-oxindole products
with good efficiency and complete γ-site- and Z-selectivity.
The reaction is wide in scope, as it can be applied with equal
convenience to different silyloxyindole donors and aromatic or
aliphatic aminal-derived aldimine acceptors. The utility of
these scaffolds is demonstrated by their easy transformation
into either spirocyclopropane oxindole or homotryptamine-
like products, featuring nontraditional indole-based skeleton connections.
he construction of small molecules equipped with
T
heteroatom-containing functional groups and a spatially
defined arrangement is an ongoing issue in organic synthesis.
Synthetic chemistry is indeed dedicated in flanking medchem
research looking for new molecular probes which may
interrogate clinically relevant biological targets.1 Accordingly,
efficient and stereoselective synthetic routes to access arrays of
such molecules are highly desirable and amenable to further
functional group adjustment, skeletal manipulation, and
physicochemical refinement. Exploitation of the indole and 2-
oxindole nuclei in synthesis represents a formidable oppor-
tunity to prove this concept, given the overwhelming presence
of these matrices in bioactive natural products and nature-
inspired synthetic drugs.2 (Poly)cyclic indole architectures are
found, for example, in spirotryprostatin B I (Figure 1), a natural
3,3′-pyrrolinyl spirooxindole exhibiting antitumor activity,3 and
sunitinib II, an artificial 3-pyrroloalkylidene oxindole currently
used as a multitargeted receptor tyrosine kinase inhibitor.4 In
most cases, a 2-aminoethyl appendage at the C3 indole core is
found, which is reminiscent of the tryptamine-derived bio-
genesis of the naturally occurring compounds. In recent years,
the faithful reproduction of natural indole products and their
structural modification by synthesis have been the focus of
extensive efforts, resulting in the invention and execution of
new powerful stereocontrolled methods.5 An even more
challenging task would include the construction of rare or
undisclosed skeletal connections, thus further broadening the
horizon of structural diversity.
Figure 1. Biologically relevant natural and unnatural indole-based
compounds.
oxindole IV, an NNRT HIV-1 inhibitor containing an unusual
spirocyclopropane oxindole frame.7
Inspired by these considerations, an indole-related synthon
was recently launched by our group, namely γ-enolizable
alkylidene oxindole A (Scheme 1), whose unprecedented
pronucleophilic character at its exocyclic vinylogous γ-carbon
site was discovered and usefully exploited in asymmetric
vinylogous aldol and Michael-type addition reactions.8 As a
further step, we were wondering whether this inherently
A couple of such examples include communesin B III
(Figure 1), a cytotoxic and insecticidal natural compound
featuring a nonconventional perhydro α-carboline nucleus,6 and
Received: December 19, 2013
Published: January 16, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
and screening of reaction conditions were carried out.
Replacing the Boc group with methoxycarbonyl within oxindole
1 resulted in diminished reaction efficiency (entry 2), while
decreasing the amount of BF3·OEt2 (from 2.0 to 1.0 mol equiv)
turned out to be fruitful, consigning the Mannich product 3a in
a good 70% isolated yield (entry 3). Choosing N-Boc
phenylmethanimine (2Ab) and using the silyloxyindole as the
limiting reagent further improved the reaction efficiency. In this
instance, Z-diastereoselectivity proved excellent, since no E-
configured isomers were detected under NMR analysis of the
crude reaction mixture (entry 4). Lowering the Lewis acid
loading further to 20 mol % led to a slight increase in product
yield, while maintaining optimal Z/E diastereoselectivity (entry
5). The use of alternative Lewis acid catalysts such as TMSOTf
or AgOTf (inter alia) disclosed that the coupling reactions
could be equally viable (entries 6 and 7). Control reactions
carried out in the absence of any Lewis acid or in the presence
of potentially activating protic solvents (iPrOH/H2O)12 gave
no appreciable results, thus emphasizing the crucial role of the
Lewis acid catalyst in triggering the vinylogous Mannich
reaction (not shown). Among the reaction temperatures and
solvents examined,13 it turned out that those initially screened
(−78 °C, CH2Cl2) corresponded to the most suitable
conditions. Noticeably, all the reactions proceeded with
exclusive formation of the vinylogous products 3, with no
detection of adducts arising from attack at the oxindole α-
position.
Although results could be considered satisfying in terms of
both efficiency and selectivity, we still remained concerned
about the operational practicality and reproducibility. The
preparation of N-Ts and N-Boc imines 2A from the
corresponding sulfonamine (and hence aldehyde) precursors
is common practice, but a real limitation was found during the
purification procedure of such substrates, whose contamination
with the respective aldehyde precursors sometimes put at risk
the good performance of the VMMnR itself.14 To overcome
these drawbacks, and following a recent brilliant report by
Maruoka et al.,15 we opted for the use of easily made, bench-
stable, and purified aminals of type 2B, which may generate the
Scheme 1. Application of the Vinylogous Mukaiyama-Type
Mannich Reaction (VMMnR) on γ-Enolizable 3-Alkylidene-
2-oxindoles
bidentate α,γ-pronucleophile could serve with equal ease as a
vinylogous donor component in a Mannich addition reaction to
aldimine acceptors;9,10 it may then be feasible to obtain unusual
α-alkylidene-δ-amino-oxindoles C, heralding possible further
elaboration into diverse indole products.11
Here, it is reported for the first time that the vinyl N,O-
ketene acetal B, derived from oxindole A by γ-enolization/O-
silylation, can undergo smooth Lewis acid catalyzed Mukaiya-
ma−Mannich addition to diverse aldimines in a strictly
vinylogous sense, giving rise to a series of variously substituted
α-alkylidene-δ-amino oxindoles C in good yield and with
excellent diastereoselectivity. We also disclose that the Mannich
base adducts are readily converted to indole-based products
which incorporate nontraditional skeleton connections.
Initially, N-Boc-protected 3-(2-propenyl)-2-trimethylsilylox-
yindole (1a), prepared from the corresponding 3-isopropyli-
dene-2-oxindole precursor (see Supporting Information), and
N-Ts phenylmethanimine (2Aa) were selected as the starting
substrates. Using an excess of BF3·OEt2 as the Lewis acid
promoter in CH2Cl2 at −78 °C, the reaction furnished the
desired Mannich base product 3a in a 58% yield and with a
95:5 Z/E diastereomeric ratio (Table 1, entry 1). Encouraged
by this result, the evaluation of differently protected substrates
a
Table 1. Optimization of the VMMnR of Propenyl Silyloxyindoles 1 with Phenylmethanimines 2A or Aminal 2Ba
b
c
entry
1 (SiR3, PG)
2A (PG′)
2B
LA (mol %)
3 (yield %)
dr (Z/E)
d
1
1a (TMS, Boc)
1b (TMS, Moc)
1a (TMS, Boc)
1a (TMS, Boc)
1a (TMS, Boc)
1a (TMS, Boc)
1a (TMS, Boc)
1a (TMS, Boc)
1a (TMS, Boc)
1c (TBS, Boc)
1c (TBS, Boc)
2Aa (Ts)
2Aa (Ts)
2Aa (Ts)
2Ab (Boc)
2Ab (Boc)
2Ab (Boc)
2Ab (Boc)
−
−
−
−
−
−
−
−
2Ba
2Ba
2Ba
2Ba
BF3·OEt2 (200)
BF3·OEt2 (200)
BF3·OEt2 (100)
BF3·OEt2 (100)
BF3·OEt2 (20)
TMSOTf (20)
AgOTf (20)
3a (58)
3b (45)
3a (70)
3c (73)
3c (75)
3c (76)
3c (79)
3c (73)
3c (78)
3c (78)
3c (23)
95:5
94:6
d
2
d
3
95:5
4
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
5
6
7
8
BF3·OEt2 (20)
TMSOTf (20)
TMSOTf (20)
BF3·OEt2 (20)
9
−
−
−
10
11
a
Unless otherwise noted, reactions were carried out on a 0.2 mmol scale of siloxyindole 1 (1.0 equiv) using 2A or 2B (1.5 equiv) in dry CH2Cl2 (0.1
b
c
1
M) at −78 °C for 20 h. Isolated yield after flash column chromatography. Determined by H NMR spectroscopic analysis of the crude reaction
mixture. The reaction was carried out using 1 (1.5 equiv) and 2A (1.0 equiv).
d
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Organic Letters
Letter
corresponding N-Boc imines in situ upon Lewis acid treatment.
Thus, after a brief adjustment of the reaction procedure and
using aminal 2Ba (entries 8−11), we found that reacting TBS-
protected oxindole 1c with aminal 2Ba in the presence of
trimethylsiloxy triflate (TMSOTf, 20 mol %) in CH2Cl2 at −78
°C easily produced the expected product 3c in a good 78%
yield with complete Z-diastereoselectivity (entry 10).16 To
provide convincing evidence of its scalability, the reaction
between 1c and 2Ba was carried out on a 5× scale (1.0 mmol);
in this instance, the TMSOTf catalyst could be minimized to as
little as a 5 mol % loading, providing product 3c with equal
convenience (78% yield, >98:2 Z/E dr).
5-fluorooxindole 3l in reasonable yields and optimal geo-
metrical selectivity.
The Z-configuration of the carbon−carbon double bond
within products 3 was unequivocally ascertained by analysis of
the 1H−1H NOESY NMR spectra of representative compounds
3c and 3j. In particular, crucial NOE contacts between the
exocyclic methyl group and the indole H-4 proton were
observed, thus defining the olefin Z-geometry. The stereo-
chemistry of the remaining products 3 was assigned by analogy.
The complete Z-selectivity of compounds 3 may be rationalized
by assuming a preferred s-cis conformation of silyloxyindoles 1
in the transition state. As suggested by internal energy
calculations (data not shown), the s-trans conformers, leading
to E-configured isomers, are slightly less stable, probably due to
unfavorable energy-raising allylic strain.
With optimal conditions found, we next explored the general
applicability of the reaction (Scheme 2). A series of aryl-
The synthetic potential of the α-alkenyl-δ-amino-2-oxindole
scaffolds in our hands was demonstrated by transformation into
varied indole products (Scheme 3). Thus, treatment of
Scheme 2. Generality of the VMMnR Varying the
Silyloxyindole and Aminal Substrates
a
Scheme 3. Exploiting the VMMnR Products in Synthesis
compound 3c with trimethylsulfoxonium iodide in NaH
under the Corey−Chaykovsky conditions17 resulted in the
synthesis of compound 4, a rare spirocyclopropane oxindole
structure featuring two contiguous quaternary stereocenters at
the α and β positions.18 Compound 4 was obtained in an
unoptimized 36% yield as a separable 1:1 diastereomeric
mixture; the relative configuration of crystalline syn-4 was firmly
established by single crystal X-ray analysis,19 as portrayed in
Scheme 3 (eq 1). Also, subjecting oxindole 3c to NaBH4 in
methanol afforded the corresponding saturated N,O-acetal (not
shown), which rapidly underwent dehydration upon acidic
conditions to give the homotryptamine analogue 5 (eq 2).
Summarizing, we herein demonstrated for the first time that
the tert-butyldimethylsilyloxydienes derived from γ-enolizable
3-alkylidene-2-oxindoles could nicely serve as extended carbon
nucleophiles in Lewis acid catalyzed vinylogous Mukaiyama-
type Mannich coupling with both aromatic and aliphatic N-Boc
aminals. The reactions performed well in most circumstances,
providing α-alkylidene-δ-amino-2-oxindoles in good yields and
complete γ-site and Z-selectivities. Starting from these func-
tional scaffolds, a couple of indole-based architectures,
including spirocyclopropaneoxindole 4 and homotryptamine
5 could be obtained in 1−2 steps, which embedded
nonconventional molecular frameworks. The results obtained
in the present VMMnR hold promise for application of the
procedure in an enantioselective format; work is presently
ongoing in this direction.
a
Conditions detailed in Table 1 (entry 10) and in the Supporting
Information.
substituted N-Boc aminals 2Ba−2Be reacted smoothly with 1c
under identical conditions, affording the corresponding
Mannich bases 3c−3g in moderate to good yields (47−78%)
and optimal levels of Z-diastereoselectivity demonstrating, in
some cases (e.g., 3e, 3g), a slight impact of the electronic or
steric nature of the aminal aryl substituents on the reaction
performances. The reaction could be applied to aliphatic
aminals derived from octanal and cyclohexanecarboxyaldehyde;
in these instances, the expected Mannich products 3i and 3j
were isolated in good 60% and 71% yields, respectively. Also,
the reaction with the cinnamaldehyde-derived aminal gave
product 3h in a 56% yield, with exclusive γ-1,2-attack.
Interestingly, even in these cases, the reaction maintained
excellent levels of diastereoselection, affording the Z-configured
product exclusively. Subsequently, oxindole substrates 1d and
1e bearing different halogen substituents in the aryl portion
were examined. Again, reaction conditions revealed to be
suitable, providing the corresponding 6-chlorooxindole 3k and
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Organic Letters
Letter
2000, 100, 1929. (b) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57,
3221. (c) Martin, S. F. Acc. Chem. Res. 2002, 35, 895. (d) Casiraghi, G.;
Zanardi, F.; Battistini, L.; Rassu, G. Synlett 2009, 1525. (e) Battistini,
L.; Zanardi, F.; Curti, C.; Casiraghi, G. Chemtracts Org. Chem. 2010,
23, 141. (f) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi,
F. Chem. Rev. 2011, 111, 3076. (g) Zanardi, F.; Rassu, G.; Battistini, L.;
Curti, C.; Sartori, A.; Casiraghi, G. In Targets in Heterocyclic Systems −
Chemistry and Properties; Attanasi, O. A., Spinelli, D., Eds.; Societa
Chimica Italiana: Roma, 2012; Vol. 16, pp 56−89.
(10) For recent reviews on the Mannich (and related) addition
reaction, see: (a) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M.
Chem. Rev. 2011, 111, 2626. (b) Greco, S. J.; Laverda, V.; Bezerra dos
Santos, R. Aldrichimica Acta 2011, 44, 15.
(11) Several brilliant works were reported, dealing with the use of 3-
substituted-2-oxindoles in direct or Mukaiyama-type Mannich addition
reactions involving their nucleophilic or electrophilic C3-position. No
reports were found on the γ-nucleophilic vinylogous counterparts. See,
for example, ref 3b and: (a) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen,
Y.-C. Org. Lett. 2008, 10, 3583. (b) Cheng, L.; Liu, L.; Jia, H.; Wang,
D.; Chen, Y.-J. J. Org. Chem. 2009, 74, 4650. (c) He, R.; Ding, C.;
Maruoka, K. Angew. Chem., Int. Ed. 2009, 48, 4559. (d) Yan, W.;
Wang, D.; Feng, J.; Li, P.; Zhao, D.; Wang, R. Org. Lett. 2012, 14,
2512. (e) Chen, X.; Chen, H.; Ji, X.; Jiang, H.; Yao, Z.-J.; Liu, H. Org.
Lett. 2013, 15, 1846.
ASSOCIATED CONTENT
* Supporting Information
Data for new compounds, experimental procedures, X-ray
analysis of syn-4, and copies of NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
̀
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: andrea.sartori@unipr.it.
*E-mail: franca.zanardi@unipr.it.
Present Address
⊥Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS
(UMR 7084), 10 rue Vauquelin, 75231 Paris Cedex 05
(France).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Thanks are due to Centro Interdipartimentale Misure “G.
■
Casnati” (Universita
instrumental facilities. Dr. Elisabetta Portioli (Universita
̀
degli Studi di Parma, Italy) for
degli
(12) For an example of uncatalyzed vinylogous Mannich addition in
aqueous or neat conditions, see: Sartori, A.; Dell’Amico, L.; Curti, C.;
Battistini, L.; Pelosi, G.; Rassu, G.; Casiraghi, G.; Zanardi, F. Adv.
Synth. Catal. 2011, 353, 3278.
̀
Studi di Parma) is gratefully acknowledged for preliminary
experiments.
(13) The following solvents and reaction temperature were screened:
THF, toluene; −50 °C, 0 °C, 23 °C (data not shown).
REFERENCES
■
(14) The copresence of imine and aldehyde precursors during the
VMMnR coupling resulted in the formation of competitive undesired
aldol products.
(1) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Kim, Y.-K.; Arai,
M. A.; Lamenzo, J. O.; Dean, E. F., III; Patterson, N.; Clemons, P. A.;
Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 14740. (c) Schreiber, S. L.
Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6699.
(2) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press:
New York, 1970. (b) Dewick, P. M. Medicinal Natural Products. A
Biosynthetic Approach; John Wiley & Sons: Chichester, U.K., 2009; pp
346−359.
(3) (a) Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832.
(b) Von Nussbaum, F.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2000,
39, 2175. (c) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000,
122, 5666. (d) Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127,
11505.
(4) Mendel, D. B.; Laird, A. D.; Xin, X.; Louie, S. G.; Christensen, J.
G.; Li, G.; Schreck, R. E.; Abrams, T. J.; Ngai, T. J.; Lee, L. B.; Murray,
L. J.; Carver, J.; Chan, E.; Moss, K. G.; Haznedar, J. O.; Sukbuntherng,
J.; Blake, R. A.; Sun, L.; Tang, C.; Miller, T.; Shirazian, S.; McMahon,
G.; Cherrington, J. M. Clin. Cancer Res. 2003, 9, 327.
(15) Kano, T.; Yurino, T.; Asakawa, D.; Maruoka, K. Angew. Chem.,
Int. Ed. 2013, 52, 5532.
(16) Contrary to TMS-oxindole 1a, which is highly unstable and
water sensitive, TBS-oxindole 1c is stable in air and is purified by silica
gel flash chromatography.
(17) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867.
(18) Spirocyclopropane 2-oxindoles constitute an uncommon class of
spirocyclic oxindoles, whose access by synthesis and application in
medicine is rapidly emerging. For synthetic approaches and/or
biological evaluation, see, for example, ref 7 and: (a) Pesciaioli, F.;
Righi, P.; Mazzanti, A.; Bartoli, G.; Bencivenni, G. Chem.Eur. J.
2011, 17, 2842. (b) Dou, X.; Lu, Y. Chem.Eur. J. 2012, 18, 8315 and
references therein. (c) Dou, X.; Yao, W.; Zhou, B.; Lu, Y. Chem.
Commun. 2013, 49, 9224.
(19) CCDC 977131 (racemic syn-4) contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/ data_request/cif.
(5) Selected reviews: (a) Bandini, M.; Eichholzer, A. Angew. Chem.,
Int. Ed. 2009, 48, 9608. (b) Trost, B. M.; Brennan, M. K. Synthesis
2009, 3003. (c) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010,
352, 1381. (d) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K. Org. Biomol.
Chem. 2012, 10, 5165. (e) Hong, L.; Wang, R. Adv. Synth. Catal. 2013,
355, 1023.
(6) (a) Siengalewicz, P.; Gaich, T.; Mulzer, J. Angew. Chem., Int. Ed.
2008, 47, 8170. (b) Schammel, W. A.; Chiou, G.; Garg, K. N. Org. Lett.
2012, 14, 4556.
(7) Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.;
Bursulaya, B.; Wu, T. Y.-H.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16,
2105.
(8) (a) Rassu, G.; Zambrano, V.; Tanca, R.; Sartori, A.; Battistini, L.;
Zanardi, F.; Curti, C.; Casiraghi, G. Eur. J. Org. Chem. 2012, 466.
(b) Curti, C.; Rassu, G.; Zambrano, V.; Pinna, L.; Pelosi, G.; Sartori,
A.; Battistini, L.; Zanardi, F.; Casiraghi, G. Angew. Chem., Int. Ed. 2012,
51, 6200. (c) Rassu, G.; Zambrano, V.; Pinna, L.; Curti, C.; Battistini,
L.; Sartori, A.; Pelosi, G.; Zanardi, F.; Casiraghi, G. Adv. Synth. Catal.
2013, 355, 1881.
(9) For reviews on the vinylogous Mannich reaction, see:
(a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev.
935
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