Cyclative Cascades of Allenamides Derived from Amino Acids: Synthesis of Annulated Indoxyl Derivatives

Article abstract of DOI:10.1002/ejoc.201600067

Allenamides derived from amino acids participate in the cascade transformations catalyzed by Pd⁰ allowing consecutive formation of two five-membered rings. The developed methodology provides an access to annulated indoles which can be transform

Full text of DOI:10.1002/ejoc.201600067

DOI: 10.1002/ejoc.201600067
Communication
Palladium-Catalyzed Cyclization
Cyclative Cascades of Allenamides Derived from Amino Acids:
Synthesis of Annulated Indoxyl Derivatives
Milos Petkovic,*[a] Veselin Nasufovic,[a] Dimitrije Djukanovic,[a] Zorana Tokic Vujosevic,[a]
Milka Jadranin,[b] Radomir Matovic,[b] and Vladimir Savic*[a]
Abstract: Allenamides derived from amino acids participate in methodology provides an access to annulated indoles which
the cascade transformations catalyzed by Pd0 allowing consecu- can be transformed to functionalized indoxyl derivatives, retain-
tive formation of two five-membered rings. The developed ing a structural motif embedded in several natural products.
Introduction
ucts. This tactical variation in transforming allenamides by com-
bining two intramolecular steps has been previously reported
but never explored in a consecutive formation of two con-
densed five-membered rings.[23,38] An additional problem
would arise from the potential isomerization of the double
bond to form indole, which would prevent the installation of
the oxygen functionality to form 2b in a straightforward man-
ner. Encouragingly, some recent results demonstrated the use-
fulness of compounds related to 2a in the synthesis of several
indole-derived natural products.[39]
Allenamides are versatile synthetic blocks, which have been
extensively studied in recent years.[1–11] They undergo numer-
ous transformations providing access to diverse structural mo-
tifs.[12–15] Amongst the reactions of allenamides, particularly in-
teresting are cascade processes promoted by transition met-
als.[3,16–21] They allow the creation of several bonds in a single
operation permitting access to complex molecules from
relatively simple starting materials. The utilization of Pd0 cataly-
sis for these purposes is arguably on the forefront in this
area.[21–31] Strategically, numerous cascades of allenamides
have been developed, usually initiated with the formation of
a π-allylpalladium intermediate followed by anion capture, ꢀ-
hydride elimination/cycloaddition, transmetallation/nucleo-
philic addition or coupling with organometallic reagents. Re-
cently, PdII-promoted cyclizations of allenamides onto the al-
kene have also been reported.[32]
The fact that the simple allenamides may afford complex
structures often in a one-pot process prompted us to study
their application in the synthesis of a 1,2-annulated indoxyl
skeleton, which is a structural arrangement present in many
natural products (Figure 1).[33–37] More precisely, we intended to
explore the transformation outlined in Scheme 1, which would
involve the formation of a five-membered ring by initial Pd0-
catalyzed cyclization followed by a second cyclization through
nucleophilic displacement to form an additional five-membered
ring. The process would also create an exocyclic double bond,
which could be further transformed into a keto functionality
leading to an indoxyl skeleton present in many natural prod-
Figure 1. Examples of natural products.
[a] Department of Organic Chemistry, Faculty of Pharmacy,
University of Belgrade,
Vojvode Stepe 450, 11221 Belgrade, Serbia
E-mail: milosp@pharmacy.bg.ac.rs
vladimir.savic@pharmacy.bg.ac.rs
http://www.pharmacy.bg.ac.rs/en/
[b] Department of Chemistry, ICTM, University of Belgrade,
Studentski trg 12–16, 11000 Belgrade, Serbia
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600067.
Scheme 1. Proposed cyclization of allenamides.
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Results and Discussion
The cyclization step was performed under typical conditions
employing Pd(OAc)2/PPh3 as catalytic system and K2CO3 as a
base in DMF as a solvent to afford product 7, albeit in only
23 %. Therefore, a series of experiments were carried out in
order to improve the yield and to optimize the reaction condi-
tions. They were performed with allene 6 and are listed in
Table 1. Amongst the solvent used (Entries c–f, Table 1), MeCN
was superior, although the yield was still relatively low (38 %;
Entry d, Table 1). Replacing Pd(OAc)2 with Pd(PPh3)2Cl2 (Entry g,
Table 1) did not significantly influence the reaction. A brief
study of bases showed that Et3N (Entry h, Table 1) and Cs2CO3
(Entry j, Table 1) were more effective than the initially used
K2CO3, with Et3N performing marginally better.
Further study of the cyclization step (presented in Table 2)
was mainly focused on the variation of the N-substituent, with
a few examples possessing a substituted benzene ring. All cycli-
zation substrates were prepared according to the methodology
described in Scheme 2. Substrates 8a and 8b with larger sub-
stituents on the nitrogen atom involved in the bond-forming
cyclization step, such as adamantyl or neopentyl motifs (En-
tries a and b, Table 2), furnished the expected products 9a and
9b in 49 % and 56 % yields, respectively. N-Substituents, which
potentially may interfere with the Pd-promoted reactions, such
as allyl and propargyl (compounds 8c, 8d, and 8g; Entries c, d,
and g, Table 2), were tolerated, although in some cases the
yields were slightly lower.
The initial allene substrate 6 used in this study was prepared
starting from iodoaniline as outlined in Scheme 2. Several
standard transformations afforded propargyl derivative 5 in
good overall yield. The propargyl/allenyl isomerization leading
to allene 6 proved to be somewhat challenging. The early isom-
erization reactions were performed in THF with various quanti-
ties of tBuOK (0.2–5 equiv.).[40,41] Although the product was
formed in most cases, the yields were low, and often the con-
version was incomplete. A further problem was caused by side
products, which were the result of a cyclization reaction due to
the presence of the nucleophilic secondary amine functional-
ity.[42] Contrary to the utilization of THF, the use of tBuOH as a
solvent produced better results. After some experiments under
different conditions, we were able to synthesize allene 6 in an
acceptable yield of 62 %.
Since naturally occurring compounds containing indoxyl-de-
rived skeletons (Figure 1) possess an additional substituent at-
tached to the imidazolidinone ring, we next attempted to incor-
porate this structural feature in the products accessible by the
disclosed methodology. For this purpose amino acids were
used, and the substituted amide side chain was introduced into
the cyclization precursor in several steps as outlined in
Scheme 3.
The three-step procedure starting from protected (S)-amino
acid derivative 10 afforded N-propargyl products 11 in good
overall yields in all cases. The following isomerization was car-
ried out in THF in the presence of tBuOK to afford allene deriva-
tives 12. The final cyclization step was performed under condi-
tions described above (Table 3). N-Unprotected amino acid de-
rivatives 12a–c smoothly formed the condensed structures 13
in acceptable yields as a mixture of cis/trans isomers.
Scheme 2. Synthesis and cyclization of allene 6.
Table 1. Optimization of the reaction conditions for the cyclization step 6 → 7.[a]
Entry
Pd source
Ligand
Base
Conditions
Time [h]
Yield of 7 [%][b]
a
b
c
d
e
f
g
h
i
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
–
PPh3
BINAP
PPh3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
DMF/95 °C
DMF/room temp.
DMF/95 °C
MeCN/81 °C
THF/67 °C
dioxane/90 °C
MeCN/81 °C
MeCN/81 °C
MeCN/81 °C
MeCN/81 °C
2.5
12
12
2.5
12
12
12
12
3
23
27
23
38
31
23
35
50
29
48
Et3N
Cs2CO3
j
12
[a] Reaction conditions: 6 (0.1 mmol), Pd source (0.01 mmol), ligand (0.02 mmol), base (0.4 mmol), solvent (5 mL). [b] Isolated yields after column chromatogra-
phy.
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Table 2. Study of the cyclization reaction.[a]
Scheme 3. Synthesis of the amino acid derived allenamides.
Table 3. Cyclization reactions of amino acid derived allenes.[a]
Entry
12
13
cis/trans
Yield [%][b]
a
b
c
12a
12b
12c
13a, R = C6H5CH2
13b, R = (CH3)2CHCH2
13c, CH3
4.2:1[c]
2.1:1[d]
2.6:1[d]
47
63
44
[a] Reaction conditions: 12 (0.5 mmol), Pd(OAc)2 (0.05 mmol), PPh3
(0.1 mmol), Et3N (2.0 mmol), MeCN (10 mL). [b] Isolated yields after column
chromatography. [c] Separated by column chromatography. [d] Determined
by 1H NMR spectroscopy.
[a] Reaction conditions:
8 (0.1 mmol), Pd(OAc)2 (0.01 mmol), PPh3
(0.02 mmol), Et3N (0.4 mmol), MeCN (5 mL). [b] Isolated yields after column
chromatography.
In all cases the major component was the cis product, with
stereochemical arrangement related to those of naturally occur-
ring substances (Figure 1).
Finally, oxidative transformation of the exocyclic double
bond was studied in order to introduce the keto functionality
and to create the indoxyl skeleton. Initial ozonolysis was per-
formed on the sulfonamides 14 derived from cis-13 (Scheme 4)
to afford indoxyls 15. Although unstable on silica, these prod-
Scheme 4. Synthesis of indoxyl derivatives.
Conclusions
ucts were isolated in good yields after standard workup (see Our exploration of the cyclization processes of allenamides
the Supporting Information).
added a novel tactical variant to the synthetic repertoire cen-
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Received: January 18, 2016
Published Online: February 19, 2016
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