PhI(OCOCF3)2-Mediated Construction of a 2-Spiropseudoindoxyl Skeleton via Cascade Annulation of 2-Sulfonamido-N-phenylpropiolamide Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b00058

A cascade annulation of 2-sulfonamido-N-phenylpropiolamide derivatives leading to the construction of the 2-spiropseudoindoxyl skeleton was realized under mild conditions with phenyliodine(III) bis(trifluoroacetate) (PIFA) as the sole oxidant. This metal-

Full text of DOI:10.1021/acs.orglett.7b00058

Letter
pubs.acs.org/OrgLett
PhI(OCOCF3)2‑Mediated Construction of a 2‑Spiropseudoindoxyl
Skeleton via Cascade Annulation of
2‑Sulfonamido‑N‑phenylpropiolamide Derivatives
Bobo Zhang,† Xiang Zhang,† Bei Hu,† Desong Sun,† Senlin Wang,† Daisy Zhang-Negrerie,†
and Yunfei Du*,†,‡
†Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, P. R. China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. China
S
* Supporting Information
ABSTRACT: A cascade annulation of 2-sulfonamido-N-phenyl-
propiolamide derivatives leading to the construction of the 2-
spiropseudoindoxyl skeleton was realized under mild conditions
with phenyliodine(III) bis(trifluoroacetate) (PIFA) as the sole
oxidant. This metal-free spirocyclization process is suggested to
encompass a sequential C(sp2)−C(sp) and C(sp2)−N bond
formation with the concomitant introduction of a carbonyl oxygen.
ver the past decades, cascade reactions,1 during which
carbon−hydrogen bond in the acyclic precursor substrates in the
Oseveral bonds are formed in one single process, have presence of a combination of iodobenzene diacetate (PIDA) and
tetrabutylammonium iodide;10 (iii) spiro products converted
received much attention. In contrast to classical multistep
from diarylacetylene through hypervalent iodine-mediated
cascade annulations upon treatment with a combination of
PIDA and BF3·Et2;11 and (iv) selective annulation at the C2
position in a 3-phenoxyalkynylindole substrate bearing an
electron-withdrawing group.12 Other reported methods include
using phenylpropiolamides and diarylacetylenes as the starting
substrates. As illustrated in Scheme 1, regioselective Au(III)-
catalyzed cycloisomerization of o-nitrophenylpropiolamides,
followed by an intramolecular dipolar cycloaddition, could result
in the formation of new tetracyclic pseudoindoxyls, which were
further hydrogenated to form the 2-spiropseudoindoxyls
(Scheme 1, a).13 The treatment of propargylamine derivatives
with the gold complex gave the requisite isoxazolidine derivatives
via a cycloisomerization−cycloaddition cascade reaction
(Scheme 1, b).14 In our previous work,15 we discovered a
hypervalent iodine-mediated cascade annulation reaction in
realizing the construction of a series of 2-spiropseudoindoxyl
compounds via two successive oxidative C−N bond formations
(Scheme 1, c). Although these methods succeeded in affording
the corresponding 2-spiropseudoindoxyl compounds, develop-
ment of new methods for the synthesis of additional
spiropseudoindoxyl derivatives that may contain novel function-
ality and/or substituent(s) is still in demand.
sequences, in most cascade reactions, it is not possible to isolate
intermediates or change the reaction conditions. For this reason,
this type of reactionis highly efficient. Furthermore, such
reactions are often highly regio- or/and stereoselective. After
much research effort, cascade annulation has become a useful
synthetic strategy for constructing spiro polycyclic rings.2
However, most ring-constructing reactions so far established
involve transition-metal reagents such as organopalladium.3
There is still a demand for methodology research in formulating
novel cascade annulation reactions that are adapted for metal-
free conditions.4
The spiropseudoindoxyl skeleton, one of the key heterocyclic
structures, is abundant in many indole alkaloids.5 It has been
found that many potent antiviral agents that exhibit promising
anticancer properties6 or potent opioid agonistic activities in
guinea pig ileum and in mouse vas deferens7 are alkaloids bearing
a spiropseudoindoxyl core. The biological significance and the
complexity of the structure of the core have aroused great interest
among both synthetic and medicinal chemists for developing
feasible and efficient synthetic routes for the assembly of this
class of compounds.
A literature survey showed that a handful of synthetic methods
have been reported for the construction of 2-spiropseudoindox-
yls thus far.8−11 The majority of the existing methods rely on the
oxidative rearrangement of the corresponding indole deriva-
tives.8 Examples include (i) coupling of N-(p-toluenesulfonyl)-2-
aminobenzaldehyde derivatives with N-substituted maleimides
using (RhCp*Cl2)2 as a catalyst through oxidative functionaliza-
tion of the formyl C−H bond;9 (ii) tandem oxidation of a
During the past decade, hypervalent iodine reagents,16 a class
of efficient and easy-to-handle, nonmetallic oxidants with low
toxicity, have been extensively employed in organic synthesis.
Received: January 7, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00058
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Letter
a
Scheme 1. Synthetic Strategies for the Construction of the 2-
Spiropseudoindoxyl Skeleton
Table 1. Optimization of Reaction Conditions
b
entry
oxidant
solvent
temp (°C)
time (h)
yield (%)
c
1
2
3
PIDA
PIDA
PIDA
PIDA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PhIO
DCM
DMF
THF
DCE
DCE
THF
DMF
MeCN
Ac2O
DCE
DCE
DCE
DCE
DCE
DCE
rt to 80
24
24
24
4
NR
c
rt to 120
NR
c
rt to 65
NR
e
4
rt
41
60
5
6
7
8
9
rt
2
c
rt to 65
24
24
7
NR
c
rt to120
NR
rt
rt
53
48
50
76
65
39
34
NR
3
e
10
rt
2
11
0
5
e
12
0
5
13
−20
−20
rt
20
20
24
e
14
Although hypervalent iodine reagents have been widely utilized
in the synthesis of various heterocyclic compounds,17,18
application of hypervalent iodine reagents in the formation of
spiroheterocycles through cascade annulation reactions is less
well established. Inspired by the results from our previous work
(Scheme 1, c), we set out to investigate the possibility of forming
a novel class of 2-spiropseudoindoxyls 2 through an oxidative
cascade annulation reaction of the corresponding 2-amino-
benzyne derivatives 1 (Scheme 1, d).
15
a
Reaction conditions: all reactions were carried out with 1a (0.5
mmol) and oxidant (1.1 mmol) in dried solvent (25 mL) unless
b
c
e
otherwise stated. Isolated yield. NR = no reaction. BF3·Et2O (0.1
equiv) was added.
(R3) for example, we found that not only the tosyl group
(Scheme 2, 2a) but also methanesulfonyl (Scheme 2, 2b),
phenylsulfonyl (Scheme 2, 2c), and p-chlorophenylsulfonyl
substituents (Scheme 2, 2d) could be well tolerated. Moreover,
the method could also be extended to substrates with the two aryl
moieties each bearing an electron-donating (methyl and
methoxy) or electron-withdrawing (halogens) substituent
(Scheme 2, 2e−p). It should be mentioned that the ortho-
substituted substrates, regardless the electronic nature of the
substituent, also proceeded to give the desired product (Scheme
2, 2j). Finally, the scope of the R4 substituent was also
investigated.22 The results showed that for substrate with R4
being either ethyl or n-butyl the reaction resulted in the
formation of product 2q or 2r in moderate yields, respectively.
However, the reaction of the substrate with R4 as a benzyl group
led to a complex mixture with no desired spirocyclized product
being detected. it should also be noted that the substrate
containing R1 as p-methoxy gave a complex mixture and
therefore failed to afford the desired product under the optimized
conditions (not shown).
We began our investigation by choosing compound 1a, a
relatively easily prepared product from commercially available
propargylic acid and N-methylaniline in a straightforward three-
step process,19 as the model substrate. However, when 1a was
treated with PIDA (1.2 equiv) in DCM, DMF, or THF, the
reaction delivered no desired product; the higher reaction
temperature did not alter the negative result at all (Table 1,
entries 1−3). To our delight, when 0.1 equiv of BF3·Et2O was
introduced, the reaction of 1a with 2.2 equiv of PIDA in DCE
afforded the desired compound 2a in 41% yield (Table 1,entry
4).20,21 When PIDA was replaced with the more potent oxidant
PIFA, the reaction gave a slightly improved yield (60%, Table 1,
entry 5). Switching to other solvents such as THF, DMF,
CH3CN, and Ac2O gave no better yield (Table 1, entries 6−9).
However, addition of 0.1 equiv of BF3·Et2O was found to very
slightly raise the yield to 50% (Table 1, entry 10). Further studies
involving many trials of various combinations of the reaction
condition parameters led us to discover that the highest yield was
achieved when the temperature was lowered to 0 °C in DCE with
PIFA as oxidant (Table 1, entry 11). Addition of BF3·Et2O (0.1
equiv) only lowered the yield (Table 1, entries 12 and 14).
Reactions at even lower temperatures not only prolonged the
reaction time but at the same time lowered the yield (Table 1,
entry 13). Another commonly applied hypervalent iodine(III)
reagent, i.e., PhIO, was tested but failed to afford the desired
product (Table 1, entry 15).
Compound 2o was successfully characterized via X-ray
crystallography (Figure 1).
Control experiments were carried out to further elucidate the
reaction mechanism (Scheme 3). According to Searcey’s work,23
there is a possibility that substrate 1a might undergo catalytic
indolization in the presence of TFA to form the indole
intermediate A. In order to verify this, we conducted the
experiments of substrate 1a with TFA (0.1−1.5 mol) in the
absence of PIDA. The results showed that no reaction occurred
under the conditions, which might indicate that no indole
intermediate A was formed during the PIFA-mediated
spirocyclization process. Since both the aniline and tosylamide
moieties might interact with the electrophilic hypervalent iodine
reagent, we carried out control experiments involving treatment
of diarylacetylene B and phenylpropiolamide derivatives E
separately with the oxidant. First the reaction of diarylacetylene B
The second part of our investigation was on the scope and
substituent tolerance of the newly developed method. A series of
2-sulfonamido-N-phenylpropiolamide derivatives were success-
fully prepared under the optimized conditions (see the
Supporting Information for details). Results listed in Scheme 2
showed that the desired products were all obtained in moderate
to good yields. Taking the substituents on the nitrogen atom
B
DOI: 10.1021/acs.orglett.7b00058
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Letter
Scheme 2. PIFA-Mediated Synthesis of 2-Spiropseudoindoxyl
Derivatives from 2-Sulfonamido-N-phenylpropiolamides
Scheme 3. Control Experiments
a
unreactive under the conditions and (d) the N-unprotected
tosylamide moiety is necessary for the transformation.24 Based
on the above results, we tentatively conclude that both the
tosylamide and the phenylpropiolamide moieties are necessary in
substrates 1 for the reaction to occur.
According to these control experimental results as well as our
previous studies,25,11 we propose two plausible mechanistic
pathways for this newly discovered PIFA-mediated tandem
oxidation reaction (Scheme 4). First, substrate 1a reacts with
Scheme 4. Proposed Mechanistic Pathways
a
All reactions were carried out at 0 °C with 1 (0.5 mmol) and PIFA
b
(1.1 mmol) in DCE (25 mL) under stirring. Isolated yields were
given. The structure of 2o was confirmed by X-ray crystallography.
c
PIFA to give the O−I intermediate F.11 Then nucleophilic attack
of the released trifluoroacetate anion onto the allene carbon
center in F initiates an indolization process, affording
intermediate G accompanied by the loss of one molecule of
iodobenzene and trifluoroacetic acid. Then intermediate G
undergoes two separate pathways to give the desired product 2a.
In path a, oxidation of G at the C3 position of the indole moiety
by PIFA affords the key C−I intermediate H with the loss of one
molecule of trifluoroacetic acid. Next, intermediate H goes
through an intramolecular annulation with the subsequent
deprotonation to give intermediate I, which is converted to the
final product 2a via reductive elimination and the subsequent
detrifluoracetylation process. In path b, intermediate G reacts
with PIFA, assisted by the released trifluoroacetate anion, to give
the O−I intermediate I′ by losing one molecule of trifluoroacetic
acid and trifluoroacetic anhydride. Intermediate I′ is eventually
converted the title product 2a after a series of redox O−I bond
cleavage, spirocyclization, and aromatization processes.
Figure 1. X-ray crystal structure of 2o.
with PIFA under the described conditions led to the isolation of
functionalized product D in 64% yield.15 This result indicates
two points: (a) the tosylamide moiety was reactive and (b) no
cyclized product was formed without the phenylpropiolamide
moiety. The various compounds E were further synthesized and
subjected to the standard conditions. Unfortunately, no desired
products were obtained under the standard conditions, which
might be because (c) phenylpropiolamide is stable enough to be
In summary, we have developed a metal-free approach for
construction of a series of diversely functionalized 2-
C
DOI: 10.1021/acs.orglett.7b00058
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Organic Letters
Letter
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propiolamide derivatives by using hypervalent iodine reagent as
the sole oxidant. The spirocyclization process involves an
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hypervalent iodine reagent. Further studies are still in progress in
our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00058.
(9) Zhang, T.; Qi, Z.; Zhang, X.; Wu, L.; Li, X. Chem. - Eur. J. 2014, 20,
3283.
(10) Sun, Y.; Gan, J.; Fan, R. Adv. Synth. Catal. 2011, 353, 1735.
(11) Zhang, X.; Hou, W.; Zhang-Negrerie, D.; Zhao, K.; Du, Y. Org.
Lett. 2015, 17, 5252.
Experimental procedures, characterization data for all new
compounds, NMR spectra, and X-ray data for 2o (PDF)
X-ray data for 2o (CIF)
(12) Zhang, Y. Q.; Zhu, D. Y.; Jiao, Z. W.; Li, B. S.; Zhang, F. M.; Tu, Y.
Q.; Bi, Z. Org. Lett. 2011, 13, 3458.
(13) Marien, N.; Brigou, B.; Pinter, B.; De Proft, F.; Verniest, G. Org.
Lett. 2015, 17, 270.
(14) Suneel Kumar, C. V.; Ramana, C. V. Org. Lett. 2014, 16, 4766.
(15) Zhang, X.; Yang, C.; Zhang-Negrerie, D.; Du, Y. Chem. - Eur. J.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: duyunfeier@tju.edu.cn.
ORCID
Yunfei Du: 0000-0002-0213-2854
Notes
(16) For selected reviews on hypervalent iodine reagents, see:
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(j) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Y.D. acknowledges the National Natural Science Foundation of
China (No. 21472136) and the Tianjin Research Program of
Application Foundation and Advanced Technology (No.
15JCZDJC32900) for financial support.
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D
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Org. Lett. XXXX, XXX, XXX−XXX