A Divergent Approach to the Diastereoselective Synthesis of 3,3-Disubstituted Oxindoles from Atropisomeric N-Aryl Oxindole Derivatives

Article abstract of DOI:10.1002/asia.201601183

3,3-Disubstituted oxindoles were divergently synthesized by diastereoselective transformations including nucleophilic addition, alkylation, and cycloaddition using common, axially chiral N-aryl oxindoles. Notably, high diastereoselectivities (up to >95:5) were observed with ortho-monosubstituted N-aryl oxindoles to give various oxindole scaffolds, and facile removal of the p-(benzyloxy)aryl moiety in axially twisted amides was achieved by a mild, two-step sequence.

Full text of DOI:10.1002/asia.201601183

CHEMISTRY
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Accepted Article
Title: A Divergent Approach to the Diastereoselective Synthesis of 3,3-Disubstituted
Oxindoles from Atropisomeric N-Aryl Oxindole Derivatives
Authors: Atsuo Nakazaki; Ayako Mori; Susumu Kobayashi; Toshio Nishikawa
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Chemistry - An Asian Journal
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A Divergent Approach to the Diastereoselective Synthesis of 3,3-Disubstituted Oxindoles from
Atropisomeric N-Aryl Oxindole Derivatives
Atsuo Nakazaki,*[a] Ayako Mori,[a] Susumu Kobayashi,[b] Toshio Nishikawa[a]
Keywords: asymmetric synthesis, C-N axial chirality, 3,3-disubstituted oxindole, isatin
Abstract: 3,3-Disubstituted oxindoles were divergently synthesized by diastereoselective
transformations including nucleophilic addition, alkylation, and cycloaddition using common,
axially chiral N-aryl oxindoles. Notably, high diastereoselectivities (up to >95:5) were observed
with ortho-monosubstituted N-aryl oxindoles to give various oxindole scaffolds, and facile removal
of the p-(benzyloxy)aryl moiety in axially twisted amides was achieved by a mild, two-step
sequence.
[a] Dr. A. Nakazaki, A. Mori, Prof. Dr. T. Nishikawa
Graduate School of Bioagricultural Sciences
Nagoya University
Furo-cho, Chikusa, Nagoya 464-8601 (Japan)
Fax: (+81)52-789-4111
E-mail: nakazaki@agr.nagoya-u.ac.jp
[b] Prof. Dr. S. Kobayashi
Faculty of Pharmaceutical Sciences
Tokyo University of Science
2641 Yamazaki, Noda, Chiba 278-8510 (Japan)
1
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Introduction
Considerable attention has been given to 3,3-disubstituted oxindoles that incorporate a stereogenic
center in the C3-position, since these particular scaffolds are widely embedded in indole alkaloids,
drug candidates, and clinical pharmaceuticals (Figure 1).[1] For instance, PF1270A displays a high
affinity for the histamine H3 receptor, whose ligands are potential therapeutic agents for diabetes,
obesity, and central nervous system disorders.[2] SM-130686 possess potent growth hormone
releasing activity and its dextro isomer is more potent than its enantiomer.[3] Therefore, a number
of synthetic methods directed at 3,3-disubstituted oxindoles have been established based on
enantioselective transformations.[4] Nevertheless diastereoselective approaches seem to be ideal
for the divergent synthesis of stereochemically defined oxindoles, but this approach has remained
relatively unexplored because the positions of the introduced chiral auxiliary is limited.[5] During
the course of our studies aimed at the stereocontrolled synthesis of 3,3-disubstituted oxindoles,[6] we
envisaged that a diastereoselective approach would allow for the divergent synthesis of
3,3-disubstituted oxindoles from a common, chiral non-racemic oxindole intermediate. Towards
this end, we newly designed N-aryl oxindole A with axial chirality on the C-N bond (Scheme 1,
a).[7,8] Thus, diastereoselective C-C bond-forming reactions of N-aryl oxindole, which is N-aryl
isatin (A: X = O) or its carbon analogues (e.g., 3-alkylidene oxindole A’: X = CHR’ or 3-alkyl
oxindole A”: X = CH2R’) as the common intermediate, would take place from the less hindered
diastereoface leading to 3,3-disubstituted oxindole B. Various diastereoselective reactions can be
used to synthesize a wide variety of oxindole scaffolds from N-aryl oxindoles A-A” because of the
versatility of these starting materials (Scheme 1, b).[9] Notably, stereochemically defined oxindole
2
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C could be obtained after removal of the aryl moiety in B under mild oxidative conditions. Herein,
we describe diastereoselective transformations including nucleophilic addition, alkylation, and
cycloaddition using chiral racemic oxindoles, which are relatively easier to synthesize than their
non-racemic counterparts; the facial selectivity is also discussed. The most striking features of this
approach are the high diastereoselectivities (up to >95:5) using ortho-monosubstituted N-aryl
oxindoles, and the high-yielded removal of the p-(benzyloxy)aryl moiety bearing a hindered
ortho-substituent in the twisted amides by a two-step sequence under mild oxidation conditions
[PhI(OCOCF3)2, MeCN-H2O, 0 °C] after deprotection of the benzyl group.[8a] This two-step
process allows for the divergent and stereoselective incorporation of various functionalities in the
C3 position into oxindole scaffolds of considerable synthetic and medicinal interest.
Figure 1. Oxindole alkaloids with a stereogenic center at C3-position.
3
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Scheme 1. a) General scheme for stereocontrol of the C3-stereogenic center of oxindoles with axial
chirality. b) Potentially accessible scaffolds from axially chiral isatin A, oxindole A' or A".
Results and Discussion
Synthetic plan for N-aryl oxindoles: Scheme 2 describes our initial synthetic plan in pursuit of
chiral non-racemic isatin A and oxindoles A' and A" bearing an ortho-monosubstituted or
ortho-disubstituted N-aryl group. We first expected that N-aryl isatin A, a versatile precursor for
oxindoles A' and A", could be synthesized through direct C-N coupling of isatin and bromoarene D.
However, in our preliminary attempts, the transition metal-catalyzed C-N coupling of isatin and
bromoarene D (e.g., R, P, and P' = Me) did not take place at all, and the related reaction using
sterically less congested 2-bromo-5-methoxy-1,3-dimethylbenzene did not furnish the desired
N-aryl isatin probably due to the severe steric hindrance.[10] Therefore we chose an alternative
4
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stepwise approach via the oxidation of N-aryl indole E. In the synthesis of ortho-disubstituted
N-aryl indole E (R = Me), asymmetric desymmetrization of achiral diester F’ via enzymatic
hydrolysis would be a viable approach to obtain chiral non-racemic N-aryl indole F. Needless to
say, stable axial chirality in the synthetic intermediates involvong indoles E and F was essential for
the transformation. Transition metal catalyzed C-N coupling of indole and bromoarene G with an
ortho-diester would be a feasible approach to obtain achiral N-aryl indole F. Through a similar
manner as the disubstituted system, ortho-monosubstituted N-aryl indole E (R = H) could be
synthesized easily via N-aryl indole H derived from indole and sterically less congested iodoarene I.
In order to clarify capability of its diastereofacial selectivity for each reaction, chiral racemic isatins
were synthesized.
Scheme 2. Synthetic strategy for chiral non-racemic N-aryl isatin A, a key intermediate for related
oxindole analogues A' and A".
5
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Synthesis of ortho-disubstituted N-aryl oxindoles: We first synthesized ortho-disubstituted N-aryl
isatin 6 via the corresponding indole 4 (Scheme 4 and Table 1). Aryl bromide 1 (= G) was
prepared from commercially available 3,5-dimethylphenol in four steps according to the
literature.[11] C-N coupling of indole and bromoarene 1 was performed with Cu and K2CO3 in
refluxing triglyme, followed by treatment with MeI to protect the partially formed carboxylate,
leading to requisite diester 2. To obtain the racemic N-aryl isatin, diester 2 was subjected to 0.7
equiv of NaOH aq. to afford the desired monocarboxylic acid 3 in moderate yield (54%) along with
recovered starting material 2 in 17% yield. Monocarboxylic acid 3 is a chiral compound and a
potentially useful precursor for the synthesis of chiral non-racemic isatins, if it possesses stable
axial chrality. The stability of the axial chirality of 3 was determined by chiral HPLC analysis of
chiral non-racemic 3;[12] which revealed that 3 was easily racemized even at room temperature.
Therefore, chiral non-racemic isatin should be synthesized by another strategy.[ 13 ]
Methoxycarbonyl and carboxy groups in both ortho-positions in 3 were transformed into
hydroxydimethylmethyl and methyl groups, respectively by the following sequence: treatment of 3
with MeLi and quenching the reaction by MeOH, followed by addition of excess LiAlH4 in the
same pot provided diol (not shown in Scheme 3). The resulting primary alcohol was converted
into the corresponding chloride, which was then reduced with NaBH4 to afford N-aryl indole 4 in
good overall yield. Isatins 6a-e bearing various protecting groups were synthesized as shown in
Table 1. Protection of the tert-alcohol in 4 and subsequent oxidation of indole 5 using CrO3
afforded the corresponding isatins 6.[14]
6
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Scheme 3. Synthesis of N-aryl indole 4.
Table 1. Synthesis of N-aryl isatins 6a-e. Nap = 2-naphthylmethyl. m-MPM =
m-methoxyphenylmethyl.
7
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Synthesis of ortho-monosubstituted N-aryl isatins 10 and 14, and oxindoles 15 and 16: We next
synthesized ortho-monosubstituted N-aryl isatins 10 and 14, and 3-alkylidene oxindole 15 and
3-alkyl oxindole 16 (Scheme 4). The three-step sequence involving C-N coupling of indole and
iodoarene 7, prepared from 2-amino-5-hydroxybenzoic acid according to the literature,[ 15 ]
nucleophilic addition of MeLi, and subsequent methylation of the resulting tert-hydroxy group
provided N-aryl indole 9. Based on the ortho-disubstituted system, oxidation of this indole with
CrO3 gave the corresponding N-aryl isatin 10 in moderate yield. Synthesis of benzyl-protected
N-aryl isatin 14 was conducted in a similar manner, and derivatives 15 and 16 were transformed
from the resulting isatin 14 under conventional conditions. Wittig olefination of isatin 14 with
phosphorane provided oxindole 15 in excellent yield as a single E-isomer, whose stereochemistry
was confirmed by the NOESY correlation between the methyl group on the ester and the
C4-hydrogen. Hydrogenation of the resulting alkene in 15 was performed with Pt/C in EtOAc
under a hydrogen atmosphere (1 atm) to provide oxindole 16 as a diastereomeric mixture.[16]
8
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1
Scheme 4. Synthesis of isatins 10 and 14, and oxindoles 15 and 16. [a] Determined by H NMR
analysis after purification.
Nucleophilic addition to ortho-disubstituted N-aryl isatins 6a-e: At the outset, we examined the
nucleophilic addition of MeLi to isatins 6a-e in order to investigate the effect of the protective
groups on the side chain in the ortho-position (Table 2). Treatment of methyl-protected isatin 6a
with 2.0 equiv of MeLi (LiBr free) in THF at –78 °C led to the corresponding adduct syn-17a and
anti-17a in quantitative yield as a 75:25 mixture (entry 1). The relative stereochemistry was
confirmed by X-ray crystallographic analysis and derivatizations as discussed below; MeLi attacked
9
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from the less hindered diastereoface, as expected. To improve the diastereoselectivity, the reaction
was examined using substrates with more hindered protective groups. Thus, the nucleophilic
addition using benzyl surrogate 6b was found to give 17b in moderate yield with the same level of
diastereoselectivity (syn:anti = 74:26, entry 2). The reactions of 6c (R = m-MPM) and 6d (R =
Nap) with MeLi did not exhibit improved stereoselectivities (entries 3 and 4). To our surprise, the
use of 6e bearing a more hindered TBS group resulted in the formation of anti-17e as the major
diastereomer, although the degree of diastereoselectivity was moderate (syn:anti = 39:61, entry 5).
The exact origin of the stereochemical changeover observed in entry 5 is still obscure at present;
however, we assumed that the top face of the carbonyl group in isatin 6e would become accessible
via a pyramidal amide structure, which was supported by X-ray crystallographic analysis of
syn-17e,[17] although this is not direct evidence for the structure of 6e in a solution. The relative
stereochemistries of the resulting methyl adducts 17a-e were determined by comparison of 1H NMR
spectra of the derivatives prepared from the major isomer of the TBS analogue anti-17e, whose
epimer syn-17e was established by X-ray crystallographic analysis.[18] The axial chirality of the
ortho-disubstituted oxindole system was found to be stable, as determined by heating 17a (syn:anti
= 75:25) in toluene at 105 °C for 19 h with no observed change in diastereomeric ratio. The
results from Table 2 indicate that two diastereofaces of the carbonyl group would not be effectively
discriminated by the ortho-disubstituted aryl group even though one side chain is a hindered
[(alkoxy)dimethyl]methyl group. We attributed the low diastereoselectivity to the shielding the
less hindered carbonyl face by the ortho-methyl group.
In order to improve the
diastereoselectivity, we next explored the diastereoselective reactions using ortho-monosubstituted
N-aryl oxindole systems.
10
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Table 2. Nucleophilic addition of MeLi to ortho-disubstituted isatins 6a-e.[a]
Nucleophilic addition to ortho-monosubstituted N-aryl isatins 10 and 14: Nucleophilic addition
to isatin 10 or 14[19] with various nucleophiles was next examined, and the results are shown in
Table 3. N-Aryl isatin 10 was subjected to LiBr-free MeLi at –78 °C to generate the
corresponding oxindole 18 in 70% yield with high diastereoselectivity (syn:anti = 88:12, entry 1).
It is worth noting that the benzyl group on the lower aryl group was found to be essential for the
high diastereoselectivity; the related reaction using benzyl surrogate 14 gave the corresponding
methyl adduct 19a in 85% yield with 92:8 diastereomeric ratio (entry 2). Addition of LiBr
dramatically improved the yield of methyl adduct 19a with the same level of diastereoselectivity
(97% yield, dr = 94:6, entry 3). This trend was observed with other nucleophiles such as
allyllithium and phenyllithium (entries 4 vs 5 and entries 6 vs 7). The reaction of N-aryl isatin 10
with EtLi under the optimized conditions provided the corresponding oxindole 19d in 68% yield
with high diastereoselectivity (syn:anti = 91:9, entry 8). The optimized conditions allowed for
11
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introduction of a versatile functionality, a trimethylsilylethynyl moiety, to afford 19e in 77% yield
with high diastereoselectivity (syn:anti = 91:9, entry 9). Nucleophilic addition with a Grignard
reagent resulted in diminished diastereoselectivity, probably due to the chelation of the
organomagnesium reagents (entry 10). The addition of MeZnCl, prepared from ZnCl2 and
LiBr-free MeLi,[20] was also attempted; however, a low chemical yield and diastereomeric ratio
were observed (7% yield, syn:anti = 81:19) along with 67% of unreacted 14 (entry 11). The
polarity of solvent was also important in this reaction; less polar solvent systems such as THF-Et2O
resulted in slightly lower diastereoselectivities (syn:anti = 84:16, entry 12). In contrast, the
addition of hexamethylphosphoramide (HMPA) enhanced the diastereoselectivity of adduct 19b,
which was obtained in 76% yield as a single diastereomer (entry 13). We finally achieved the
remote asymmetric induction by taking advantage of the axial chirality.
12
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Table 3. Nucleophilic addition of various nucleophiles to racemic N-aryl isatin 10 or 14.[a]
The relative stereochemistry of the major diastereomer, syn-19a, was established by X-ray
crystallographic analysis.[21] The relative stereochemistry of syn-19d was confirmed by NOESY
analysis. The stereochemistry of syn-19e was determined by NOESY after transformation into
syn-19d.[18] The stereochemistry of oxindoles 18, 19b, and 19c could be tentatively assigned by
assuming analogous diastereoselectivity.
13
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Other transformations using ortho-monosubstituted N-aryl oxindoles: Having found a
promising oxindole system bearing an ortho-monosubstituted aryl group, we moved to investigate
the construction of a quaternary carbon center at C3 in the oxindole scaffold by alkylation or
cycloaddition. Alkylation of oxindole 16 with an aqueous solution of NaOH and excess MeI in
the presence of tetrabutylammonium hydrogensulfate provided syn-20a in 70% yield as a single
diastereomer (Table 4, entry 1).[22] Allylation and prenylation were also effective to synthesize
syn-20b and syn-20c in moderate to high yields with high diastereoselectivities (entries 2 and 3).
The relative stereochemistry of the resulting allylation product syn-20b was determined by NOESY
analysis of syn-20c after conversion by olefin cross metathesis with 2-methyl-2-butene.[18]
Table 4. Alkylation of oxindole 16 with several alkylation agents.
We next examined the [3 + 2] cycloaddition of 15 with two different azomethyne ylides derived
from N,O-acetals 21a[23] and 21b (Table 5). The reaction provided the corresponding [3 + 2]
adducts 22a and 22b in excellent yields with low diastereoselectivities, irrespective of the steric
hindrance of the azomethyne ylides and reaction conditions.[24]
14
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Table 5. [3 + 2] cycloaddition of 15 with azomethyne ylides under various conditions.
In contrast, the Diels-Alder cycloaddition of 15 with 2,3-dimethyl-1,3-butadiene in the presence
of various Lewis acids gave the corresponding adduct in good yields with high facial selectivities
(Table 6). Although the addition of MgCl2 or LiBr afforded desired adduct 23 in low yield with
good diastereoselectivity (syn:anti = 88:12, entries 1 and 2),[25] the reaction with Sc(OTf)3 resulted
in the formation of 23 in 91% yield with the same level of diastereoselectivity (entry 3). Changing
the reaction conditions did not significantly affect the diastereoselectivities (entries 4-6). The
relative stereochemistry of the resulting major diastereomer of Diels-Alder adduct syn-23 was
confirmed by NOESY analysis.[18]
Table 6. Diels-Alder reaction of 15 with 2,3-dimethylbutadiene in the presence of Lewis acids.
15
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Removal of the aryl group: The final task was to remove the aryl moiety in the stereochemically
defined oxindoles by oxidative cleavage of the C-N bond. Removal of the 4-(alkoxy)phenyl group
on the nitrogen of amides has been easily achieved using CAN.[26,7q] However, we anticipated that
it might be difficult to remove the aryl moiety, because the formation of the indispensable iminium
intermediate could be interrupted by steric hindrance owing to the buttressing effect of the
ortho-substituent(s) on the N-aryl group in our systems. Indeed, attempted cleavage of the C-N
bond of ortho-disubstituted N-aryl oxindole 17a or its phenol derivative did not give desired
3-hydroxy-3-methyloxindole 25a with oxidants such as CAN, AgO/HNO3, PhI(OAc)2,
PhI(OCOCF3)2, Fremy's salt, and IBX.
In contrast, removal of the aryl group in the ortho-monosubstituted system was achieved with
PhI(OCOCF3)2.[27] Thus, deprotection of the benzyl group in 19a[28] and subsequent oxidative
cleavage using 2 equiv of PhI(OCOCF3)2 in MeOH at room temperature afforded N,O-acetal 24 in
excellent overall yield (Scheme 5). Interestingly, introduction of the methoxy group took place
stereoselectively (dr = 87:13), indicating that the axial chirality in 19a was transmitted to the central
16
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chirality of the N,O-acetal carbon with high diastereoselectivity. Hydrolysis of the resulting 24
under acidic conditions (1 M of HCl aq. at 45 to 50 °C) furnished the desired oxindole 25a in 91%
yield.
Scheme 5. Stepwise removal of the aryl moiety in oxindole 19a. [a] Diastereomeric ratio was
determined by 1H NMR analysis.
Oxidation and subsequent hydrolysis were carried out in a one-pot manner when aqueous
MeCN was employed instead of MeOH (Table 7).[29] Deprotection of the benzyl group in the
oxindoles under hydrogenolysis (method A: Pd/C, H2) or under Lewis acidic conditions (AlCl3 and
Me2NPh), followed by treatment of the resulting phenol with 1-1.3 equiv of PhI(OCOCF3)2 in
aqueous MeCN at 0 °C furnished 25 in moderate to high overall yields. Especially in the case of
acid-labile systems such as esters 20a and 23, the use of this one-pot method allowed for a clean
transformation in high yield. In contrast, the stepwise method including hydrolysis with aqueous
HCl resulted in a complex mixture for 25e or the formation of desired 25f in <41% yield.
Pyrrolidine derivative 22a smoothly underwent removal of the aryl moiety in the same manner after
conversion of the N-benzyl group into a methoxycarbonyl group (Scheme 6).[30] To the best of our
knowledge, this is the first example of the effective removal of an aryl moiety from amides after
17
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atroposelective transformation; this procedure would be applicable to the oxidative cleavage of aryl
groups in other acid-labile N-aryl amides as well.
Table 7. Improved method for removal of aryl moiety.
1
Scheme 6. Removal of aryl moiety in 22a. [a] Diastereomeric ratio was determined by H NMR
18
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analysis.
Conclusions
In summary, we developed a divergent approach towards the diastereoselective synthesis of
3,3-disubstituted oxindoles with a stereogenic center at C3, from newly designed axially chiral
N-aryl oxindoles. Removal of the p-(benzyloxy)aryl moiety was achieved under mild conditions,
implying that this protocol is applicable to other amide systems as well. Our method allows for
the divergent and stereoselective incorporation of various functionalities at C3 into oxindole
scaffolds of considerable synthetic and medicinal interest.[31]
Acknowledgments
This work was supported by the Uehara Memorial Foundation, and Grant-in-Aid for Young
Scientists (B) (No. 21790026 and 23780115) and Grant-in-Aid for Scientific Research (C) (No.
25450151) from MEXT. We thank Dr. Kenji Yoza (Bruker AXS) for the X-ray crystallographic
analysis.
19
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References and Notes
[1] For reviews on the stereoselective construction of 3,3-disubstituted oxindoles, see: a) C. Marti,
E. M. Carreira, Eur. J. Org. Chem. 2003, 2209-2219; b) B. M. Trost, M. K. Brennan, Synlett 2009,
3003-3025; c) J. E. M. N. Klein, R. J. K. Taylor, Eur. J. Org. Chem. 2011, 6821-6841.
[2] N. Kushida, N. Watanabe, T. Okuda, F. Yokoyama, Y. Gyobu, T. Yaguchi, J. Antibiot. 2007, 60,
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Nagamine, H. Seki, M. Taiji, H. Noguchi, R. Nagata, J. Med. Chem. 2001, 44, 4641-4649.
[4] For recent reviews of enantioselective synthesis of 3,3-disubstituted oxindoles, see: a) F. Zhou,
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[5] For an example of the diastereoselective construction of 3,3-disubstituted oxindoles from
oxindoles bearing central chirality, see: a) G. Palmisano, R. Annunziata, G. Papeo, M. Sisti,
Tetrahedron: Asymm.1996, 7, 1-4. For examples of the construction of aminooxindoles, see: b) G.
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Kobayashi, J. Synth. Org. Chem. Jpn. 2008, 66, 124-138. For the diastereoselective construction of
spirocyclic oxindole in this group, see: c) H. Miyamoto, Y. Okawa, A. Nakazaki, S. Kobayashi,
Angew. Chem. Int. Ed. 2006, 45, 2274-2277; d) H. Miyamoto, Y. Okawa, A. Nakazaki, S.
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Nakazaki, S. Kobayashi, Tetrahedron 2013, 69, 9481-9493.
[7] For reviews on the asymmetric synthesis of atropisomeric compounds having C-N axial
chirality, see: a) I. Takahashi, Y. Suzuki, O. Kitagawa, Org. Prep. Proc. Int. 2014, 46, 1-23; b) M.
Takahashi, O. Kitagawa, J. Synth. Org. Chem. Jpn. 2011, 69, 985-993; c) E. Kumarasamy, R.
Raghunathan, M. P. Sibi, J. Sivaguru, Chem. Rev. 2015, 115, 11239-11300. For selected examples
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Chemistry - An Asian Journal
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Chem. Soc. 2006, 128, 12923-12931; f) K. Tanaka, K. Takeishi, K. Noguchi, J. Am. Chem. Soc.
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For
the
diastereoselective
construction
of
3,3-disubstituted
oxindoles
from
N-aryl-3-chlorooxindoles bearing C-N axial chirality via nucleophilic substitution, see: b) A.
Nakazaki, K. Miyagawa, T. Nishikawa, Synlett 2015, 1116-1120.
[9] For recent reviews of isatins as versatile intermediate for the construction of oxindole
frameworks, see: a) J. F. M. da Silva, S. J. Garden, A. C. Pinto, J. Braz. Chem. Soc. 2001, 12,
273-324; b) G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112, 6104-6155; c) M. Xia, R.-Z. Ma, J.
Heterocycl. Chem. 2014, 51, 539-554; d) G. M. Ziarani, R. Moradi, N. Lashgari, Tetrahedron:
Asymm. 2015, 26, 517-541.
[10] For the construction of oxindoles bearing a ortho-hydroxy group on the N-aryl group via a
formal insertion reaction of arynes, see: Z. Chen, Q. Wang Org. Lett. 2015, 17, 6130-6133.
[11] a) R. Holzwarth, R. Bartsch, Z. Cherkaoui, G. Solladié, Chem. Eur. J. 2004, 10, 3931-3935; b)
A. Bugarin, B. T. Connell, Organometallics 2008, 27, 4357-4369.
[12] Chiral non-racemic monocarboxylic acid 3 was obtained by the optical resolution of racemic 3
using analytical chiral column with HPLC.
[ 13 ] We have recently established the alternative approach to chiral non-racemic
ortho-monosubstituted N-aryl isatin through asymmetric intramolecular Buchwald-Hartwig
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N-arylation. A. Nakazaki, K. Miyagawa, N. Miyata, T. Nishikawa, Eur. J. Org. Chem. 2015,
4603-4606.
[14] Although stability of the axial chirality on the resulting N-aryl isatins 6a-e has not been
elucidated, we estimated that the isatins are stable enough not to epimerize based on the observation
of no epimerization in 17a (Table 2) by heating in toluene at 105 °C for 19 h. Vide infra.
[15] M. Mülbaier, A. Giannis, ARKIVOC 2003, 228-236.
[16] Newly generated stereogenic center in 6 was found to be easily epimerized during the
purification (diastereomeric ratio of the crude mixture = 88:12).
[17] Crystallographic data for syn-17e (TBS analogue) have been deposited in the Cambridge
Crystallographic Data Centre (CCDC 1496936).
[18] For details see, the Supporting Information.
[19] The rotational barrier of N-aryl isatins 14 for racemization was estimated to be 31.1 kcal/mol
(298 K). For details, see the Supplementary data.
[20] R. Shintani, T. Yamagami, T. Hayashi, Org. Lett. 2006, 8, 4799-4801.
[21] Crystallographic data for syn-19a have been deposited in the Cambridge Crystallographic Data
Centre (CCDC 895008).
[22] M. S.Morales-Ríos, E. Rivera-Becerril, P. Joseph-Nathan, Tetrahedron: Asymm. 2005, 16,
2493-2499.
[23] P. L. Kotian, T.-H. Lin, Y. El-Kattan, P. Chand, Org. Process Res. Dev. 2005, 9, 193-197.
[24] Relative stereochemistry of each diastereomer has not been determined.
[25] Addition of representative Lewis acid such as AlCl3, TiCl4, TMSOTf, ZnCl2, BiCl3, or In(OTf)3
gave no desired Diels-Alder adduct 23 due to deprotection of benzyl or methyl group on the phenol
and/or elimination of the methoxy group of the desired Diels-Alder adduct 23.
[26] For the oxidative removal of 4-(alkoxy)phenyl group on the amide nitrogen using CAN, see: a)
T. Fukuyama, R. K. Frank, C. F. Jewell, Jr. J. Am. Chem. Soc. 1980, 102, 2122-2123; b) D. R.
Kronenthal, C. Y. Han, M. K. Taylor J. Org. Chem. 1982, 47, 2765-2768.
[27] For recent reviews of hypervalent iodine-mediated phenol oxidation, see: a) S. Quideau, L.
Pouységu, D. Deffieux, Synlett 2008, 467-495; b) L. Pouységu, D. Deffieux, S. Quideau,
Tetrahedron 2010, 66, 2235-2261.
[28] In this sequential transformation, conversion into the corresponding phenol is crucial for
achievement of removal of the lower aryl moiety.
Direct oxidative cleavage from
N-(4-methoxyaryl) oxindole 18 did not succeed with oxidants such as CAN, AgO/HNO3, and
PhI(OH)OTs. Related unsuccessful results were reported in reference [7g].
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[29] For a related example of removal of p-siloxyphenyl group on an amine by oxidation with
PhI(OCOCF3)2 in MeCN/H2O after deprotection of the silyl group, see: Y. Hayashi, W. Tsuboi, M.
Shoji, N. Suzuki, J. Am. Chem. Soc. 2003, 125, 11208-11209.
[30] Based on the observation of high diastereoselectivities of cycloadducts 25f (>95:5) and 25g
(90:10), we attributed that low diastereoselectivities of compounds 23 (88:12) and 22a (65:35) were
derived from the facial selectivities induced by the axial chirality. In addition, we did not detected
epimerization of the -carbonyl position under the reaction conditions of removal of the lower aryl
moiety.
[31] We have demonstrated the synthesis of enantioenriched 3,3-disubstituted oxindole from a
chiral non-racemic N-aryl isatin. Nucleophilic addition of MeLi and subsequent removal of the
aryl moiety furnished 3-hydroxy-3-metheyloxindole in good overall yield without loss of
stereochemical integrity. For details, see: ref [13].
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Table of Contents
3,3-Disubstituted oxindoles were divergently synthesized by diastereoselective transformations
including nucleophilic addition, alkylation, and cycloaddition using common, axially chiral N-aryl
oxindoles.
Notably, high diastereoselectivities (up to >95:5) were observed with
ortho-monosubstituted N-aryl oxindoles to give various oxindole scaffolds, and facile removal of
the p-(benzyloxy)aryl moiety in axially twisted amides was achieved by a mild, two-step sequence.
24
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