Synthesis of Spiroindanyl-2-oxindoles via PPA-mediated Intramolecular Friedel–Crafts Reaction

Full text of DOI:10.1002/bkcs.11234

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DOI: 10.1002/bkcs.11234
BULLETIN OF THE
D. Y. Seo et al.
KOREAN CHEMICAL SOCIETY
Synthesis of Spiroindanyl-2-oxindoles via PPA-mediated
Intramolecular Friedel–Crafts Reaction
*
Da Young Seo, Beom Kyu Min, Hwa Jung Roh, and Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University,
Gwangju 500-757, Korea. *E-mail: kimjn@chonnam.ac.kr
Received June 23, 2017, Accepted July 28, 2017
Keywords: Spirooxindoles, Polyphosphoric acid, Intramolecular Friedel–Crafts reaction, Indane
Spirooxindoles are found in numerous biologically interest-
ing synthetic and natural substances.1 As a result, various
synthetic methods of spirooxindoles have been developed.1,2
Recently, many spirooxindoles bearing indane or indene
moieties have been reported.3,4 As shown in Scheme 1,
spiroindanyl-2-oxindole 3a has been synthesized by Pd or
Cu-catalyzed intramolecular coupling of acetanilide
derivatives,3a–c trifluoroacetic acid-promoted double intramo-
lecular arylation of α-ketoanilides,3d Pd-catalyzed domino
carbopalladation/C–C bond forming process of N-
arylacrylamides,3e,f and other methods.3g–l
The use of Bi(OTf )3 (entry 8) or Yb(OTf )3 (entry 9) was
inefficient. The use of montmorillonite K-10 (entry 10) was
less effective.
Encouraged by the successful results, various spirooxin-
doles 3b–3l were synthesized from 3-arylethyl-2-oxindoles
2b–2l under the optimized condition (entry 5 in Table 1),
and the results are summarized in Table 2. The reactions of
5-methyl-, 5-chloro-, 6-chloro-, and 5,7-dimethylisatin deri-
vatives 2b–2e provided the corresponding spirooxindoles
3b–3e in good yields (73–90%). Similarly, the reactions of
2f–2i bearing 4-methylphenyl group (Ar = 4-MeC6H4)
afforded 3f–3i in good yields (75–91%). The reactions of
3-methoxyphenyl derivatives 2j and 2k (Ar = 3-MeOC6H4)
provided 3j (71%) and 3k (62%) in moderate yields.11 N-
Unsubstituted spirooxindole 3l could also be synthesized in
moderate yield (63%) by using the NH derivative 2l. It is
interesting to note that the reactions of 5-chloroisatin deri-
vatives 2c, 2g, and 2k required a slightly longer reaction
time (2 h).
As shown in Scheme 2, spirooxindole 3a could also be
synthesized by IMFC reaction of the chloride derivative 4,
which was prepared readily by treatment of 2a with
SOCl2,12 under the influence of PPA in high yield (84%).
However, a longer reaction time (15 h) was required for the
completion.
As a next experiment, the thionation of 3a with Lawes-
son’s reagent (LR) was examined, as shown in Scheme 3.2a,b
The reaction of 3a and LR (2.5 equiv.) in refluxing toluene
afforded spirothiooxindole 5a in high yield (96%) in short
time (1 h). Similarly, 5c was obtained in high yield (95%).
We also examined the synthesis of spiroindenyl-2-oxindole
6a from 3a, as also shown in Scheme 3.4 The dehydrogen-
ation of 3a was carried out in the presence of
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 4.0 equiv.)13
in 1,2-dichlorobenzene (ODCB) for 2 h, albeit in low yield
(34%).14 Similarly, compound 6c was obtained in a similar
yield (35%).
Recently, we reported the synthesis of spirooxindoles5a
and 3-aryl-2-oxindoles2d,5b from isatin-derived propargylic
alcohol 1a. As a continuous study, we reasoned out that
catalytic hydrogenation of the triple bond of 1a would
provide 3-phenylethyl-2-oxindole 2a, which could be con-
verted to spiroindanyl-2-oxindole 3a by intramolecular
Friedel–Crafts (IMFC) reaction,6–8 as shown in Scheme 1.
Zhu and co-workers reported the synthesis of 3a by
applying the above-mentioned trifluoroacetic acid-
promoted double intramolecular arylation of α-ketoani-
lides; however, the yield was low (34%).3d The interme-
diate in their synthesis of 3a was reported as 3-
phenylethyl-2-oxindole 2a. In these respects, we decided
to examine the synthesis of 3a by the IMFC reaction of
readily available 2a.
The required starting material 2a was prepared from 1a
in high yield (98%) under H2 balloon atmosphere in EtOAc
in the presence of Pd/C (10%, w/w), according to the
reported method.9 In order to find an optimum condition,
we examined the reaction of 2a in the presence of various
acid catalysts, as shown in Table 1. The reaction of 2a in
the presence of CF3COOH (entry 1)3d gave 3a in low yield
(37%). The reaction in the presence of CF3SO3H (entry 2)
in 1,2-dichloroethane (DCE) afforded 3a in a slightly
improved yield (43%). The use of H2SO4 (entry 3) was not
effective. When we used polyphosphoric acid (PPA) as a
reaction medium, the yield of 3a increased to 47% (entry
4).8 The best yield of 3a (68%) was obtained when we use
PPA (500%, w/w) in refluxing DCE (entry 5).10 It is inter-
esting to note that the reaction was completely ineffective
in CH3CN (entry 6) and less effective in benzene (entry 7).
In summary, various spiroindanyl-2-oxindoles have been
synthesized via PPA-mediated intramolecular Friedel–
Crafts reaction of 3-arylethyl-2-oxindoles. 3-Arylethyl-2-
oxindoles were prepared by catalytic hydrogenation of the
propargylic alcohols derived from N-methylisatins.
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Table 2. Synthesis of spiroindanyl-2-oxindole.
Scheme 1. Synthetic rationale of spiroindanyl-2-oxindole.
Experimental
Typical procedure for the synthesis of 3a. To a stirred
solution of 2a (134 mg, 0.5 mmol) in DCE (2.0 mL) was
added PPA (670 mg, 500%, w/w), and the reaction mixture
was heated to reflux for 1 h. After the usual aqueous
extractive workup and column chromatographic purification
process (n-hexane/CH2Cl2/Et2O, 10:5:2), compound 3a
was isolated as a pale yellow solid, 85 mg (68%).3a–d Other
compounds were synthesized similarly, and the selected
spectroscopic data of 3b, 3e, 3l, and 5a are as follows.
Compound 3b3d: 73%; yellow oil; IR (film) 1705, 1497,
1
1346 cm−1; H NMR (CDCl3, 500 MHz) δ 2.31 (s, 3H),
2.38–2.48 (m, 1H), 2.67–2.76 (m, 1H), 3.20–3.30 (m, 1H),
3.28 (s, 3H), 3.42–3.52 (m, 1H), 6.72 (d, J = 7.5 Hz, 1H),
6.83 (d, J = 7.8 Hz, 1H), 6.90 (s, 1H), 7.08–7.15 (m, 2H),
7.26 (t, J = 7.5 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H); 13C
NMR (CDCl3, 125 MHz) δ 21.1, 26.5, 31.8, 37.9, 60.3,
107.7, 123.4, 124.2, 125.0, 126.9, 127.9, 128.4, 132.4,
134.7, 141.2, 144.3, 145.0, 179.6; ESIMS m/z
264 [M + H]+. Anal. calcd for C18H17NO: C, 82.10; H,
6.51; N, 5.32. Found: C, 81.94; H, 6.75; N, 5.28.
a
Substrate (0.5 mmol): 2a: X = H, Ar = Ph; 2b: X = 5-Me, Ar = Ph;
2c: X = 5-Cl, Ar = Ph; 2d: X = 6-Cl, Ar = Ph; 2e: X = 5,7-Me2,
Ar = Ph; 2f: X = H, Ar = 4-MeC6H4; 2g: X = 5-Cl, Ar = 4-
MeC6H4; 2h: X = 6-Cl, Ar = 4-MeC6H4; 2i: X = 5-Me, Ar = 4-
MeC6H4; 2j: X = H, Ar = 3-MeOC6H4; 2k: X = 5-Cl,
Ar = 3-MeOC6H4; 2l: NH derivative of 2a.
Compound 3e: 75%; yellow solid, mp 102–104ꢀC; IR
(KBr) 1703, 1375, 1341 cm−1; 1H NMR (CDCl3,
b
Reaction time was 2 h.
500 MHz) δ 2.23 (s, 3H), 2.32–2.42 (m, 1H), 2.61 (s, 3H),
2.63–2.72 (m, 1H), 3.16–3.26 (m, 1H), 3.37–3.49 (m, 1H),
3.53 (s, 3H), 6.70 (d, J = 7.5 Hz, 1H), 6.70 (s, 1H), 6.84
(s, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H),
7.36 (d, J = 7.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ
18.9, 20.8, 29.7, 31.8, 38.4, 59.8, 119.2, 122.1, 123.4,
124.9, 126.8, 127.8, 132.26, 132.27, 135.5, 138.8, 144.6,
Table 1. Optimization of reaction conditions for the synthesis
of 3a.
Entry Conditionsa
3a (%)b
1
2
3
4
5
6
7
8
9
10
a
CF3COOH, reflux, 2 h
37
43
<5
47
68
0
ClCH2CH2Cl, CF3SO3H (10 equiv.), 0ꢀC, 1 h
ClCH2CH2Cl, H2SO4 (10 equiv.), rt, 1 h
PPA, 80ꢀC, 2 h
ClCH2CH2Cl, PPA (500%, w/w), reflux, 1 h
CH3CN, PPA (500%, w/w), reflux, 1 h
Benzene, PPA (500%, w/w), reflux, 1 h
ClCH2CH2Cl, Bi(OTf )3 (10 mol%), reflux, 2 h
CH3NO2, Yb(OTf )3 (10 mol%), 80ꢀC, 2 h
Toluene, K-10 (500%, w/w), reflux, 3 h
Ph
SOCl2
pyridine
0 oC, 30 min
Cl
44
0
PPA, DCE
reflux, 15 h
3a (84%)
2a
O
0
N
14
Me
4 (75%)
2a (0.5 mmol).
b
Scheme 2. Synthesis of 4 and its IMFC reaction.
Isolated yield.
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References
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Scheme 3. Synthesis of 5 and 6.
145.0, 180.3; ESIMS m/z 278 [M + H]+. Anal. calcd for
C19H19NO: C, 83.28; H, 6.90; N, 5.05. Found: C,
83.19; H, 7.01; N, 4.84.
Compound 3l: 63%; yellow solid, mp 204–206ꢀC; IR
(KBr) 3211, 1702, 1618, 1470 cm−1; 1H NMR (CDCl3,
500 MHz) δ 2.40–2.50 (m, 1H), 2.70–2.79 (m, 1H),
3.18–3.28 (m, 1H), 3.40–3.50 (m, 1H), 6.76 (d, J = 7.5 Hz,
1H), 6.95 (d, J = 7.8 Hz, 1H), 7.01–7.04 (m, 2H), 7.11 (t,
J = 7.5 Hz, 1H), 7.19–7.28 (m, 2H), 7.38 (d, J = 7.5 Hz,
1H), 8.11 (br s, 1H); 13C NMR (CDCl3, 125 MHz) δ 31.7,
37.9, 60.6, 109.6, 122.9, 123.4, 123.8, 125.0, 127.0, 128.0,
128.1, 135.2, 140.5, 143.9, 145.0, 181.7; ESIMS m/z
236 [M + H]+. Anal. calcd for C16H13NO: C, 81.68; H,
5.57; N, 5.95. Found: C, 81.40; H, 5.77; N, 5.89.
Compound 5a: 96%; white solid, mp 102–104ꢀC; IR
(KBr) 1610, 1463, 1428, 1361, 1309 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 2.42–2.52 (m, 1H), 2.77–2.87 (m,
1H), 3.23–3.32 (m, 1H), 3.51–3.61 (m, 1H), 3.71 (s, 3H),
6.55 (d, J = 7.7 Hz, 1H), 7.03–7.15 (m, 4H), 7.23 (td,
J = 7.5, 1.1 Hz, 1H), 7.31–7.40 (m, 2H); 13C NMR
(CDCl3, 125 MHz) δ 31.6, 31.8, 41.7, 71.0, 109.3, 123.5,
123.6, 124.5, 124.9, 127.0, 127.9, 128.1, 139.6, 144.2,
144.6, 146.3, 210.0; ESIMS m/z 266 [M + H]+. Anal. calcd
for C17H15NS: C, 76.94; H, 5.70; N, 5.28. Found: C,
77.07; H, 5.90; N, 5.03.
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spirooxindoles-bearing
indene
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Acknowledgments. This work was supported by National
Research Foundation of Korea (NRF) grant funded by the
Korea government (NRF-2015R1A4A1041036). Spectro-
scopic data were obtained from the Korea Basic Science
Institute, Gwangju branch.
Supporting Information. Additional supporting informa-
tion including experimental procedure and spectroscopic
data is available in the online version of this article.
Bull. Korean Chem. Soc. 2017
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KOREAN CHEMICAL SOCIETY
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oxindole was isolated in low yield (5%). The amount of PPA
was not critical in the reaction. Actually, the yield of 3a was
similar (64–68%) with variable amounts of PPA (50–1000%,
w/w) in refluxing DCE; however, a longer reaction time (3 h)
was required when we use small amount of PPA (50%, w/w).
1
11. Based on the H NMR spectra of 3j and 3k, a small amount
(ca. 5%) of the corresponding regioisomer was contaminated.
12. For chlorination of similar compounds with thionyl chloride,
see: (a) S. Ma, X. Han, S. Krishnan, S. C. Virgil, B. M. Stoltz,
Angew. Chem. Int. Ed. 2009, 48, 8037; (b) P. Magnus,
R. Turnbull, Org. Lett. 2006, 8, 3497.
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(a) T. Thiemann, M. Watanabe, S. Mataka, New J. Chem.
2001, 25, 1104; (b) Y.-S. Chung, H. Kruk, O. M. Barizo,
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14. The dehydrogenation was slow below 170ꢀC. In addition,
compound 6a was somewhat unstable under the condition,
and it was decomposed slowly into intractable polar com-
pounds. The synthesis of 6a by Pd/C-catalyzed dehydrogena-
tion was ineffective even at high temperature (diphenyl ether,
reflux).
9. N. Xu, D.-W. Gu, J. Zi, X.-Y. Wu, X.-X. Guo, Org. Lett.
2016, 18, 2439.
10. In the reaction, an acid-catalyzed dehydration reaction
occurred to some extent and N-methyl-3-phenylethylidene-2-
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