Conversion of 1-Boc-indoles to 1-Boc-oxindoles

Article abstract of DOI:10.1016/j.tetlet.2004.07.053

A facile synthesis of substituted oxindoles 2 from the corresponding indole is described. The reaction, which proceeds through the 2-(indolyl) borate intermediate, is general and applicable to several indoles.

Full text of DOI:10.1016/j.tetlet.2004.07.053

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6549–6550
Conversion of 1-Boc-indoles to 1-Boc-oxindoles
Enrique Vazquez* and Joseph F. Payack*
Department of Process Research, Merck & Co. Inc., PO Box 2000, Rahway, NJ 07065-0900, USA
Received 28 May 2004; revised 12 July 2004; accepted 13 July 2004
Abstract—A facile synthesis of substituted oxindoles 2 from the corresponding indole is described. The reaction, which proceeds
through the 2-(indolyl) borate intermediate, is general and applicable to several indoles.
Ó 2004 Elsevier Ltd. All rights reserved.
The oxindole ring is found in many natural products1
1) (iPrO)3B, LDA, THF
and pharmaceutically active compounds.2 While many
O
R
R
2) NaOH, NaHCO3, Oxone,
THF, Acetone, H2O,
NaHSO3
methods exist for the construction of oxindoles from
nonindole precursors,3 fewer options exist for the
conversion of indoles into the corresponding oxindoles.
Methods for the oxidation of substituted indoles to yield
their respective oxindoles are often multi-step proce-
dures,4 or involve an aqueous enzymatic system,5 since
straightforward oxidation of indole generally takes
place at the electron rich 3-position.6 Sometimes these
methods require hydrogenation7,8 to yield the desired
oxindole. Recently we reported on an improved process
to convert N-Boc protected indoles into 2-(indolyl)
borates9 and here we describe an extension of that chem-
istry to give substituted oxindoles in good yields.
N
Boc
N
Boc
1 a - e
2 a, 5-Me, 89%
2 b, 4-Cl, 70%
2 c, 7-Me, 63%
2 d, 5-Br, 62%
2 e, H, 78%
Scheme 1.
doles. The method provides a convenient and rapid
one-pot transformation of Boc-indoles to Boc-oxindoles
employing an environmentally friendly oxidation.
OzoneÒ has been used to oxidize boronic acid and bo-
ronic esters to their corresponding alcohols.10 A number
of commercially available indoles were N-Boc protected
under standard conditions (Scheme 1). The resulting N-
Boc indoles were taken forward without further purifi-
cation to yield the desired boronic acids after hydrolysis
of the isopropylborate esters.6 These acids were then
oxidized to the desired oxindoles.11 It is worth noting
that the procedures were not optimized but consistently
good yields were obtained. Additionally, protection of
the 3-position on the indole was not necessary, which al-
lowed for the two reactions to be simply run in one pot.
References and notes
1. Goehring, R. R.; Sachdeva, Y. P.; Pisipati, J. S.; Sleevi, M.
C.; Wolfe, J. F. J. Am. Chem. Soc. 1985, 107, 435–443, and
references cited therein.
2. Woodard, C. L.; Li, Z.; Kathcart, A. K.; Terrell, J.;
Gerena, L.; Lopez-Sanchez, M.; Kyle, D. E.; Bhattachar-
jee, A. K.; Nichols, D. A.; Ellis, W.; Prigge, S. T.; Geyer, J.
A.; Waters, N. C. J. Med. Chem. 2003, 46(18), 3877–3882;
Tokunaga, T.; Hume, W. E.; Umezome, T.; Okazaki, K.;
Ueki, Y.; Kumagai, K.; Hourai, S.; Nagamine, J.; Seki,
H.; Taiji, M.; Noguchi, H.; Nagata, R. J. Med. Chem.
2001, 44(26), 4641–4649; Bramson, H. N.; Corona, J.;
Davis, S. T.; Dickerson, S. H.; Edelstein, M.; Frye, S. V.;
Gampe, R. T., Jr.; Harris, P. A.; Hassell, A.; Holmes, W.
D.; Hunter, R. N.; Lackey, K. E.; Lovejoy, B.; Luzzio, M.
J.; Montana, V.; Rocque, W. J.; Rusnak, D.; Shewchuk,
L.; Veal, J. M.; Walker, D. H.; Kuyper, L. F. J. Med.
Chem. 2001, 44(25), 4339–4358.
In conclusion, we have demonstrated a convenient and
efficient protocol for the synthesis of substituted oxin-
Keywords: Indole; Oxindole; Oxidation; OxoneÒ.
*
Corresponding authors. Tel.: +1-732-594-1614; fax: +1-732-594-
1499; e-mail addresses: enrique_vazquez@merck.com; joseph_
payack@merck.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.053

6550
E. Vazquez, J. F. Payack / Tetrahedron Letters 45 (2004) 6549–6550
3. Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
3.68 (2H, s), 2.28 (3H, s), 1.55 (9H, s); 13C NMR (DMSO-
d6, 100MHz) d 173.0, 149.3, 138.6, 133.5, 128.3, 125.4,
124.6, 114.5, 83.7, 36.5, 28.2, 21.0; Anal. Calcd for
C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C, 67.98;
H, 6.94; N, 5.60.
125, 12084–12085, and references cited therein.
4. Lo, Y. S.; Walsh, D. A.; Welstead, W. J.; Mays, R. P.;
Rose, E. K.; Causey, D. H.; Duncan, R. L. J. Heterocycl.
Chem. 1980, 17, 1663–1664.
5. Van Deurzen, M. P. J.; van Rantwijk, F.; Sheldon, R. A.
J. Mol. Catal. B: Enzym. 1996, 2, 33–42.
6. Szabo-Pusztay, K.; Sazabo, L. Synth. Commun. 1979,
276–278.
7. Marfat, A.; Carta, M. P. Tetrahedron Lett. 1987, 28,
4027–4030.
1
Compound 2b 1.50g (70% yield); mp 100.0–101.0°C; H
NMR (DMSO-d6, 400MHz) d 7.65 (1H, d, J = 8.0Hz),
7.34 (1H, t, J = 8.2, 8.2Hz), 7.21 (1H, dd, J = 0.47,
0.66Hz), 3.72 (2H, s), 1.56 (9H, s); 13C NMR (DMSO-d6,
100MHz) d 171.6, 149.0, 142.2, 129.8, 129.4, 124.2, 123.5,
113.5, 84.3, 36.1, 28.1; Anal. Calcd for C13H14ClNO3:
C, 58.32; H, 5.27; N, 5.23. Found: C, 58.44; H, 5.24; N,
5.07.
8. Lawson, W. B.; Witkop, B. J. Org. Chem. 1961, 26,
263–264.
9. Vazquez, E.; Davies, I. W.; Payack, J. F. J. Org. Chem.
2002, 67, 7551–7552.
10. Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36,
5117–5118.
Compound 2c 1.34g (63%yield); mp 65.0–66.0°C; 1H
NMR (DMSO-d6, 400MHz) d 7.13 (2H, t, J = 7.4,
10.3Hz), 7.05 (1H, t, J = 7.42, 7.47Hz), 3.76 (2H, s),
2.16 (3H, s), 1.55 (9H, s); 13C NMR (DMSO-d6, 100MHz)
d 174.2, 149.8, 139.6, 130.8, 125.7, 124.3, 122.5, 84.7, 36.4,
27.8, 19.2; Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93;
N, 5.66. Found: C, 67.96; H, 6.97; N, 5.64.
11. In a typical procedure, to a solution of N-Boc-5-methyl-
indole 1a (2.00g; 8.65mmol) in THF (10mL) was added
triisopropylborate (3.0mL; 13.0mmol). The solution was
cooled to 0–5°C and LDA (1.8M, 11.2mmol) was added
over 1h. After 30min the reaction was quenched by the
addition of 2N HCl (15.6mL, 31.1mmol). The organic
layer was separated, and washed with water (10mL). To
the organic layer was added acetone (20.0mL), water
(20.0mL) followed by NaOH (0.519g, 13.0mmol), and
NaHCO3 (5.81g, 69.2mmol) then cooled to 0°C. To the
reaction mixture was added OxoneÒ (5.3g, 8.62mmol) in
water (20mL). The reaction was aged for 15–30min and
quenched with NaHSO3. The product was partitioned into
MTBE (20mL), dried (Na2SO4), concentrated, and puri-
fied by flash chromatography (20% EtOAc/hex) to give 2a
(1.90g, 89% yield); mp 89.0–90.0°C; 1H NMR (DMSO-d6,
400MHz) d 7.56 (1H, d, J = 8.6Hz), 7.10–7.08 (2H, m),
Compound 2d 0.66g (62% yield); mp 95.0–96.0°C. 1H
NMR (DMSO-d6, 400MHz) d 7.63 (1H, d, J = 8.5Hz),
7.50–7.47 (2H, m), 3.75 (2H, s), 1.55 (9H, s); 13C NMR
(DMSO-d6,100MHz) d 172.3, 149.1, 140.4, 130.7, 127.7,
127.5, 116.7, 116.4, 84.2, 36.4, 28.1; Anal. Calcd for
C13H14BrNO3: C, 50.02; H, 4.52; N, 4.49. Found: C,
50.19; H, 4.39; N, 4.42.
Compound 2e 1.67g, 78% yield); mp 66.0–67.0°C; 1H
NMR (DMSO-d6, 400MHz) d 7.68 (1H, d, J = 8.59Hz),
7.30–7.27 (2H, m), 7.13 (1H, t, J = 7.46, 7.55Hz), 3.72
(2H, s), 1.56 (9H, s); 13C NMR (DMSO-d6, 100MHz) d
172.9, 149.3, 141.0, 128.0, 124.8, 124.7, 124.4, 114.7, 83.9,
36.5, 28.2; Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48;
N, 6.00. Found: C, 66.74; H, 6.47; N, 5.89.