TABLE 2. 3,3′-Bioxindole Formation from 3-Hydroxy-
3,3′-Bioxindolesa
69.2 (CH2), 65.6 (CH2), 55.8 (CH3), 49.3 (CH), 29.8 (CH3), 17.5
(CH2), -1.3 (CH3); IR (film) 3365, 2952, 1733, 1713, 1615 cm-1
;
HRMS-ESI (m/z) [M + Na]+ calcd for C24H30N2NaO5Si 477.1822,
found 477.1823.
Representative Procedure for Converting Aldol Adducts to
3,3′-Bioxindoles. Preparation of 7′-Methoxy-N′-methyl-N-(2-
(trimethylsilyl)ethoxymethyl)-3,3′-dihydroisoindigo (13a). To a
solution of tertiary alcohol 11b (14.8 g, 32.5 mmol, 1.0 equiv) and
dichloromethane (275 mL) at 0 °C were added over 5 min
diisopropylethylamine (17.0 mL, 97.5 mmol, 3.0 equiv) and then
freshly distilled thionyl chloride (2.85 mL, 39.0 mmol, 1.2 equiv).
The resulting solution was maintained for 25 min at 0 °C, before
being allowed to warm to rt, where it was maintained for 45 min.
The reaction mixture was then poured into a saturated aqueous
solution of sodium hydrogencarbonate (150 mL). The aqueous layer
was separated and extracted with dichloromethane (4 × 200 mL).
The combined organic layers were dried over MgSO4 and concen-
trated under reduce pressure to yield a brown oil that was used
without further purification in the subsequent reaction.
entry
11
R1
R3
R2
R4
13
yield (%)b
1
2
3
4
5
11b
11c
11d
11e
11f
Me
Me
SEM
Bn
SEM
MeO
MeO
H
H
H
SEM
Bn
Bn
SEM
Bn
H
H
H
7-F
6-Ph
13a
13b
13c
13d
13e
87c
89
85
79
90
a Conditions: step 1: 11 (1.0 equiv), SOCl2 (1.2 equiv), i-Pr2NEt (3.0
equiv), 0 °C to rt; step 2: Zn (30 equiv), AcOH (18 equiv), 0 °C to rt.
b Yield over two steps after purification of 13 by silica gel flash column
chromatography. c Reduction performed with a modified procedure: Zn
(6.0 equiv), AcOH (5.6 equiv), 0 °C to rt.
In a separate experiment, purification of this product by silica
gel flash column chromatography (1:9 EtOAc/hexanes) gave the
corresponding isoindigo S20 as a dark burgundy solid: mp 84-85
°C; 1H NMR (500 MHz, CDCl3) δ 9.17 (d, J ) 8.0 Hz, 1H), 8.73
(m, 1H), 7.36 (td, J ) 7.7, 0.9 Hz, 1H), 7.09 (d, J ) 7.5 Hz, 1H),
7.01 (d, J ) 7.8 Hz, 1H), 6.96 (m, 2H), 5.24 (s, 2H), 3.87 (s, 3H),
3.62 (t, J ) 8.2 Hz, 2H), 3.57 (s, 3H), 0.94 (t, J ) 8.2 Hz, 2H),
-0.02 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 168.2, 168.0, 144.8,
143.8, 134.8, 134.3, 133.7, 133.3, 132.6, 129.6, 122.9, 122.7, 122.3,
121.6, 116.8, 109.1, 69.5, 66.2, 56.3, 29.7, 17.9, -1.4; IR (film)
2954, 1698, 1609 cm-1; HRMS-ESI (m/z) [M + H]+ calcd for
C24H29N2O4Si 437.1897, found 437.1912.
These aldol products can be reduced in good yield to give the
corresponding 3,3′-bioxindoles. By use of this method, a variety
of substituents, including those that are acid-sensitive, can be
introduced at various positions of the 3,3′-bioxindole product.
Experimental Section
Representative Procedure for Generating 2-Siloxyindole In-
termediates and Their Mukaiyama Aldol Reaction with Isatins.
Preparation of 3-Hydroxy-7′-methoxy-N′-methyl-N-((2-(trimeth-
ylsilyl)ethoxy)methyl)-3,3′-biindoline-2,2′-dione (11b). To a stirring
solution of 7-methoxy-N-methyloxindole (S5) (6.60 g, 37.3 mmol,
1.0 equiv), triethylamine (15.6 mL, 112 mmol, 3.0 equiv), and
dichloromethane (700 mL) at 0 °C was added dropwise tert-bu-
tyldimethylsilyl trifluoromethanesulfonate (12.8 mL, 55.9 mmol,
1.5 equiv). The resultant solution was maintained at 0 °C for 25
min and then allowed to warm to rt. Methanol (1.5 mL, 37 mmol,
1.0 equiv) was added, and the solution was concentrated under
reduced pressure (∼30 mmHg). The resulting biphasic mixture was
extracted with pentane (3 × 120 mL), and the combined organic
extracts were concentrated under reduced pressure to provide the
corresponding 2-siloxyindole as a pale red/pink solid, which was
used in the subsequent reaction without further purification.
A solution of the crude 2-siloxyindole, N-((2-(trimethylsilyl)-
ethoxy)methyl)isatin (10.4 g, 37.6 mmol, 1.01 equiv), 2,6-di-tert-
butyl-4-methylpyridine (19.1 g, 93.2 mmol, 2.5 equiv), and dichlo-
romethane (630 mL) was cooled to -78 °C, and boron trifluoride
diethyl ether complex (9.20 mL, 74.6 mmol, 2.0 equiv) was added
dropwise. After 2 h at -78 °C, the solution was allowed to warm
to -50 °C, where it was maintained overnight. This solution was
then poured into water (250 mL), and the layers were separated.
The aqueous layer was extracted with dichloromethane (3 × 250
mL). The combined organic extracts were washed with brine (40
mL), dried over Na2SO4, and concentrated under reduced pressure
to provide a brown oil. Purification of this oil by silica gel flash
column chromatography (dry loaded on Celite, gradient: 1:6 EtOAc/
hexanes to 1:3 EtOAc/hexanes) provided alcohol 11b (14.8 g, 87%)
as a pale brown solid: mp 129-132 °C; Rf 0.54 (1:4 EtOAc/
hexanes); 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J ) 7.4 Hz, 1H),
7.42 (ddd, J ) 8.8, 8.0, 7.7 Hz, 1H), 7.24 (t, J ) 7.6 Hz, 1H), 7.02
(d, J ) 7.7 Hz, 1H), 6.76 (d, J ) 8.3 Hz, 1H), 6.67 (dd, J ) 8.3,
7.7 Hz, 1H), 6.45 (br s, 1H), 5.60 (d, J ) 7.6 Hz, 1H), 4.90 (d, J
) 11.4 Hz, 1H), 4.82 (d, J ) 11.4 Hz, 1H), 3.91(s, 1H), 3.80 (s,
3H), 3.55 (s, 3H), 3.10 (ddd, J ) 10.4, 9.9, 6.4 Hz, 1H), 3.02 (ddd,
The unpurified isoindigo intermediate was dissolved in THF (315
mL) and cooled to 0 °C. To this solution were added zinc dust
(12.8 g, 195 mmol, 6.0 equiv) and glacial acetic acid (3.2 mL, 180
mmol, 5.6 equiv). The resulting suspension was vigorously stirred
at 0 °C for 1.5 h, and then allowed to warm to rt over 45 min. The
reaction mixture was then filtered through a pad of Celite eluting
with EtOAc (250 mL). The organic solution was washed with
saturated aqueous sodium hydrogencarbonate (200 mL), dried over
MgSO4, and concentrated under reduced pressure to yield a black
foamy oil. This residue was further purified by silica gel flash
column chromatography (dry loaded on Celite, gradient: 1:4 EtOAc/
hexanes to 1:1 EtOAc/hexanes) to afford bioxindole 13a as a 1.6:1
mixture of epimers (12.4 g, 87%) as an orange foam: Rf 0.20 (1:1
1
EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.28 (t, J ) 7.8
Hz, 0.6H), 7.12 (t, J ) 7.7 Hz, 0.4H), 7.06-7.02 (m, 0.6H), 6.99
(t, J ) 7.3 Hz, 0.6H), 6.93-6.80 (m, 3.0H), 6.74-6.65 (m, 0.8H),
6.55 (d, J ) 7.2 Hz, 0.3H), 6.33 (m, 0.5H), 5.22 (d, J ) 10.8 Hz,
0.4H), 5.18 (d, J ) 10.9 Hz, 0.4H), 5.04 (s, 1.2H), 4.34 (d, J ) 3.5
Hz, 0.3H), 4.25 (m, 0.8H), 4.12 (d, J ) 3.3 Hz, 0.6H), 3.87-3.81
(m, 1.9H), 3.80-3.74 (m, 1.1H), 3.59-3.52 (m, 1.1H), 3.47 (s,
0.5H), 3.55-3.44 (m, 2.7H), 0.97 (m, 0.8H), 0.84 (t, J ) 7.8 Hz,
1.3H), 0.10 (s, 3.2H), -0.05 (s, 5.8H); 13C NMR (125 MHz, CDCl3)
δ 176.4 (C), 175.9 (C), 175.0 (C), 174.8 (C), 145.2 (C), 145.1 (C),
143.4 (C), 142.7 (C), 132.9 (C), 131.9 (C), 128.7 (CH), 128.3 (CH),
127.1 (C), 126.3 (C), 125.5 (C), 124.4 (C), 123.4 (CH), 123.3 (CH),
122.9 (CH), 122.82 (CH), 122.78 (CH), 122.75 (CH), 116.1 (CH),
115.9 (CH), 112.6 (CH), 112.3 (CH), 109.8 (CH), 109.4 (CH), 69.8
(CH2), 69.3 (CH2), 66.6 (CH2), 65.8 (CH2), 55.74 (CH3), 55.71
(20) Additional methods have been demonstrated for the conversion of
3-hydroxy-3,3′-bioxindoles to 3,3′-bioxindoles. These include acid-mediated
dehydration of the tertiary alcohol to afford an isoindigo that is subsequently
reduced by catalytic hydrogenation,6-9 and direct reduction with trimethylsilyl
iodide21 or HI.22
(21) (a) Sakai, T.; Miyata, K.; Utaka, M.; Takeda, A. Tetrahedron Lett. 1987,
28, 3817–3818. (b) For an example of the reduction of a 3-hydroxy-3,3′-
bioxindole, see: Peterson, E. A. Ph.D. Dissertation, University of California,
Irvine, 2005.
J ) 10.4, 9.9, 6.1 Hz, 1H), 0.80-0.66 (m, 2H), -0.07 (s, 9H); 13
C
NMR (125 MHz, CDCl3) δ 176.0 (C), 175.5 (C), 145.5 (C), 143.0
(C), 132.8 (C), 130.8 (CH), 127.5 (C), 124.5 (CH), 124.1 (C), 123.9
(CH), 123.1 (CH), 116.6 (CH), 112.8 (CH), 110.2 (CH), 77.4 (C),
(22) Metwally, S. A. M.; Younes, M. I.; Abbas, H. H. Acta Chim. Hung.
1989, 126, 591–597.
J. Org. Chem. Vol. 73, No. 22, 2008 9153