Decarboxylative Claisen rearrangement reactions: Synthesis and reactivity of alkylidene-substituted indolines

Article abstract of DOI:10.1039/c1ob06212c

Microwave-assisted decarboxylative Claisen rearrangement (dCr) reactions of substituted acetate derivatives of 3-(hydroxyalkyl)indoles give de-aromatised products. The reactivity of the resultant compounds was evaluated.

Full text of DOI:10.1039/c1ob06212c

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PAPER
Decarboxylative Claisen rearrangement reactions: synthesis and reactivity of
alkylidene-substituted indolines†
Jason E. Camp,a,b Donald Craig,*a Kiyohiko Funaia and Andrew J. P. Whitec
Received 20th July 2011, Accepted 30th August 2011
DOI: 10.1039/c1ob06212c
Microwave-assisted decarboxylative Claisen rearrangement (dCr) reactions of substituted acetate
derivatives of 3-(hydroxyalkyl)indoles give de-aromatised products. The reactivity of the resultant
compounds was evaluated.
Introduction
The decarboxylative Claisen rearrangement (dCr) reaction de-
veloped in our laboratory1 is a variant of the Ireland–Claisen
rearrangement,2–4 in which allylic tosylacetates undergo in
situ silyl ketene acetal formation, [3,3]-sigmatropic rearrange-
ment, and desilylation–decarboxylation on exposure to N,O-
bis(trimethylsilyl)acetamide (BSA) and KOAc in a cycle catalysed
by acetate. We have applied this transformation to reactants
possessing heteroaromatic rings in place of the more conventional
allylic moieties: thiophene-, pyrrole- and furan-containing sub-
strates gave dCr reaction products in good yields, by a mechanism
involving de-aromatisation of the heterocyclic nucleus.5,6 In some
instances the de-aromatised compounds could be isolated and
characterised (Scheme 1).7 In the case of furan derivatives, these
non-aromatic species entered into aldol-type reactions character-
istic of enol ethers.8 This article describes de-aromatising dCr
reactions of a range of indole-containing substrates, and shows
Scheme 1 De-aromatising dCr reactions of heteroaromatic substrates.5,8
that compounds possessing quaternary centres may be accessed
via this unusual pathway.
of 0.4 M toluene9 solutions of 1 with BSA and stoichiometric
KOAc under microwave conditions gave the alkylidene-substitued
Results and discussion
indolines 2 in moderate to good yields; the use of alternating
sequences of microwave heating followed by cooling was found to
be optimal.1f,10 The reactions are depicted in Scheme 2, and the
results collected in the Table 1.
In the first part of this study, the versatility of de-aromatising
dCr reactions of indole-containing esters with respect to the
electron-withdrawing group a- to the ester and the indole N-
substituent was evaluated. Substrates 1a–g were synthesised from
the corresponding alcohols using standard methods. Treatment
aDepartment of Chemistry, Imperial College London, South Kensington
Campus, London, UK, SW7 2AZ. E-mail: d.craig@imperial.ac.uk; Tel: +44
(0)20 7594 5771
bCurrent address: School of Chemistry, University of Nottingham, University
Park, Nottingham, UK, NG7 2RD. E-mail: jason.camp@nottingham.ac.uk;
Tel: +44 (0)11 5846 8464
Scheme 2 De-aromatising dCr reactions of indoles 1a–g. Reagents and
conditions: (i) BSA (1.5 equiv.), KOAc (1.0 equiv.), PhMe (0.4 M solution
of reactants), microwave, 150 ◦C.
cChemical Crystallography Laboratory, Imperial College London, South
Kensington Campus, London, UK, SW7 2AZ
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of compounds 1–12, and further information concerning the X-
ray crystallographic analysis of Z-3. CCDC reference number 775144. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob06212c
Several features of the dCr reactions depicted above are
noteworthy. Initial experiments showed that N-Boc indoles gave
higher yields than the N-tosyl analogues (entries 1, 2). Substrates
having cyano substituents a- to the ester gave similar yields to the
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Table 1 De-aromatising dCr reactions of indoles 1a–g
Entry
Substrate
R1
R2
R3
Conditionsa
Product
Yield (%)b
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Ts
H
H
H
H
Me
Me
Me
Ts
Ts
CN
CO2Et
Ts
CN
CO2Et
5 ¥ 1 min
4 ¥ 1 min
4 ¥ 1 min
4 ¥ 1 min
4 ¥ 1 min
5 ¥ 1 min
4 ¥ 1 min
2a
2b
2c
2d
2e
2f
32
68
Boc
Boc
Boc
Boc
Boc
Boc
70
22c
87d
82d
53d
1g
2g
◦
a All reactions were carried out at 150 C, with 1 min cooling between the stated number of heating cycles. b Isolated yield following chromatographic
purification on silica gel. c Prolonged exposure of product 2d to silica gel resulted in re-aromatisation to the isomeric indole, which was fully characterised.
d Product was obtained as a mixture of geometric isomers.
a-tosyl analogues (entries 2, 3 and 5, 6). The efficiency of dCr
reaction of ester-containing substrates 1d and 1g was diminished
in part by the instability on silica gel of the products 2d and 2g;
in the case of 2d significant quantities of the indolic product of
re-aromatisation were observed. With R2 = CH3 in 1, an increase
in the yield of 2 was observed relative to the less highly substituted
compound (compare entries 2 and 5, 3 and 6, 4 and 7).
One of the de-aromatising dCr reaction substrates studied
showed markedly different behaviour from that of 1a–g. Exposure
of indolic ester 1h to the standard reaction conditions gave in
good yield two products which were isomeric with the expected
ethylidene-substituted indoline 2h; The structure of 3 followed
from extensive NMR experimentation, and was confirmed by
X-ray crystallographic analysis of the major (2 : 1) isomer (Fig.
1).11 Additionally, ozonolysis of 3 with mildly reductive work-up
gave 3-oxoindoline 4. Under the milder dCr reaction conditions
studied previously5 we had observed conversion of 1h into 2h
in good yields. Therefore, it seems likely in the present case
that elimination of the elements of tolylsulfinic acid from 2h
gives a bis(alkylidene)indoline, which undergoes re-aromatisation
via a [1,5]-sigmatropic hydrogen shift and/or protonation–
deprotonation. Protonation at C2 then gives a delocalised cationic
intermediate, which is intercepted by tolylsulfinate anion to give
3.12 Support for this mechanistic interpretation came from the
observation that subjection of 2h synthesised under the milder
conditions to the standard microwave procedure resulted in the
formation of 3. The formation of 3, together with the mechanism
postulated for its generation are shown in Scheme 3.
Scheme 3 Unusual dCr reaction of 1h, and postulated mechanism.
Reagents and conditions: (i) BSA (1.5 equiv.), KOAc (1.0 equiv.), PhMe (0.4
M solution of reactants), microwave, 150 ◦C, 5 ¥ 1 min; (ii) O3, CH2Cl2,
-78 ◦C, 5 min; SMe2.
accessed using the de-aromatising transformation. Subjection of
the cyanoacetate ester 5 to the usual dCr conditions gave in
56% yield the N-Boc-substituted 3-methyleneindoline 6, which
possesses a quaternary centre at C2 (Scheme 4).
Scheme 4 De-aromatising dCr reaction of 5. Reagents and conditions: (i)
BSA (1.5 equiv.), KOAc (1.0 equiv.), PhMe (0.4 M solution of reactants),
microwave, 150 ◦C, 4 ¥ 1 min.
The second phase of this work was directed towards devel-
oping the utility of the exocyclic methylene group for further
synthetic manipulation post-dCr reaction. De-aromatised indoles
have been subjected to hydroboration–oxidation,13 imino-ene,14
ozonolysis15 and ring-closing metathesis15 reactions. Exposure
of 3-methyleneindoline 2a to ethanal in the presence of ZnCl2
at 0 ◦C gave in low yield the re-aromatised secondary alcohol
7; at room temperature, high-yielding isomerisation to indole 8
was the sole pathway observed. Oxidation of 2b with mCPBA
gave the re-aromatised alcohol 9, while hydroboration–oxidation
gave indoline 10. Finally, treatment of dCr product 2c with
Fig. 1 The molecular structure of Z-3.
The final dCr substrate studied in this work was selected to
ascertain whether more sterically congested indolines could be
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DIBAL-H gave aldehyde 11, with no evidence of re-aromatisation.
Compound 2c also was subjected to ozonolytic cleavage, giving 3-
oxoindoline 12 (Scheme 5).
reagent-grade. Petrol refers to the fraction of petroleum ether with
◦
◦
bp760 40–60 C. KOAc was oven-dried at 120 C for several days
prior to use. All other reagents were purchased from Aldrich,
Fluka, Acros, Alfa Aesar, Lancaster and used as such unless
otherwise stated. Microwave-assisted reactions were carried out in
a Biotage Initiator instrument. Ozonolyses were performed with
an Ozonia Triogen LAB2B ozone generator.
(1-Tosyl-1H-indol-3-yl)methyl 2-tosylacetate (1a)
To a stirred solution of (1-tosyl-1H-indol-3-yl)methanol (2.3 g,
7.6 mmol) in dry CH2Cl2 (75 mL) at rt were added Et3N (5.3 mL,
38.2 mmol) and chloroacetyl chloride (1.8 mL, 22.8 mmol) and
the resultant solution was stirred at rt for 5 min. CH2Cl2 (50 mL)
and brine (50 mL) were added. The organic layer was dried over
sodium sulfate, the solvent removed under reduced pressure and
the residue was purified by flash column chromatography on silica
gel (7 : 3 petrol : EtOAc with 1% Et3N) to afford (1-tosyl-1H-indol-
3-yl)methyl 2-chloroacetate (1.89 g, 66%). nmax (film) 3189, 2923,
2852, 1741, 1659, 1632, 1597, 1469, 1410, 1372, 1326, 1291, 1189,
Scheme
5 Derivatisation reactions of 3-methyleneindolines 2a–c.
1
1174, 1150, 1122, 1084, 973, 813, 747, 722, 703, 672 cm-1; H
Reagents and conditions: (i) MeCHO, ZnCl2, CH2Cl2, 0 ◦C; (ii) MeCHO,
ZnCl2, CH2Cl2, rt; (iii) mCPBA, CH2Cl2, rt; (iv) BH3·SMe2; H2O2, NaOH,
NMR (400 MHz, CDCl3) d 8.01 (d, J = 8.0 Hz, 1H), 7.80 (d,
J = 8.4 Hz, 2H), 7.69 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.35–7.30
(m, 1H), 7.31–7.24 (m, 3H), 5.37 (s, 2H), 4.08 (s, 2H), 2.35 (s,
3H); 13C NMR (100 MHz, CDCl3) d 167.1, 145.1, 134.9, 129.1,
126.8, 126.2, 125.1, 123.4, 119.5, 116.2, 113.6, 59.2, 40.7, 21.4;
HRMS-ES+: [M CO2CH2Cl] calcd for C16H14NO2S, 284.0745;
found, 284.0743.
To a stirred solution of (1-tosyl-1H-indol-3-yl)methyl 2-
chloroacetate (950 mg, 2.5 mmol) in MeCN (25 mL) at rt were
added Et3N (0.70 mL, 5.0 mmol) and sodium p-toluenesulfinate
hydrate (530 mg, 3.0 mmol) and the resultant solution was stirred
at rt for 12 h. EtOAc (50 mL) and brine (50 mL) were added. The
organic layer was dried over sodium sulfate, the solvent removed
under reduced pressure and the residue was purified by flash
column chromatography on silica gel (7 : 3 petrol : EtOAc with 1%
Et3N) to afford (1-tosyl-1H-indol-3-yl)methyl 2-tosylacetate (1a,
890 mg, 72%), which had data in agreement with those reported;5
1H NMR (400 MHz, CDCl3) d 8.0 (d, J = 8.4 Hz, 1H), 7.79 (d, J =
8.4 Hz, 2H), 7.61–7.57 (m, 3H), 7.44–7.42 (m, 1H), 7.37–7.33 (m,
1H), 7.22–7.20 (m, 3H), 7.06–7.04 (m, 2H), 5.23 (s, 2H), 4.13 (s,
2H), 2.32 (br s, 3H), 2.28 (br s, 2H); 13C NMR (100 MHz, CDCl3) d
162.1, 145.1, 135.1, 134.6, 129.8, 129.4, 129.0, 128.0, 126.6, 126.2,
124.9, 123.3, 119.5, 115.8, 113.3, 60.7, 58.8, 21.3, 21.2.
0
◦C–rt; (v) DIBAL-H, PhMe, -78 ◦C–rt; (vi) O3, CH2Cl2 (0.007 M),
–78 ◦C; Me2S, rt.
Conclusions
In summary, we have demonstrated that the de-aromatising dCr
reaction of indole-containing substituted esters is an effective
method for the generation of 3-alkylideneindolines, and that
these products may be usefully elaborated in a variety of ways.
In particular, we note the amenability of this approach to the
generation of products containing quaternary centres. Ongoing
work is concerned with developing asymmetric versions of this
process, and applications to natural products synthesis. The results
of these studies will be reported in due course.
Experimental
General
Infrared spectra were recorded on a Mattson 5000 FT-IR spec-
trometer and on a Perkin–Elmer Spectrum RX FT-IR System.
Proton magnetic resonance (1H NMR) and carbon magnetic
resonance (13C NMR) spectra were recorded in CDCl3 unless
otherwise stated on a Bruker AV-400 spectrometer. Chemical
shifts are in parts per million (ppm) and are referenced relative
to the residual proton-containing solvent (1H NMR: 7.26 ppm for
CDCl3; 13C NMR: 77.0 ppm for CDCl3). The following abbrevia-
tions are used to indicate the multiplicities: s, singlet, br s, broad
signal; d, doublet; t, triplet; m multiplet. Mass spectra (CI) were
recorded using Micromass AutoSpec-Q, Micromass Platform II or
Micromass AutoSpec Premier instruments. Analytical thin layer
chromatography (TLC) was performed on pre-coated aluminium-
backed Merck Kiesegel 60 F254 plates. Visualisation was effected
with ultraviolet light, potassium permanganate or vanillin as
appropriate. Flash chromatography was performed using BDH
(40-63 mm) silica gel unless otherwise stated. CH2Cl2 were distilled
under nitrogen from CaH2 prior to use. All other solvents were
tert-Butyl 3-((2-tosylacetoxy)methyl)-1H-indole-1-carboxylate
(1b)
To a stirred solution of tert-butyl 3-(hydroxymethyl)-1H-indole-
1-carboxylate (2.0 g, 8.0 mmol) in dry CH2Cl2 (80 mL) at rt
were added Et3N (5.6 mL, 40.4 mmol) and chloroacetyl chloride
(1.9 mL, 24.0 mmol) and the resultant solution was stirred at rt
for 5 min. CH2Cl2 (50 mL) and brine (50 mL) were added. The
organic layer was dried over sodium sulfate, the solvent removed
under reduced pressure and the residue was purified by flash
column chromatography on silica gel (7 : 3 petrol : EtOAc with 1%
Et3N) to afford tert-butyl 3-((2-chloroacetoxy)methyl)-1H-indole-
1-carboxylate (1.91 g, 74%). nmax (film) 3440, 3125, 2979, 2935,
1738, 1731, 1610, 1477, 1455, 1392, 1307, 1257, 1229, 1156, 1090,
7906 | Org. Biomol. Chem., 2011, 9, 7904–7912
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1018, 958, 855, 768, 747, 579 cm-1; 1H NMR (400 MHz, CDCl3)
d 8.18 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.63 (d, J = 8.0 Hz,
1H), 7.40–7.36 (m, 1H), 7.32–7.28 (m, 1H), 5.40 (s, 2H), 4.09 (s,
2H), 1.70 (s, 9H); 13C NMR (100 MHz, CDCl3) d 167.1, 149.2,
135.4, 128.9, 126.1, 124.7, 122.8, 118.9, 115.2, 114.4, 84.0, 59.5,
40.7, 28.0; HRMS-ES+: [M Boc/-CO2CH2Cl] calcd for C9H7N,
130.0657; found, 130.0646.
7.73 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.42–7.38 (m, 1H), 7.34–7.29
(m, 1H), 5.43 (s, 2H), 3.49 (s, 2H), 1.70 (s, 9H); 13C NMR (100
MHz, CDCl3) d 162.9, 149.3, 135.5, 128.9, 126.6, 125.0, 123.1,
119.0, 115.4, 114.0, 112.8, 84.3, 60.4, 60.2, 28.1, 24.7; HRMS-
ES+: [M Boc/-CO2CH2CN] calcd for C9H7N, 130.0657; found,
130.0650.
To a stirred solution of 3-((2-chloroacetoxy)methyl)-1H-indole-
1-carboxylate (200 mg, 0.62 mmol) in MeCN (6.0 mL) at rt were
added Et3N (0.17 mL, 1.2 mmol) and sodium p-toluenesulfinate
hydrate (130 mg, 0.74 mmol) and the resultant solution was stirred
at rt for 2 d. EtOAc (50 mL) and brine (50 mL) were added. The
organic layer was dried over sodium sulfate, the solvent removed
under reduced pressure and the residue was purified by flash
column chromatography on silica gel (7 : 3 petrol : EtOAc with 1%
Et3N) to afford tert-butyl 3-((2-tosylacetoxy)methyl)-1H-indole-
1-carboxylate (1b, 185 mg, 67%). nmax (film) 3054, 2980, 2937,
2258, 1738, 1716, 1597, 1455, 1385, 1329, 1274, 1229, 1150, 1097,
912, 814, 768, 733, 648, 515 cm-1; 1H NMR (400 MHz, CDCl3) d
8.18 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.63 (s, 1H),
7.50 (d, J = 7.6 Hz, 1H), 7.40–7.36 (m, 1H), 7.29–7.25 (m, 1H),
7.15 (d, J = 8.4 Hz, 2H), 5.29 (s, 1H), 4.14 (s, 2H), 3.82 (s, 3H),
1.70 (s, 9H); 13C NMR (100 MHz, CDCl3) d 162.3, 149.2, 145.1,
135.37, 135.30, 129.5, 128.8, 128.2, 126.2, 124.7, 122.8, 119.0,
115.1, 114.1, 84.0, 60.8, 59.3, 28.0, 21.4. HRMS-ES+: [M+Na]
calcd for C23H25NO6SNa, 466.1300; found, 466.1293.
(1-(tert-Butoxycarbonyl)-1H-indol-3-yl)methyl ethyl malonate
(1d)
To a stirred solution of tert-butyl 3-(hydroxymethyl)-1H-indole-
1-carboxylate (1.35 g, 5.5 mmol) in dry CH2Cl2 (5.0 mL) at rt
were added Et3N (1.7 mL, 12.1 mmol), DIC (0.98 mL, 6.6 mmol),
DMAP (cat.) and ethyl hydrogen malonate (0.78 mL, 6.6 mmol)
and the resultant solution was stirred at rt for 2 d. CH2Cl2 (50 mL)
and brine (50 mL) were added. The organic layer was dried over
sodium sulfate, the solvent removed under reduced pressure and
the residue was purified by flash column chromatography on silica
gel (8 : 2 petrol : EtOAc containing 1% Et3N) to afford (1-(tert-
butoxycarbonyl)-1H-indol-3-yl)methyl ethyl malonate (1d, 1.65 g,
84%). nmax (film) 2979, 2934, 1737, 1732, 1454, 1370, 1259, 1162,
1
1090, 748 cm-1; H NMR (400 MHz, CDCl3) d 8.18–8.16 (m,
1H), 7.70–7.55 (m, 2H), 7.38–7.25 (m, 3H), 5.37 (s, 2H), 4.17 (q,
J = 7.2 Hz, 2H), 3.45 (s, 2H), 1.70 (br s, 9H), 1.24 (t, 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 166.6, 166.3, 149.4, 135.6,
129.1, 125.9, 124.8, 122.9, 119.2, 115.3, 114.9, 84.0, 61.5, 60.3,
59.1, 59.0, 41.6, 41.5, 28.1, 14.2; HRMS-ES+: [M+Na] calcd for
C19H23NO6Na, 384.1423; found, 384.1414.
tert-Butyl 3-((2-cyanoacetoxy)methyl)-1H-indole-1-carboxylate
(1c)
tert-Butyl 3-(1-(2-tosylacetoxy)ethyl)-1H-indole-1-carboxylate
(1e)
To
a
stirred solution of tert-butyl 3-formyl-1H-in◦dole-1-
carboxylate (9.0 g, 36.5 mmol) in MeOH (100 mL) at 0 C was
added sodium borohydride (6.9 g, 183 mmol) and the resultant
solution was stirred at rt for 1 h. Acetone (100 mL) was added and
the solvent was removed under reduced pressure. Brine (100 mL)
and CH2Cl2 (100 mL) were added. The organic layer was dried over
sodium sulfate, the solvent removed under reduced pressure to give
tert-butyl 3-(hydroxymethyl)-1H-indole-1-carboxylate, which was
used without further purification. nmax (film) 3390, 2980, 2933,
2874, 1737, 1715, 1608, 1455, 1372, 1308, 1257, 1223, 1157, 1087,
1018, 911, 856, 767, 747 cm-1; 1H NMR (400 MHz, CDCl3) d 8.16
(d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.59 (s, 1H), 7.37–7.33
(m, 1H), 7.29–7.25 (m, 1H), 4.84 (s, 2H), 2.09 (br s, 1H), 1.68 (s,
9H); 13C NMR (100 MHz, CDCl3) d 149.7, 135.7, 129.2, 124.6,
123.7, 122.7, 120.5, 119.3, 115.3, 83.7, 57.1, 28.2, 27.9; HRMS-
ES+: [M Boc/-OH] calcd for C9H7N, 130.0657; found, 130.0647.
To a stirred solution of the above alcohol (720 mg, 2.9 mmol) in
dry CH2Cl2 (30 mL) at rt were added Et3N (0.91 mL, 6.5 mmol),
N,N¢-diisopropylcarbodiimide (0.55 mL, 3.5 mmol), DMAP (cat.)
and cyanoacetic acid (300 mg, 3.5 mmol) and the resultant solution
was stirred at rt for 2 d. CH2Cl2 (50 mL) and brine (50 mL) were
added. The organic layer was dried over sodium sulfate, the solvent
removed under reduced pressure and the residue was purified by
flash column chromatography on silica gel (6 : 4 petrol : EtOAc
with 1% Et3N) to afford tert-butyl 3-((2-cyanoacetoxy)methyl)-
1H-indole-1-carboxylate (1c, 510 mg, 55% over 2 steps). nmax (film)
3458, 3056, 2980, 2933, 2264, 2112, 1755, 1734, 1716, 1610, 1477,
1455, 1392, 1359, 1300, 1258, 1157, 1091, 1010, 984, 855, 767, 748,
581 cm-1; 1H NMR (400 MHz, CDCl3) d 8.19 (d, J = 8.4 Hz, 1H),
To a stirred solution of 1H-indole-3-carbaldehyde (2.25 g,
15.5 mmol) in dry CH2Cl2 (50 mL) at rt were added DMAP (cat.),
Et3N (3.2 mL, 23.2 mmol) and BOC2O (5.3 mL, 23.2 mmol) and
the resultant solution was stirred at rt overnight. Brine (50 mL)
and CH2Cl2 (50 mL) were added. The organic layer was dried over
magnesium sulfate, the solvent removed under reduced pressure
to give tert-butyl 3-formyl-1H-indole-1-carboxylate (3.8 g, 100%),
which was used without further purification and had spectra
identical to that reported in the literature;16 1H NMR (400 MHz,
CDCl3) d 10.13 (s, 1H), 8.31 (d, J = 6.9 Hz, 1H), 8.26 (s, 1H), 8.17
(d, J = 7.7 Hz, 1H), 7.45–7.28 (m, 2H), 1.73 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 185.8, 148.8, 136.5, 135.9, 126.1, 124.6, 122.1,
121.5, 115.1, 85.6, 28.1.
To a stirred solution of the above crude aldehyde (1.3 g,
5.3 mmol) in dry THF (50 mL) at 0 ◦C was added MeMgCl
(3.8 mL, 2.8 M solution in THF, 10.6 mmol) and the resultant
solution was stirred for 1 h at 0 ◦C. Brine (40 mL) and EtOAc
(40 mL) were added. The organic layer was dried over magnesium
sulfate, the solvent removed under reduced pressure to give
tert-butyl 3-(1-hydroxyethyl)-1H-indole-1-carboxylate, which was
used without further purification.1H NMR (400 MHz, CDCl3) d
8.16 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H),
7.36–7.33 (m, 1H), 7.28–7.25 (m, 1H), 5.19 (q, 6.8 Hz, 1H), 2.00
(br s, 1H), 1.69 (s, 9H), 1.67 (d, J = 6.8 Hz, 3H).
To a stirred solution of the above crude alcohol (5.0 mmol) in
dry CH2Cl2 (20 mL) at rt were added Et3N (1.5 mL, 11.0 mmol),
DIC (0.93 mL, 6.0 mmol) and tosylacetic acid (1.2 g, 5.0 mmol)
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and the resultant mixture was stirred at rt for 2 d. Brine (50 mL)
and CH2Cl2 (50 mL) were added. The organic layer was dried over
magnesium sulfate, the solvent removed under reduced pressure
and the residue was purified by flash column chromatography
on silica gel (7 : 3 petrol : EtOAc with 1% Et3N) to afford tert-
butyl 3-(1-(2-tosylacetoxy)ethyl)-1H-indole-1-carboxylate (1e, 1.2
g, 52%). nmax (film) 2981, 2934, 1738, 1732, 1455, 1371, 1257, 1152,
over sodium sulfate, the solvent removed under reduced pressure
and the residue was purified by flash column chromatography on
silica gel (8 : 2 petrol : EtOAc with 1% Et3N) to afford 1-(1-(tert-
butoxycarbonyl)-1H-indol-3-yl)ethyl ethyl malonate (1g, 1.57 g,
69%). nmax (film) 2981, 2936, 1737, 1731, 1454, 1371, 1157, 765
cm-1; 1H NMR (400 MHz, CDCl3) d 8.18–8.16 (m, 1H), 7.66–7.63
(m, 2H), 7.37–7.33 (m, 1H), 7.29–7.25 (m, 1H), 6.30 (q, J = 6.4
Hz, 1H), 4.49 (q, J = 7.2 Hz, 2H), 3.41 (s, 2H), 1.75 (d, J = 6.4
Hz, 3H), 1.70 (br s, 9H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) d 166.4, 166.0, 149.5, 135.7, 128.3, 124.6, 123.4,
122.7, 120.4, 119.7, 115.4, 83.9, 67.2, 61.5, 41.9, 28.1, 20.2, 14.0;
HRMS-ES+: [M+Na] calcd for C20H25NO6Na, 398.1580; found,
398.1577.
1
1025, 767 cm-1; H NMR (400 MHz, CDCl3) d 8.15 (d, J = 8.0
Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.57 (s, 1H), 7.48 (d, J = 8.0
Hz, 1H), 7.33–7.29 (m, 1H), 7.21–7.18 (m, 1H), 7.13 (d, J = 8.0
Hz, 2H), 6.21 (q, J = 6.8 Hz, 1H), 4.12 (s, 2H), 2.33 (s, 3H), 1.66
(s, 9H), 1.62 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
161.9, 149.5, 145.3, 135.7, 129.7, 128.5, 128.1, 124.8, 123.7, 122.8,
119.7, 115.4, 84.1, 68.3, 61.2, 28.2, 21.7, 20.2; HRMS-ES+: [M+]
calcd for C24H27NO6SNa, 480.1457; found, 480.1456.
1-(1-Tosyl-1H-indol-3-yl)ethyl 2-tosylacetate (1h)
To a stirred solution of 1-tosyl-1H-indole-3-carbaldehyde (1.9 g,
6.4 mmol) in dry THF (100 ml) at 0 ◦C was added MeMgCl
(4.5 mL, 2.8 M solution in THF, 12.7 mmol) and the resultant
solution was stirred at 0 ◦C for 1 h. A saturated aqueous solution
of ammonium chloride (50 mL) and EtOAc (50 mL) were added.
The organic layer was dried over magnesium sulfate, the solvent
removed under reduced pressure to give an alcohol, which was
used without further purification.
To a stirred solution of the above crude alcohol (6.4 mmol) in
dry CH2Cl2 (40 mL) at rt were added Et3N (1.9 mL, 13.9 mmol),
EDCI (1.4 g, 7.6 mmol) and tosylacetic acid (1.4 mg, 6.3 mmol)
and the resultant solution was stirred at rt for 2 d. CH2Cl2 (50 mL)
and brine (50 mL) were added. The organic layer was dried over
sodium sulfate, the solvent removed under reduced pressure and
the residue was purified by flash column chromatography on silica
gel (7 : 3 petrol : EtOAc with 1% Et3N) to afford 1-(1-tosyl-1H-
indol-3-yl)ethyl 2-tosylacetate (1h, 2.3 g, 71% over 2 steps). nmax
(film) 2936, 1740, 1653, 1596, 1494, 1448, 1327, 1175, 1152, 1129,
1086, 748 cm-1;1H NMR (400 MHz, CDCl3) d 8.00–7.98 (m, 1H),
7.81–7.79 (m, 2H), 7.65–7.63 (m, 2H), 7.60 (s, 1H), 7.47–7.45 (m,
1H), 7.35–7.32 (m, 1H), 7.22–7.20 (m, 3H), 7.12–7.10 (m, 2H),
6.17 (q, J = 6.8 Hz, 1H), 4.14 (br s, 2H), 2.34 (br s, 3H), 2.28 (br
s, 3H), 1.62 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
161.8, 145.5, 145.2, 135.5, 135.0, 134.9, 130.0, 129.7, 128.3, 126.9,
125.0, 123.9, 123.4, 121.5, 120.2, 113.6, 67.9, 61.1, 21.6, 21.5, 20.2;
HRMS-ES+: [M+Na] calcd for C26H25NO6S2Na, 534.1021; found,
534.1017.
tert-Butyl 3-(1-(2-cyanoacetoxy)ethyl)-1H-indole-1-carboxylate
(1f)
To
a
stirred solution of tert-butyl 3-formyl-1H-in◦dole-1-
carboxylate (2.7 g, 11.0 mmol) in dry THF (100 ml) at 0 C was
added MeMgCl (7.9 mL, 2.8 M solution in THF, 22.0 mmol) and
the resultant solution was stirred at 0 ◦C for 1 h. A saturated
aqueous solution of ammonium chloride (50 mL) and EtOAc
(50 mL) were added. The organic layer was dried over magnesium
sulfate, the solvent removed under reduced pressure to give
tert-butyl 3-(1-hydroxyethyl)-1H-indole-1-carboxylate, which was
used without further purification. 1H NMR (400 MHz, CDCl3) d
8.16 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H),
7.36–7.33 (m, 1H), 7.28–7.25 (m, 1H), 5.19 (q, 6.8 Hz, 1H), 2.00
(br s, 1H), 1.69 (s, 9H), 1.67 (d, J = 6.8 Hz, 3H).
To a stirred solution of the above crude alcohol (2.5 g,
9.57 mmol) in dry CH2Cl2 (25 mL) at rt were added Et3N (2.9 mL,
21.0 mmol), DIC (1.8 mL, 11.5 mmol) and cyanoacetic acid
(980 mg, 11.5 mmol) and the resultant solution was stirred at
rt for 4 d. CH2Cl2 (50 mL) and brine (50 mL) were added. The
organic layer was dried over sodium sulfate, the solvent removed
under reduced pressure and the residue was purified by flash
column chromatography on silica gel (7 : 3 petrol : EtOAc with 1%
Et3N) to afford tert-butyl 3-(1-(2-cyanoacetoxy)ethyl)-1H-indole-
1-carboxylate (1f, 2.25 g, 72% over 2 steps). nmax (film) 2981, 2934,
1733, 1730, 1455, 1371, 1319, 1257, 1225, 1152, 1098, 1025, 855,
1
767, 749 cm-1; H NMR (400 MHz, CDCl3) d 8.18 (d, J = 8.0
Hz, 1H), 7.66–7.65 (m, 2H), 7.38–7.35 (m, 1H), 7.31–7.27 (m,
1H), 6.31 (q, J = 6.8 Hz, 1H), 3.47 (s, 2H), 1.78 (d, J = 6.8 Hz,
3H), 1.70 (s, 9H); 13C NMR (100 MHz, CDCl3) d 162.4, 149.4,
135.7, 128.0, 124.8, 123.8, 122.9, 119.5, 115.5, 113.0, 84.2, 69.1,
28.1, 24.9, 20.3; HRMS-ES+: [M Boc/-CO2CH2CN] calcd for
C10H10N, 144.0813; found, 144.0804.
3-Methylene-1-tosyl-2-(tosylmethyl)indoline (2a)
To a microwave vial containing (1-tosyl-1H-indol-3-yl)methyl 2-
tosylacetate (1a, 880 mg, 1.8 mmol) at rt in dry toluene (4.5
ml, 0.4 M solution of reactants) were added KOAc (175 mg,
1.8 mmol) and BSA (0.65 mL, 2.7 mmol). The resultant mixture
was exposed to 5 cycles of microwave irradiation of 1 min
each at 150 ◦C with one minute of air assisted cooling between
cycles. The solution was allowed to cool, and brine (30 mL)
and CH2Cl2 (30 mL) were added. The organic layer was dried
over sodium sulfate, the solvent removed under reduced pressure
and the residue was purified by flash column chromatography on
silica gel (6 : 4 petrol : EtOAc with 1% Et3N) to give 3-methylene-
1-tosyl-2-(tosylmethyl)indoline (2a, 260 mg, 32%), which had
data in agreement with that reported in the literature;51H NMR
1-(1-(tert-Butoxycarbonyl)-1H-indol-3-yl)ethyl ethyl malonate
(1g)
To a stirred solution of tert-butyl 3-(1-hydroxyethyl)-1H-indole-
1-carboxylate (1.6 g, 6.1 mmol) in dry CH2Cl2 (15 mL) at rt were
added Et3N (1.9 mL, 13.5 mmol), DIC (1.1 mL, 7.4 mmol), DMAP
(cat.) and ethyl hydrogen malonate (0.87 mL, 7.4 mmol) and
the resultant solution was stirred at rt for 2 d. CH2Cl2 (50 mL)
and brine (50 mL) were added. The organic layer was dried
7908 | Org. Biomol. Chem., 2011, 9, 7904–7912
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(400 MHz, CDCl3) d 7.87–7.85 (m, 2H), 7.71–7.69 (m, 1H), 7.51–
7.49 (m, 2H), 7.39–7.35 (m, 2H), 7.33–7.31 (m, 1H), 7.29–7.27 (m,
1H), 7.19–7.17 (m, 2H), 7.11–7.07 (m, 1H), 5.59–5.57 (m, 2H),
5.03–5.00 (m, 1H), 4.06–4.02 (m, 1H), 3.73–3.67 (m, 1H), 2.49 (s,
3H), 2.35 (s, 3H); HRMS-ES+: [M+Na] calcd for C22H25NO4SNa,
422.1402; found, 422.1390.
mixture was exposed to 4 cycles of microwave irradiation of 1 min
each at 150 ◦C with one minute of air assisted cooling between
cycles. The solution was allowed to cool, and brine (30 mL)
and EtOAc (30 mL) were added. The organic layer was dried
over sodium sulfate, the solvent removed under reduced pressure
and the residue was purified by flash column chromatography
on silica gel (7 : 3 petrol : EtOAc with 1% Et3N) to give tert-
butyl 2-(2-ethoxy-2-oxoethyl)-3-methyleneindoline-1-carboxylate
(2d, 220 mg, 22%), which upon exposure to silica gel rearomatised
to give tert-butyl 2-(2-ethoxy-2-oxoethyl)-3-methyl-1H-indole-1-
tert-Butyl 3-methylene-2-(tosylmethyl)indoline-1-carboxylate (2b)
To a microwave vial containing tert-butyl 3-((2-tosylacetoxy)-
methyl)-1H-indole-1-carboxylate (1b, 1.5 g, 3.4 mmol) at rt in dry
toluene (8.5 ml, 0.4 M solution of reactants) were added KOAc
(330 mg, 3.4 mmol) and BSA (1.3 mL, 5.1 mmol). The resultant
mixture was exposed to 4 cycles of microwave irradiation of 1 min
each at 150 ◦C with one minute of air assisted cooling between
cycles. The solution was allowed to cool, and brine (30 mL)
and CH2Cl2 (30 mL) were added. The organic layer was dried
over sodium sulfate, the solvent removed under reduced pressure
and the residue was purified by flash column chromatography on
silica gel (8 : 2 petrol : EtOAc with 1% Et3N) to give tert-butyl
3-methylene-2-(tosylmethyl)indoline-1-carboxylate (2b, 910 mg,
68%). nmax (film) 2979, 2929, 1732, 1597, 1453, 1370, 1323, 1158,
1
carb-oxylate. H NMR (400 MHz, CDCl3) d 8.12–8.10 (m, 1H),
7.51–7.49 (m, 1H), 7.33–7.24 (m, 2H), 4.22 (q, J = 7.2 Hz, 2H),
4.06 (s, 2H), 2.25 (s, 2H), 1.68 (br s, 9H), 1.28 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 170.4, 150.6, 135.7, 130.3, 128.8,
124.0, 122.3, 118.4, 116.4, 115.6, 83.7, 60.8, 33.2, 28.2, 14.2, 8.7;
HRMS-ES+: [M+Na] calcd for C18H23NO4Na, 340.1525; found,
340.1512.
tert-Butyl 3-ethylidene-2-(tosylmethyl)indoline-1-carboxylate (2e)
To a microwave vial containing tert-butyl 3-(1-(2-tosylacetoxy)-
ethyl)-1H-indole-1-carboxylate (1e, 1.1 g, 2.4 mmol) at rt in dry
toluene (5.8 ml, 0.4 M solution of reactants) were added KOAc
(225 mg, 2.4 mmol) and BSA (0.85 mL, 3.5 mmol). The resulting
mixture was exposed to 4 cycles of microwave irradiation of 1 min
each at 150 ◦C with one minute of air assisted cooling between
cycles. The solution was allowed to cool, and brine (30 mL)
and EtOAc (30 mL) were added. The organic layer was dried
over sodium sulfate, the solvent removed under reduced pressure
and the residue was purified by flash column chromatography on
silica gel (7 : 3 petrol : EtOAc with 1% Et3N) to give tert-butyl
3-ethylidene-2-(tosylmethyl)indoline-1-carboxylate (2e, 860 mg,
87%) as a 1 : 0.6 mixture of alkene isomers. nmax (film) 2976, 2929,
1710, 1701, 1597, 1477, 1392, 1318, 1165, 1140, 1086, 750 cm-1;1H
NMR (400 MHz, CDCl3) d 7.60–7.58 (m, 2H), 7.47–7.43 (m,
2.5 H), 7.29–7.22 (m, 3.5 H), 7.18–7.16 (m, 2H), 5.96–5.90 (m,
0.6H), 5.87–5.82 (m, 1H), 5.38 (br s, 0.6H), 5.23 (br s, 1H), 3.83
(br s, 1.2H), 3.61–3.50 (m, 2H), 2.42–2.41 (m, 5H), 1.95 (dd,
J = 7, 2 Hz, 3H), 1.86 (br s, 1.8H), 1.55 (br s, 15H);13C NMR
(100 MHz, CDCl3) d 144.1, 137.7, 137.3, 129.4, 129.2, 128.6,
128.4, 127.7, 127.6, 124.4, 122.7, 122.6, 120.3, 116.3, 115.8, 115.6,
81.9, 59.7, 28.2, 21.4, 14.8, 14.1; HRMS-ES+: [M+Na] calcd for
C23H27NO4SNa, 436.1559; found, 435.1547.
1
1085, 751 cm-1; H NMR (400 MHz, CDCl3) d 7.85 (br s, 1H),
7.61 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.28–7.23 (m,
3H), 7.03–6.99 (m, 1H), 5.59 (d, J = 1.6 Hz, 1H), 5.32 (br s, 1H),
5.28 (br s, 1H), 3.86 (br s, 1H), 3.62–3.58 (m, 1H), 2.42 (s, 3H), 1.52
(s, 9H); 13C NMR (100 MHz, CDCl3) d 144.4, 137.7, 129.9, 129.6,
127.8, 122.9, 120.6, 104.9, 82.2, 60.4, 59.0, 28.3, 21.6; HRMS-ES+:
[M+Na] calcd for C24H23NO4S2Na, 476.0966; found, 476.0966.
tert-Butyl 2-(cyanomethyl)-3-methyleneindoline-1-carboxylate (2c)
To a microwave vial containing tert-butyl 3-((2-cyanoacetoxy)-
methyl)-1H-indole-1-carboxylate (1c, 315 mg, 1.0 mmol) at rt in
dry toluene (2.5 ml, 0.4 M solution of reactants) were added KOAc
(49 mg, 0.5 mmol) and BR SA (0.37 mL, 1.5 mmol). The resulting
mixture was exposed to 4 cycles of microwave irradiation of 1 min
each at 150 ◦C with one minute of air assisted cooling between
cycles. The solution was allowed to cool, and brine (30 mL)
and EtOAc (30 mL) were added. The organic layer was dried
over sodium sulfate, the solvent removed under reduced pressure
and the residue was purified by flash column chromatography on
silica gel (7 : 3 petrol : EtOAc with 1% Et3N) to give tert-butyl
2-(cyanomethyl)-3-methyleneindoline-1-carboxylate (2c, 190 mg,
70%). nmax (film) 2979, 2931, 2253, 1728, 1456, 1370, 1357, 1329,
1231, 1133, 1119, 756 cm-1;1H NMR (400 MHz, CDCl3) d 7.95
(br s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.30–7.27 (m, 1H), 7.06–
7.02 (m, 1H), 5.66 (s, 1H), 5.27 (s, 1H), 4.95 (br s, 1H), 3.05–2.90
(m, 2H), 1.61 (s, 9H); 13C NMR (100 MHz, CDCl3) d inter alia
[significant line broadening obr served] 130.5, 123.3, 120.8, 116.4,
115.9, 104.2, 59.4, 28.4; HRMS-ES+: [M Boc] calcd for C11H9N2,
169.0766; found, 169.0754.
tert-Butyl 2-(cyanomethyl)-3-ethylideneindoline-1-carboxylate (2f)
To a microwave vial containing tert-butyl 3-(1-(2-cyanoacetoxy)-
ethyl)-1H-indole-1-carboxylate (1f, 1.5 g, 4.5 mmol) at rt in dry
toluene (10 ml, 0.4 M solution of reactants) were added KOAc
(450 mg, 4.5 mmol) and BSA (1.69 mL, 6.8 mmol). The resulting
mixture was exposed to 5 cycles of microwave irradiation of 1 min
each at 150 ◦C with one minute of air assisted cooling between
cycles. The solution was allowed to cool, and brine (30 mL)
and EtOAc (30 mL) were added. The organic layer was dried
over sodium sulfate, the solvent removed under reduced pressure
and the residue was purified by flash column chromatography on
silica gel (8 : 2 petrol : EtOAc with 1% Et3N) to give tert-butyl
2-(cyanomethyl)-3-ethylideneindoline-1-carboxylate (2f, 1.06 g,
82%) as a 1 : 1 mixture of alkene isomers. nmax (film) 3446, 2977,
tert-Butyl 2-(2-ethoxy-2-oxoethyl)-3-methyl-1H-indole-1-carboxy-
late (2d)
To a microwave vial containing (1-(tert-butoxycarbonyl)-1H-
indol-3-yl)methyl ethyl malonate (1d, 1.15 g, 3.2 mmol) at rt in dry
toluene (8.0 ml, 0.4 M solution of reactants) were added KOAc
(315 mg, 3.2 mmol) and BSA (1.2 mL, 4.8 mmol). The resulting
This journal is
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Org. Biomol. Chem., 2011, 9, 7904–7912 | 7909
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2926, 2854, 2253, 1732, 1599, 1478, 1455, 1371, 1289, 1256, 1150,
1119, 748 cm-1;1H NMR (400 MHz, CDCl3) d 7.95 (br s, 1H), 7.61
(d, J = 7.6 Hz, 1H), 7.50 (br s, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.28–
7.25 (m, 2H), 7.09–7.00 (m, 2H), 6.15 (br s, 1H), 5.91–5.85 (m,
1H), 5.27–5.16 (m, 1H), 4.89 (br s, 1H), 3.25 (br s, 1H), 3.05–2.75
(m, 3H), 2.10 (dd, J = 1.6, 7.6 Hz, 3H), 1.94 (d, J = 7.2 Hz, 3H),
1.63 (s, 9H), 1.61 (s, 9H); 13C NMR (100 MHz, CDCl3) d inter alia
[significant line broadening observed] 129.2, 124.8, 123.2, 120.0,
116.7, 115.8, 60.2, 57.6, 28.4, 14.4; HRMS-ES+: [M-BOC] calcd
for C12H11N2, 183.0922; found, 183.0914.
129.8, 129.5, 128.7, 128.1, 126.9, 124.3, 121.0, 116.5, 104.3, 60.8,
56.6, 22.4, 21.5, 21.3; HRMS-ES+: [M+H] calcd for C25H26NO4S2,
468.1303; found, 468.1296.
2-Methyl-1-tosylindolin-3-one (4)
To a stirred solution of 2-methyl-1-tosyl-3-(2-tosylethylidene)-
indoline (3, 285 mg, 0.61 mmol) in dry CH2Cl2 (20 mL) at -78 ◦C
was bubbled though O3/O2 (30 min). Me2S (1.0 mL) was added
and the resultant mixture was stirred at rt overnight. The solvent
was removed under reduced pressure and the residue was purified
by flash column chromatography on silica gel (6 : 4 petrol : EtOAc)
to give 2-methyl-1-tosylindolin-3-one (4, 150 mg, 82%). nmax (film)
3067, 2979, 2926, 1721, 1603, 1462, 1360, 1171, 1087, 954, 764,
661 cm-1;1H NMR (400 MHz, CDCl3) d 8.04 (d, J = 8.4 Hz,
1H), 7.70–7.61 (m, 4H), 7.23–7.17 (m, 3H), 3.98 (q, J = 6.8 Hz,
1H), 2.34 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 198.3, 152.6, 144.8, 137.2, 133.3, 131.0, 129.8, 127.0,
124.4, 123.8, 116.6, 63.2, 21.3, 17.7; HRMS-ES+: [M+H] calcd
for C16H16NO3S, 302.0851; found, 302.0836.
tert-Butyl 2-(2-ethoxy-2-oxoethyl)-3-ethylideneindoline-1-
carboxylate (2g)
To a microwave vial containing 1-(1-(tert-butoxycarbonyl)-1H-
indol-3-yl)ethyl ethyl malonate (1g, 1.2 g, 3.2 mmol) at rt in dry
toluene (8.0 ml, 0.4 M solution of reactants) were added KOAc
(310 mg, 3.2 mmol) and BSA (1.2 mL, 4.8 mmol). The resulting
mixture was exposed to 4 cycles of microwave irradiation of 1 min
each at 150 ◦C with one minute of air assisted cooling between
cycles. The solution was allowed to cool, and brine (30 mL)
and EtOAc (30 mL) were added. The organic layer was dried
over sodium sulfate, the solvent removed under reduced pressure
and the residue was purified by flash column chromatography
on silica gel (7 : 3 petrol : EtOAc with 1% Et3N) to give tert-
butyl 2-(2-ethoxy-2-oxoethyl)-3-ethylideneindoline-1-carboxylate
(2g, 560 mg, 53%) as a 2 : 1 mixture of alkene isomers. nmax (film)
2977, 2931, 1734, 1709, 1464, 1391, 1163, 748 cm-1;1H NMR (400
MHz, CDCl3) d 7.90 (br s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.20 (t,
J = 10.9 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 5.68 (q, J = 7.2 Hz, 1H),
5.07 (br s, 1H), 4.11–4.03 (m, 2H), 2.87–2.65 (m, 2H), 2.00 (d, J =
7.2 Hz, 3H), 1.56 (br s, 9H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) d inter alia [significant line broadening observed]
170.6, 128.7, 124.6, 122.5, 118.1, 115.5, 61.2, 60.4, 28.4, 14.3, 14.1;
HRMS-ES+: [M+Na] calcd for C19H25NO4Na, 354.1681; found,
354.1680.
tert-Butyl 3-((2-cyanoacetoxy)methyl)-2-phenyl-1H-indole-1-
carboxylate (5)
To a stirred solution of tert-butyl 3-(hydroxymethyl)-2-phenyl-1H-
indole-1-carboxylate (2.1 g, 6.5 mmol) in dry CH2Cl2 (13 mL) at
rt were added Et3N (2.0 mL, 14.3 mmol), EDCI (1.5 g, 7.8 mmol),
DMAP (cat.) and cyanoacetic acid (660 mg, 7.8 mmol) and the
resultant solution was stirred for 2 d at rt. CH2Cl2 (50 mL) and
brine (50 mL) were added. The organic layer was dried over
sodium sulfate, the solvent removed under reduced pressure and
the residue was purified by flash column chromatography on silica
gel (8 : 2 petrol : EtOAc with 1% Et3N) to afford tert-butyl 3-((2-
cyanoacetoxy)methyl)-2-phenyl-1H-indole-1-carboxylate (5, 1.5
g, 59%). nmax (film) 3056, 2980, 2932, 2256, 1731, 1454, 1369,
1324, 1222, 1152, 1081, 911, 734, 701 cm-1; 1H NMR (400 MHz,
CDCl3) d 8.32 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H),
7.52–7.41 (m, 6H), 7.38–7.34 (m, 1H), 5.25 (s, 2H), 3.44 (s, 2H),
1.28 (s, 9H); 13C NMR (100 MHz, CDCl3) d 162.7, 149.6, 139.8,
136.2, 132.5, 129.5, 128.2, 128.0, 127.9, 124.9, 123.1, 118.7, 115.2,
113.5, 112.8, 83.6, 59.8, 27.2, 24.5; HRMS-ES+: [M+Na] calcd
for C23H22N2O4Na, 413.1477; found, 413.1481.
2-Methyl-1-tosyl-3-(2-tosylethylidene)indoline (3)
To a microwave vial containing 1-(1-tosyl-1H-indol-3-yl)ethyl 2-
tosylacetate (1h, 2.0 g, 3.9 mmol) at rt in dry toluene (10 ml, 0.4
M solution of reactants) were added KOAc (380 mg, 3.9 mmol)
and BSA (0.98 mL, 5.9 mmol). The resulting mixture was exposed
to 5 cycles of microwave irradiation of 1 min each at 150 ◦C
with one minute of air assisted cooling between cycles. The
solution was allowed to cool, and brine (30 mL) and CH2Cl2
(30 mL) were added. The organic layer was dried over sodium
sulfate, the solvent removed under reduced pressure and the
residue was purified by flash column chromatography on silica
gel (6 : 4 petrol : EtOAc with 1% Et3N) to give 2-methyl-1-tosyl-
3-(2-tosylethylidene)indoline (3, 1.1 g, 60%) as a 2 : 1 mixture of
alkene isomers. Data is for the major isomer. nmax (film) 3408,
2979, 2927, 1598, 1463, 1352, 1168, 1086, 731 cm-1;1H NMR (400
MHz, CDCl3) d 7.69 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.0 Hz,
1H), 7.60 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.30 (d,
J = 7.6 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.06–7.02 (m, 1H), 5.65
(dt, J = 2.0, 8.0 Hz, 1H), 4.97–4.93 (m, 1H), 3.99–3.82 (m, 2H),
2.45 (s, 3H), 2.32 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) d 146.6, 145.0, 143.9, 142.8, 135.8, 134.5, 130.5,
tert-Butyl 2-(cyanomethyl)-3-methylene-2-phenylindoline-1-
carboxylate (6)
To a microwave vial containing tert-butyl 3-((2-cyanoacetoxy)-
methyl)-2-phenyl-1H-indole-1-carboxylate (5, 1.0 g, 2.6 mmol) at
rt in dry toluene (10.5 ml, 0.4 M solution of reactants) were added
KOAc (410 mg, 3.4 mmol) and BSA (1.6 mL, 6.3 mmol). The
resulting mixture was exposed to 4 cycles of microwave irradiation
◦
of 1 min each at 150 C. The solution was allowed to cool, and
brine (30 mL) and CH2Cl2 (30 mL) were added. The organic
layer was dried over sodium sulfate, the solvent removed under
reduced pressure and the residue was purified by flash column
chromatography on silica gel (8 : 2 petrol : EtOAc with 1% Et3N)
to give tert-butyl 2-(cyanomethyl)-3-methylene-2-phenylindoline-
1-carboxylate (6, 500 mg, 56%). nmax (film) 2979, 2932, 2350,
1
2341, 2264, 1736, 1453, 1389, 1259, 1157, 1091, 768 cm-1; H
NMR (400 MHz, CDCl3) d 8.18 (br s, 1H), 7.52–7.50 (m, 1H),
7910 | Org. Biomol. Chem., 2011, 9, 7904–7912
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7.42–7.32 (m, 4H), 7.22–7.20 (m, 2H), 7.13–7.09 (m, 1H), 5.62 (s,
1H), 4.84 (s, 1H), 3.73 (br s, 1H), 3.45–3.41 (m, 1H), 1.22 (br s,
9H); 13C NMR (100 MHz, CDCl3) d 150.4, 149.4, 144.0, 142.8,
130.6, 128.5, 127.5, 126.0, 123.8, 123.2, 120.6, 116.0, 115.4, 104.3,
82.0, 70.4, 28.3, 27.6; HRMS-ES+: [M+H] calcd for C22H23N2O2,
347.1760; found, 347.1756.
gel (1 : 1 petrol : EtOAc) to afford tert-butyl 3-(hydroxymethyl)-2-
(tosylmethyl)-1H-indole-1-carboxylate (9, 55 mg, 58%). nmax (film)
3444, 2926, 2360, 1732, 1597, 1453, 1325, 1159, 1128, 750 cm-1; 1H
NMR (400 MHz, CDCl3) d 7.96 (d, J = 8.0 Hz, 1H), 7.74 (d, J =
7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.37–7.24 (m, 4H), 5.30 (s,
2H), 4.74 (s, 2H), 2.42 (s, 3H), 1.58 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 150.0, 144.9, 136.3, 135.5, 129.7, 128.6, 125.5, 125.0,
124.4, 123.2, 119.4, 115.8, 84.4, 54.9, 53.8, 29.7, 28.0, 22.7, 21.6;
HRMS-ES+: [M+ -BOC/-OH] calcd for C17H16NO2S, 298.0902;
found, 298.0888.
3-(2-Hydroxypropyl)-1-tosyl-2-(tosylmethyl)indole (7)
To a stirred solution of 3-methylene-1-tosyl-2-(tosylmethyl)-
indoline (2a, 18 mg, 0.039 mmol) in dry CH2Cl2 (1.5 mL) at
0
◦C were added acetaldehyde (0.004 mL, 0.079 mmol) and
ZnCl2 (10 mg, 0.079 mmol) and the resultant mixture was stirred
at 0 ◦C for 3.5 h followed by stirring overnight at rt. Brine
(10 mL) and CH2Cl2 (10 mL) were added. The organic layer
was dried over magnesium sulfate, the solvent removed under
reduced pressure and the residue was purified by preparative
chromatography (6 : 4 petrol : EtOAc) to give 3-(2-hydroxypropyl)-
1-tosyl-2-(tosylmethyl)indole (7, 4 mg, 21%). nmax (film) 3524,
2964, 2925, 1596, 1451, 1360, 1168, 1147, 1086, 752, 659, 577
cm-1;1H NMR (400 MHz, CDCl3) d 8.02 (d, J = 8.4 Hz, 1H), 7.70
(d, J = 8. Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.38–7.36 (m, 1H),
7.33–7.31 (m, 2H), 7.28–7.22 (m, 2H), 7.01 (d, J = 8.0 Hz, 2H),
5.25 and 5.05 (d, J = 14.4 Hz, both 1H), 3.43–3.40 (m, 1H), 2.86–
2.83 (m, 1H), 2.70–2.65 (m, 1H), 2.48 (s, 3H), 2.25 (s, 3H), 0.36 (d,
J = 6.0 Hz, 3H); HRMS-ES+: [M+Na] calcd for C26H27NO5S2Na,
520.1228; found, 520.1224.
tert-Butyl 3-(hydroxymethyl)-2-(tosylmethyl)indoline-1-
carboxylate (10)
To a stirred solution of tert-butyl 3-methylene-2-(tosylmethyl)-
indoline-1-carboxylate (2b, 130 mg, 0.32 mmol) in dry THF (6 mL)
at 0 ◦C was added borane-dimethylsulfide complex (0.8 mL, 2.0 M
solution in THF, 1.6 mmol) and◦the resultant mixture was stirred
at rt for 1.5 h then cooled to 0 C. Water (1.5 mL), 1 M NaOH
(1.5 mL) and 30% H2O2 (0.50 mL) were added and the solution
was stirred at rt for 12 h. EtOAc (50 mL) and brine (50 mL) were
added. The organic layer was dried over sodium sulfate, the solvent
removed under reduced pressure and the residue was purified by
flash column chromatography on silica gel (7 : 3 petrol : EtOAc)
to afford tert-butyl 3-(hydroxymethyl)-2-(tosylmethyl)indoline-1-
carboxylate (10, 90 mg, 69%). nmax (film) 3497, 2975, 2926, 2854,
1704, 1598, 1482, 1386, 1317, 1288, 1252, 1145, 1086, 1017, 754
3-Methyl-1-tosyl-2-(tosylmethyl)indole (8)
1
cm-1; H NMR (400 MHz, CDCl3) d 7.78 (d, J = 8.0 Hz, 2H),
To a stirred solution of 3-methylene-1-tosyl-2-(tosylmethyl)-
indoline (2a, 24 mg, 0.05 mmol) in dry CH2Cl2 (0.5 mL) at rt were
added acetaldehyde (0.006 mL, 0.10 mmol) and ZnCl2 (14 mg,
0.1 mmol) and the resultant mixture was stirred at rt for 3.5 h.
Brine (10 mL) and CH2Cl2 (10 mL) were added. The organic
layer was dried over magnesium sulfate, the solvent removed
under reduced pressure and the residue was purified by preparative
chromatography (6 : 4 petrol : EtOAc) to give 3-methyl-1-tosyl-2-
(tosylmethyl)indole (8, 22 mg, 92%). nmax (film) 3063, 2925, 1597,
1452, 1371, 1319, 1190, 1144, 1088, 753 cm-1;1H NMR (400 MHz,
CDCl3) d 7.97 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.49
(d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.32–7.27 (m, 4H),
7.11 (d, J = 8.0 Hz, 2H), 5.08 (s, 2H), 2.45 (s, 3H), 2.29 (s, 3H),
2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) d 144.9, 144.7, 135.7,
129.6, 129.5, 128.8, 126.4, 125.7, 1238, 119.4, 115.4, 98.4, 53.8,
21.7, 21.5, 20.6; HRMS-ES+: [M+Na] calcd for C24H23NO4S2Na,
476.0966; found, 476.0959.
7.60–7.59 (m, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.21–7.14 (m, 2H),
7.01–6.97 (m, 1H), 5.19–5.16 (m, 1H), 4.34 (dd, J = 4.0, 12.4 Hz,
1H), 4.13–4.09 (m, 1H), 3.87–3.82 (m, 2H), 3.53–3.49 (m, 1H),
2.44 (s, 3H), 1.56 (s, 9H); 13C NMR (100 MHz, CDCl3) d 151.7,
144.9, 142.0, 137.2, 129.9, 128.2, 127.7, 123.4, 123.1, 115.7, 82.1,
60.0, 57.3, 55.9, 46.2, 28.3, 21.6; HRMS-ES+: [M+Na] calcd for
C22H26NO5SNa, 440.1508; found, 440.1519.
tert-Butyl 3-methylene-2-(2-oxoethyl)indoline-1-carboxylate (11)
To a stirred solution of tert-butyl 2-(cyanomethyl)-3-methyl-
eneindoline-1-carboxylate (2c, 140 mg, 0.51 mmol) in dry toluene
(5 mL) at -78 ◦C was added DIBAL-H (0.48 mL, 1.2 M in toluene,
0.57 mmol) and the resultant solution was stirred at 0 ◦C for 3 h
and then at rt for 2 d. Brine (50 mL) and EtOAc (50 mL) were
added. The organic layer was dried over sodium sulfate, the solvent
removed under reduced pressure and the residue was purified
by preparative TLC (8 : 2 petrol : EtOAc) to give tert-butyl 3-
methylene-2-(2-oxoethyl)indoline-1-carboxylate (11, 82 mg, 59%).
nmax (film) 2976, 1707, 1478, 1468, 1382, 1167, 1146, 1118, 750
cm-1; 1H NMR (400 MHz, CDCl3) d 9.76 (t, J = 1 Hz, 1H), 7.44
(d, J = 7.5 Hz, 1H), 7.29 (br t, J = 8 Hz, 1H), 7.03 (t, J = 8
Hz, 1H), 5.57 (d, J = 2 Hz, 1H), 5.27 (br s, 1H), 5.10 (br s, 1H),
3.08–2.90 (m, 2H), 1.60 (s, 9H); 13C NMR (100 MHz, CDCl3) d
inter alia [significant line broadening observed] 199.6, 151.5, 151.2,
145.2, 145.1, 130.2, 127.8, 122.9, 120.5, 115.9, 102.9, 82.1, 59.0,
50.5, 28.3; HRMS-ES+: [M-BOC] calcd for C11H10NO, 172.0762;
found, 172.0758.
tert-Butyl 3-(hydroxymethyl)-2-(tosylmethyl)-1H-indole-1-
carboxylate (9)
To a stirred solution of tert-butyl 3-methylene-2-(tosylmethyl)-
indoline-1-carboxylate (2b, 90 mg, 0.23 mmol) in dry CH2Cl2
(3 mL) at rt was added mCPBA (85 mg, 50% by weight,
0.25 mmol) and the resultant mixture was stirred at rt for 12
h. A saturated aqueous solution of sodium sulfate (10 mL), a
saturated aqueous solution of sodium bicarbonate (10 mL) and
CH2Cl2 (20 mL) were added. The organic layer was dried over
sodium sulfate,15 the solvent removed under reduced pressure and
the residue was purified by flash column chromatography on silica
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tert-Butyl 2-(cyanomethyl)-3-oxoindoline-1-carboxylate (12)
and J. E. MacDonald, J. Org. Chem., 1979, 44, 1885; (c) H. Nemoto,
E. Shitara, K. Fukumoto and T. Kametani, Heterocycles, 1985, 23,
549; (d) K. Shishido, E. Shitara, K. Fukumoto and T. Kametani, J.
Am. Chem. Soc., 1985, 107, 5810; (e) O. Reinaud, P. Capdevielle and
M. Maumy, Synthesis, 1988, 293; (f) S. V. Kuznetsova, A. V. Anisimov
and E. A. Viktorova, Zh. Org. Khim., 1988, 24, 861; (g) D. E. Vogel
and G. H. Bu¨chi, Org. Synth., 1988, 66, 29; (h) S. V. Kuznetsova, A.
M. Egorov, A. V. Anisimov and E. A. Viktorova, Khim. Geterotsikl.
Soedin., 1989, 27; (i) K. Burger, K. Gaa, K. Geith and C. Schierlinger,
Synthesis, 1989, 850; (j) M. Tsubuki, T. Kamata, H. Okita, M. Arai,
A. Shigihara and T. Honda, Chem. Commun., 1999, 2263; (k) F. A.
Akbutina, S. A. Yumagulova, E. V. Vasil’eva and M. S. Miftakhov, Russ.
J. Org. Chem., 2002, 38, 759; (l) K. Burger, L. Hennig, P. Tsouker, J.
Spengler, F. Albericio and B. Koksch, Amino Acids, 2006, 31, 55; (m) Y.-
J. Li, Y.-K. Chang, G.-M. Ho and H.-M. Huang, Org. Lett., 2009, 11,
4224.
7 For other de-aromatising sigmatropic rearrangement reactions of
heteroaromatic substrates, which gave isolable, non-aromatic products,
see: (a) A. Padwa and L. A. Cohen, Tetrahedron Lett., 1982, 23, 915
(oxazoles); (b) T. Usami, N. Shirai and Y. Sato, J. Org. Chem., 1992, 57,
5419 (furans and thiophenes); (c) W. H. Miles, C. L. Berreth and P. M.
Smiley, Tetrahedron Lett., 1993, 34, 5221; W. H. Miles, C. L. Berreth
and C. A. Anderton, Tetrahedron Lett., 1996, 37, 7893; W. H. Miles
and K. B. Connell, Tetrahedron Lett., 2003, 44, 1161; W. H. Miles, E.
A. Dethoff, H. H. Tuson and G. Ulas, J. Org. Chem., 2005, 70, 2862
(Miles’ work was carried out exclusively on furans); (d) P. A. Caruana
and A. J. Frontier, Tetrahedron, 2004, 60, 10921 (furans).
Through a stirred solution of tert-butyl 2-(cyanomethyl)-3-
ethylideneindoline-1-carboxylate (2c, 300 mg, 1.11 mmol) in dry
◦
CH2Cl2 (150 mL) at -78 C was bubbled O3/O2 (15 min). Me2S
(2.0 mL) was added and the resultant mixture was stirred at
rt overnight. The solvent removed under reduced pressure and
the residue was purified by flash column chromatography on
silica gel (7 : 3 petrol : EtOAc) to give tert-butyl 2-(cyanomethyl)-
3-oxoindoline-1-carboxylate (12, 120 mg, 40%). nmax (film) 2979,
1716, 1606, 1466, 1370, 1286, 1152, 1078, 758 cm-1;1H NMR (400
MHz, CDCl3) d 8.09 (br s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.73–7.69
(m, 1H), 7.29 (s, 1H), 7.24–7.21 (m, 1H), 4.37 (br s, 1H), 3.40 (br
s, 1H), 3.12 (dd, J = 3.2, 16.8 Hz, 1H), 1.66 (s, 9H); 13C NMR (100
MHz, CDCl3) d 195.2, 153.2, 150.4, 137.8, 124.1, 123.5, 122.8,
116.8, 114.8, 83.8, 60.1, 28.0, 19.7; HRMS-ES+: [M+H] calcd for
C15H17N2O3, 273.1239; found, 273.1232.
Acknowledgements
This work was supported by the EPSRC (postdoctoral asso-
ciateships to J.E.C. and K.F. through responsive-mode grant
EP/F015356). We thank Mr. Pete Haycock for the NMR experi-
ments.
8 J. E. Camp and D. Craig, Tetrahedron Lett., 2009, 50, 3503.
9 Solvents which we have found to be effective in other dCr reactions,
such as DMF and MeCN performed poorly in these transformations.
See: S. J. Gore, PhD thesis, Imperial College, 2009.
10 (a) T. Durand-Reville, L. B. Gobbi, B. L. Gray, S. V. Ley and J. S. Scott,
Org. Lett., 2002, 4, 3847; (b) J. Siu, I. R. Baxendale and S. V. Ley, Org.
Biomol. Chem., 2004, 2, 160.
Notes and references
1 (a) D. Bourgeois, D. Craig, N. P. King and D. M. Mountford, Angew.
Chem., Int. Ed., 2005, 44, 618; (b) D. Craig and F. Grellepois, Org.
Lett., 2005, 7, 463; (c) D. Bourgeois, D. Craig, F. Grellepois, D. M.
Mountford and A. J. W. Stewart, Tetrahedron, 2006, 62, 483; (d) D.
Craig and G. D. Henry, Eur. J. Org. Chem., 2006, 3558; (e) D. Craig,
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Craig, F. Paina and S. C. Smith, Chem. Commun., 2008, 3408; (g) D.
Craig and N. K. Slavov, Chem. Commun., 2008, 6054.
2 R. E. Ireland and R. H. Mueller, J. Am. Chem. Soc., 1972, 94, 5897.
For reviews of the Ireland–Claisen rearrangement, see: (a) S. Pereira
and M. Srebnik, Aldrichim. Acta, 1993, 26, 17; (b) Y. Chai, S. Hong, H.
A. Lindsay, C. McFarland and M. McIntosh, Tetrahedron, 2002, 58,
2905.
11 Crystal data for Z-3: C25H25NO4S2·0.10H2O, M = 469.38, triclinic,
¯
˚
P1 (no. 2), a = 9.1743(3), b ◦= 9.9834(4), c = 13.0708(4) A, a = 79.253(3),
3
-3
˚
b = 76.645(3), g = 86.290(3) , V = 1144.06(7) A , Z = 2, Dc = 1.363 g cm ,
m(Mo-Ka) = 0.266 mm-1, T = 173 K, pale yellow platy needles, Oxford
Diffraction Xcalibur 3 diffractometer; 5098 independent measured
reflections (Rint = 0.0160), F2 refinement, R1(obs) = 0.0392, wR2(all) =
0.1024, 3652 independent observed absorption-corrected reflections
[|Fo| > 4s(|Fo|), 2qmax = 58◦], 295 parameters. CCDC 775144.
12 It is not clear why 1,2-addition of TsH is not observed across the C3-
vinyl group in the second of the two dienes formed during conversion
of 2h into 3. We thank a referee for raising this point.
13 For examples, see: (a) T. Sakamoto, Y. Kondo, M. Uchiyama and H
Yamanaka, J. Chem. Soc., Perkin Trans. 1, 1993, 1941; (b) D. L. Boger,
T. Ishizaki, R. J. Wysocki Jr. and S. A. Munk, J. Am. Chem. Soc., 1989,
111, 6461.
3 For a review of the Claisen and related rearrangements, see: A. M.
Castro, Chem. Rev., 2004, 104, 2939.
4 For a review of catalysis of the Claisen rearrangement, see: K. C.
Majumdar, S. Alam and B. Chattopadhyay, Tetrahedron, 2008, 64, 597.
5 D. Craig, N. P. King, J. T. Kley and D. M. Mountford, Synthesis, 2005,
3279.
14 For examples, see: (a) M. Yamanaka, A Nishida and M. Nakagawa,
J. Org. Chem., 2003, 68, 3112; (b) D. Ferraris, B. Young, C. Cox, T.
Dudding, W. J. Drury III, L. Ryzhkov, A. E. Taggi and T. Lectka, J.
Am. Chem. Soc., 2002, 124, 67.
6 For other transiently de-aromatising sigmatropic rearrangement reac-
tions of furans, which gave aromatic products, see: (a) A. F. Thomas and
M. J. Ozainne, J. Chem. Soc. C, 1970, 220; (b) S. Raucher, A. S. T. Lui
15 M. Arisawa, Y Terada, K Takahashi, M. Nakagawa and A. Nishida,
J. Org. Chem., 2006, 71, 4255.
16 N. S. Freeman, M. Hurevich and C. Gilon, Tetrahedron, 2009, 65, 1737.
7912 | Org. Biomol. Chem., 2011, 9, 7904–7912
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The Royal Society of Chemistry 2011
©