The coumarin→indole transformation - A method for preparing 4-halo-5-hydroxyindoles from coumarins

Article abstract of DOI:10.1039/b914580j

Readily accessible 3-alkoxycarbonyl-6-hydroxy-5-halocoumarins can be converted into 4-halo-5-hydroxyindoles by a sequence whose essential steps are conjugate reduction or conjugate addition, decarboxylation, lactone opening with ammonia, phenolic oxygen p

Full text of DOI:10.1039/b914580j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The coumarin→indole transformation—a method for preparing
4-halo-5-hydroxyindoles from coumarins†
Elia J. L. Stoffman and Derrick. L. J. Clive*
Received 20th July 2009, Accepted 19th August 2009
First published as an Advance Article on the web 30th September 2009
DOI: 10.1039/b914580j
Readily accessible 3-alkoxycarbonyl-6-hydroxy-5-halocoumarins can be converted into
4-halo-5-hydroxyindoles by a sequence whose essential steps are conjugate reduction or conjugate
addition, decarboxylation, lactone opening with ammonia, phenolic oxygen protection, Hofmann
rearrangement to an N-Boc ethylamine, oxidation to a quinone and deprotection of the nitrogen. The
resulting b-aminoethyl quinone cyclizes to a mixture of quinone imine and indole, and the imine
tautomerizes to the indole spontaneously or on treatment with rhodium on alumina.
1.311 by the same general9a malonate condensation used with 1.1.
Introduction
The phenolic hydroxyl was then protected by mesylation (1.4→1.5,
100%), and treatment with LiBH412 served to generate (100%) the
dihydrocoumarin 1.6. The conversion of 1.5 into 1.6 is a key
step, as the presence of halogen (especially in the subsequent
examples with bromine and iodine) is expected to preclude the
use of catalytic hydrogenation, which is a standard method13 for
making dihydrocoumarins from coumarins. Treatment with 20%
aqueous hydrochloric acid at reflux for 3 h, followed by heating
in PhMe in the presence of a catalytic amount of TsOH·H2O,
served to effect overall decarboxylation of 1.6 to 1.7. This two-step
method was used because attempted Krapcho decarboxylation14
of the methyl ester corresponding to 1.6 was unsuccessful. The
lactone was then opened by passing NH3 through a THF solution
of 1.7.15 At that point, the phenolic hydroxyl was protected by
silylation (1.8→1.9), and then Hofmann rearrangement, mediated
by Pb(OAc)4 in t-BuOH,16 gave the protected amine 1.10 in 68%
overall yield from 1.2. We had initially wanted to avoid the
protection step (1.8→1.9) by oxidizing 1.8 with PhI(OAc)2 in the
presence of water,17 hoping to effect sequential oxidation to a
quinone, Hofmann rearrangement,18 and cyclization to a quinone
imine 419,20 (eqn (1))—all without isolation of intermediates—but
experiments to this end were not successful.21 When the silylated
compound 1.10 was treated with a mixture of NaF and
During preliminary studies on the synthesis of an alkaloid con-
taining a 5-oxyindole subunit, we needed to prepare a protected
4-haloserotonin (1), and became interested in routes to the parent
4-halo-5-hydroxyindoles (2) that have substituents only at C(4) and
C(5). Although there is a very large literature on the preparation
of indoles,1 there are no reports of the 4-halo-5-hydroxyindoles 2,
apart from the 4-fluoro compound,2 which was not relevant to our
requirements. 4-Halo-5-oxyindole derivatives are not very easily
accessed by current methodology. The patent literature describes
the use of 4-mercuration, followed by replacement of mercury by
halogen,3 but a much more convenient method is the Snieckus
lateral deprotonation procedure.4 A few 5-alkoxy-4-haloindoles
are known3,5,6 and, in principle, O-dealkylation could afford the
5-hydroxy-4-haloindoles that were needed; however, we decided
to develop a new synthetic route and report here an approach
that is based on the conversion of readily available coumarins7,8
into indoles. In this new procedure, many of the intermediates are
easily crystallized so that chromatographic purification is usually
not needed.
(1)
Results and discussion
The coumarin 1.2, which served as a common starting material
for the chloro-, bromo- and iodoindoles of type 2, is readily made
(79%) from aldehyde 1.1 by condensation with diethyl malonate
according to a classical procedure (Scheme 1).9 Chlorination with
PhI(OAc)2 in aqueous MeCN it was converted (73–100%)
into quinone 1.11. Finally, treatment with Me3SiOSO2CF3 in
the presence of 2,6-lutidine gave a mixture of indoles 1.12a and
1.12b, which were separated by chromatography.23 The silyl ether
1.12a was transformed cleanly in aqueous MeOH-K2CO3 into the
desired unprotected indole 1.12b, the total yield of this substance
being 78% from 1.11.
During the sequence from the starting aldehyde 1.1, filtration
through a short pad of silica gel (or Florisil) was used to separate
inorganic impurities in the steps using LiBH4 and Pb(OAc)4, but
10
SO2Cl2 gave 1.4 which was also accessible from chloroaldehyde
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada
T6G 2G2. E-mail: derrick.clive@ualberta.ca
† Electronic supplementary information (ESI) available: Experimental
procedures. CCDC reference number 724736. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/b914580j
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Scheme 1 Formation of 4-chloro-5-hydroxyindole. aThe reaction gives
1.12a (15%) and 1.12b (63%). bConversion of 1.11 into 1.12b can also be
done by treatment with BF3·Et2O, followed by Pd–C (cat), PhH, reflux,
60% overall.
Scheme 2 Formation of 4-bromo-5-hydroxyindole. aWith PhI(OAc)2, the
yield was 61–64%. bThe quinone imine is the main product, but some 2.11a
and 2.11b are also formed; the mixture was processed without separation.
cPresumed intermediate, which is accompanied by silylated material. d2.11a
isolated in 26% yield and 2.11b in 74% yield from 2.9.
flash chromatography was used only for isolation of 1.11 and the
final indoles 1.12a and 1.12b; presumably, deliberate isolation of
1.12a is unnecessary, but this modification has not been tried. The
N-Boc group of 1.11 could also be removed with BF3·Et2O to
afford a mixture of 1.12b and the quinone imine 4 (eqn (1)); but
the use of Me3SiOSO2CF3 gave a better yield. The cyclization of
amino quinones of type 3 is reminiscent of the Nenitzescu indole
synthesis.1
4-Bromo-5-hydroxyindole (2.11b) was synthesized (Scheme 2)
by a similar route beginning with bromination of 1.2, which
was then subjected to an identical series of steps as used in the
chloro series, until phenolic amide 2.5 was reached. As shown
in the Scheme, bromination (1.2→2.1), mesylation (2.1→2.2),
conjugate reduction (2.2→2.3), decarboxylation (2.3→2.4) and
lactone opening (2.4→2.5) all worked in high yield. Our attempt to
silylate the phenolic hydroxyl of 2.5 did not give a satisfactory yield
and partial reclosure back to lactone 2.4 was observed. However,
the hydroxyl could be protected efficiently by allylation, after
which Hofmann rearrangement [Pb(OAc)4, t-BuOH] gave 2.7, as
expected. The presence of an allyl group instead of a silyl group
(cf 1.9) provided several possibilities for the deprotection–
oxidation sequence leading to quinone 2.9. The most effective
procedure involved removal of the methanesulfonyl group by
◦
treatment of 2.7 with Triton B in aqueous dioxane at 45 C,24
followed by oxidation to quinone 2.9, using (NH4)2Ce(NO2)6,
which gave a higher yield than PhI(OAc)2. Removal of the nitrogen
protecting group then led to a mixture of quinone imine20 2.10
and the indoles 2.11a and 2.11b, with the quinone imine being the
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major product. The mixture was heated in PhH with a catalytic
amount of 5% Rh–Al2O3 (catalyst loading <1% of Rh)20 and the
two resulting indoles 2.11a and 2.11b were then separated. The
former was hydrolyzed (MeOH, water, K2CO3) to afford 2.11b,
the overall yield of 2.11b from 2.9 being 100%. The Rh-catalyzed
isomerization was not necessary in the chloro series.
When the allyl group is removed first (Scheme 3, 2.7→3.1),
oxidation with PhI(OAc)2 gave quinone 2.9, but we prefer the route
via 2.8 because this compound can be isolated pure by aqueous
workup alone. The outcome of the oxidation of 2.8 is sensitive to
the type of oxidant, as use of Fre´my’s salt led to the ortho-quinone
3.2.25 We made the incidental observation that the phenethylamine
salt 3.3 could be obtained in high yield by treatment of 2.8 with
HCl in EtOAc.
Scheme 3 Formation of bromoquinone 2.9.
Iodoindole 4.11 was also made (Scheme 4) along the lines
used for the bromo compound. Iodination of coumarin 1.2
was best done with benzyltrimethylammonium dichloroiodate
(BnNMe3Cl2I26) rather than with ICl. The product (4.1) partially
loses iodine on isolation and should be mesylated in situ to
afford 4.2 in high yield (87–100% from 1.2). Fortunately, the
mesylate shows no tendency to lose the iodine. The 3,4-double
bond was reduced with LiBH4 (4.2→4.3), and from that point,
the sequence of reactions used in the bromo series was applied to
afford the iodoindole 4.11. Apart from the need to avoid isolation
of iodophenol 4.1, the sequence proceeded without incident in a
manner exactly analogous to our observations in the bromo series,
and with comparable yields.
Scheme 4 Formation of 5-hydroxy-4-iodoindole. aThe iodophenol is
unstable and should be mesylated without any attempt at purification, the
iodination–mesyaltion being best done in the same flask. bInverse addition,
i.e. the phenol is added to the reagents. Some quinone imine (30%) was
also recovered.
c
with catalytic 5% Rh–Al2O3 to afford the desired iodoindole
4.11. The overall yield of this sequence was slightly higher than
that of the first route, and it avoids use of the sensitive reagent
Me3SiOSO2CF3. Additionally, the method of Scheme 5 avoids the
necessity of chromatographing the quinone 4.9 (Scheme 4), and
the salt 5.1 is isolated simply by trituration.
We also examined a minor modification, by removing the
allyl group of 4.7 with Pd(PPh3)4 and then carrying out the
oxidation to 4.9. However, this sequence gave a lower overall
yield than the route via 4.8. In addition, an alternative route
from phenol 4.8 was developed (Scheme 5). In this approach
the nitrogen was deprotected, again with HCl in EtOAc, and the
resulting hydrochloride salt 5.1 was oxidized in aqueous MeCN
with PhI(OAc)2. The crude quinone imine 4.10 was then treated
The above approach to 4-haloindoles gives products lacking a
substituent at C(3) because the a,b-unsaturated ester subunit in
early coumarin intermediates is subjected to conjugate reduction.
However, these same intermediates can also undergo conjugate
addition of alkyl groups, so as to eventually give indoles bearing a
substituent at C(3). To illustrate this versatility, the iodocoumarin
4.2 was subjected to the action of a methylcopper species27 and
was found to undergo efficient conjugate addition (Scheme 6,
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group and the nitrogen protecting group were removed with
Triton B and HCl, respectively (6.5→6.6→6.7). Finally, oxida-
tion [PhI(OAc)2] and isomerization (5% Rh–Al2O3) produced
5-hydroxy-4-iodo-3-methylindole (6.9).
Conclusion
Our experiments show that 6-hydroxycoumarins can be converted
into 4-halo-5-hydroxyindoles using a series of efficient reactions
and with little dependence on the need for chromatography. Direct
halogenation at C(4) of 5-oxyindoles is usually unsatisfactory,28
because other positions such as C(3) and C(2) can react pref-
erentially, if not blocked. In contrast, direct C(5) halogenation
of 6-hydroxycoumarins (leading to 4-haloindoles) is easily ac-
complished, and forms the basis of the present method.26a This
method is general for the three halogens examined and its ability
to accommodate the introduction of a substituent at C(3) of the
indole nucleus was demonstrated for the simple case of a methyl
group.
Scheme 5 Formation of 5-hydroxy-4-iodoindole by second route.
Experimental
5-Iodo-6-[(methanesulfonyl)oxy]-2-oxo-2H-chromene-3-carboxylic
acid ethyl ester (4.2)
Attempts to isolate the intermediate 4.1 resulted in formation of a
mixture of 4.2 and 1.2.
Benzyltrimethylammonium
dichloroiodate26
(8.80
g,
25.3 mmol) was added in one portion to a stirred suspension
of 1.2 (5.39 g, 23.0 mol) in 1 : 1 t-BuOH-CH2Cl2 (100 mL) (N2
atmosphere) and stirring was continued for 45 min. The mixture
was then cooled in an ice bath and Et3N (8.0 mL, 57 mmol)
was added by syringe, resulting in a red solution. MsCl (2.0 mL,
26 mmol) was then added by syringe, the color being discharged
by the end of the addition. After 30 min, the mixture was diluted
with CH2Cl2 (150 mL) and then washed with water (2 ¥ 100 mL)
and dried (MgSO4). The solution was filtered through a pad
of flash chromatography silica gel (5 ¥ 5 cm), using CH2Cl2
(300 mL). Evaporation of the filtrate gave a residue which was
dissolved in boiling 95% EtOH (250 mL) and the solution was
allowed to cool and stand overnight. The resulting platelets were
◦
collected to afford 4.2 (8.85 g, 88%): mp 156–158 C; FTIR nmax
(microscope)/cm-1 1767, 1713; 1H-NMR (400 MHz, CDCl3):
d 1.45 (t, J = 7.1 Hz, 3 H), 3.40 (s, 3 H), 4.47 (q, J = 7.1 Hz,
2 H), 7.40 (d, J = 9.1 Hz, 1 H), 7.68 (d, J = 9.1 Hz, 1 H), 8.74
(s, 1 H); 13C-NMR (100 MHz, CDCl3): d 14.4 (q), 39.9 (q), 62.7
(t), 96.1 (s), 118.5 (d), 120.9 (s), 122.3 (s), 127.8 (d), 147.0 (s),
151.5 (d), 153.6 (s), 155.8 (s), 162.6 (s); exact mass m/z calcd for
C13H11INaO7S (M + Na) 460.9163, found 460.9164.
Scheme 6 Formation of 5-hydroxy-4-iodo-3-methylindole. atrans stereo-
chemistry established by X-ray analysis.
5-Iodo-6-[(methanesulfonyl)oxy]-2-oxochroman-3-carboxylic acid
ethyl ester (4.3)
4.2→6.1). Acid hydrolysis of the lactone and ester groups was
accompanied by spontaneous decarboxylation, and then acid
catalyzed relactonization of the resulting crude phenolic acid, gave
the dihydrocoumarin 6.2.
Lactone opening with NH3, O-allylation and Hofmann re-
arrangement (6.2→6.3→6.4→6.5)—using similar conditions to
those already established in making 2.11b and 4.11—gave the
protected amine 6.5, as expected. Once again, the methanesulfonyl
LiBH4 (1 M in THF, 2.6 mL, 2.6 mmol) was added by syringe
to a stirred and cooled (-15 ◦C, ice–acetone bath) solution of
4.2 (3.74 g, 8.54 mmol) in THF (50 mL). Stirring was continued
for 20 min and then another aliquot of LiBH4 (1 M in THF,
1.0 mL) was added by syringe. After a further 15 min, the reaction
flask was transferred to an ice bath and aqueous tartaric acid
(0.5 M, 36 mL) was added, followed by Et2O (30 mL). The resulting
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biphasic mixture was stirred for 3.5 h and then the organic phase
was washed with saturated aqueous NaHCO3 (20 mL) and brine
(20 mL), dried (MgSO4) and evaporated. Flash chromatography of
the residue over silica gel (4.5 ¥ 4 cm), using CH2Cl2 (500 mL), gave
4.3 (3.40 g, 91%): mp 137–138 ◦C; FTIR nmax (microscope)/cm-1
(s), 134.2 (s), 144.1 (s), 155.2 (s), 177.1 (s); exact mass m/z calcd
for C10H12INNaO5S (M + Na) 407.9373, found 407.9373.
Methanesulfonic acid 4-allyloxy-3-(2-carbamoylethyl)-2-
iodophenyl ester (4.6)
1
1780, 1737; H-NMR (400 MHz, CDCl3): d 1.16–1.20 (m, 3 H),
K2CO3 (0.909 g, 6.58 mmol), followed by allyl bromide (0.45 mL,
5.2 mmol), were added to a stirred solution of 4.5 (1.84 g,
4.78 mmol) in 2-butanone. The reaction flask was fitted with a
condenser and the mixture was heated at 70 ◦C overnight. At
this stage the reaction was still incomplete (TLC control) and
so an additional portion of allyl bromide (0.08 mL, 0.9 mmol)
was added. More 2-butanone was added to replace that lost
by evaporation and the mixture was heated at 70 ◦C until the
starting material (4.5) had been consumed (ca. 3 h, TLC control).
Surprisingly, the product 4.6 has a lower Rf than the starting
material 4.5 (silica gel, 80% EtOAc–hexanes.) The mixture was
diluted with EtOAc (ca. 50 mL) and then washed with water
(2 ¥ 20 mL) and brine (20 mL), dried (MgSO4), and evaporated to
afford pure 4.6 (2.03 g, 100%): FTIR nmax (film cast)/cm-1 3349,
2539, 2481, 2385, 1633; 1H-NMR (400 MHz, acetone-d6): d 2.34–
2.38 (m, 2 H), 3.18–3.22 (m, 2 H), 3.37 (s, 3 H), 4.65 (ddd as an
apparent dt, J = 4.9, 1.7, 1.7 Hz, 2 H), 5.25 (ddt as an apparent
dq, J = 10.6, 1.5, 1.5 Hz, 1 H), 5.46 (ddt as an apparent dq,
J = 17.3, 1.7, 1.7 Hz, 1 H), 6.08 (ddt, J = 17.3, 10.6, 4.9 Hz, 1 H),
6.18 (br s, 1 H), 6.73 (br s, 1 H), 7.05 (d, J = 9.0 Hz, 1 H), 7.28
(d, J = 8.9 Hz, 1 H); 1H-NMR (400 MHz, CD3OD): d 2.38–2.42
(m, 2 H), 3.21–3.25 (m, 2 H), 4.61 (ddd as an apparent dt, J = 5.0,
1.6, 1.6 Hz, 2 H), 4.83 (s, 3 H), 5.26–5.26 (m, 1 H), 5.41–5.47 (m,
1 H), 6.08 (ddt, J = 17.2, 10.5, 4.9 Hz, 1 H), 7.00 (d, J = 9.0 Hz,
1 H), 7.27 (d, J = 8.9 Hz, 1 H); 13C-NMR (100 MHz, acetone-d6):
d 32.4 (t), 34.3 (t), 39.3 (q), 70.1 (t), 98.7 (s), 113.2 (d), 117.5 (t),
121.5 (d), 134.1 (d), 136.1 (s), 144.4 (s), 155.5 (s), 173.7 (s); 13C-
NMR (100 MHz, CD3OD): d 31.4, 33.5, 37.9, 69.5, 97.6, 112.2,
116.6, 120.8, 133.1, 134.8, 143.7, 154.8; exact mass m/z calcd for
C13H16INNaO5S (M + Na) 447.9686, found 447.9683.
3.24 (dd overlapping with a singlet, J = 6.2, 16.7 Hz, 1 H), 3.26 (s,
3 H), 3.50 (dd, J = 8.6, 16.7 Hz, 1 H), 3.71 (dd, J = 6.3, 8.6 Hz,
1 H), 4.15–4.20 (m, 2 H), 7.06 (d, J = 8.9 Hz, 1 H), 7.31 (dd, J =
0.6, 8.9 Hz, 1 H); 13C-NMR (100 MHz, CDCl3): d 14.2 (q), 33.6
(t), 39.7 (q), 46.0 (d), 62.8 (t), 95.9 (s), 118.4 (d), 122.7 (d), 127.5
(s), 146.5 (s), 149.5 (s), 163.8 (s), 166.9 (s); exact mass m/z calcd
for C13H13INaO7S (M + Na) 462.9319, found 462.9314.
In a larger scale experiment, using 4.2 (8.8 g), the product 4.3
was obtained in 89% yield.
Methanesulfonic acid 5-iodo-2-oxochroman-6-yl ester (4.4)
Dilute hydrochloric acid (20%, 100 mL) was added to a stirred
solution of 4.3 (2.62 g, 5.95 mmol) in acetone (25 mL). The
resulting white suspension was then refluxed for 5 h open to the
atmosphere. The solution was cooled and extracted with EtOAc
(2 ¥ 30 mL) and the combined organic extracts were washed
with brine, dried (MgSO4) and evaporated. The crude residue
was covered with PhMe (60 mL) and TsOH·H2O (46.7 mg) was
added with stirring and the mixture was then refluxed. After 3 h
the nearly colorless solution was cooled to room temperature
and extracted with EtOAc (30 mL). The organic extract was
washed with saturated aqueous NaHCO3 and the aqueous layer
was back-extracted once with EtOAc. The combined organic
extracts were washed with brine and dried (MgSO4). Evaporation
of the solvent gave 4.4 (1.76 g, 80%): mp 125–128 ◦C; FTIR nmax
(microscope)/cm-1 1777; 1H-NMR (400 MHz, CDCl3): d 2.82 (t,
J = 7.7 Hz, 2 H), 3.15 (t, J = 7.7 Hz, 2 H), 3.34 (s, 3 H), 7.11 (d,
J = 8.9 Hz, 1 H), 7.37 (d, J = 8.9 Hz, 1 H); 13C-NMR (100 MHz,
CDCl3): d 28.6 (t), 30.1 (t), 39.5 (q), 95.7 (s), 118.3 (d), 122.1 (d),
128.8 (s), 146.0 (s), 150.0 (s), 167.1 (s); exact mass m/z calcd for
C10H10IO5S 368.9288, found 368.9290.
Methanesulfonic acid 4-Allyloxy-3-[(2-tert-butoxycarbonylamino)-
ethyl]-2-iodo-phenyl ester (4.7)
In a smaller scale experiment [4.3 (0.39 g, 0.89 mmol)], a higher
a yield of 91% was obtained.
Pb(OAc)4 (2.49 g, 5.61 mmol) was added in one portion to a stirred
and heated (80 ◦C) solution of 4.6 (2.03 g, 4.78 mmol) in dry
t-BuOH (50 mL). Reaction was complete in less than 1 h (TLC
control, silica, 80% EtOAc–hexane). The mixture was cooled and
filtered through Florisil (2 ¥ 2.5 cm), using CH2Cl2 (ca. 100 mL).
The residue obtained by evaporation of the filtrate was filtered
through flash chromatography silica gel (2 ¥ 2.5 cm), using 25%
EtOAc–hexanes, complete elution being monitored by TLC (silica,
80% EtOAc–hexane). These filtrations through Florisil and silica
were necessary to remove lead residues. Evaporation of the filtrate
gave pure 4.7 (2.14 g, 88%): mp 105.5–108.5 ◦C (silky, white needles
from heptane); FTIR nmax (film cast)/cm-1 3424, 2977, 2933, 1707;
1H-NMR (300 MHz, CDCl3): d 1.40 (s, 9 H), 3.15 (t, J = 6.7 Hz,
2 H), 3.27 (s, 3 H), (dt as an apparent q, J = 6.0, 6.0 Hz, 2 H),
4.57 (ddd as an apparent dt, J = 5.1, 1.5, 1.5 Hz, 2 H), 4.70 (br s,
1 H), 5.32 (ddt as an apparent dq, J = 10.5, 1.3, 1.3 Hz, 1 H), 5.43
(ddt as an apparent dq, J = 17.3, 1.5, 1.5 Hz, 1 H), 6.05 (ddt, J =
17.3, 10.4, 5.1 Hz, 1 H), 6.85 (d, J = 9.0 Hz, 1 H), 7.30 (d, J =
9.0 Hz, 1 H); 13C-NMR (100 MHz, CDCl3): d 28.7 (q), 35.8 (s),
39.3 (q), 39.6 (two t overlapping), 70.0 (t), 98.9 (s), 112.3 (d), 118.4
Methanesulfonic acid 3-(2-carbamoylethyl)-4-hydroxy-2-
iodophenyl ester (4.5)
A three-necked round bottomed flask was charged with 4.4 (1.76 g,
4.78 mmol) and THF (50 mL). The flask was fitted with a drying
tube containing NaOH pellets, a stopper and an adapter carrying
a Pasteur pipette extending ca. 1 cm below the surface of the
solution. The pipette was connected by Tygon tubing to another
flask containing liquid NH3 as a source of gaseous NH3, which
was bubbled through the THF solution for 30 min. Evaporation
of the solvent, followed by trituration of the residue under CHCl3
(3 mL) at room temperature, gave 4.5 (1.84 g, 100%) as a white
solid: mp 145–147 ◦C; FTIR nmax (microscope)/cm-1 3455, 3356,
3199, 3030, 2937, 1662; 1H-NMR (400 MHz, acetone-d6): d 2.72
(t, J = 6.2 Hz, 2 H), 3.10 (t, J = 6.2 Hz, 2 H), 3.35 (s, 3 H),
6.75 (br s, 1 H), 6.90 (d, J = 8.9 Hz, 1 H), 7.19 (d, J = 8.9 Hz,
1 H), 7.26 (br s, 1 H), 10.10 (br s, 1 H); 13C-NMR (100 MHz,
acetone-d6): d 30.7 (t), 34.5 (t), 39.2 (q), 98.9 (s), 118.8 (d), 122.0
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(t), 121.5 (d), 132.7 (d), 133.6 (s), 143.5 (s), 155.2 (s), 156.0 (s);
exact mass m/z calcd for C17H24INNaO6S (M + Na) 520.0261,
found 520.0210.
sieves (ca. 0.3 g, activated >200 ◦C). After the addition the ice bath
was removed and the mixture was refluxed overnight, cooled to
room temperature, washed with water (2 ¥ 2 mL), dried (MgSO4)
and evaporated. The residue was passed through a Pasteur pipette
containing flash chromatography silica gel (0.5 ¥ 10 cm), using
40% EtOAc–hexanes, to give a mixture of quinone imine 4.10 and
indole 4.11 (32.2 mg, 87% in all). This mixture was dissolved in
PhH (3.6 mL) and Rh–Al2O3 (1.6 mg, 5% Rh, 0.00080 mmol) was
added. The mixture was refluxed for 3 h, cooled and evaporated.
Flash chromatography of the residue over silica gel (0.5 ¥ 10 cm),
using 25% EtOAc–hexanes, gave indole 4.11 (19.8 mg, 61%) as an
oil and recovered quinone imine (9.5 mg, 30%). Indole 4.11 had:
FTIR nmax (microscope)/cm-1 3416; 1H-NMR (400 MHz, CDCl3):
d 5.12 (s, 1 H), 6.38–6.39 (m, 1 H), 6.93 (dd, J = 8.6, 0.5 Hz, 1 H),
7.24–7.26 (two overlapping m, 2 H), 8.25 (br s, 1 H);13C-NMR
(100 MHz, CDCl3): d 76.2 (s), 105.9 (d), 111.0 (d), 112.5 (d),
125.6 (d), 130.0 (s), 132.6 (s), 149.7 (s); exact mass m/z calcd for
C8H6INO 258.9494, found 258.9487.
[2-(6-Allyloxy-3-hydroxy-2-iodophenyl)ethyl]carbamic acid
tert-butyl ester (4.8)
Benzyltrimethylammonium hydroxide (Triton B, 40% w/w in
MeOH, 4.8 mL, 11 mmol) was added to a stirred solution of
4.7 (1.00 g, 2.01 mmol) in 1,4-dioxane (24 mL) and water (9 mL).
The mixture was heated at 45 ◦C for 5 h open to the atmosphere,
cooled, acidified (litmus test) with dilute hydrochloric acid (5%),
diluted with water (30 mL) and extracted with Et2O (2 ¥ 30 mL).
The combined organic extracts were washed with water and brine,
dried (Na2SO4) and evaporated to afford 4.8 (0.827 g, 98%) as an
oil which◦solidified to a white amorphous solid on standing: mp
105–106 C; FTIR nmax (film cast)/cm-1 3318, 2978, 2933, 1682;
1H-NMR (400 MHz, CDCl3): d 1.41 (s, 9 H), 3.08 (t, J = 6.7 Hz,
2 H), 3.34–3.36 (m, 2 H), 4.50 (ddd as an apparent dt, J = 5.1,
1.6, 1.6 Hz, 2 H), 4.82 (br s, 1 H), 5.27 (ddt as an apparent dq, J =
10.5, 1.4, 1.4 Hz, 1 H), 5.40 (apparent dd, J = 17.3, 1.6 Hz, 1 H),
5.64 (br s, 1 H), 6.03 (ddt, J = 17.3, 10.5, 5.2 Hz, 1 H), 6.76 (d,
J = 8.9 Hz, 1 H), 6.85 (d, J = 8.7 Hz, 1 H); 13C-NMR (100 MHz,
CDCl3): d 28.5 (q), 35.4 (t), 39.8 (t), 70.0 (t), 79.0 (s), 94.8 (s),
112.8 (d), 113.5 (d), 117.6 (t), 131.4 (s), 133.2 (d), 149.5 (s), 150.2
(s), 156.0 (s); exact mass m/z calcd for C16H22INNaO4 (M + Na)
442.0486, found 442.0484.
The quinone imine 4.10 had: 1H-NMR (400 MHz, CDCl3) (data
taken from a spectrum of a mixture of the quinone imine 4.10 and
indole 4.11): d 2.91–2.93 (m, 2 H), 4.42–4.44 (m, 2 H), 6.81 (dt,
J = 9.8, 1.0 Hz, 1 H), 7.45 (d, J = 9.8 Hz, 1 H).
trans-5-Iodo-6-[(methanesulfonyl)oxy]-4-methyl-2-oxochroman-3-
carboxylic acid ethyl ester (6.1)
LiCl (1.37 g, 32.3 mmol) was dried in a round-bottomed flask
by heating (heat gun) under oil-pump vacuum for ca. 3 min.
CuI (4.7 g, 25 mmol) was then added and the flask was flushed
with Ar. THF (60 mL) was added and the mixture was stirred at
room temperature until all solids dissolved (10 min). The stirred
solution was cooled to -40 ◦C (dry ice–MeCN bath) and MeMgI
(3 M in Et2O, 7.50 mL, 22.5 mmol) was added by syringe. After
10 min a solution of 4.2 (4.91 g, 11.2 mmol) in THF (100 mL)
was added by syringe over ca. 10 min. The mixture was stirred
for 20 min and then quenched by addition of saturated aqueous
NH4Cl (30 mL). Acetone (20 mL) was then added to prevent the
formation of copper-containing solids. The mixture was diluted
with EtOAc (50 mL) and water (20 mL) and stirred open to the
atmosphere at room temperature for 1 h. The dark blue aqueous
layer was extracted with EtOAc (30 mL) and the combined organic
extracts were washed with brine, dried (MgSO4) and evaporated.
CH2Cl2 (ca. 15 mL) was added to the residue to produce a beige–
orange suspension which was filtered through a pad of flash
chromatography silica gel (4 ¥ 4 cm), using 1 : 1 EtOAc–hexanes
(300 mL). Some of the product crystallized from the eluent as
square plates on standing overnight at room temperature. The
supernatant liquid was decanted and evaporated to afford 6.1.
The original crystals were dried, and X-ray analysis showed that
the material had trans stereochemistry. The total yield of product
amounted to 4.69 g (92%): mp 112–115 ◦C; FTIR nmax (film cast
[2-(2-Iodo-3,6-dioxocyclohexa-1,4-dienyl)ethyl]carbamic acid
tert-butyl ester (4.9)
A solution of 4.8 (0.142 g, 0.339 mmol) in t-BuOH (3 mL) and
water (1 mL) was added dropwise by Pasteur pipette to a stirred
mixture of PhI(OAc)2 (0.120 g, 0.374 mmol), t-BuOH (2 mL) and
water (2 ml) open to the atmosphere. Stirring was continued for
ca. 30 min and then the mixture was diluted with water (15 mL)
and extracted with Et2O (3 ¥ 7 mL). The combined organic
extracts were washed with brine, dried (MgSO4) and evaporated.
The residue was purified by filtration through a pad of flash
chromatography silica gel (2 ¥ 4 cm), using hexanes (25 mL) and
then 20% EtOAc–hexanes (20 mL). The eluent was discarded and
the pad was then eluted with 26% EtOAc–hexanes (ca. 50 mL).
The canary yellow fraction was evaporated to afford 4.9 (0.111 g,
87%): mp 126–129 ◦C; FTIR nmax (film cast)/cm-1 3380, 2977,
2931, 1693, 1664; 1H-NMR (400 MHz, C6D6): d 1.33 (s, 9 H), 2.54
(t, J = 6.2 Hz, 2 H), 3.00 (dt as an apparent q, J = 6.3 Hz, 2 H),
3.99 (br s, 1 H), 6.00 (d, J = 9.8 Hz, 1 H), 6.13 (d, J = 9.9 Hz,
1
1 H); H-NMR (498 MHz, CDCl3): d 1.41 (s, 9 H), 3.04 (t, J =
6.0 Hz, 2 H), 3.44 (m, 2 H), 4.70 (br s, 1 H), 6.86 (d, J = 10.0 Hz,
1 H), 7.01 (d, J = 9.5 Hz, 1 H); 13C-NMR (100 MHz, C6D6): d
28.4 (q), 37.7 (t), 39.3 (t), 78.8 (s), 122.6 (s), 133.8 (d), 135.9 (d),
153.2 (s), 155.9 (s), 180.1 (s), 181.8 (s); exact mass m/z calcd for
C13H16INNaO4 (M + Na) 400.0016, found 400.0017.
1
microscope)/cm-1 1786, 1737; H-NMR (300 MHz, CDCl3): d
1.08 (t, J = 7.1 Hz, 3 H), 1.30 (d, J = 7.3 Hz, 3 H), 3.32 (s, 3 H),
3.77 (d, J = 1.9 Hz, 1 H), 3.90 (dq, J = 7.3, 1.9 Hz, 1 H), 4.08
(q, J = 7.1 Hz, 2 H), 7.13 (dd, J = 9.0, 0.4 Hz, 1 H), 7.37 (d, J =
8.9 Hz, 1 H); 13C-NMR (100 MHz, CDCl3): d 14.1 (q), 18.1 (q),
39.4 (q), 40.1 (d), 53.0 (d), 62.5 (t), 95.0 (s), 118.4 (d), 122.4 (d),
131.2 (s), 146.3 (s), 148.4 (s), 163.1 (s), 166.0 (s); exact mass m/z
calcd for C14H15INaO7S (M + Na) 476.9476, found 476.9475.
4-Iodo-1H-indol-5-ol (4.11)
2,6-Lutidine (10% v/v in CH2Cl2, 0.23 mL, 0.20 mmol) and then
Me3SiOSO2CF3 (10% v/v in CH2Cl2, 0.30 mL, 0.17 mmol) were
added dropwise by syringe to a stirred and cooled (0 ◦C) mixture of
˚
4.9 (53.9 mg, 0.143 mmol) in CH2Cl2 (4.4 mL) and 4 A molecular
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Methanesulfonic acid 5-iodo-4-methyl-2-oxochroman-6-yl ester
(6.2)
Methanesulfonic acid 4-allyloxy-3-(2-carbamoyl-1-methylethyl)-2-
iodophenyl ester (6.4)
Dilute hydrochloric acid (30%, 22 mL) was added to a stirred
solution of 6.1 (2.18 g, 4.80 mmol) in acetone (6 mL), causing
the material to precipitate. The resulting suspension was then
refluxed open to the atmosphere for 3 h and then stirred at
room temperature overnight. The mixture was extracted with
EtOAc (3 ¥ 20 mL), and the combined organic extracts were
dried (MgSO4) and evaporated. The residue was covered with
PhMe (12 mL), and TsOH·H2O (50 mg, 0.26 mmol) was added
with stirring. The mixture was then refluxed for 5 h, cooled,
diluted with EtOAc (20 mL), and washed with saturated aqueous
NaHCO3. The combined organic extracts were dried (MgSO4) and
evaporated. The residue was purified by filtration through flash
chromatography silica gel (1.5 ¥ 2 cm), using 1 : 1 EtOAc–hexanes,
to afford 6.2 (1.73 g, 94%) as an oil. In some runs this filtration
step was not necessary, while in others flash chromatography was
done in order to obtain pure 6.2, the choice of isolation procedure
being made on the basis of TLC analysis. Compound 6.2 had: mp
86–88 ◦C; FTIR nmax (film cast)/cm-1 1779; 1H-NMR (400 MHz,
CDCl3): d 1.26 (d, J = 7.3 Hz, 3 H), 2.82 (d, J = 2.6 Hz, 1 H), 2.83
(d, J = 5.4 Hz, 1 H), 3.34 (s, 3 H), 3.42–3.49 (m, 1 H), 7.11 (dd, J =
8.9, 0.4 Hz, 1 H), 7.35 (d, J = 8.9 Hz, 1 H); 13C-NMR (100 MHz,
CDCl3): d 18.8 (q), 35.9 (t), 36.3 (d), 39.7 (q), 95.2 (s), 118.8 (d),
122.3 (d), 133.4 (s), 146.2 (s), 149.3 (s), 167.2 (s); exact mass m/z
calcd for C11H11INaO5S (M + Na) 404.9264, found 404.9267.
K2CO3 (0.185 g, 1.34 mmol) was added to a stirred solution of 6.3
(0.243 g, 0.609 mmol) in 2-butanone (6.6 mL) and allyl bromide
(0.07 mL, 0.8 mmol) was added by syringe (Ar atmosphere). The
mixture was then heated at 55 ◦C overnight. A second portion
of allyl bromide (0.03 mL, 0.3 mmol) was added, heating was
continued for 2 h, and the mixture was cooled and partitioned
between Et2O (15 mL) and water (20 mL). The aqueous phase was
extracted with Et2O (10 mL) and the combined organic extracts
were washed with saturated aqueous NaHCO3, dried (Na2SO4)
and evaporated. Trituration of the solid residue with two portions
of cold (ice bath) 1 : 1 CHCl3–hexane afforded 6.4 (0.204 g, 76%)
as a white solid: mp 155 ◦C; FTIR nmax (film cast)/cm-1 3084, 2965,
2933, 2872, 2588, 2401, 1649; 1H-NMR (500 MHz, acetone-d6): d
1.30 (d, J = 7.0 Hz, 3 H), 2.61 (ddt, J = 14.9, 5.6, 1.4 Hz, 1 H),
2.82 (dd, J = 14.8, 8.7 Hz, 1 H), 2.75 (d, J = 16.6 Hz, 1 H), 3.34
(s, 1 H), 3.98–4.05 (m, 1 H), 4.63–4.70 (m, 2 H), 5.28 (apparent
dd, J = 10.6, 1.5 Hz, 1 H), 5.45 (ddt as an apparent dq, J = 17.3,
1.6, 1.6 Hz, 1 H), 5.98 (br s, 1 H), 6.14 (ddt, J = 17.3, 10.5, 5.1 Hz,
1 H), 6.58 (br s, 1 H), 7.05 (d, J = 9.1 Hz, 1 H), 7.24 (d, J = 9.0 Hz,
1 H); 13C-NMR (125 MHz, acetone-d6): d 17.5, 38.6, 40.1, 42.5,
69.8, 99.6, 113.4, 117.4, 120.6, 133.6, 139.0, 143.8, 155.6, 173.1;
exact mass m/z calcd for C14H18INNaO5S (M + Na) 461.9843,
found 461.9843.
In a larger scale experiment, using the dihydrocoumarin 6.2
(5.55 g, 14.5 mmol), compound 6.4 was obtained in 82% yield
over the two steps.
Methanesulfonic acid 3-(2-carbamoyl-1-methylethyl)-4-
hydroxy-2-iodophenyl ester (6.3)
[2-[(6-Allyloxy-2-iodo-3-methanesulfonyl)phenyl]propyl]carbamic
acid tert-butyl ester (6.5)
A three-necked round bottomed flask was charged with 6.2
(0.368 g, 0.962 mmol) and THF (8 mL). The flask was fitted with
a drying tube containing NaOH pellets, a stopper and an adapter
carrying a Pasteur pipette extending ca. 1 cm below the surface
of the solution. The pipette was connected by Tygon tubing to
another flask containing liquid NH3 as a source of gaseous NH3.
After NH3 had been bubbled into the solution for 30 min, more
THF (5 mL) was added and passage of NH3 was continued for 1 h.
The flask was completely stoppered and stirring was continued.
When all the starting dihydrocoumarin had reacted (TLC control,
ca. 3 h) the solvent was evaporated and the residue was purified by
trituration under hot CHCl3. Without separation, the two-phase
mixture was allowed to cool and filtration afforded 6.3 (0.289 g,
75%): FTIR nmax (microscope)/cm-1 3460, 3366, 3198, 1776, 1661;
1H-NMR (400 MHz, acetone-d6): d 1.32 (d, J = 7.0 Hz, 3 H),
2.67 (dd, J = 14.8, 5.3 Hz, 1 H), 2.85 (dd, J = 14.8, 8.1 Hz,
1 H), 3.32 (s, 3 H), 3.93–3.98 (m, 1 H), 6.13 (br s, 1 H), 6.73
(br s, 1 H), 6.87 (d, J = 8.7 Hz, 1 H), 7.12 (d, J = 8.8 Hz, 1 H),
Pb(OAc)4 (0.223 g, 0.504 mmol) was added in one portion to a
stirred and heated (75 ◦C) suspension of 6.4 (0.195 g, 0.443 mmol)
in dry t-BuOH and heating was continued for 20 min (Ar
atmosphere). The mixture was cooled to room temperature and
filtered through a pad of Florisil (1 ¥ 2 cm), using 10 mL-aliquots
of 30%, 40%, and 50% EtOAc–hexanes, to afford 6.5 (0.224 g,
99%) as an oil: FTIR nmax (film cast)/cm-1 3421, 2977, 2934, 1706;
1H-NMR (500 MHz, CDCl3): d 1.30 (d, J = 6.9 Hz, 3 H), 1.39
(s, 9 H), 3.28 (s, 3 H), 3.49–3.54 (m, 1 H), 3.56–3.62 (m, 1 H),
3.66–3.69 (m, 1 H), 4.47 (br s, 1 H), 4.53–4.60 (m, 2 H), 5.33
(apparent dd, J = 10.5, 1.2 Hz, 1 H), 5.41 (ddt as an apparent dq,
J = 17.2, 1.6 Hz, 1 H), 6.07 (ddt, J = 17.2, 10.5, 5.3 Hz, 1 H),
6.85 (d, J = 9.0 Hz, 1 H), 7.28 (d, J = 9.0 Hz, 1 H); 13C-NMR
(125 MHz, CDCl3): d 15.9 (q), 28.4 (q), 39.2 (q), 44.1 (t), 46.7 (d),
69.7 (t), 79.0 (s), 100.7 (s), 112.7 (d), 118.4 (t), 121.0 (d), 132.4 (d),
136.7 (s), 143.2 (s), 155.3 (s), 155.8 (s); exact mass m/z calcd for
C18H26INNaO6S (M + Na) 534.0418, found 534.0417.
1
9.22 (br s, 1 H); H-NMR (500 MHz, CD3OD): d 1.33 (d, J =
In a larger scale experiment, using 6.4 (5.21 g, 11.9 mmol),
removal of the methanesulfonyl group with Triton B (see below)
gave compound 6.6 in 94% yield over two steps.
7.0 Hz, 3 H), 2.75–2.84 (m, 2 H), 3.27 (s, 3 H), 3.89–3.96 (m, 1 H),
6.77 (d, J = 8.8 Hz, 1 H), 7.11 (d, J = 8.8 Hz, 1 H); 13C-NMR
(125 MHz, CD3OD): d 17.9 (q), 39.1 (d), 40.9 (t), 43.8 (q), 100.2
(s), 117.3 (d), 121.7 (d), 137.1 (s), 143.9 (s), 155.8 (s), 178.1 (s); exact
mass m/z calcd for C11H14INNaO5S (M + Na) 421.9530, found
421.9533.
[2-(6-allyloxy-3-hydroxy-2-iodophenyl)propyl]carbamic acid
tert-butyl ester (6.6)
In a larger scale experiment, using 6.2 (5.55 g, 14.5 mmol), a
yield of 82% was obtained over two steps after conversion of 6.3
to the allyl ether 6.4.
Benzyltrimethylammonium hydroxide (Triton B, 40% w/w in
MeOH, 0.76 mL, 1.7 mmol) was added to a stirred solution of
6.5 (0.224 g, 0.438 mmol) and the mixture was then kept at 45 ◦C
4868 | Org. Biomol. Chem., 2009, 7, 4862–4870
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open to the atmosphere. Stirring was continued for 6.5 h and
then the mixture was partitioned between water (15 mL) and
Et2O (15 mL). The organic extract was washed with water and
brine, dried (Na2SO4) and evaporated. Flash chromatography of
the residue over silica gel (1.5 ¥ 20 cm), using 36% EtOAc–hexanes,
gave 6.6 (0.189 g, 99%) as an oil: FTIR nmax (film cast)/cm-1 3312,
refluxed for 2 h (N2 atmosphere). Evaporation of the solvent and
flash chromatography of the residue over silica gel (0.5 ¥ 10 cm) in
a Pasteur pipette, using 20% EtOAc–hexanes, gave 6.9 (10.9 mg,
100%) as an oil, making the total yield 93% over the two steps
from 6.7. Indole 6.9 is sensitive to light.
Quinone imine 6.8 had: mp 80 ◦C; 1H-NMR (300 MHz, C6D6):
d 0.76 (d, J = 7.3 Hz, 3 H), 2.28–2.38 (m, 1 H), 3.44 (d, J =
20.4 Hz, 1 H), 3.76 (dd, J = 20.5, 5.7 Hz, 1 H), 6.23 (apparent dt,
J = 9.7, 0.9 Hz, 1 H), 6.75 (d, J = 9.7 Hz, 1 H).
1
2977, 2930, 1682; H-NMR (400 MHz, CDCl3): d 1.29 (d, J =
5.8 Hz, 3 H), 1.40 (s, 9 H), 3.52–3.58 (m, 3 H), 4.44–4.50 (m, 2 H),
4.53 (br s, 1 H), 5.27 (ddt as an apparent dq, J = 10.6, 1.3, 1.3 Hz,
1 H), 5.38 (ddt as an apparent dq, J = 17.3, 1.6, 1.6 Hz, 1 H),
5.86 (br s, 1 H), 6.03 (ddt, J = 17.3, 10.6, 5.3 Hz, 1 H), 6.76 (d,
J = 8.9 Hz, 1 H), 6.85 (d, J = 8.9 Hz, 1 H); 13C-NMR (100 MHz,
CDCl3): d 16.4, 28.7, 44.7, 46.9, 70.1, 79.3, 97.3, 112.9, 114.2,
117.9, 133.4, 134.9, 149.7, 150.7, 156.3; exact mass m/z calcd for
C17H24INNaO4 (M + Na) 456.0642, found 456.0646.
Indole 6.9 had: FTIR nmax (film cast)/cm-1 3418; 1H-NMR
(300 MHz, C6D6): d 2.47 (s, 3 H), 5.20 (s, 1 H), 6.28 (s and
br s coincident, 2 H), 6.63 (d, J = 8.6 Hz, 1 H), 6.94 (d, J =
8.6 Hz, 1 H); 13C-NMR (100 MHz, C6D6): d 12.7, 75.6, 110.7,
112.6, 112.7, 124.7, 128.9, 131.8, 149.5; exact mass m/z calcd for
C9H8INO 272.9651, found 272.9646.
In a larger scale experiment, using 6.4 (5.21 g, 11.9 mmol),
compound 6.6 was obtained in 94% yield over two steps.
The above procedure should be followed closely: In a subsequent
experiment, using 6.7 (93.7 mg, 0.254 mmol), the intermediate
quinone imine was simply filtered through a short pad of flash
chromatography silica gel in a filter funnel and the final yield of
the indole 6.9 was 62% over the two steps from 6.7. A larger scale
experiment, using 6.7 (1.78 g, 4.80 mmol), and the same simple
filtration method, gave 6.9 (0.567 g, 43%) and recovered quinone
imine 6.8 (0.187 g, 14%), corresponding to a corrected yield of
57% over two steps from 6.7.
4-Allyloxy-3-(2-amino-1-methylethyl)-2-iodophenol hydrochloride
(6.7)
A solution of HCl in EtOAc (ca. 2.6 M, 25 mL, 65 mmol) was
added by syringe to a stirred and cooled (0 ◦C) solution of 6.6
(4.99 g, 11.2 mmol) in EtOAc (25 mL) (Ar atmosphere). After
the addition the ice bath was removed and, when the mixture
reached room temperature, the Ar inlet was removed. Stirring
was continued for 4 h and then a second aliquot of the solution
of HCl in EtOAc (ca. 2.6 M, 8.0 mL, 21 mmol) was added.
When deprotection was complete (ca. 3 h, TLC control, silica,
1 : 1 EtOAc–hexanes) the solvent was evaporated and the residue
was triturated under CHCl3 to afford 6.7 (3.67 g, 89%): FTIR nmax
Acknowledgements
We thank the Natural Sciences and Engineering Research Council
of Canada for financial support and Dr. R. MacDonald for the
X-ray analysis.
1
(microscope)/cm-1 2970, 2213, 1647, 1573; H-NMR (400 MHz,
CD3OD): d 1.35 (d, J = 7.0 Hz, 3 H), 3.33 (dd, J = 12.5, 7.4 Hz,
1 H), 3.48 (dd, J = 12.5, 7.5 Hz, 1 H), 3.82 (apparent sextet, J =
7.2 Hz, 1 H), 4.50–4.58 (m, 2 H), 5.33 (apparent dd, J = 10.5,
1.1 Hz, 1 H), 5.40 (apparent dd, J = 17.3, 1.5 Hz, 1 H), 6.10 (ddt,
J = 17.2, 10.6, 5.3 Hz, 1 H), 6.77 (d, J = 8.9 Hz, 1 H), 6.90 (d, J =
8.9 Hz, 1 H); 13C-NMR (100 MHz, CD3OD): d 16.6, 44.4, 44.9,
70.8, 94.8, 114.3, 115.0, 118.1, 133.4, 134.5, 151.0, 152.4; exact
mass m/z calcd for C12H17INO2 334.0299, found 334.0298.
Notes and references
1 Indole synthesis: (a) G. R. Humphrey and J. T. Kuethe, Chem. Rev.,
2006, 106, 2875–2911.
2 (a) S. Huang, R. Li, P. J. Connolly, G. Xu, M. D. Gaul, S. L. Emanuel,
K. R. LaMontagne and L. M. Greenberger, Bioorg. Med. Chem. Lett.,
2006, 16, 6063–6066; (b) L. F. A. Hennequin, WO 03/064413.
3 M. E. Flaugh, US pat. 6,022,980, 2000.
4 E. J. Griffen, D. G. Roe and V. Snieckus, J. Org. Chem., 1995, 60,
1484–1485.
5 (a) L. I. Kruse, R. C. Young and A. J. Kaumann, WO 93/00333;
(b) M. A. Brown and M. A. Kerr, Tetrahedron Lett., 2001, 42, 983–985;
(c) M. D. Meyer and L. I. Kruse, J. Org. Chem., 1984, 49, 3195–3199;
(d) M. E. Flaugh, T. A. Crowell, J. A. Clemens and B. D. Sawyer,
J. Med. Chem., 1979, 22, 63–69; (e) J. H. Tidwell and S. L. Buchwald,
J. Am. Chem. Soc., 1994, 116, 11797–11810; (f) A. J. Peat and S. L.
Buchwald, J. Am. Chem. Soc., 1996, 118, 1028–1030; (g) C. J. Moody
and E. Swan, J. Chem. Soc., Perkin Trans. 1, 1993, 2561–2565.
6 For halogenation of indoles at C(4), see (a) reference 5e; (b) J. H.
Tidwell, D. R. Senn and S. L. Buchwald, J. Am. Chem. Soc., 1991, 113,
4685–4686; (c) C. R. Hurt, R. Lin and H. Rapoport, J. Org. Chem.,
1999, 64, 225–233.
7 Reviews on synthesis of coumarins: (a) F. Borges, F. Roleira, N.
Milhazes, L. Santana and E. Uriarte, Curr. Med. Chem., 2005, 12,
887–916; (b) L. Bonsignore, F. Cottiglia, S. M. Lavagna, G. Loy and D.
Secci, Farmaco, 1998, 53, 693–697; (c) M. A. Musa, J. S. Cooperwood
and M. O. F. Khan, Curr. Med. Chem., 2008, 15, 2664–2679; (d) Y.-L.
Shi and M. Shi, Org. Biomol. Chem., 2007, 5, 1499–1504.
4-Iodo-3-methyl-1H-indol-5-ol (6.9)
The best yield was obtained on a small scale, as follows: PhI(OAc)2
(20 mg, 0.06 mmol) was added in one portion to a stirred and
◦
cooled (0 C) solution of 6.7 (21.7 mg, 0.0510 mmol) in MeCN
(1.3 mL) and water (0.5 mL). Stirring was continued under air
for 30 min and then the mixture was partitioned between EtOAc
(10 mL) and water (10 mL). The organic phase was washed with
brine, dried (Na2SO4) and evaporated. Flash chromatography of
the residue over silica gel (0.5 ¥ 10 cm) in a Pasteur pipette,
using 30% EtOAc–hexanes (10 mL) and then 40% EtOAc–hexanes
(10 mL), gave quinone imine intermediate 6.8 (12.9 mg, 93%). The
freshly isolated material is a yellow crystalline solid: mp 80 ◦C. This
material isomerizes partially to indole 6.9 in the solid state, the
ratio of quinone imine to indole being 2 : 1 after 4.5 h (1H-NMR).
The above quinone imine–indole mixture (10.9 mg,
0.0400 mmol) was dissolved in PhH (2.5 mL). Rh–Al2O3 (2.3 mg,
5% Rh, 0.0011 mmol) was added with stirring and the mixture was
8 Recent examples of coumarin and dihydrocoumarin synthesis:
(a) N. M. F. S. A. Cerqueira, A. M. F. Oliveira-Campos, P. J. Coelho,
L. H. M. de Carvalho, A. Samat and R. Guglielmetti, Helv. Chim. Acta,
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Malhotra and T. Sitler, J. Org. Chem., 2006, 71, 409–412; (c) K. Zeitler
and C. A. Rose, J. Org. Chem., 2009, 74, 1759–1762.
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4870 | Org. Biomol. Chem., 2009, 7, 4862–4870
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