Kharasch-type cyclizations of 2-substituted indole derivatives surprisingly lead to spiroindoles

Article abstract of DOI:10.1002/ejoc.201000757

Starting from l/H-indole-2-carboxylic acid, a series of spiro[2oxoindole-pyrrolidines] could be synthesized in a straightforward manner. The key reaction is a Kharasch radical cyclization reaction of trichloroacetylated precursors. The identity of the tricyclic final products that were formed could be de-termined as spiro[2-oxoindole-pyrrolidines] by using a combination of different analytical techniques (¹H NMR, ¹³C NMR, gHMBC, HRMS) and additional reactions. The produced skeletons are interesting from a medicinal point of view.

Full text of DOI:10.1002/ejoc.201000757

FULL PAPER
DOI: 10.1002/ejoc.201000757
Kharasch-Type Cyclizations of 2-Substituted Indole Derivatives Surprisingly
Lead to Spiroindoles
Sarah Van der Jeught,[a,b] Nils De Vos,[a] Kurt Masschelein,[a] Ion Ghiviriga,[c] and
Christian V. Stevens*[a]
Keywords: Nitrogen heterocycles / Spiro compounds / Cyclization / Radicals
Starting from 1H-indole-2-carboxylic acid, a series of spiro[2-
oxoindole-pyrrolidines] could be synthesized in a straightfor-
ward manner. The key reaction is a Kharasch radical cycliza-
tion reaction of trichloroacetylated precursors. The identity
of the tricyclic final products that were formed could be de-
termined as spiro[2-oxoindole-pyrrolidines] by using a com-
bination of different analytical techniques (1H NMR, 13C
NMR, gHMBC, HRMS) and additional reactions. The pro-
duced skeletons are interesting from a medicinal point of
view.
Introduction
Heterocyclic spiro compounds have raised a lot of inter-
est because of their biological properties (such as anticancer
activity, complexing agents, etc.)[1] as well as their synthetic
use. From a synthetic point of view, in many cases the spiro
carbon atom is difficult to construct and causes strain in
the molecule. Often facile rearrangements opening perspec-
tives for new pathways result.[2] Spirooxindoles belong to
this class of spiro heterocycles and have been intensively
investigated.[3] Their presence in several natural products
and medicinal compounds have learned that these struc-
tures are interesting targets for synthetic programmes. The
spiro[oxindole-3,3Ј-pyrrolidine] ring system in particular is
a structural part in a number of bioactive compounds.[4]
For example, pseudoindoxyl alkaloids (1, Figure 1) have an
important antiviral activity and have raised attention in the
area of cancer research.[5] Two other oxindole alkaloids
used as antitumor compounds are horsfiline (2)[6] and
coerusceline (3).[7] Recently a few spiro[oxindole-pyrrolid-
ine] alkaloids were isolated as secondary metabolites from
a.o. Aspergillus fumigatus, with as major function the dis-
turbance of the animal cell cycle. The most important me-
tabolites are spirotryprostatine A (4) and spirotryprostatine
B (5).[8]
Figure 1. A few examples of biologically active spirooxindoles.
These examples mostly concern spirooxindole systems, hav-
ing a C-3 spiro carbon atom. In earlier work, the HATRC
(Halogen Atom Transfer Radical Cyclization) reaction and
a domino radical cyclization route have been evaluated on
highly functionalized 3-substituted indoles.[9] Related cycli-
zations of other substituted benzenes were also performed
via radical reactions.[10] In this article, a straightforward
synthetic route is presented towards spiroindoles having a
spiro center at the C-2 position. The key step in this synthe-
sis is a Kharasch-type ring closure resulting in the envisaged
end products.
Some work has been performed on the synthesis of in-
dole derivatives substituted at the C-3 position, since these
can be synthesized more easily than 2-substituted ones.
[a] Department of Organic Chemistry, Faculty of Bioscience
Engineering, Ghent University,
Results and Discussion
Coupure Links 653, 9000 Ghent, Belgium
E-mail: Chris.stevens@UGent.be
The synthesis of 1H-indole-2-carbaldehyde (8) has al-
ready been reported several times[11] and most of the pro-
cedures start with the reduction of the carboxylic acid 6 to
indole-2-methanol (7), followed by oxidation to the alde-
[b] Aspirant of the Research Foundation Flanders
(FWO Vlaanderen), Belgium
[c] Department of Chemistry, University of Florida,
393 Leigh Hall, PO Box 117200, Gainesville, FL 32611-7200,
USA
View this journal online at
wileyonlinelibrary.com
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Kharasch-Type Cyclizations of 2-Substituted Indoles
hyde 8. Several procedures were evaluated: reduction of the benzyl bromide in a mixture of methyl-THF and 25%
carboxylic acid 6 with LiAlH4 followed by oxidation with NaOHaq (1:2) in the presence of TBAB as phase-transfer cat-
MnO2 in one step,[11a] reduction of the corresponding ester alyst[15] was evaluated and resulted in the benzyl-protected
with DIBAH again followed by oxidation,[11b] Rosenmund indole-2-carbaldehyde 9b in good yield (80%) (Scheme 2).
reduction of the corresponding acid chloride[12] and varia-
Having the protected aldehydes 9a,b in hand, several
tions on these methods. However, the yields published by imines were prepared thereof. For each protecting group,
the authors (yields ranging from 64[11d] to 91[11a] and four different amines were used: isopropylamine, benzyl-
95%[11f]) could not be repeated. The best results were ob- amine, p-MeO-benzylamine and tritylamine. These amines
tained by reduction of indole-2-carboxylic acid (6) with Li- were randomly picked, except for tritylamine. The trityl
AlH4 in THF at 0 °C. After completion of the reaction, the group was introduced to increase the molecular weight of
mixture was quenched with saturated aqueous Na/K tar- the compounds in an attempt to prepare crystalline deriva-
trate solution and filtered through Celite®. The tartrate en- tives. A standard imination method was evaluated: the alde-
ables the formed LiAl salts to dissolve again, releasing the hyde together with 1 equiv. of amine (3 equiv. in the case of
indole-2-methanol 7 and making it again available for oxi- the volatile isopropylamine) and 3 equiv. of MgSO4 were
dation or isolation. The water layer and organic layer were refluxed overnight, which led to good results in most of the
then separated and the solvent was evaporated to give 7 as cases (Scheme 3, Table 1). The imination of 9b with iso-
an intermediate. This alcohol was oxidized in CH2Cl2 with propylamine, however, resulted in an incomplete conver-
activated MnO2 to give aldehyde 8. The combined yield of sion. With tritylamine, even no conversion was detected.
this two-step synthesis was 66% (Scheme 1).
Therefore, imines 10d,e,h were prepared in the presence of
0.6 equiv. of the Lewis acid TiCl4 and with an extra amount
of amine (3.4 equiv. of isopropylamine or 1 equiv. of trityl-
amine + 2.4 equiv. of triethylamine) in dry diethyl ether.
After work-up the imines could be recrystallized from
methanol in fairly good yields: 57% for 10d, 75% for 10e
and 61% for 10h.
Scheme 1. Synthesis of starting compound 1H-indole-2-carb-
aldehyde (8).
The carbaldehyde 8 was then first protected on the indole
nitrogen to avoid the formation of byproducts in the follow-
ing steps. Two protective groups were evaluated: a Boc
group and a benzyl group. A literature procedure (reported
yield 96%) was evaluated for the Boc protection, Boc anhy-
dride (Boc2O) and 4-(dimethylamino)pyridine in acetoni-
trile gave a complete conversion.[13] The protected carbal-
dehyde 9a could be isolated in 95% yield after filtration
through silica (Scheme 2). The benzyl group enlarges the
electron density in the indole ring and thus promotes radi-
cal reactions with electrophilic radicals. The synthesis of
this benzylated compound 9b was also described several
times in literature with a maximum yield of 94%.[14] Stan-
dard reaction conditions in one organic phase were evalu-
ated (BnBr in dry acetone with K2CO3), but resulted in bad
yields. Therefore, a benzylation procedure with 1 equiv. of
Scheme 3. Synthetic pathway from protected indole-2-carbal-
dehydes 9 to precursors for the ring-closure reaction of 12.
Table 1. Reaction conditions for Scheme 3, towards the precursors
for the ring closure of 12.
Entry R1
R2
Imine 10
Amine 11 Acetylated amine 12
yield (%)
yield (%)
yield (%)
a
b
c
d
e
f
g
h
Boc iPr
Boc Bn
Boc p-MeO-Bn
Boc trityl
95
79
84
82
80
83
–
98
83
82
–
94
24
44
–
74
53
62
–
57[a]
75[a]
81
Bn
Bn
Bn
Bn
iPr
Bn
p-MeO-Bn
trityl
83
61[a]
[a] Prepared with TiCl4 instead of MgSO4.
Subsequent reduction of these imines was accomplished
with NaBH4 in methanol while overnight stirring. This long
reaction time was needed due to the poor solubility of the
starting imines in methanol, but gave complete conversion
and good yields in most of the cases (Table 1). However, no
Scheme 2. N-protection of 1H-indole-2-carbaldehyde (8). Reaction
conditions Scheme 2: a) 1.22 equiv. Boc2O, 0.1 equiv. DMAP,
CH3CN, o.n., room temp.; b) 1 equiv. BnBr, 1.5 mol-% TBAB, m-
THF/NaOH(25%) (2:1), 2.5 h, reflux.
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C. V. Stevens et al.
FULL PAPER
reduction occurred in entry d and h with the tritylimines sulting from two different ways of ring closing (Scheme 4).
10d and 10h. Another reduction method with LiAlH4 in The spiro five-membered ring 13 results from a 5-exo-trig
dry THF was evaluated on these imines, but this reaction cyclization, while the annulated six-membered ring 14
resulted in degradation. Therefore, the reaction sequence would be formed by a 6-endo-trig cyclization. Many efforts
was continued with the other derivatives.
were made to grow crystals from the obtained powders.
Since the key ring-closing step in this synthesis is a Khar- This would enable X-ray crystallography on the resulting
asch reaction, the precursors have to bear a halogen substit- ring-closed compounds as a method for the unambiguous
uent to enable this radical reaction. Therefore, a tri- identification of the structure. Unfortunately, these efforts
chloroacetyl group was introduced on the nitrogen atom failed and no suitable crystals could be obtained. To deter-
using trichloroacetyl chloride. Pyridine was added as a base mine which of the two possible compounds was formed, the
and the reaction was completed overnight. The resulting spectroscopic data were thoroughly analyzed and a series
precursors 12 could be prepared in good yields (Table 1), of additional reactions were performed on the products
however, exclusion of light was necessary (during work-up (Table 2).
and afterwards) due to their light-sensitive character. Split-
1
ting of the signals in H-NMR- and 13C-NMR spectra was
observed for the acetylated products 12b and 12c. This is
due to the presence of rotamers caused by hindered rotation
of the amide function in the proximity of the bulky Boc
group, the trichloroacetyl group and the benzyl group. In
the case of smaller side chains, no rotamers were observed.
Scheme 4. Radical ring-closing reaction via HATRC.
The final key step in this synthetic route is the Kharasch
cyclization. This radical reaction was performed under ar-
gon atmosphere in the presence of CuICl and with
Table 2. Conditions for the radical ring-closing reaction.
Entry R1
R2
Product
Crude yield[a]
Pure yield[b]
PMDETA (N,N,NЈ,NЈ,NЈЈ-pentamethyldiethylenetriamine)
as a ligand. After 24 h of stirring in refluxing dichloro-
methane, the starting products were completely conversed
into the new ring-closed products. These ring-closed prod-
ucts could be isolated after work-up in 81–85% crude yield.
In most of the cases, several byproducts (ca. 20%) were
formed and were difficult to remove. After a combination
of chromatographic steps and recrystallizations, the com-
pounds 13a,c,e,f,g were obtained as powders in more than
95% purity. Unfortunately, this resulted in loss of product,
which could not be avoided. In the case of 13b, however,
(%)
(%)
1
2
3
4
5
6
Boc
iPr
Bn
13a or 14a
13b or 14b
84
85
83
85
83
81
84[c]
–
20
14
37
22
Boc
Boc
Bn
Bn
Bn
p-MeO-Bn 13c or 14c
iPr
Bn
13e or 14e
13f or 14f
p-MeO-Bn 13g or 14g
[a] Yield after work-up, without purification. [b] Yield after purifi-
cation. [c] No purification necessary.
In theory, the radical formed with CuICl on the tri-
the impurities could not be removed and no spectroscopic chloroacetamide function should attack the double bond at
data of this compound were included due to insufficient the most electron-rich position, which is C-3. When the rad-
purity.
ical reacts on this position, it would result in intermediate
1
Although the AB-systems that appear in the H-NMR compound 17. Termination of the reaction would occur
spectra prove that the newly formed products are certainly when this radical reacts with a chlorine radical from
cyclized molecules, two structures (13 and 14, same mass, CuIICl2, resulting in the annulated six-membered ring 14
functionalities and very similar spectra) were possible, re- (Scheme 5).
Scheme 5. Reaction mechanism towards the six-membered annulated ring 14.
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Kharasch-Type Cyclizations of 2-Substituted Indoles
1
From the H-NMR spectrum can be concluded that the
compound is a ring closed product, since the signal from
the CH2 in the side chain is no longer a singlet, but an AB-
system. The signal from the 3-H, however, has an abnormal
high chemical shift: 6.02 ppm. This led to the consideration
of another possible structure for this ring closed product,
being a spiropyrrolidin-2-one-indole 13. In this case, ring
closing of the compound occurs at C-2 instead of C-3, re-
sulting in the presence of a chlorine atom on the 3-position
(Scheme 6). This could explain the upfield shift of the 3-H
signal and the other signals could also be assigned to pro-
tons in the spiro structure.
Figure 2. Important long-range H-13C cross-couplings for 13a,e,f.
1
Scheme 6. Reaction mechanism towards the five-membered spiro
compound 13.
compounds, no X-ray analysis could be performed. From
the NMR spectra, it was clear that the carbon signal at δ =
64.7 ppm is connected to a chlorine, which can be syn or
anti to 88.8. The absence of a cross-peak between 6.00 ppm
and 45.9 ppm in the gHMBC spectrum of 13a indicated a
small coupling constant and the presence of a cross-
coupling of 6.00 ppm with 88.8 ppm indicated a larger
coupling with this carbon. This is in agreement with an anti
geometry of the chlorine at δ = 64.7 ppm and the carbon
at δ = 88.8 ppm, relative to the five-membered ring of the
indole moiety. Therefore, the anti diastereoisomer of the
spiropyrrolidin-indol-2-one is suggested as the isolated
compound.
HRMS (High Resolution Mass Spectrometry) confirmed
that the exact mass of the investigated product was 433.7
g/mol, so corresponding to the compound containing all
three chlorine atoms. This matches both of the proposed
ring-closed products, but structure 14 would probably show
more tendency to expel a chlorine atom, assisted by the
nitrogen lone pair. In addition to the standard NMR analy-
ses (1H NMR, 13C NMR, HSQC, DEPT), also a gHMBC
(gradient-selected Heteronuclear Multiple Bond Corre-
lation) spectrum was taken from 13a. Some relevant long-
1
range H-13C cross-couplings were observed and the most
important ones are summarized in Table 3 and depicted in
Figure 2.
Cyclic derivative 13f, possessing a benzyl substituent on
the indole nitrogen and a p-methoxy-benzyl substituent on
the other nitrogen atom was also analyzed via HMBC spec-
troscopy. In this case, a clear cross-coupling was visible be-
tween one of the protons of the AB-system (at δ =
3.25 ppm) and the carbon containing two chlorine atoms
(at δ = 88.13 ppm). Identical cross-couplings were visible in
the HMBC spectrum of derivative 13e. These findings con-
firm that the cyclic compounds are indeed spiro[indole-2,3Ј-
pyrrolidines].
Table 3. Most important long-range 1H-13C cross-couplings for
13a.
C-2 C-3 C-4 C-5 C-6 C-7 C-1Ј C-2Ј C-4Ј
76.2 64.7 125.0 124.1 131.1 116.4 88.8 164.5 45.9
H-3 6.00
H-4 7.39
H-5 7.11
H-6 7.35
H-7 7.60
Ha-4Ј 4.13
Hb-4Ј 4.25
+
+
+
+
+
+
+
+
To get additional proof of the structure, a series of reac-
tions were performed on one of the cyclic products, 13a. In
Some conclusions could be made from these findings. an aqueous solution, the compound remains stable, even
The coupling of the protons at δ = 4.25 and 4.13 ppm with after addition of NaOH. If the product would be an annu-
the carbon at δ = 88.8 ppm indicate that these atoms are lated six-membered ring 14a, the chlorine atom on C-2
three bonds apart, which is only possible on a five-mem- would probably be expelled under influence of the indole
bered structure. Hence it can be presumed that the ring- nitrogen, followed by the addition of OH–. This does not
closed products are spirocyclic derivatives. These com- occur which gives an indication that the structure is the
pounds possess two stereocenters, but only one dia- spiropyrrolidin-2-one-indole 13a. Attempts to remove the
stereomer was isolated after ring-closure for each of the protective Boc group (to create a more electron-rich nitro-
derivatives. This indicates the diastereoselectivity of the re- gen atom, thus speeding up the expelling of the chlorine)
action towards only one of the diastereomers. However, failed under several reaction conditions, and therefore did
since it was impossible to create single crystals of these not provide any additional information.
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C. V. Stevens et al.
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High resolution mass spectra were recorded on a Finnigan MAT
95 XP-API-GC-Trap tandem mass spectrometer system. IR spectra
were obtained from a Perkin–Elmer Spectrum BX FT-IR System
Spectrometer. Spectra for all of the compounds, liquid as well as
crystalline were collected on a ZnSe-crystal in ATR mode. Only
If a compound such as 14a were treated with a base, a
deprotonation of C-3 would be expected, followed by expul-
sion of the chlorine atom and thus restoring the aromatic
system. In the case of a spiro compound 13a, the addition
of a base would have no result, since elimination of HCl
is impossible from this structure. Upon treatment of the
compound with the strong base KOtBu, no reaction oc-
curred and the compound remained completely intact. This
is again indicative of the five-membered spiro-ring in 13a.
Repeating the reaction with K-HMDS resulted in complete
decomposition, concluding that these reaction conditions
were too harsh for the compound.
Removal of the chlorine atoms would result in different
coupling patterns in the 1H-NMR spectrum for the two
possible structures. This hydrogenation was evaluated with
zinc in acetic acid,[16] with H2 and palladium on carbon
and with -Selectride. However, these reactions resulted in
complex mixtures without identifiable products.
selected absorbances (νmax /cm–1) were reported. Melting points of
˜
crystalline compounds were measured with a Büchi B-540 appara-
tus. Elemental analyses were obtained by means of a Perkin–Elmer
2400 Series II apparatus.
Synthesis of Indole-2-methyleneamines 10a–h: As a representative
example, the synthesis of [1-(tert-butoxycarbonyl)indole-2-methyl-
ene]isopropylamine (10a) is described here. To a solution of tert-
butyl 2-formylindole-1-carboxylate (9a) (1.5 g; 6.12 mmol) in
CH2Cl2 was added isopropylamine (1.09 g; 18.36 mmol) and
MgSO4 (2.21 g; 18.36 mmol). After stirring overnight at reflux tem-
perature, the MgSO4 was filtered off and the solvent was evapo-
rated under vacuum. The product 10a (1.66 g; 5.81 mmol; 95%
yield) was obtained as a brown solid. The compound was too hy-
groscopic and sticky to take a reproducible melting point.
tert-Butyl 2-[(E)-(Isopropylimino)methyl]-1H-indole-1-carboxylate
1
(10a): H NMR (300 MHz, CDCl3): δ = 1.28 [d, J = 6.4 Hz, 6 H,
CH(CH3)2], 1.69 [s, 9 H, C(CH3)3], 3.59 [sept, J = 6.4 Hz, 1 H,
CH(CH3)2], 7.16 (s, 1 H, 3-H), 7.22 (dd, J = 7.6, J = 7.6 Hz, 1 H,
5-H or 6-H), 7.33 (ddd, J = 8.0, J = 7.6, J = 1.1 Hz, 1 H, 5-H or
6-H), 7.55 (J = 7.6 Hz, 1 H, d, 4-H or 7-H), 8.11 (d, J = 8.0 Hz, 1
H, 4-H or 7-H), 8.79 (s, 1 H, CH=N) ppm. 13C NMR (75 MHz,
CDCl3): δ = 24.11 [CH(CH3)2], 28.88 [C(CH3)3], 61.81 [CH-
(CH3)2], 84.55 [C(CH3)3], 110.82 (C-3), 115.75 (C-4 or C-7), 121.49
(C-4 or C-7), 123.21 (C-5 or C-6), 125.38 (C-5 or C-6), 128.89 (Cq),
137.06 (Cq), 137.29 (Cq), 150.27 (O=C–O), 152.24 (CH=N) ppm.
Conclusions
A straightforward synthesis of unexpected spiroindoles
with a C-2 spiro atom is presented, starting from the com-
mercial indole-2-carboxylic acid. The key ring closing step
is a Kharasch reaction resulting in a tricyclic compound.
Instead of the expected six-membered annulated indole de-
rivative a five-membered spiro compound was formed. The
identification of the structure as a spiro[indole-2,3Ј-pyrrol-
idine] could be concluded from a series of analytical results
combined with synthetic reactions. The most decisive argu-
ments are: 1) the coupling between the carbon bearing two
chlorine atoms and the H-atoms from the AB-system in the
side chain is clearly visible in the HMBC spectra, which is
impossible in the case of a six-membered ring; 2) the recov-
ery of the intact compound after treatment with base, so
no deprotonation on C-3 followed by expelling of a chloride
IR: ν = 1731 (νO=C–O) 1628 (νC=N) cm–1. MS (ESI, POS): m/z (%)
˜
= 287.3 (100) [M + H+].
tert-Butyl
2-[(E)-(Benzylimino)methyl]-1H-indole-1-carboxylate
(10b): Compound 10b was prepared from 9a (2.2 g; 8.97 mmol) by
the procedure described for 10a. In this case, 1 equiv. of benzyl-
amine was added. The product 10b was obtained as a brown oil
1
(2.37 g; 7.09 mmol; 79% yield). H NMR (300 MHz, CDCl3): δ =
1.69 [s, 9 H, C(CH3)3], 4.85 (s, 2 H, CH2-Ph), 7.24–7.36 (m, 8 H,
8ϫ CHar), 7.57 (d, J = 7.7 Hz, 1 H, 4-H or 7-H), 8.11 (d, J =
occurred, restoring the aromatic system (this deprotonation 8.8 Hz, 1 H, 4-H or 7-H), 8.96 (s, 1 H, CH=N) ppm. 13C NMR
(75 MHz, CDCl3): δ = 28.45 [C(CH3)3], 65.40 (CH2-Ph), 84.79
[C(CH3)3], 111.29 (CHar), 115.81 (C-4 or C-7), 121.70 (C-4 or C-
7), 123.31 (CHar), 125.64 (CHar), 127.05 (CHar), 128.09 (2ϫ CHar),
128.54 (CHar), 128.64 (Cq), 128.80 (Cq), 137.06 (Cq), 139.20 (Cq),
would be expected in the case of a six-membered ring) and
3) the stability of the compound in an aqueous solution,
proving that nitrogen does not provide neighbouring group
assistance to expel the chloride, followed by addition of
OH–.
150.35 (C=O), 155.81 (CH=N) ppm. IR: ν = 1730 (νC=O) 1631
˜
(νC=N) cm–1. MS (ESI, POS): m/z (%) = 335.2 (100) [M + H+].
tert-Butyl 2-[(E)-(4-Methoxybenzylimino)methyl]-1H-indole-1-carb-
oxylate (10c): Compound 10c was prepared from 9a (2.0 g;
8.15 mmol) by the procedure described for 10a. In this case,
1 equiv. of p-methoxybenzylamine was added. The product 10c was
Experimental Section
General: High-resolution 1H NMR (300 MHz), 13C NMR
(75 MHz) and 31P NMR (121 MHz) spectra were run on a Jeol
Eclipse FT 300 NMR spectrometer. Peak assignments were ob-
tained with the aid of DEPT, HSQC, DQFCOSY and HMBC spec-
tra. The compounds were diluted in deuterated solvents and the
used solvent is indicated for each compound. As internal standard,
tetramethylsilane (TMS) was used. Multiplicities are described by
the following symbols: s for singlet, d for doublet, t for triplet, q
for quadruplet, p for pentuplet, m for multiplet; br.: broad, ps:
pseudo. Low-resolution mass spectra of pure compounds were re-
corded via direct injection on an Agilent 1100 Series LC/MSD type
SL mass spectrometer with Electron Spray Ionisation geometry
(ESI 70 eV) and using a Mass Selective Detector (quadrupole).
1
obtained as a brown oil (2.50 g; 6.85 mmol; 84% yield). H NMR
(300 MHz, CDCl3): δ = 1.69 [s, 9 H, C(CH3)3], 3.81 (s, 3 H, O-
CH3), 4.78 (s, 2 H, CH2-Ph), 6.89 (d, J = 8.3 Hz, 2 H, 2ϫ CHar),
7.21–7.37 (m, 5 H, 5ϫ CHar), 7.56 (d, J = 7.7 Hz, 1 H, 4-H or 7-
H), 8.11 (d, J = 8.8 Hz, 1 H, 4-H or 7-H), 8.93 (s, 1 H, CH=N)
ppm. 13C NMR (75 MHz, CDCl3): δ = 28.29 [C(CH3)3], 55.33 (O-
CH3), 64.86 (CH2-Ph), 84.75 [C(CH3)3], 111.21 (CHar), 113.95 (2ϫ
CHar), 115.81 (C-4 or C-7), 121.67 (C-4 or C-7), 123.29 (CHar),
125.61 (CHar), 128.80 (Cq), 129.29 (2ϫ CHar), 131.31 (Cq), 137.06
(Cq), 137.11 (Cq), 150.35 (Cq), 155.42 (CH=N), 158.73 (Cq) ppm.
IR: ν = 1730 (νC=O) 1627 (νC=N) cm–1. MS (ESI, POS): m/z (%) =
˜
365.2 (100) [M + H+].
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Kharasch-Type Cyclizations of 2-Substituted Indoles
tert-Butyl
2-[(E)-(Tritylimino)methyl]-1H-indole-1-carboxylate 1 equiv. of p-methoxybenzylamine was added. After recrystalli-
(10d): To a solution of 1-benzylindole-2-carbaldehyde 9a (0.75 g;
3.06 mmol) in dry diethyl ether (40 mL) was added dropwise TiCl4
(0.35 g; 0.6 equiv.; 1.84 mmol) in dry petroleum ether (20 mL) at
0 °C under a nitrogen atmosphere. After following dropwise ad-
dition of tritylamine (0.79 g; 3.06 mmol) and triethylamine (0.74 g;
7.34 mmol) in dry diethyl ether (20 mL), the mixture was stirred
overnight at room temperature under nitrogen. The reaction mix-
ture was then poured into an aqueous 2  NaOH solution (40 mL)
and extracted with diethyl ether (2ϫ40 mL). The organic phase is
dried with MgSO4 and K2CO3, filtered and the solvents evaporated
in vacuo. Recrystallization from methanol resulted in the product
10d (0.85 g; 1.74 mmol; 57% yield) as a yellow glass-like powder;
recrystallization from MeOH. No reproducible melting point could
be determined due to the high hygroscopicity and stickyness of the
zation from methanol, product 10g was obtained as pale yellow
crystals (3.63 g; 10.23 mmol; 83% yield). 1H NMR (300 MHz,
CDCl3): δ = 3.76 (s, 3 H, OCH3), 4.66 (s, 2 H, =N-CH2-Ph), 5.98
(s, 2 H, Ph-CH2-Nind), 6.78 [ps (d), J = 8.8 Hz, 2 H, 2ϫ CHar],
6.88 (s, 1 H, 3-H), 6.98–7.24 (m, 9 H, 9ϫ CHar), 7.30 (d, J =
8.3 Hz, 1 H, CHar), 7.65 (d, J = 7.7 Hz, 1 H, 4-H of 7-H), 8.41 (s,
1 H, CH=N) ppm. 13C NMR (75 MHz, CDCl3): δ = 48.03 (CH2-
Nind), 55.37 (O-CH3), 65.07 (=N-CH2-Ph), 110.49 (2ϫ CHar),
110.61 (CHar), 113.85 (2ϫ CHar), 120.41 (CHar), 121.85 (C-4 of C-
7), 124.31 (CHar), 126.64 (CHar), 126.93 (CHar), 127.32 (Cq),
128.51 (2ϫ CHar), 128.89 (2ϫ CHar), 131.81 (Cq), 135.07 (Cq),
138.87 (Cq), 139.84 (Cq), 154.10 (CH=N), 158.55 (Cq-OMe) ppm.
IR: ν = 1632 (νC=N) cm–1. MS (ESI, POS): m/z = 355.2 (M + H+,
˜
100), m.p. 117.4–119.2 °C.
1
product. H NMR (300 MHz, CDCl3): δ = 1.43 [s, 9 H, C(CH3)3],
N-[(E)-(1-Benzyl-1H-indol-2-yl)methylidene]tritylamine (10h): Com-
pound 10h was prepared from 9b (0.61 g; 2.58 mmol) by the pro-
cedure described for 10d. In this case, tritylamine (0.67 g;
2.58 mmol) and triethylamine (0.63 g; 2.4 equiv.; 6.2 mmol) in dry
diethyl ether (20 mL) were added. The product 10h was obtained
as a white glass-like powder (0.75 g; 1.58 mmol; 61% yield) and
was again too hygroscopic to take a reproducible melting point. 1H
NMR (300 MHz, CDCl3): δ = 6.16 (s, 2 H, CH2-Ph), 6.77 (s, 1 H,
3-H), 6.96–7.00 (m, 2 H, 2ϫ CHar), 7.06–7.35 (m, 21 H, 21ϫ
CHar), 7.61 (d, J = 7.7 Hz, 1 H, 4-H or 7-H), 7.92 (s, 1 H, CH=N)
ppm. 13C NMR (75 MHz, CDCl3): δ = 48.41 (CH2-Ph), 79.46
(CPh3), 110.54 (CHar), 111.83 (C-3), 120.54 (CHar), 121.96 (C-4 or
C-7), 124.63 (CHar), 126.35 (2ϫ CHar), 126.89 (3ϫ CHar), 127.04
(CHar), 127.36 (Cq), 127.89 (6ϫ CHar), 128.67 (3ϫ CHar), 129.97
(6ϫ CHar), 135.56 (Cq), 138.82 (Cq), 140.17 (Cq), 145.68 (3ϫ Cq),
7.21–7.36 (m, 17 H, 17ϫ CHar), 7.44 (s, 1 H, 3-H), 7.61 (d, J =
7.7 Hz, 1 H, 4-H or 7-H), 8.14 (d, J = 8.3 Hz, 1 H, 4-H or 7-H),
8.42 (s, 1 H, CH=N) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.10
[C(CH3)3], 79.03 (CPh3), 84.62 [C(CH3)3], 111.12 (CHar), 115.67
(CHar), 121.58 (CHar), 123.26 (CHar), 125.58 (CHar), 126.89 (3ϫ
CHar), 127.83 (6ϫ CHar), 128.76 (Cq), 129.84 (Cq), 129.99 (6ϫ
CHar), 137.63 (Cq), 145.66 (3ϫ Cq), 150.05 (C=O), 153.87 (CH=N)
ppm. IR: ν = 1732 (νC=O) 1629 (νC=N) cm–1. MS (ESI, POS): m/z
˜
(%) = 300.3 (100), 305.2 (80), 487.3 (60) [M + H+].
N-[(E)-(1-Benzyl-1H-Indol-2-yl)methylidene]isopropylamine (10e):
Compound 10e was prepared from 9b (0.76 g; 3.23 mmol) by the
procedure described for 10d. In this case, 3.5 equiv. of isopro-
pylamine (0.67 g; 11.31 mmol) was added (instead of tritylamine
and triethylamine). The product 10e was obtained as yellow-brown
crystals (0.51 g; 1.84 mmol; 75% yield), m.p. 85.2–87.4 °C. 1H
NMR (300 MHz, CDCl3): δ = 1.17 [d, J = 6.4 Hz, 6 H, CH-
(CH3)2], 3.39 [sept, J = 6.4 Hz, 1 H, CH(CH3)2], 5.99 (s, 2 H, CH2-
Ph), 6.83 (s, 1 H, 3-H), 7.07–7.26 (m, 7 H, 7ϫ CHar), 7.33 (~d, J
= 8.3 Hz, 1 H, 4-H or 7-H), 7.64 (d, J = 8.3 Hz, 1 H, 4-H or 7-H),
8.36 (s, 1 H, CH=N) ppm. 13C NMR (75 MHz, CDCl3): δ = 24.36
[CH(CH3)2], 47.95 (CH2-Ph), 62.44 [CH(CH3)2], 109.59 (CHar),
110.40 (CHar), 120.20 (CHar), 121.68 (C-4 or C-7), 123.92 (CHar),
126.90 (3ϫ CHar), 127.33 (Cq), 128.37 (2ϫ CHar), 135.25 (Cq),
153.38 (CH=N) ppm. IR: ν = 1633 (νC=N) cm–1. MS (ESI, POS):
˜
m/z (%) = 261.2 (100), 305.2 (80), 300.3 (60), 243.3 (60).
Synthesis of Indole-2-methylamines 11a,b,c,e,f,g: As a representative
example, the synthesis of 11a is described here. To a solution of [1-
(tert-butoxycarbonyl)indole-2-methylene]isopropylamine
(10a)
(3.31 g; 11.56 mmol) in MeOH (150 mL), NaBH4 (0.875 g;
23.12 mmol) was added stepwise at 0 °C under a nitrogen atmo-
sphere. After stirring the mixture overnight at room temperature,
50 mL of NaOH (2 ) was added and again stirred for 10 min. The
solution was poured into CH2Cl2 and the organic phase washed
with NaOH (3ϫ25 mL) and dried with MgSO4. This was filtered
through a fresh layer of MgSO4 and after evaporation of the sol-
vent, the product 11a (2.73 g; 9.48 mmol; 82% yield) was obtained
as a brown solid. No reproducible melting point could be deter-
mined due to the high hygroscopicity and stickyness of the product.
138.98 (C ), 139.68 (C ), 150.54 (C=N) ppm. IR: ν = 1638 (ν )
˜
q
q
C=N
cm–1. MS (ESI, POS): m/z (%) = 277.2 (100) [M + H+].
N-[(E)-(1-Benzyl-1H-indol-2-yl)methylidene]-1-phenylmethanamine
(10f): Compound 10f was prepared from 9b (3.20 g; 13.60 mmol)
by the procedure described for 10a. In this case, 1 equiv. of benzyl-
amine was added. After recrystallization from methanol, product
10f was obtained as yellow crystals (3.57 g; 11.02 mmol; 81%
yield), m.p. 87.9–89.3 °C. Recrystallization (MeOH). 1H NMR
(300 MHz, CDCl3): δ = 4.73 (s, 2 H, =N-CH2-Ph), 6.01 (s, 2 H,
Ph-CH2-Nind), 6.90 (s, 1 H, 3-H), 6.99–7.02 (m, 2 H, 2ϫ CHar),
7.09–7.28 (m, 10 H, 10ϫ CHar), 7.31 [ps (d), 1 H, CHar], 7.66 (d,
J = 7.7 Hz, 1 H, 4-H or 7-H), 8.45 (s, 1 H, CH=N) ppm. 13C NMR
(75 MHz, CDCl3): δ = 48.06 (CH2-Nind), 65.63 (=N-CH2-Ph),
110.50 (CHar), 110.76 (CHar), 120.40 (CHar), 121.87 (C-4 or C-7),
124.38 (CHar), 126.63 (CHar), 126.83 (2ϫ CHar), 126.95 (CHar),
127.30 (Cq), 127.68 (2ϫ CHar), 128.46 (2ϫ CHar), 128.52 (2ϫ
CHar), 135.03 (Cq), 138.84 (Cq), 139.73 (Cq), 139.88 (Cq), 154.46
tert-Butyl
2-[(Isopropylamino)methyl]-1H-indole-1-carboxylate
1
(11a): Brown solid; yield 82%. H NMR (300 MHz, CDCl3): δ =
1.08 [d, J = 6.1 Hz, 6 H, CH(CH3)2], 1.70 [s, 9 H, C(CH3)3], 2.83
[sept, J = 6.1 Hz, 1 H, CH(CH3)2], 4.11 (s, 2 H, NH-CH2), 7.19
(ddd, J = 7.6, J = 7.2, J = 1.7 Hz, 1 H, 5-H or 6-H), 7.25 (ddd, J
= 8.0, J = 7.6, J = 1.8 Hz, 1 H, 5-H or 6-H), 7.48 (dd, J = 7.2, J
= 1.8 Hz, 1 H, 4-H or 7-H), 8.06 (d, J = 8.0 Hz, 1 H, 4-H or 7-H)
ppm. 13C NMR (75.6 MHz, CDCl3): δ = 22.95 [CH(CH3)2], 28.26
[C(CH3)3], 45.58 (CH2-NH), 46.81 [CH(CH3)2], 84.11 [C(CH3)3],
108.91 (C-3), 115.67 (C-4 or C-7), 120.19 (C-4 or C-7), 122.76 (C-
5 or C-6), 123.72 (C-5 or C-6), 129.11 (Cq), 136.63 (Cq), 139.95
(CH=N) ppm. IR: ν = 1629 (νC=N) cm–1. MS (ESI, POS): m/z (%)
(C ), 150.56 (O=C–O) ppm. IR: ν = 1726 (νC=O) cm–1. MS (ESI,
˜
˜
q
= 325.2 (100) [M + H+]. C23H20N2 (324.42): calcd. C 85.16, H 6.21,
N 8.63; found C 84.86, H 6.43, N 8.57.
POS): m/z (%) = 289.2 (100) [M + H+].
tert-Butyl 2-[(Benzylamino)methyl]-1H-indole-1-carboxylate (11b):
N-[(E)-(1-Benzyl-1H-indol-2-yl)methylidene]-1-(4-methoxyphenyl)- Compound 11b was prepared from 10b (2.30 g; 6.88 mmol) by the
methanamine (10g): Compound 10g was prepared from 9b (2.90 g;
12.33 mmol) by the procedure described for 10a. In this case,
procedure described for 11a. The product 11b was obtained as a
pale brown oil (1.85 g; 5.50 mmol; 80% yield). 1H NMR
Eur. J. Org. Chem. 2010, 5444–5453
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5449

C. V. Stevens et al.
FULL PAPER
(300 MHz, CDCl3): δ = 1.68 [s, 9 H, C(CH3)3], 2.17 (br. s, 1 H,
NH): 3.83 [s, 2 H, (Ph)-CH2], 4.13 (s, 2 H, NH-CH2), 6.54 (s, 1 H,
3-H), 7.18–7.38 (m, 7 H, 5-H, 6-H and 5ϫ CHar), 7.50 (dd, J =
procedure described for 11a. The product 11g was obtained as a
yellow oil (2.89 g; 8.10 mmol; 82% yield). 1H NMR (300 MHz,
CDCl3): δ = 1.49 (br. s, 1 H, NH), 3.70 (s, 2 H, N-CH2), 3.77 (s, 3
6.3, J = 1.4 Hz, 1 H, 4-H), 8.06 (d, J = 8.3 Hz, 1 H, 7-H) ppm. H, OCH3), 3.82 (s, 2 H, NH-CH2), 5.44 (s, 2 H, Ph-CH2-Nind),
13C NMR (75 MHz, CDCl3): δ = 28.25 [3ϫ C(CH3)3], 47.47 (NH- 6.47 (s, 1 H, 3-H), 6.82 [ps (d), J = 8.8 Hz, 2 H, 2ϫ CHar], 6.91–
CH2), 52.40 [(Ph)-CH2], 84.20 [C(CH3)3], 109.32 (C-3), 115.66 (C-
7), 120.25 (C-4), 122.79 (C-6), 123.79 (C-5), 126.91 (CHar), 12819
6.94 (m, 2 H, 2ϫ CHar), 7.06–7.24 (m, 8 H, 8ϫ CHar), 7.59 (dd,
J = 6.6, J = 1.7 Hz, 1 H, 4-H or 7-H) ppm. 13C NMR (75 MHz,
(2ϫ CHar), 128.37 (2ϫ CHar), 129.05 (C-7a), 136.63 (C-3a), 139.47 CDCl3): δ = 45.22 (CH2-N), 46.71 (CH2-Nind), 52.62 (NH-CH2),
(C-2), 140.30 (C ), 150.57 (C=O) ppm. IR: ν = 3346 (νNH) 1726
55.36 (O-CH3), 101.88 (C-3), 109.62 (CHar), 113.83 (2ϫ CHar),
119.65 (CHar), 120.43 (C-4 or C-7), 121.59 (CHar), 126.09 (2ϫ
CHar), 127.21 (CHar), 1127.76 (Cq), 128.76 (2ϫ CHar), 129.45 (2ϫ
CHar), 132.26 (Cq), 137.83 (Cq), 138.37 (Cq), 138.46 (Cq), 158.72
˜
q
(νC=O) cm–1. MS (ESI, POS): m/z (%) = 337.2 (100) [M + H+].
tert-Butyl 2-[1-(4-Methoxybenzylamino)methyl]-1H-indole-1-carb-
oxylate (11c): Compound 11c was prepared from 10c (2.40 g;
6.59 mmol) by the procedure described for 11a. After purification
via preparative TLC (PE/EtOAc: 4:1; 4 runs, Rf = 0.14), The prod-
uct 11b was obtained as a dark yellow oil (2.00 g; 5.47 mmol; 83%
(C -OMe) ppm. IR: ν = 3336 (νNH) cm–1. MS (ESI, POS): m/z (%)
˜
q
= 357.2 (100) [M + H+].
Trichloroacetyl Derivatives 12a,b,c,e,f,g: As a representative exam-
ple, the synthesis of 2,2,2-trichloro-N-[1-(tert-butoxycarbonyl)in-
dole-2-methyl]-N-isopropylacetamide (12a) is described here. To a
dry 100 mL bulb with a solution of 11a (2.00 g; 6.95 mmol) in dry
THF (60 mL) was added pyridine (1.10 g; 13.90 mmol) with a dry
syringe. Then followed by dropwise addition (with a dry syringe)
of a solution of tricholoroacetylchloride (2.53 g; 13.90 mmol) in
dry THF (15 mL) at 0 °C and under a nitrogen atmosphere. The
reaction mixture was shielded from the light and reacted for 15 min
at 0 °C and was then warmed up to room temperature during the
overnight reaction. Afterwards, the mixture was poured into a satu-
rated NaHCO3 solution (45 mL) and extracted with CH2Cl2
(3ϫ40 mL). The organic layer was washed with 1  HCl
(3ϫ40 mL) and then dried with MgSO4. After filtration through
a fresh layer of MgSO4 and evaporation, the product 12a (2.83 g;
6.52 mmol; 94% yield) was obtained as a red oil.
1
yield). H NMR (300 MHz, CDCl3): δ = 1.68 [s, 9 H, OC(CH3)3],
2.16 (br. s, 1 H, NH), 3.76 (2 H, s. CH2-NH), 3.9 (s, 3 H, OCH3),
4.11 (s, 2 H, CH2-NH), 6.52 (s, 1 H, 3-H), 6.84–6.88 (m, 2 H, 2ϫ
CHar), 718–7.28 (m, 4 H, 4ϫ CHar), 7.49 (dd, J = 6.9, J = 1.4 Hz,
1 H, 4-H or 7-H), 8.07 (d, J = 8.3 Hz, 1 H, 4-H or 7-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 28.23 [OC(CH3)3], 47.39 (CH2-NH),
51.82 (Ph-CH2-NH), 55.23 (OCH3), 84.13 [C(CH3)3], 109.20 (C-3),
113.72 (2ϫ CHar), 115.64 (C-4 or C-7), 120.21 (C-4 or C-7), 122.74
(CHar), 123.75 (CHar), 129.06 (Cq), 129.32 (2ϫ CHar), 132.47 (Cq),
136.63 (Cq), 139.61 (Cq), 150.57 (C=O), 158.56 (Cq-OMe) ppm. IR:
ν = 1726 (νC=O) cm–1. MS (ESI, POS): m/z (%) = 367.2 (100) [M
˜
+ H+].
N-[(1-Benzyl-1H-indol-2-yl)methyl]propan-2-amine (11e): Com-
pound 11e was prepared from 10e (0.50 g; 1.81 mmol) by the pro-
cedure described for 11a. The product 11e was obtained as orange
crystals (0.42 g; 1.52 mmol; 98% yield), m.p. 77.7–79.1 °C. 1H
NMR (300 MHz, CDCl3): δ = 0.99 [d, J = 6.4 Hz, 6 H, CH-
(CH3)2], 2.79 [sept, J = 6.4 Hz, 1 H, CH(CH3)2], 3.84 [s, 2 H, (Ind)-
CH2-NH], 5.48 (s, 2 H, Ph-CH2), 6.46 (s, 1 H, 3-H), 6.96–6.98 (m,
2 H, 2ϫ CHar), 7.19–7.31 (m, 4 H, 4ϫ CHar), 7.57–7.60 (m, 1 H,
4-H or 7-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.77
[CH(CH3)2], 43.58 [(Ind)-CH2-NH], 46.55 (Ph-CH2), 47.99
[CH(CH3)2], 101.35 (C-3), 109.41 (C-4 or C-7), 119.53 (C-5 or C-
6), 120.30 (C-4 or C-7), 121.43 (C-5 or C-6), 125.93 (2ϫ CHar),
127.18 (CHar), 127.67 (Cq), 128.73 (2ϫ CHar), 137.72 (Cq), 138.28
tert-Butyl 2-{[Isopropyl(trichloroacetyl)amino]methyl}-1H-indole-1-
1
carboxylate (12a): H NMR (300 MHz, CDCl3): δ = 1.33 [d, J =
6.6 Hz, 6 H, CH(CH3)2], 1.71 [s, 9 H, C(CH3)3], 4.90 (s, 2 H, N-
CH2), 5.00 [sept, J = 6.6 Hz, 1 H, CH(CH3)2], 6.34 (s, 1 H, 3-H),
7.15–7.25 (m, 2 H, 5-H or 6-H), 7.45 (d, J = 6.6 Hz, 1 H, 4-H or 7-
H), 8.04 (d, J = 8.3 Hz, 1 H, 4-H or 7-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 20.24 [CH(CH3)2], 28.26 [C(CH3)3], 43.15 (N-CH2),
51.07 [CH(CH3)2], 84.37 [C(CH3)3], 93.59 (CCl3), 106.42 (C-3),
115.46 (C-4 or C-7), 120.27 (C-4 or C-7), 122.77 (C-5 or C-6),
123.66 (C-5 or C-6), 129.00 (Cq), 136.46 (Cq), 136.83 (Cq), 150.60
(C ), 138.83 (C ) ppm. IR: ν = 3316 (νNH) cm–1. MS (ESI, POS):
˜
q
q
m/z (%) = 220 (100) [(M – NH – iPr)+], 279 (70) [M + H+].
C19H22N2 (278.39): calcd. C 81.97, H 7.97, N 10.06; found C 81.48,
H 8.46, N 9.81.
(O-C=O), 160.03 (CCl -C=O) ppm. IR: ν = 1729 (νC=O) 1676
˜
3
(νC=O) cm–1. MS (ESI, POS): m/z (%) = 420.2 (100) [M + H+],
289.2 (65) [M + H+ – COCCl3].
N-Benzyl-1-(1-benzyl-1H-indol-2-yl)methanamine (11f): Compound
11f was prepared from 10f (3.50 g; 10.79 mmol) by the procedure
described for 11a. The product 11f was obtained as yellow crystals
(2.92 g; 8.95 mmol; 83% yield), m.p. 81.4–83.8 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.48 (s, 1 H, NH), 3.77 (s, 2 H, N-CH2),
3.85 (s, 2 H, N-CH2), 5.47 (s, 2 H, Ph-CH2-Nind), 6.48 (s, 1 H, 3-
H), 6.95 (dd, J = 8.0, J = 1.9 Hz, 2 H, 2ϫ CHar), 7.06–7.16 (m, 2
H, 2ϫ CHar), 7,18–7.33 (m, 9 H, 9ϫ CHar), 7.60 (dd, J = 6.9, J
= 1.9 Hz, 1 H, 4-H or 7-H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 45.25 (CH2-NH), 46.61 (CH2-Nind), 53.12 (NH-CH2), 101.87
(CHar), 109.52 (CHar), 119.56 (CHar), 120.34 (CHar), 121.52
(CHar), 125.98 (2ϫ CHar), 126.97 (CHar), 127.11 (CHar), 127.64
(Cq), 128.16 (2ϫ CHar), 128.36 (2ϫ CHar), 128.66 (2ϫ CHar),
tert-Butyl
2-{[Benzyl(trichloroacetyl)amino]methyl}-1H-indole-1-
carboxylate (12b): Compound 12b was prepared from 11b (1.80 g;
5.35 mmol) by the procedure described for 12a. After purification
via preparative TLC (PE/EtOAc: 15:1, 6 runs), the product 12b was
obtained as a brown oil (2.37 g; 4.92 mmol; 24% yield). The signals
of two rotamers were observed in the spectroscopic data of this
1
compound (A and B; each 50%). H NMR (300 MHz, CDCl3): δ
= 1.54 and 1.61 [s, 9 H, C(CH3)3], 4.84 and 4.91 [s, 2 H, (Ind)-
CH2], 5.14 and 5.26 (s, 2 H, Ph-CH2), 6.45 and 6.57 (s, 1 H, 3-H),
7.19–7.40 (m, 7 H, 5ϫ CHar, 5-H, 6-H), 7.49 and 7.55 (d, J =
7.2 Hz, 1 H, 4-H or 7-H), 8.09 (d, J = 7.7 Hz, 1 H, 4-H or 7-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 28.20 and 28.27 [C(CH3)3],
47.40 and 52.29 [(Ind)-CH2], 49.23 and 53.37 [(Ph)-CH2], 84.57 and
84.93 [C(CH3)3], 92.98 and 93.12 (CCl3), 106.37 and 108.12 (C-3),
115.65 (CHar), 120.38 and 120.52 (C-4 or C-7), 123.07 and 123.30
(CHar), 124.12 and 124.32 (CHar), 127.00 (CHar), 127.77 (CHar),
128.03 (CHar), 128.93 (Cq), 129.01 (2ϫ CHar), 135.00 and 135.39
(Cq), 135.82 and 135.94 (Cq), 136.64 and 136.86 (Cq), 150.17 and
137.76 (C ), 138.22 (C ), 138.27 (C ), 140.02 (C ) ppm. IR: ν =
˜
q
q
q
q
1454 cm–1. MS (ESI, POS): m/z (%) = 220.2 (100), 327.2 (60) [M
+ H+]. C23H22N2 (326.43): calcd. C 84.63, H 6.79, N 8.58; found
C 84.43, H 6.64, N 8.65.
N-4-Methoxybenzyl-1-(1-benzyl-1H-indol-2-yl)methanamine (11g):
Compound 11g was prepared from 10g (3.50 g; 9.87 mmol) by the
150.29 (O-C=O), 161.06 and 161.50 (CCl -C=O) ppm. IR: ν =
˜
3
5450
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Eur. J. Org. Chem. 2010, 5444–5453

Kharasch-Type Cyclizations of 2-Substituted Indoles
1731 (νO–C=O) 1679 (νC=O) cm–1. MS (ESI, POS): m/z (%) = 174.0
(100), 181.1 (75), [539.1 (25), 541.1 (30), 543.1 (10), 545.1 (1), Cl
isotopes].
cm–1. MS (ESI, POS): m/z (%) = [471.0 (100), 473.1 (95), 475.0 (35),
477.0 (5), M + H+, Cl isotopes]. C25H21Cl3N2O (471.81): calcd. C
63.64, H 4.49, N 5.94; found C 62.96, H 4.34, N 6.12.
N-[(1-Benzyl-1H-indol-2-yl)methyl]-2,2,2-trichloro-N-(4-methoxy-
benzyl)acetamide (12g): Compound 12g was prepared from 11g
(2.80 g; 7.86 mmol) by the procedure described for 12a. The prod-
uct 12g was obtained as a pale yellow powder (2.45 g; 4.87 mmol;
62% yield), m.p. 61.0 °C–63.1 °C. Signals of two rotamers were ob-
served in the spectroscopic data of this compound [A (70%) and B
(30%)]. 1H NMR (300 MHz, CDCl3): δ = 3.81 (br. s, 3 H, O-CH3),
4.71 and 4.83 (br. s, 2 H, CH2-N), 4.66 and 4.87 (br. s, 2 H, CH2-
N), 5.18 and 5.31 (br. s, 2 H, Nind-CH2-Ph), 6.36 and 6.53 (br. s, 1
H, 3-H), 6.75–6.92 (m, 4 H, 4ϫ CHar), 7.13–7.23 (m, 8 H, 8ϫ
CHar), 7.61 (d, J = 7.2 Hz, 1 H, 4-H or 7-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 41.97 and 45.58 (N-CH2), 46.71 (Nind-CH2-
Ph), 50.77 and 51.01 (N-CH2), 55.27 (O-CH3), 93.00 (CCl3), 102.16
and 103.64 (C-3), 109.30 and 110.02 (CHar), 114.28 (2ϫ CHar),
120.02 (CHar), 120.59 (C-4 or C-7), 122.18 (CHar), 125.84 (2ϫ
CHar), 126.42 (Cq), 127.31 (CHar), 127.41 (CHar), 127.64 (CHar),
128.53 (CHar), 128.75 (CHar), 129.66 (Cq), 133.29 and 133.70 (Cq),
136.92 and 137.40 (Cq), 137.80 (Cq), 159.28 (Cq-OMe), 160.86
tert-Butyl 2-{[1-(4-Methoxybenzyl)(trichloroacetyl)amino]methyl}-
1H-indole-1-carboxylate (12c): Compound 12c was prepared from
11c (1.90 g; 5.18 mmol) by the procedure described for 12a. After
purification via preparative TLC (PE/EtOAc: 8:1; 4 runs), The
product 12c was obtained as a pale yellow oil (2.20 g; 4.30 mmol;
44% yield). Again signals of two rotamers were observed in the
spectroscopic data of this compound (A and B; each 50%). 1H
NMR (300 MHz, CDCl3): δ = 1.55 and 1.62 [s, 9 H, C(CH3)3], 3.79
(s, 3 H, OCH3), 4.76 and 4.89 (s, 2 H, CH2-N), 5.07 and 5.23 (s, 2
H, CH2-N), 6.43 and 6.55 (s, 1 H, 3-H), 6.88 (dd, J = 8.3, J2
=
8.3 Hz, 2 H, 2ϫ CHar), 7.16–7.33 (m, 4 H, 4ϫ CHar), 7.49 and
7.54 (d, J = 7.2 Hz, 1 H, 4-H or 7-H), 8.07–8.11 (m, 1 H, 4-H or
7-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.27 [OC(CH3)3],
47.02 and 51.78 (N-CH2), 48.85 and 52.85 (N-CH2), 55.46 (OCH3),
84.55 and 84.92 [C(CH3)3], 93.08 and 93.22 (CCl3), 106.40 and
108.17 (C-3), 114.37 (2ϫ CHar), 115.65 (C-4 or C-7), 120.40 and
120.52 (C-4 or C-7), 123.06 and 123.29 (CHar), 124.09 and 124.31
(CHar), 127.18 and 127.87 (Cq), 128.42 (CHar), 128.96 (Cq), 129.48
(CHar), 135.13 and 136.00 (Cq), 136.64 and 136.83 (Cq), 150.23 and
150.31 (O-C=O), 158.56 (Cq-OMe), 160.97 and 161.41 (Cl3C-C=O)
(C=O) ppm. IR: ν = 1674 (νC=O) cm–1. MS (ESI, POS): m/z (%) =
˜
[501.0 (100), 503.0 (95), 505.0 (40), 507.0 (5), M + H+, Cl isotopes].
C26H23Cl3N2O (501.83): calcd. C 62.23, H 4.62, N 5.58; found C
61.97, H 4.38, N 5.48.
ppm. IR: ν = 1731 (νC=O) 1679 (νC=O) cm–1. MS: m/z (%) = 294.1
˜
(100).
Spiropyrrolidin-indol-2-ones 13a,c,e,f,g: As a representative exam-
ple, the synthesis of 13a is described here. To a dry 100 mL bulb
with a solution of N-isopropyl-N-[1-(tert-butoxycarbonyl)indole-2-
methyl]-2,2,2-trichloroacetamide (12a) (2.00 g; 4.61 mmol) in dry
CH2Cl2 (75 mL) under argon was added PMDETA (0.641 g;
3.7 mmol; 0.77 mL) with a dry syringe. This mixture was stirred at
room temperature for 15 min, followed by addition of CuICl
(0.182 g; 1.84 mmol). The reaction mixture was heated up to reflux
temperature and stirred at this temperature and under an argon
atmosphere for 24 h. The reaction was stopped by pouring the mix-
ture into H2O (50 mL) and extracting this aqueous phase again
with CH2Cl2 (50 mL). The combined organic phases were washed
with H2O (3ϫ50 mL) until the blue color disappeared and dried
with MgSO4. After filtration through a fresh layer of MgSO4 and
evaporation, the product 13a (1.68 g; 3.87 mmol; 84% yield) was
obtained as a pale brown powder.
N-[(1-Benzyl-1H-indol-2-yl)methyl]-2,2,2-trichloro-N-isopropyl-
acetamide (12e): Compound 12e was prepared from 11e (0.40 g;
1.44 mmol) by the procedure described for 12a. After recrystalli-
zation from methanol, the product 12e was obtained as brown crys-
tals (0.45 g; 1.06 mmol; 74% yield), m.p. 133.5–134.6 °C;
recrystallization from MeOH. 1H NMR (300 MHz, CDCl3): δ =
1.19 [d, J = 6.6 Hz, 6 H, CH(CH3)2], 4.50 (s, 2 H, N-CH2), 4.91
[m, 1 H, CH(CH3)2], 5.41 (s, 2 H, CH2-N), 6.35 (s, 1 H, 3-H), 7.03
(d, J = 7.2 Hz, 2 H, 2ϫ CHar), 7.07–7.17 (m, 2 H, 2ϫ CHar), 7.21–
7.32 (m, 4 H, 4ϫ CHar), 7.57 (d, J = 7.2 Hz, 1 H, 4-H or 7-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 20.42 [CH(CH3)2], 40.13
(N-CH2), 46.87 (N-CH2), 51.13 [CH(CH3)2], 93.59 (CCl3), 100.31
(C-3), 109.27 (CHar), 119.91 (CHar), 120.52 (C-4 or C-7), 121.65
(CHar), 126.17 (2ϫ CHar), 127.68 (CHar), 127.77 (Cq), 129.06 (2ϫ
CHar), 135.79 (Cq), 137.59 (Cq), 137.64 (Cq), 160.32 (C=O) ppm.
IR: ν = 1673 (νC=O) cm–1. MS (ESI, POS): m/z (%) = [423.0 (100),
˜
425.0 (75), 427.0 (25), 429.0 (5),
M +
H+, Cl isotopes].
tert-Butyl 3,4Ј,4Ј-Trichloro-5Ј-oxo-1Ј-(propan-2-yl)spiro[indole-2,3Ј-
pyrrolidine]-1(3H)-carboxylate (13a): M.p. 75.4 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.26 [d, J = 6.7 Hz, 3 H, CH(CH3)], 1.29
[d, J = 6.7 Hz, 3 H, CH(CH3)], 1.59 [s, 9 H, C(CH3)3], 4.13 (d, J
= 11.6 Hz, 1 H, CONCHAHB), 4.25 (d, J = 11.6 Hz, 1 H, CON-
CHAHB), 4.43 [sept, J = 6.7 Hz, 1 H, CH(CH3)2], 6.00 (s, 1 H, 3-
H), 7.11 (dd, J = 7.7, J = 7.6 Hz, 1 H, 5-H), 7.35 (dd, J = 8.1, J
= 7.7 Hz, 1 H, 6-H), 7.39 (d, J = 7.6 Hz, 1 H, 4-H), 7.60 (d, J =
8.1 Hz, 1 H, 7-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.60
[CH(CH3)], 19.72 [CH(CH3)], 28.23 [C(CH3)3], 44.82 [CH(CH3)2],
45.89 (N-CHAHB), 64.72 (ClHC-3), 76.19 (C-2), 83.73 [C(CH3)3],
88.81 (CCl2), 116.41 (C-7), 124.11 (C-5), 125.00 (C-4), 127.62 (Cq),
131.10 (C-6), 142.76 (Cq), 151.63 (O-C=O), 164.52 (C=O) ppm.
C21H21Cl3N2O (423.76): calcd. C 59.52, H 4.99, N 6.61; found C
59.33, H 4.86, N 6.37.
N-[(1-Benzyl-1H-indol-2-yl)methyl]-2,2,2-trichloro-N-benzyl-
acetamide (12f): Compound 12f was prepared from 11f (2.90 g;
8.88 mmol) by the procedure described for 12a. The product 12f
was obtained as yellow-brown crystals (3.44 g; 7.28 mmol; 53%
yield), m.p. 49.1–51.3 °C. Signals of two rotamers (A and B) were
observed in the spectroscopic data of this compound [for A (printed
in italics, 70%) and for B (underlined, 30%)]. 1H NMR (300 MHz,
CDCl3): δ = 4.72 and 4.85 (br. s, 2 H, N-CH2), 4.72 and 4.93 (br.
s, 2 H, N-CH2), 5.13 and 5.28 (br. s, 2 H, Ph-CH2-Nind), 6.35 and
6.52 (br. s, 1 H, 3-H), 6.84–6.86 (m, 2 H, 2ϫ CHar), 7.01–7.36 (m,
11 H, 11ϫ CHar), 7.59 (d, J = 7.7 Hz, 1 H, 4-H or 7-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 42.20 and 45.86 (N-CH2), 46.64 (N-
CH2), 51.22 and 54.45 (N-CH2), 92.89 (CCl3), 102.13 and 103.40
(C-3), 109.27 and 109.99 (CHar), 119.99 (CHar), 120.76 (C-4 or C-
IR: ν = 1715 (2ϫ νC=O) cm–1. MS (ESI, POS): m/z (%) = [415.3
˜
(100), 417.0 (90), 419.0 (20), M – Cl + OH2+, Cl isotopes].
13c: Compound 13c was prepared from 12c (2.00 g; 3.91 mmol)
by the procedure described for 13a. After column chromatography
7), 122.19 (CHar), 125.78 (2ϫ CHar), 127.09 (CHar), 127.26 (Cq), (CH2Cl2/MeOH, 40:1, Rf = 0.32), the product 13c was obtained as
127.35 (CHar), 127.89 (2ϫ CHar), 128.71 (2ϫ CHar), 128.86 (2ϫ a brown powder (0.40 g; 0.78 mmol; 20% yield). The compound
CHar), 133.11 en 133.58 (Cq), 134.60 and 135.49 (Cq), 136.79 and was too hygroscopic to take a reproducible melting point. 1H NMR
137.34 (C ), 137.75 (C ), 160.90 (C=O) ppm. IR: ν = 1674 (ν (300 MHz, CDCl3): δ = 1.55 [s, 9 H, C(CH3)3], 3.25 (s, 3 H, OCH3),
)
C=O
˜
q
q
Eur. J. Org. Chem. 2010, 5444–5453
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5451

C. V. Stevens et al.
FULL PAPER
3.87 (d, J = 12.1 Hz, 1 H, CONCHAHB), 4.08 (d, J = 12.1 Hz, 1 (m, 3 H, 3ϫ CHar), 7.19–7.30 (m, 3 H, 3ϫ CHar), 7.34 (d, J =
H, CONCHAHB), 4.23 (d, J = 16.0 Hz, 1 H, Ph-CHAHB), 4.98 (d,
7.2 Hz, 1 H, 4-H or 7-H) ppm. 13C NMR (75 MHz, CDCl3): δ
J = 16.0 Hz, 1 H, Ph-CHAHB), 5.01 (s, 1 H, 3-H), 7.07 (dd, J = = 47.19 (p-MeO-Ph-CHAHB), 47.38 (Nind-CHAHB. CONCHAHB),
7.4, J = 7.4 Hz, 2 H, 5-H or 6-H), 7.17–7.36 (m, 5 H, 5ϫ CHar), 55.15 (OCH3), 74.65 (ClHC-3), 78.42 (C-2), 88.13 (CCl2), 107.01
7.69 (d, J = 8.8 Hz, 1 H, 4-H or 7-H) ppm. 13C NMR (75 MHz, (CHar), 114.19 (2ϫ CHar), 118.66 (CHar), 124.88 (C-4 or C-7),
CDCl3): δ = 28.27 [C(CH3)3], 47.54 (CONCHAHB), 48.05 (Ph-
CHAHB), 55.74 (OCH3), 76.23 (C-2), 81.91 (ClHC-3), 83.33
[C(CH3)3], 88.07 (CCl2), 116.40 (C-4 or C-7), 122.97 (C-5 or C-6),
125.92 (Cq), 126.25 (2ϫ CHar), 127.21 (CHar), 128.65 (2ϫ CHar),
129.76 (Cq), 129.87 (2ϫ CHar), 130.86 (CHar), 137.81 (Cq), 149.78
(C ), 159.43 (C -OMe), 165.81 (C=O) ppm. IR: ν = 1705 (ν )
˜
q
q
C=O
125.31; 126.27 (Cq), 127.92; 128.47 (2ϫ CHar), 128.76 (2ϫ CHar), cm–1. MS (ESI, NEG): m/z (%) = {517.0 (90), 519.0 (100), 521.0
130.54; 134.94 (Cq), 143.46 (Cq), 151.73 (O-C=O), 166.07
(35), 523.0 (5), [M + OH]–, Cl isotopes}.
(CCl C=O) ppm. IR: ν = 1726 (νC=O) cm–1. MS (ESI, POS): m/z
˜
2
(%) = 289.2 (100).
Acknowledgments
13e: Compound 13e was prepared from 12e (0.4 g; 0.94 mmol) by
the procedure described for 13a. After column chromatography
(CH2Cl2/MeOH, 40:1, Rf = 0.26) and recrystallization from diethyl
ether, the product 13e was obtained as a brown powder (0.06 g;
0.13 mmol; 14% yield). The compound was again too hygroscopic
to take a reproducible melting point. 1H NMR (300 MHz, CDCl3):
δ = 0.81 [d, J = 6.8 Hz, 3 H, CH(CH3)], 1.13 [d, J = 6.8 Hz, 3 H,
CH(CH3)], 3.49 (d, J = 11.3 Hz, 1 H, CONCHAHB), 4.11 (d, J =
11.3 Hz, 1 H, CONCHAHB), 4.32 [sept, J = 6.8 Hz, 1 H, CH-
(CH3)2], 4.33 (d, J = 17.6 Hz, 1 H, Ph-CHAHB), 4.56 (d, J =
17.6 Hz, 1 H, Ph-CHAHB), 5.67 (s, 1 H, 3-H), 6.26 (d, J = 7.7 Hz,
1 H, 4-H or 7-H), 6.79 (dd, J = 7.6, J = 7.3 Hz, 1 H, 5-H or 6-H),
7.14 (ddd, J = 7.7, J = 7.6, J = 1.1 Hz, 1 H, 5-H or 6-H), 7.22–
7.34 (m, 5 H, 5ϫ CHar), 7.38 (d, J = 7.3 Hz, 1 H, 4-H or 7-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 18.67 [CH(CH3)], 18.99
[CH(CH3)], 43.38 (CONCH2), 44.66 [CH(CH3)2], 47.61 (CH2-Ph),
74.89 (ClHC-3), 78.13 (C-2), 88.53 (CCl2), 107.21 (C-4 or C-7),
118.74 (C-5 or C-6), 124.83 (C-4 or C-7), 125.96 (2ϫ CHar), 126.79
(Cq), 127.21 (CHar), 128.83 (2ϫ CHar), 130.94 (C-5 or C-6), 137.84
The authors wish to thank the Research Foundation Flanders
(FWO Vlaanderen) and Special Research Fund of Ghent Univer-
sity (BOF-UGent) for financial support.
[1] a) M. H. Chen, P. Pollard, A. Patchett, K. Cheng, L. Wei, W.-
S. Chan, B. Butler, T. M. Jacks, R. G. Smith, Bioorg. Med.
Chem. Lett. 1999, 9, 1261–1266; b) R. K. Behera, A. K. Be-
hera, R. Pradhan, A. Pati, M. Patra, Synth. Commun. 2006, 36,
3729–3742; c) C. C. Moldoveanu, P. G. Jones, I. I. Mangalagiu,
Tetrahedron Lett. 2009, 50, 7205–7208.
[2] a) C. Roussel, R. Fihi, K. Ciamala, J. Vebrel, T. Zair, C. Riche,
Org. Biomol. Chem. 2003, 1, 2689–2698; b) R. K. Howe, B. R.
Shelton, J. Org. Chem. 1990, 55, 4603–4607.
[3] a) T. Kosuge, K. Tsuji, K. Hirai, K. Yamaguchi, T. Okamoto,
Y. Iitaka, Tetrahedron Lett. 1981, 22, 3417–3420; b) P. Baran,
J. M. Richter, J. Am. Chem. Soc. 2005, 127, 15394–15396; c)
S. T. Hilton, T. C. T. Ho, G. Pljevaljcic, K. Jones, Org. Lett.
2000, 2, 2639–2641; d) M.-Y. Chang, C.-L. Pai, Y.-H. Kung,
Tetrahedron Lett. 2005, 46, 8463–8465.
[4] Some general reviews on spiropyrrolidine-3,3Ј-oxindoles: a) C.
Marti, E. M. Carreira, Eur. J. Org. Chem. 2003, 2209–2219; b)
C. V. Galliford, K. A. Scheidt, Angew. Chem. Int. Ed. 2007, 46,
8748–8758.
(C ), 149.87 (C ), 165.43 (C=O) ppm. IR: ν = 1708 (νC=O) cm–1.
˜
q
q
MS (ESI, POS): m/z (%) = {405.2 (100), 407.0 (55), [M – Cl +
OH2]+, Cl isotopes}.
[5] a) H. Takayama, M. Kurihara, S. Subhadhirasakul, M. Kita-
jima, N. Aimi, S.-I. Sakai, Heterocycles 1996, 42, 87–92; b) H.
Takayama, H. Ishikawa, M. Kurihara, M. Kitajima, N. Aimi,
D. Ponglux, F. Koyama, K. Matsumoto, T. Moriyama, L. T.
Yamamoto, K. Watanabe, J. Med. Chem. 2002, 45, 1949–1956;
c) M. J. Kornet, A. P. Thio, J. Med. Chem. 1976, 19, 892–898.
[6] A. Jossang, P. Jossang, H. A. Hadi, T. Sevenet, B. Bodo, J. Org.
Chem. 1991, 56, 6527–6530.
13f: Compound 13f was prepared from 12f by the procedure de-
scribed for 13a. After preparative TLC as a purification step [PE/
EtOAc (8:1), 3 runs, Rf = 0.17], the product 13f was obtained as a
yellow liquid (37% yield). H NMR (300 MHz, CDCl3): δ = 3.24
(d, J = 11.5 Hz, 1 H, CONCHAHB), 3.74 (d, J = 14.3 Hz, 1 H, Ph-
CHAHB), 3.97 (d, J = 11.5 Hz, 1 H, CONCHAHB), 4.08 (d, J =
1
17.3 Hz, 1 H, Nind-CHAHB), 4.55 (d, J = 17.3 Hz, 1 H, Nind
-
[7] N. Anderton, A. P. Cockrum, S. M. Colegate, J. A. Edgar, K.
Flower, I. Vit, R. I. Willing, Phytochemistry 1998, 48, 437–439.
[8] a) C. Marti, E. M. Carreira, J. Am. Chem. Soc. 2005, 127,
11505–11515; b) S. Edmonson, S. J. Danishefsky, L. Sepp-Lo-
renzino, N. Rosen, J. Am. Chem. Soc. 1999, 121, 2147–2155; c)
P. R. Sebahar, R. M. Williams, J. Am. Chem. Soc. 2000, 122,
5666–5667; d) P. R. Sebahar, H. Osada, T. Usui, R. M. Wil-
liams, Tetrahedron 2002, 58, 6311–6322.
[9] a) C. V. Stevens, E. Van Meenen, Y. Eeckhout, B. Vanderhoy-
donck, W. Hooghe, Chem. Commun. 2005, 38, 4827–4829; b)
C. V. Stevens, E. Van Meenen, K. G. R. Masschelein, Y. Eeck-
hout, W. Hooghe, B. DЈhondt, V. N. Nemykin, V. V. Zhdankin,
Tetrahedron Lett. 2007, 48, 7108–7111.
CHAHB), 4.68 (d, J = 14.3 Hz, 1 H, Ph-CHAHB), 5.62 (s, 1 H, 3-
H), 6.31 (d, J = 7.7 Hz, 1 H, CHar), 6.78 (dd, J = 7.4, J = 7.4 Hz,
1 H, CHar), 7.09–7.35 (m, 12 H, 12ϫ CHar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 47.60 (Ph-CHAHB), 47.69 (Nind-CHAHB),
47.91 (CONCHAHB), 74.79 (ClHC-3), 78.63 (C-2), 88.17 (CCl2),
107.10 (CHar), 118.83 (CHar), 125.04 (CHar), 126.45 (2ϫ CHar),
126.71 (Cq), 127.45 (CHar), 128.38 (CHar), 128.57 (2ϫ CHar),
128.86 (2ϫ CHar), 129.03 (2ϫ CHar), 131.01 (CHar), 134.14 (Cq),
137.97 (C ), 149.96 (C ), 166.13 (C=O) ppm. IR: ν = 1708 (ν )
˜
q
q
C=O
cm–1. MS (ESI, POS): m/z (%) = {453.1 (100), 455.1 (75), 457.1
(15), [M – Cl + OH2]+, Cl isotopes}.
13g: Compound 13g was prepared from 12g by the procedure de-
scribed for 13a. After preparative TLC as a purification step
(CH2Cl2/MeOH, 95:5, Rf = 0.50), the product 13g was obtained as
a yellow liquid (22% yield). 1H NMR (300 MHz, CDCl3): δ = 3.25
(d, J = 11.8 Hz, 1 H, CONCHAHB), 3.72 (s, 3 H, OCH3), 3.84 (d,
J = 14.3 Hz, 1 H, Ph-CHAHB), 3.97 (d, J = 11.8 Hz, 1 H, CON-
CHAHB), 4.05 (d, J = 17.3 Hz, 1 H, Nind-CHAHB), 4.50 (d, J =
17.3 Hz, 1 H, Nind-CHAHB), 4.53 (d, J = 14.3 Hz, 1 H, Ph-
CHAHB), 5.62 (s, 1 H, 3-H), 6.27 (d, J = 7.7 Hz, 1 H, CHar), 6.65–
6.79 (m, 3 H, 3ϫ CHar), 7.01–7.06 (m, 2 H, 2ϫ CHar), 7.10–7.14
[10] Amongst others: J. Boivin, M. Yousfi, S. Z. Zard, Tetrahedron
Lett. 1997, 37, 5985–5988.
[11] Some literature procedures on the synthesis of 1H-indole-2-
carbaldehyde are: a) M. Agnusdei, M. Bandini, A. Melloni,
A. Umani-Ronchi, J. Org. Chem. 2003, 68, 7126–7129; b) T.
Kumamoto, S.-I. Nagayama, Y. Hayashi, H. Kojima, L. David,
W. Nakanishi, T. Ishikawa, Heterocycles 2008, 76, 1155–1170;
c) L. Perez-Serrano, L. Casarrubios, G. Dominguez, P. Gonza-
les-Perez, J. Perez-Castells, Synthesis 2002, 1810–1812; d) R. B.
Kolhatkar, S. K. Ghorai, C. George, M. E. A. Reith, A. K.
Dutta, J. Med. Chem. 2003, 46, 2205–2215; e) A. Tsotinis, P. A.
5452
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5444–5453

Kharasch-Type Cyclizations of 2-Substituted Indoles
Afroudakis, K. Davidson, A. Prashar, D. Sugden, J. Med.
Chem. 2007, 50, 6436–6440; f) M. Dekhane, R. H. Dodd, Tet-
rahedron 1994, 50, 6299–6306.
A. Burgstahler, L. Weigel, C. Shaefer, Synthesis 1976, 11, 767–
768.
4023–4034; c) P. R. Carlier, P. C.-H. Lam, D. M. Wong, J. Org.
Chem. 2002, 67, 6256–6259.
[14] A. Kalir, S. Szara, J. Med. Chem. 1966, 9, 793–794.
[15] D. H. Brown Ripin, M. Vetelino, Synlett 2003, 2353–2353.
[16] a) A. Hassner, J. L. Dillon Jr., J. Org. Chem. 1983, 48, 3382–
3386; b) C. V. Stevens, N. De Kimpe, J. Org. Chem. 1996, 61,
2174–2178.
[12]
[13] a) G. Bringmann, S. Tasler, H. Endress, K. Peters, E.-M. Peters,
Synthesis 1998, 15501–1505; b) M. Reggelin, B. Junker, T.
Heinrich, S. Slavik, P. Buhle, J. Am. Chem. Soc. 2006, 128,
Received: May 26, 2010
Published Online: August 16, 2010
Eur. J. Org. Chem. 2010, 5444–5453
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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