Synthesis and reactions of 1-hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2- (3H)-ones

Article abstract of DOI:10.1016/j.tet.2011.03.044

1-Hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-ones, as a new type of azaheterocyclic hydroxamic acids, have been synthesized regioselectively from 1-carbamoylmethyl- or 1-(methoxycarbonyl)methyl-2,3,3-trimethyl-3H-indolium salts by reaction with hydroxylamine in the presence of a strong base. The alkylation and reduction with sodium borohydride of these novel heterocycles have been investigated. When treated with protic acids 1-hydroxy- or 1-alkoxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-ones underwent ring opening of the imidazolidine to afford 1-[2-(hydroxyamino)-2-oxoethyl]-2,3,3-trimethyl- 3H-indolium salts. The structural assignments are based on extensive ¹H, ¹³C and ¹⁵N NMR spectroscopic studies and single crystal X-ray analyses.

Full text of DOI:10.1016/j.tet.2011.03.044

Tetrahedron 67 (2011) 3945e3953
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and reactions of 1-hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2-
(3H)-ones
a
a
b
c
,
y
ꢀ ꢁ _ a
ꢀ
_
Vytas Martynaitis , Rasa Steponaviciute , Sonata Krikstolaityte , Joana Solovjova , Sven Mangelinckx
,
c
d
a,b,
*
ꢀ
ꢀ
Norbert De Kimpe , Wolfgang Holzer , Algirdas Sackus
a Department of Organic Chemistry, Kaunas University of Technology, LT-50270 Kaunas, Lithuania
b Institute of Synthetic Chemistry, Kaunas University of Technology, LT-50270 Kaunas, Lithuania
c Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Gent, Belgium
d Department of Drug Synthesis, Faculty of Life Sciences, University of Vienna, Pharmaziezentrum, A-1090 Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
1-Hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-ones, as a new type of azaheterocyclic hydroxa-
mic acids, have been synthesized regioselectively from 1-carbamoylmethyl- or 1-(methoxycarbonyl)
methyl-2,3,3-trimethyl-3H-indolium salts by reactionwith hydroxylamine in the presence of a strong base.
The alkylation and reduction with sodium borohydride of these novel heterocycles have been investigated.
When treated with protic acids 1-hydroxy- or 1-alkoxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-ones
underwent ring opening of the imidazolidine to afford 1-[2-(hydroxyamino)-2-oxoethyl]-2,3,3-trimethyl-
3H-indolium salts. The structural assignments are based on extensive 1H, 13C and 15N NMR spectroscopic
studies and single crystal X-ray analyses.
Received 14 February 2011
Received in revised form 14 March 2011
Accepted 16 March 2011
Available online 23 March 2011
Keywords:
Hydroxamic acids
Indolium salts
Imidazolidinones
Ring opening
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
indole.2 Furthermore, 9a-styryl-9,9a-dihydro-1H-imidazo[1,2-a]
indol-2(3H)-one derivatives were designed as colour formers for
1-Substituted 3H-indolium salts are important synthetic pre-
cursors in the preparation of functionalized organic dyes with wide
technical and biomedical applications.1 Quaternisation of 2,3,3-tri-
methyl-3H-indole with 2-haloacetamides affords reactive 1-carba-
moylmethyl-2,3,3-trimethyl-3H-indolium salts,2 possessing several
reactive centres, whichallowthem to participateinvariouschemical
transformations. The reaction of the latter with squaric acid afforded
squaraine dyes, which have been investigated as non-covalent
protein probes with high fluorescence quantum yield and good
photostability.3 When condensed with salicylic aldehydes, they
underwent spirocyclization due to intramolecular addition of the
phenolic oxygen atom across the carbon atom at the 2-position of
the indole to give photochromic and thermochromic 1-carba-
moylmethylindoline[2,20]spirobenzopyrans.4 It is known also that
1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium chloride upon
treatment with base undergoes cyclization to 9,9a-dihydro-1H-
imidazo[1,2-a]indol-2(3H)-ones by nucleophilic addition of the
amide nitrogen atom across the carbon atom at the 2-position of the
pressure- and heat-sensitive recording materials.5 Finally, reaction
of 1-carbamoylmethyl-3H-indolium chloride with hydrazine
bishydrate selectively afforded 1-amino-9,9a-dihydro-1H-imidazo
[1,2-a]indol-2(3H)-ones, possessing a cyclic hydrazide moiety,
which was easily transformed to various heterocyclic structures.6
In an effort to expand the chemical space of ring fused indoline
derivatives bearing an annelated heterocycle at the N-1‒C-2 bond of
the indole nucleus, the objective of this work was to investigate the
reaction of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium salts
with hydroxylamine, and the structure of the indolyl hydroxamic
acid derivatives obtained. The targeted heterocyclic compounds
contain a 1-hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-
one core (Fig. 1), which is, to the best of our knowledge, unreported
in the literature. This new azaheterocyclic scaffold is however in-
teresting in view of its similarity with the isomeric 1-hydroxy-9,9a-
dihydro-1H-imidazo[1,2-a]indol-3(2H)-one core which is present in
the natural hydroxylamine alkaloids tryptoquivaline, possessing
tremorgenic activity, and asperlicin B, which is a competitive cho-
lecystokinin (CCK) antagonist (Fig. 1).7 Hydroxamic acids are ver-
satile analytical reagents for the analysis and separation of metals8
and possess also wide biomedical applications.9 More specifically,
5-bromo-1H-indole-3-acetohydroxamic acid was recently identi-
fied as a potent inhibitor of bacterial deformylases (Fig. 1),10 while
* Corresponding author. Fax: þ370 37 451432; e-mail address: algirdas.sackus@
ꢀ
ꢀ
ktu.lt (A. Sackus).
y
Postdoctoral Fellow of the Research FoundationdFlanders (FWO), Belgium.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.044

3946
V. Martynaitis et al. / Tetrahedron 67 (2011) 3945e3953
O
OH
O
AcO
O
H
N
N
N
N
N
H
N
NH
O
O
1-hydroxy-9,9a-dihydro-
1H-imidazo[1,2-a]indol-2(3H)-one
OH
O
OH
OH
N
N
H
N
N
H
O
O
O
OH
N
H
Br
tryptoquivaline
asperlicin B
N
H
5-bromo-1H-indole-3-acetohydroxamic acid
Fig. 1. 1-Hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one and related biologically active hydroxylamine alkaloids.
1H-indole-1-acetohydroxamic acid derivatives were used for the
preparation of electroconductive polymer films.11 O-Alkylated
hydroxamic acids are active inhibitors of lypogenase-mediated
processes,12 while cyclic hydroxamic acids exhibit metal chelating
abilities and various biological activities.13
3a showed absorption bands at 3110 and 1702 cmꢀ1 attributable to
OeH and C]O groups, respectively. The 15N NMR spectrum of 3a
showed two different N-atoms with chemical shifts at ꢀ193.0 (N-1)
and ꢀ298.6 (N-4) ppm. In 15N DEPT experiments without 1H-
decoupling, the resonance signal (ꢀ193.0 ppm) of the N-1 atom of
3a appeared as a singlet, thus indicating the absence of an NH
moiety. This definitely ruled out the corresponding six-membered
structure 4, for which signals of an NH substructure and tertiary
nitrogen atom would be expected. The assignments presented in
Fig. 2 were based on the combined application of standard NMR
techniques, suchasNOE-difference(Fig. 2b), NOESY, APT, DEPT, HSQC,
HMBC and long-range INEPT spectra with selective excitation.18
The single crystal X-ray structure of 3a (Fig. 3)19 shows that the
skeleton of the asymmetric unit contains the imidazo[1,2-a]indole
ring system, with the external hydroxy group attached to the atom
N(1). The bond lengths, bond angles and dihedral angles are typical
for the azaheterocyclic hydroxamic acid core and related to 1-hy-
droxy-1,3-imidazolidin-4-one.20e22
2. Results and discussion
It is known that a hydroxamic acid moiety can be easily in-
troduced by treatment of amides with hydroxylamine at neutral or at
alkaline pH,14 while the corresponding reaction with esters requires
alkaline conditions (pH >10).15 When 1-carbamoylmethyl-2,3,3-tri-
methyl-3H-indolium chlorides 1 were heated with hydroxylamine
hydrochloride in the presence of sodium hydroxide, selective for-
mation of the 1-hydroxy-9,9,9a-trimethyl-9,9a-dihydro-1H-imidazo
[1,2-a]indol-2(3H)-ones 3 took place without any observation of the
corresponding six-membered compounds 4. Similarly, 1-(methox-
ycarbonyl)methyl-3H-indolium perchlorate 5, prepared by treat-
ment of 2,3,3-trimethyl-3H-indole with methyl 2-bromoacetate,16
efficiently reacted with hydroxylamine under basic conditions to
afford the five-membered compound 3a (Scheme 1).
The packaging of the chiral molecules 3a into a racemic crystal
occurs in such a way that mirror R- and S-enantiomers are self-
assembled into alternate chiral chains of opposite chirality, which
H3C CH3
R
H3C CH3
R
CH3
N
OH
CH3
+
N
N
Cl-
NH2
3 equiv NH2OH.HCl
4 equiv NaOH
O
H3C CH3
CH2
NHOH
3a (86% from 1a;
73% from 5)
3b (77% from 1b)
3c (47% from 1c)
O
R
1a R = H
MeOH, Δ, 0.5 h
1b R = CH3
1c R = Br
N
3 equiv NH2OH.HCl
4 equiv NaOH
H3C CH3
O
H3C CH3
CH3
MeOH, Δ, 0.5 h
2
CH3
OCH3
R
+
N
O
-
N
NH
ClO4
O
O
5
4
Scheme 1.
The formation of derivatives 3 likely proceeds through a mecha-
nism that includes formation of the enamine intermediate 2 that
undergoes cyclization to the tricyclic compound by intramolecular
additionof thehydroxamicnitrogenacrosstheelectrophilicindoleC-
2 atom. Formation of cyclic hydroxamic acid derivatives by addition
of the hydroxamic nitrogen across a triple bond has been reported
earlier by Elguero et al.17
are connected by strong intermolecular OeH/O]C type hydrogen
bonds (Fig. 3b).
Hydroxamic acids are ambident nucleophiles. However, deproto-
nation of the OH group usually results in O-alkylation products. Leggio
et al. used diazomethane as selective O-alkylation agent of aliphatic
hydroxamic acids.23 In that case diazomethane reacted as a base to
deprotonate the hydroxamic acid, resulting in a methyldiazonium ion,
which selectively methylated the generated hydroxamate anions.24
The structure of azaheterocyclic hydroxamic acids 3aec was
determined by microanalyses and spectral data. The IR spectrum of
The
alkylation
of
hydroxamic
acid
3a
with

V. Martynaitis et al. / Tetrahedron 67 (2011) 3945e3953
3947
7.11
1.10
78% yield, respectively. The reaction with benzyl chloride resulted
similarly benzyl ether 6c in 66% yield (Scheme 2).
27.29
46.95
22.36
1.43
(a)
(b)
122.15
6.88
The deprotonation of N-substituted lactams with a strong lith-
ium base in THF, followed by reaction of the formed enolates with
H
H3C CH3
15.73
1.45
92.49
9.45
H3C CH3
CH3
H
H
H
haloalkanes is known to lead to a
-C-alkylated lactams.27 However,
121.50
127.41
CH3
N OH
N OH
treatment of compounds 6 possessing the N-(alkyloxy)lactam
moiety, with n-BuLi in THF followed by the addition of iodo-
methane afforded exclusively the O-methylated products 7. The
structure of the latter was confirmed by the presence of a singlet of
H-3 in the range of 4.98e5.16 ppm in the 1H NMR spectra and
a signal of C-3 at w89.0 ppm in the 13C NMR spectra (CDCl3).
Under the influence of strong protic acids 9,9a-dihydro-1H-imi-
dazo[1,2-a]indol-2(3H)-ones undergo imidazolidine ring opening
and are converted to 1-carbamoylmethyl-3H-indolium salts.2 When
the ethanolic solution of 1-hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]
N
H
N
150.76
O
O
H
7.10
138.67
-193.0
H
H
H H
111.46
6.85
171.93
3.84 3.84
50.87
-298.6
Fig. 2. (a) 1H NMR (italics), 13C NMR (plain) and 15N NMR (bold) chemical shifts [ppm;
ref. TMS (1H and 13C) and CH3NO2
correlations.
(
15N)] for 3a in DMSO-d6. (b) Relevant NOE
Fig. 3. (a) ORTEP drawing of 1-hydroxyimidazo[1,2-a]indol-2(3H)-one 3a. (b) Fragment of the heterochiral layer of the racemic crystals of 3a.
trimethylsilyldiazomethaneda mild and efficient reagent used for the
O-methylation of carboxylic acids and alcohols as a safer alternative for
highly toxic and explosive diazomethanedwas investigated.25
indol-2(3H)-one 3awastreated with perchloric acid in ethanol at 5 ꢁC
for 16 h, formation of 1-[2-(hydroxyamino)-2-oxoethyl]-2,3,3-tri-
methyl-3H-indolium perchlorate (8a) took place (Scheme 3). X-ray
diffractionanalysis ofthecrystalstructureof8arevealedthepresence
of the tautomeric keto form and Z-configuration of the hydroxamic
acid moiety (Fig. 4).28 Nevertheless, the 1H and 13C NMR spectra of
perchlorate 8a at room temperature (20 ꢁC) in TFA-d exhibited two
sets of resonance signals. The appearance of signals at 203.39 and
203.43 ppm in the 13C NMR spectrum, was indicative of a Nþ]C
carbon. The 1H NMR spectrum of 8a contained signals at 1.69 (non-
resolved signals of 3,3-CH3), 2.86 and 2.90 (minor and major peaks of
2-CH3, respectively), 5.49 and 5.78 ppm (major and minor peaks of
CH2, respectively), with a 7:3 ratio of the major and minor isomers.
The analogous 1H and 13C NMR spectra obtained from the solution of
Treatment of hydroxamic acid 3a with trimethylsilyldiazo-
methane in a mixture of benzene and methanol (3:1) at room
temperature afforded 1-methoxy-1H-imidazo[1,2-a]indol-2(3H)-
one 6a in 71% yield after column chromatography (Scheme 2).
O-Ethylation of compound 3a was easily achieved by the reaction of
hydroxamic acid 3a with triethyloxonium tetrafluoroborate, a re-
agent used for the selective alkylation of O-alkylarylhydroxamic
acids,26 and gave compound 6b in 54% yield. Further experiments
showed that the hydroxy functionality of 3a can be smoothly
O-alkylated with methyl and ethyl iodide in the presence of po-
tassium carbonate, providing the desired products 6a,b in 90% and
2.51 equiv Me3SiCHN2
C6H6/MeOH (3:1), rt, 4 h
71% for R = Me
1.3 equiv
H3C CH3
H3C CH3
CH3
H3C CH3
1. 1.25 equiv n-BuLi
-
Et3O+BF4
CH3
N
CH3
THF, -78 °C, 1 h
OR
OH
OR
O
N
N
N
N
N
2. 1.2 equiv MeI
THF, -78 °C, 1 h
CH2Cl2, rt, 18 h
54% for R = Et
OMe
O
3a
6a (R = Me)
6b (R = Et)
6c (R = Bn)
7a (R = Me, 54%)
7b (R = Et, 58%)
7c (R = Bn, 63%)
1.2 equiv RX
1.1 equiv K2CO3
DMF, rt, 16 h
90% for R = Me, X = I
78% for R = Et, X = I
66% for R = Bn, X = Cl
Scheme 2.

3948
V. Martynaitis et al. / Tetrahedron 67 (2011) 3945e3953
H3C CH3
CH3
H3C CH3
CH3
N
OCH3
O
N
N
N
O
H
OH
6a
Z conformer 12 (88%)
TFA-d, rt
for 9
3.25 equiv
NaBH4
AcOH, rt, 3 h
TFA-d, rt
for 10
H3C CH3
CH3
H3C CH3
CH3
H3C CH3
CH3
60% HClO4
EtOH, 5 °C, 16 h
OH
+
+
N
N
N
N
64% for 8
X-
X-
O
O
O
3a
N
N
H
OR
RO
H
48% HBF4
+
-
Z conformer
E conformer
-[NH3OH] BF4
EtOH
5 °C, 24 h
8a R = H, X = ClO4
9a R = H, X = CF3COO
10a R = CH3, X = CF3COO
8b R = H, X = ClO4
9b R = H, X = CF3COO
10b R = CH3, X = CF3COO
H3C CH3
CH3
O
+
N
-
BF4
OH
11 (53%)
Scheme 3.
not present in a detectable amount.30 It was established by Brown
et al. that acetoxyhydroxamic acids are present in DMSO solutions as
an equilibrium mixture of Z- and E-conformers with the Z-con-
former prevailing.31 In the solid state, acetohydroxamic acid hemi-
hydrate exists as the Z-isomer only.32 Most secondary hydroxamic
acids, except N-aryl derivatives, in turn, exist as E-conformers.33
Therefore, the presence of two sets of signals in the NMR spectra
of perchlorate 8 in TFA-d can be rationalized by the formation of an
equilibrium mixture of isomeric salts 8a and 8b possessing a differ-
ent geometry (Z or E) of the hydroxamic acid moiety (Scheme 3).
Neutralization of the perchlorate 8 with a solution of sodium car-
bonate gave the starting tricyclic compound 3a only.
Analogously, the 1H and 13C NMR spectra of 1-methoxy-9,9a-
dihydro-1H-imidazo[1,2-a]indol-2(3H)-one 6a in TFA-d at room
temperature (20 ꢁC) exhibited two sets of peaks, which can be at-
tributed to the Z- and E-cations 10a and 10b. The 1H NMR spectrum
contained the singlets of the 2-CH3 group at 3.89 ppm (major iso-
mer) and 4.06 ppm (minor isomer), and the singlets of the CH2CO
group at 5.40 ppm (major isomer) and 5.65 ppm (minor isomer),
with a 5:2 ratio of the major/minor isomer. The corresponding 13C
NMR spectrum showed the characteristic carbon signal of the þN]
C moiety at 201.4 ppm.
Itisknownthathydroxamicacids are morestableinbasicmedium
than in acidic medium. The products resulting from their acidic hy-
drolysis usually are hydroxylamine and the parent carboxylic acid.34
Prolonged storage of the solution of 1-hydroxy-9,9a-dihydro-1H-
imidazo[1,2-a]indol-2(3H)-one 3 in ethanol, containing water and
HBF4, at 5 ꢁC, afforded crystalline 1-carboxymethyl-3H-indolium
tetrafluoroborate monohydrate 11 (Scheme 3). Incontrast tothe 1-[2-
(hydroxyamino)-2-oxoethyl]-2,3,3-trimethyl-3H-indolium perchlo-
rate (8a), the NMR spectra of tetrafluoroborate 11 in TFA-d contain
only one set of signals. In the 13C NMR spectrum, the characteristic
carbon signal of the þN]C moiety is present at 203.3 ppm.
Fig. 4. Crystal structure of perchlorate 8a showing the most significant intermolecular
interactions.
1-hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one 3a in
TFA-d demonstrated the cleavage of the imidazolidine ring with for-
mation of the corresponding 3H-indolium cations.
Theoretically, hydroxamic acids can exist in solution as
an equilibrium mixture of the two tautomers: RC(]O)NHOH (I)$
RC(OH)]NOH (II), where (I) is the hydroxamide (or hydroxamic
acid) form, and (II) the hydroxyimine form.29 As such, structural
complications of hydroxamic acids can occur due to different con-
formations of the CeN bond of the hydroxamic tautomer and, as
well, different configurations of the C]N bond of the hydroximic
form. Nevertheless, recent NMR structural investigations of
hydroxamic acids (for example, of 15N-enriched dihydroxamic acids
in solutions of DMSO) showed that hydroximic forms of the acids are

V. Martynaitis et al. / Tetrahedron 67 (2011) 3945e3953
3949
The single crystal X-ray analysis of tetrafluoroborate 11 discloses
that a molecule of crystallization water is present in the crystal
lattice, which bridges the oxygen of the carboxyl group and the
BFꢀ4 anion via hydrogen bonding (Fig. 5a). The crystal structure is
assembled from hydrogen-bonded dimers (Fig. 5b).35
It has been reported recently that 1-amino-9,9a-dihydro-1H-
imidazo[1,2-a]indol-2(3H)-ones smoothly underwent reductive ring
opening upon treatment with NaBH4 in ethanol to give 1-substituted
1H NMR spectrum exhibited only one set of signals attributed to the
more stable Z-isomer form in accordance with literature data.32e34
After having explored the reactivity of 1-hydroxy-9,9a-dihydro-
1H-imidazo[1,2-a]indol-2(3H)-ones, it was decided also to explore
the chemistry of the corresponding known N-methylated com-
pound 13 in more detail.4d It is interesting to note that the 1H NMR
spectrum of the cyclic lactam 13 in TFA-d, possessing the methyl
group at the nitrogen atom N-1 exhibited, as it was expected, only
Fig. 5. (a) Crystal structure of tetrafluoroborate monohydrate 11 showing the most significant intermolecular interactions. (b) Hydrogen-bonded dimer of 11.
2,3-dihydro-1H-indole derivatives.6 When 1-hydroxy-9,9a-dihydro-
1H-imidazo[1,2-a]indol-2(3H)-one 3a was reacted under similar re-
ducing conditions, the expected reaction did not occur and most of
the starting material was recovered unchanged. However, trans-
formation of cyclic hydroxamic acid 3a to the reduced compound 12
was easily achieved by treatment with NaBH4 in glacial acetic acid as
solvent instead of ethanol (Scheme 3). It can be assumed that in the
first step of this reductive ringopening, acetic acidpromotes cleavage
of the annelated lactam moiety leading to the formation of the cor-
responding 1-[2-(hydroxyamino)-2-oxoethyl]-3H-indolium acetate.
Subsequently, in situ generated acetoxyborohydride36,37 smoothly
reduces the iminium group to afford indoline 12.
one set of signals, including the characteristic singlets at 1.44 [3,3-
(CH3)2], 2.61 (N2HCH3), 2.76 (2-CH3) and 5.14 ppm (CH2) corre-
sponding with the formation of the ring opened cation Z-14
(Scheme 4). It is known that N-substituted amides exist in solution
generally as the Z-conformers, and only in the case of N-methyl-
acetamide the E-conformer was found experimentally to occur in
a low population of 1.5% besides the prevailing Z-conformer.38
The methylation of lactam 13 via formation of the corresponding
lithium enolate was next evaluated. It was found that the deproto-
nation of 13 with n-BuLi at ꢀ78 ꢁC in THF, and subsequent alkylation
by treatment with iodomethane proceeded diastereoselectively to
affordC-3-methylatedlactam15. Thestructureandstereochemistryof
lactam 15 was confirmed by methods of NMR spectroscopy (Fig. 6a,b).
The assignments presented in Fig. 6a,b were based on the combined
application of standard NMR techniques such as NOE-difference,
NOESY, APT, DEPT, HSQC, HMBC and long-range INEPT spectra with
The structure of 1-[2-(hydroxyamino)-2-oxoethyl]-2,3,3-trime-
thylindoline 12 was confirmed by the presence of characteristic
signals of the CHCH3 moiety, consisting of a doublet at 1.26 ppm
and a quadruplet at 3.15 ppm, in the 1H NMR spectrum (CDCl3). The
H3C CH3
H3C CH3
CH3
H3C CH3
CH3
1. 1.2 equiv n-BuLi
THF, -78 °C, 1 h
CH3
TFA-d
+
NCH3
NCH3
N
N
N
2. 1.2 equiv MeI
-78 °C - rt, 3 h
O
O
O
CF3COO-
H3C H
N
H
Me
14
13
15 (51%)
Scheme 4.
7.01 1.429
29.4
49.5
22.2
(a)
122.2
6.94
(b)
1.01
H3C CH3
H
H
H3C CH3
CH3
24.1
1.426
H
CH3
122.4
128.2
89.4
2.95
N
CH3
N
CH3
N
H
N
H
27.2
-257.1
148.4
H
H
O
O
7.15
CH3
CH3
H
113.9
173.3
141.6
6.83
1.56
3.78
61.2
-289.1
21.6
Fig. 6. (a) 1H NMR (italics), 13C NMR (plain) and 15N NMR (bold) chemical shifts [ppm; ref. TMS (1H and 13C) and CH3NO2
(
15N)] for 15 in CDCl3. (b) Relevant NOE correlations.

3950
V. Martynaitis et al. / Tetrahedron 67 (2011) 3945e3953
selective excitation.18 The 1H NMR spectrum of substituted lactam 15
contained a doublet at 1.56 ppm (J¼6.9 Hz) and a quadruplet at
3.78 ppm characteristic for the CH3CH moiety. The NOE experiments
(NOESY, NOE-difference) of compound 15 revealed a through-space
interaction between H-3 (3.78 ppm) and the 9-CH3 group resonating
at 1.01 ppm, but no interaction between H-3 and 9a-CH3 (1.426 ppm).
On the other hand, both geminal CH3 groups at C-9 were easily
identified on the basis of NOE’s with aromatic ring proton H-8 and via
HMBC (correlation to C-8a). These observations indicate that com-
formed were removed by filtration and the filtrate was concentrated
under reduced pressure. The residue was purified by column chro-
matographyon silicagel withhexane/EtOAc (2:1v/v)aseluentto give
3a (2.98 g, 86%) as colourless crystals. Mp168e169 ꢁC (fromEtOH).1H
NMR (500 MHz, DMSO-d6):
d 1.10 (s, 3H, 9-CH3), 1.43 (s, 3H, 9-CH3),
1.45 (s, 3H, 9a-CH3), 3.84 (s, 2H, CH2), 6.83e6.94 (m, 2H, 5-H, 7-H),
7.07e7.13 (m, 2H, 6-H, 8-H), 9.45 (s, 1H, OH). 13C NMR (125 MHz,
DMSO-d6): d 15.7 (9a-CH3), 22.4 (9-CH3), 27.3 (9-CH3), 47.0 (C-9), 50.9
(C-3), 92.5 (C-9a),111.5 (C-5),121.5 (C-7),122.1 (C-8),127.4 (C-6),138.7
pound 15 corresponds to the structure possessing the (3R
*
,9aS
*
)-rel-
(C-8a), 150.8 (C-4a), 171.9 (C]O). 15N NMR (50.69 MHz, DMSO-d6):
ative configuration. Molecularmodelling39 confirmedthatinthelatter
d
ꢀ193.0 (N-1), ꢀ298.6 (N-4). IR (KBr, cmꢀ1): nOH¼3110, nC¼O¼1702.
case H-3 and the 9-CH3 group occupy a spatial orientation for which
MS (ESþ) m/z (%): 233 (MþHþ, 100). Anal. Calcd for C13H16N2O2: C,
the observed NOE effects are expected, while (3R
*
,9aR )-relative
*
67.22; H, 6.94; N, 12.06. Found: C, 66.95; H, 6.68; N, 12.33.
configuration would lead to interaction of H-3 with the 9a-CH3.
Method B: A mixture of 2,3,3-trimethyl-3H-indole (2.39 g,
15 mmol), methyl 2-bromoacetate (2.29 g, 15 mmol) and o-xylene
(5 mL) was heated at 70 ꢁC for 5 h and then left to reach ambient
temperature. The solvent was decanted, the residue was dissolved in
ethanol (8 mL), perchloric acid (70%) was added to pH 1 and the
mixture was kept at 5 ꢁC for 16 h. Crystals formed were filtered and
recrystallized from ethanol to yield perchlorate 5 (2.24 g, 45%), mp
172e174 ꢁC (with decomposition). The obtained perchlorate 5 (1.66 g,
5 mmol) was dissolved in dry methanol (8 mL), hydroxylamine hy-
drochloride (1.04g,15 mmol) and powdered sodiumhydroxide(0.8g,
20 mmol) were added and the mixture was refluxed for 0.5 h. The
insolubles formed were removed by filtration and the filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel with hexane/EtOAc (2:1 v/v) as
eluent to give 3a (0.85 g, 73%). Mp and NMR spectroscopy data of the
title product 3a were identical with those obtained by Method A.
3. Conclusion
1-Carbamoylmethyl- and 1-(methoxycarbonyl)methyl-3H-
indolium salts 1 and 5, respectively, are regioselectivelycyclized into
five-membered ring compounds, as new azaheterocyclic hydroxa-
mic acids, that is, 1-hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-
2(3H)-ones 3. Alkylation of 1-hydroxy-9,9a-dihydro-1H-imidazo
[1,2-a]indol-2(3H)-ones with trimethylsilyldiazomethane, triethyl-
oxonium tetrafluoroborate or haloalkanes in the presence of base
gave exclusively O-substituted products 6aec. The action of strong
protic acids on 1-hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-
2(3H)-ones causes opening of the imidazolidine ring, annelated to
indole system, to afford 1-[2-(hydroxyamino)-2-oxoethyl]-3H-
indolium salts 10, 11, while treatment with sodium borohydride in
acetic acid led to reductive ring opening with formation of N-hy-
droxy-2-(2,3,3-trimethyl-2,3-dihydro-1H-indol-1-yl)acetamide 12.
4.2.2. 1-Hydroxy-7,9,9,9a-tetramethyl-9,9a-dihydro-1H-imidazo
[1,2-a]indol-2(3H)-one (3b). Similar treatment (MethodA) of chloride
1b (1.33 g, 5 mmol) with hydroxylamine hydrochloride (1.04 g,
15 mmol) in the presence of sodium hydroxide (0.8 g, 20 mmol) gave
the title compound 3b (0.95 g, 77%) as colourless crystals, mp
4. Experimental
4.1. General
161e162 ꢁC (from EtOH). 1H NMR (300 MHz, DMSO-d6):
d 1.08 (s, 3H,
The melting points were determined in open capillary tubes on
9-CH3),1.40 (s, 3H, 9-CH3),1.42 (s, 3H, 9a-CH3), 2.22 (s, 3H, 7-CH3), 3.79
€
a Buchi B-540 melting point apparatus and are uncorrected. Infrared
(s, 2H, CH2), 6.73 (d, J¼7.8 Hz, 1H, 5-H), 6.89e6.92 (m, 2H, 6-H, 8-H),
spectra were recorded with a PerkineElmer Spectrum One spec-
trometer using potassium bromide pellets. 1H NMR spectra were
recorded at 300 MHz on a Varian Unity Inova spectrometer and at
500 MHz on a Bruker Avance 500 spectrometer; 13C NMR spectra
were registered at 75 and 125 MHz, respectively. Chemical shifts,
expressed in parts per million, were relative to tetramethylsilane
(TMS). 15N NMR spectra (50.69 MHz) were obtained on a Bruker
Avance 500 spectrometer using a ‘directly’ detecting broadband
observe probe and were referenced against neat, external nitro-
methane (coaxial capillary). Mass spectra were measured using
a Waters ZQ instrument (ion spray). Diffraction data were collected
on a Bruker-Nonius KappaCCD diffractometer at room temperature
and also at ꢀ100 ꢁC. The crystal structures were solved using known
programs.40 Elemental analyses were conducted using an Elemental
Analyzer CE-440 (Exeter Analytical, Inc.) by the Microanalytical
Laboratory, Department of Organic Chemistry, Kaunas University of
Technology. For thin layer chromatographic (TLC) analyses, Merck
precoated TLC plates (silica gel 60 F254) were used. Dry THF was
distilled from sodium and benzophenone.
9.44 (s,1H, OH).13C NMR (75 MHz, DMSO-d6):
d 15.9 (9a-CH3), 20.6 (9-
CH3), 22.2 (7-CH3), 27.3 (9-CH3), 46.9 (C-9), 50.9 (C-3), 92.7 (C-9a),
111.2, 122.7, 127.7, 130.3, 138.7, 148.5, 172.0 (C]O). IR (KBr, cmꢀ1):
nOH¼3111, nC]O¼1702. MS (ESþ) m/z (%): 247 (MþHþ, 20), 269
(MþNaþ, 100). Anal. Calcd for C14H18N2O2: C, 68.27; H, 7.37; N, 11.37.
Found: C, 68.47; H, 7.53; N, 11.35.
4.2.3. 7-Bromo-1-hydroxy-9,9,9a-trimethyl-9,9a-dihydro-1H-imi-
dazo[1,2-a]indol-2(3H)-one (3c). Similar treatment (Method A) of
chloride 1c (1.66 g, 5 mmol) with hydroxylamine hydrochloride
(1.04 g, 15 mmol) in the presence of sodium hydroxide (0.8 g,
20 mmol) gave the title compound 3c (0.73 g, 47%) as colourless
crystals, mp 186e187 ꢁC (from EtOH). 1H NMR (300 MHz, DMSO-
d6):
d 1.11 (s, 3H, 9-CH3), 1.41 (s, 3H, 9-CH3), 1.42 (s, 3H, 9a-CH3),
3.85 (s, 2H, CH2), 6.85 (d, J¼8.1 Hz, 1H, 5-H), 7.26 (dd, J¼8.1 Hz,
J¼2.1 Hz, 1H, 6-H), 7.32 (d, J¼2.1 Hz, 8-H), 9.44 (s, 1H, OH). 13C NMR
(75 MHz, DMSO-d6):
d 15.8 (9a-CH3), 22.0 (9-CH3), 27.0 (9-CH3),
47.2 (C-9), 50.8 (C-3), 92.7 (C-9a), 111.8, 113.5, 125.2, 130.0, 141.5,
150.1, 171.9 (C]O). IR (KBr, cmꢀ1): nOH¼3138, nC]O¼1704. MS (ESþ)
m/z (%): 313/315 (MþHþ, 100). Anal. Calcd for C13H15BrN2O2: C,
50.18; H, 4.86; N, 9.00. Found: C, 50.46; H. 4.97; N, 9.02.
4.2. Procedures for preparation of 1-hydroxy-9,9,9a-trimethyl-
9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-ones (3)
4.3. Procedures for preparation of 1-alkoxy-9,9,9a-trimethyl-
4.2.1. 1-Hydroxy-9,9,9a-trimethyl-9,9a-dihydro-1H-imidazo[1,2-a]
indol-2(3H)-one (3a). Method A: To a solution of chloride 1a (3.79 g,
15 mmol) in dry methanol (20 mL) hydroxylamine hydrochloride
(3.13 g, 45 mmol) and powdered sodium hydroxide (2.40 g, 60 mmol)
were added and the mixture was refluxed for 0.5 h. The insolubles
9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-ones (6)
4.3.1. 1-Methoxy-9,9,9a-trimethyl-9,9a-dihydro-1H-imidazo[1,2-a]
indol-2(3H)-one (6a). Method A: To a solution of compound 3a
(100 mg, 0.43 mmol) in 4 mL of benzene/methanol (3:1 v/v) 2.0 M

V. Martynaitis et al. / Tetrahedron 67 (2011) 3945e3953
3951
solution of trimethylsilyldiazomethane in Et2O (0.54 mL, 1.08 mmol)
was added dropwise and the reaction mixture was stirred for 4 h at
room temperature. Then the solvent was evaporated under reduced
pressure, the residue dissolved in Et2O (4 mL) and the solution was
washed with water (5 mL). The organic layer was separated and the
aqueouslayerwasextractedwithanother5 mL ofEt2O. Thecombined
organic layers were dried over MgSO4 and filtered. The solvent was
evaporated under reduced pressure and the product was isolated by
flash chromatography on a silica gel column using hexane/EtOAc (3:1
v/v) as eluent to give the title compound 6a (75 mg, 71%) as colourless
CH3), 3.89 (s, 2H, NCH2), 4.83 (d, J¼9.0 Hz, 1H, OCH2), 5.33 (d,
J¼9.0 Hz, d, 1H, OCH2), 6.75e7.46 (m, 9H, AreH). 13C NMR (75 MHz,
CDCl3):
d 17.2 (CH3), 23.1 (CH3), 27.4 (CH3), 47.2 (C-9), 51.4 (C-3),
76.2 (OCH2), 94.0 (C-9a),111.3,122.1,122.3,127.8,128.5 (2ꢂC),128.6,
129.1 (2ꢂC), 134.9, 138.7, 150.3 (AreC), 175.2 (C]O). IR (KBr, cmꢀ1):
nC]O¼1739. MS (ESþ) m/z (%): 323 (MþHþ, 50), 345 (MþNaþ, 100).
Anal. Calcd for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C,
74.03; H, 7.13; N, 8.75.
4.4. General procedure for the preparation of 1-alkoxy-2-
methoxy-9,9,9a-trimethyl-9,9a-dihydro-1H-imidazo[1,2-a]
indoles (7)
crystals, mp 89e90 ꢁC (from EtOH). 1H NMR (300 MHz, CDCl3):
d 1.21
(s, 3H, CH3), 1.50 (s, 3H, CH3), 1.53 (s, 3H, CH3), 3.81 (AB-d, J¼17.0 Hz,
1H, 3-HA), 3.83 (AB-d, J¼17.0 Hz, 1H, 3-HB), 3.84 (s, 3H, CH3O),
6.71e7.20 (m, 4H, AreH).13C NMR (75 MHz, CDCl3):
d
17.0 (CH3), 22.6
n-BuLi (1.25 mL, 1.25 mmol, 2.5 M in cyclohexane) was added
dropwise to a solution of appropriate 1-alkoxyimidazo[1,2-a]indole
6 (1 mmol) in dry THF (5 mL) under argon at ꢀ78 ꢁC. After 1 h
a solution of methyl iodide (170 mg, 1.2 mmol) in dry THF (2 mL)
was added dropwise over 0.5 h. The mixture was stirred at ꢀ78 ꢁC
for 1 h and then left to reach ambient temperature. The reaction
mixture was quenched with 15 mL of ammonium chloride solution
(10%) and extracted with EtOAc (3ꢂ10 mL). The combined organic
layers were washed with water (15 mL), dried over Na2SO4 and the
solvent was evaporated under reduced pressure. The residue was
chromatographed on a silica gel column with hexane/EtOAc (2:1 v/
v) as eluent to yield compounds 7aec.
(CH3), 27.4 (CH3), 47.0 (C-9), 51.3 (C-3), 62.4 (OCH3), 93.8 (C-9a),111.3,
122.1, 122.3, 127.8, 138.6, 150.2 (AreC), 175.2 (C]O). IR (KBr, cmꢀ1):
nC]O¼1748. MS (ESþ) m/z (%): 247 (MþHþ, 100), 269 (MþNaþ, 60).
Anal. Calcd for C14H18N2O2: C, 68.27; H, 7.37; N,11.37. Found: C, 67.89;
H, 7.26; N, 11.13
Method B: To a solution of compound 3a (465 mg, 2 mmol) in
DMF (5 mL), K2CO3 (304 mg, 2.2 mmol) was added and the
mixture was stirred for 15 min. Then methyl iodide (0.15 mL,
0.34 g, 2.4 mmol) was added to the mixture and stirring was
continued for 16 h. The reaction mixture was poured into water
(15 mL), extracted with EtOAc (3ꢂ15 mL), the combined organic
layers were dried over Na2SO4 and filtered. The solvent was
evaporated under reduced pressure and the product was isolated
by chromatography on a silica gel column using hexane/EtOAc as
eluent (3:1 v/v) to give the compound 6a (0.44 g, 90%). Mp and
NMR spectroscopy data of the title product 6a were identical
with those obtained by Method A
4.4.1. 1,2-Dimethoxy-9,9,9a-trimethyl-9,9a-dihydro-1H-imidazo[1,2-
a]indole (7a). Yield 54%. Oil.1H NMR (300 MHz, CDCl3):
d 0.93 (s, 3H,
CH3),1.47 (s, 3H, CH3),1.50 (s, 3H, CH3), 2.98 (s, 3H, OCH3), 3.47 (s, 3H,
OCH3), 4.98 (s,1H, NCH), 6.92e7.20 (m, 4H, AreH).13C NMR (75 MHz,
CDCl3):
d 21.7 (CH3), 22.6 (CH3), 27.2 (CH3), 28.7 (CH3), 49.1 (C-9),
52.5 (CH3), 88.9 (C-3), 91.2 (C-9a), 113.9, 122.0, 123.0, 128.4, 141.5,
145.5,167.9 (AreC, C-2). IR (KBr, cmꢀ1): nC]C(OMe)¼1715. MS (ESþ) m/
z (%): 283 (MþNaþ, 100). Anal. Calcd for C15H20N2O2: C, 69.20; H,
7.74; N, 10.76. Found: C, 68.97; H, 7.82; N, 11.04.
4.3.2. 1-Ethoxy-9,9,9a-trimethyl-9,9a-dihydro-1H-imidazo[1,2-a]in-
dol-2(3H)-one (6b). Method A: To a solution of compound 3a
(100 mg, 0.43 mmol) in dichloromethane (3 mL), triethyloxonium
tetrafluoroborate (106 mg, 0.56 mmol) was added and the re-
action mixture was stirred for 18 h at room temperature. Then the
mixture was washed with water (5 mL), dried over MgSO4 and
filtered. The solvent was evaporated under reduced pressure and
the product was isolated by chromatography on a silica gel column
using hexane/EtOAc (4:1 v/v) as eluent to give the title compound
6b as a colourless oil (60 mg, 54%). 1H NMR (300 MHz, CDCl3):
4.4.2. 1-Ethoxy-2-methoxy-9,9,9a-trimethyl-9,9a-dihydro-1H-imi-
dazo[1,2-a]indole (7b). Yield 58%. Oil. 1H NMR (300 MHz, CDCl3):
d
0.94 (s, 3H, CH3), 1.32 (t, J¼7.0 Hz, 3H, CH2CH3), 1.46 (s, 3H, CH3), 1.49
(s, 3H, CH3), 2.97 (s, 3H, OCH3), 3.65 (dq, J¼8.7 Hz, J¼7.0 Hz, 1H, OCH2),
3.84 (dq, J¼8.7, 7.0 Hz, 1H, OCH2), 5.0 (s, 1H, NCH), 6.91e7.20 (m, 4H,
AreH). 13C NMR (75 MHz, CDCl3):
d 15.2 (CH3), 21.8 (CH3), 22.6 (CH3),
d
1.21 (s, 3H, CH3), 1.24 (t, J¼7.2 Hz, 3H, CH2CH3), 1.49 (s, 3H, CH3),
27.2 (CH3), 28.6 (CH3), 49.1 (C-9), 61.1 (OCH2), 88.9 (C-3), 90.5 (C-9a),
113.7,122.0,122.9,128.3,141.4,145.6,168.3 (AreC, C-2). IR (KBr, cmꢀ1):
nC]C(OMe)¼1715. MS (ESþ) m/z (%): 297 (MþNaþ, 95). Anal. Calcd for
C16H22N2O2:C, 70.04; H, 8.08;N,10.21. Found:C, 69.89;H, 7.76; N,10.13.
1.55 (s, 3H, CH3), 3.80 (AB-d, J¼16.8 Hz, 1H, 3-HA), 3.83 (AB-d,
J¼16.8 Hz, 1H, 3-HB), 3.83e3.91 (m, 1H, OCH2), 4.33 (dq, J¼8.4,
7.2 Hz, 1H, OCH2), 6.71e7.20 (m, 4H, AreH). 13C NMR (75 MHz,
CDCl3):
d 13.6 (CH3), 17.2 (CH3), 22.5 (CH3), 27.4 (CH3), 47.1 (C-9),
51.5 (C-3), 70.5 (OCH2), 93.7 (C-9a), 111.4, 122.1, 122.2, 127.8, 138.8,
150.3 (AreC), 174.7 (C]O). IR (KBr, cmꢀ1): nC]O¼1739. MS (ESþ)
m/z (%): 261 (MþHþ, 100), 283 (MþNaþ, 60). Anal. Calcd for
C15H20N2O2: C, 69.20; H, 7.74; N, 10.76. Found: C, 68.89; H, 7.26; N,
10.36.
4.4.3. 1-Benzyloxy-2-methoxy-9,9,9a-trimethyl-9,9a-dihydro-1H-
imidazo[1,2-a]indole (7c). Yield 63%. Oil. 1H NMR (300 MHz, CDCl3):
d
0.97 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.55 (s, 3H, CH3), 3.02 (s, 3H,
OCH3), 4.65(d, J¼11.1Hz,1H,OCH2), 4.86(d, J¼11.1 Hz,1H, OCH2), 5.16
(s, 1H, NCH), 6.88e7.49 (m, 9H, AreH). 13C NMR (75 MHz, CDCl3):
Method B: The procedure for the synthesis of 6a (Method B) was
followed using compound 3a (465 mg, 2 mmol), K2CO3 (304 mg,
2.2 mmol) and ethyl iodide (0.192 mL, 374 mg, 2.4 mmol) at room
temperature for 16 h to give 6b (405 mg, 78%). NMR spectroscopy
data of the title product 6b were identical with those obtained by
Method A.
d 21.9 (CH3), 22.7 (CH3), 27.3 (CH3), 28.6 (CH3), 49.1 (C-9), 67.2 (OCH2),
89.1 (C-3), 90.2 (C-9a), 113.9, 122.1, 123.0, 126.9, 127.6, 128.2 (2ꢂC),
128.3, 128.4, 137.7, 141.4, 145.5,168.1 (AreC, C-2). IR (KBr, cmꢀ1): nC]
¼1713. MS (ESþ) m/z (%): 359 (MþNaþ, 100). Anal. Calcd for
C(OMe)
C21H24N2O2: C, 74.97; H, 7.19; N, 8.33. Found: C, 74.40;H, 7.33; N, 8.35.
4.5. Procedure for the preparation of 1-[2-(hydroxyamino)-2-
4.3.3. 1-Benzyloxy-9,9,9a-trimethyl-9,9a-dihydro-1H-imidazo[1,2-a]
indol-2(3H)-one (6c). The procedure for the synthesis of 6a
(Method B) was followed using compound 3a (465 mg, 2 mmol),
K2CO3 (304 mg, 2.2 mmol) and benzyl chloride (0.335 mL, 304 mg,
2.4 mmol) at room temperature for 16 h to give 6c as colorless
crystals (425 mg, 66%), mp 86e87 ꢁC (from EtOH). 1H NMR
oxoethyl]-2,3,3-trimethyl-3H-indolium perchlorate (8a)
To a solution of compound 3a (232 mg,1 mmol) in ethanol (3 mL),
60% perchloric acid was added dropwise to pH 2 and the solution
was kept at 5 ꢁC for 16 h. The precipitated crystalline material was
filtered, washed with cold ethanol (1 mL) and recrystallized from
ethanol, to give perchlorate 8a (213 mg, 64%), mp 192e195 ꢁC (from
(300 MHz, CDCl3):
d 1.23 (s, 3H, CH3), 1.56 (s, 3H, CH3), 1.60 (s, 3H,

3952
V. Martynaitis et al. / Tetrahedron 67 (2011) 3945e3953
EtOH, with decomposition). 1H NMR (300 MHz, TFA-d):
d
1.69 (s, 6H,
27.2, 29.4, 49.5, 61.2, 89.4 (9a-C),113.9, 122.2,122.4,128.2,141.6, 148.4
3,3-CH3, major and minor isomers), 2.86 (s, 3H, 2-CH3, minor iso-
mer), 2.90 (s, 3H, 2-CH3, major isomer), 5.49 (s, 2H, CH2, major iso-
mer), 5.78 (s, 2H, CH2, minor isomer), 7.59e7.70 (m, 4H, major and
minor isomers). 13C NMR (75 MHz, TFA-d), mixture of isomers:
(AreC),173.3.15N NMR(50.69 MHz, CDCl3):
d
ꢀ257.1 (N-1), ꢀ289.1 (N-
4). IR (KBr, cmꢀ1): nC]O¼1699. Anal. Calcd for C15H20N2O: C, 73.74; H,
8.25; N, 11.47. Found: C 73.51; H 8.15; N 11.68.
d
15.50, 15.60, 23.84, 49.23, 49.44, 57.66, 57.69, 116.33, 116.42, 116.5,
125.30, 131.90, 131.94, 133.01, 133.08, 142.97, 143.22, 143.30, 164.82,
203.39, 203.43. IR (KBr, cmꢀ1): nOH,
Acknowledgements
¼3310, 3271, 3212,
NH
This research was funded by a grant (No. 104/2010) from the
Research Council of Lithuania.
nC]O¼1690, nClO4¼1111,1098. Anal. Calcd for C13H17ClN2O6: C, 46.93;
H, 5.15; N, 8.42. Found: C, 46.84; H, 5.06; N, 8.28.
Supplementary data
4.6. Procedure for the preparation of 1-carboxymethyl-2,3,3-
trimethyl-3H-indolium tetrafluoroborate monohydrate (11)
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.03.044. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
To a solution of compound 3a (232 mg,1 mmol) in ethanol (3 mL),
tetrafluoroboric acid (48%) was added dropwise to pH 2 and the
solution was kept at 5 ꢁC for 24 h. The precipitated crystalline ma-
terial was filtered, washed with cold ethanol (1 mL) and recrystal-
lized from ethanol, to give tetrafluoroborate 11 (172 mg, 53%), mp
References and notes
195e197 ꢁC (from EtOH). 1H NMR (300 MHz, TFA-d):
d
1.85 (s, 6H,
2ꢂ3-CH3), 3.04 (s, 3H, 2-CH3), 5.67 (s, 2H, CH2), 7.80e7.87 (m, 4H,
AreH). 13C NMR (75 MHz, TFA-d):
1. (a) Raue, R. In Methine Dyes and Pigments, in Ullmann’s Encyclopedia of Industrial
Chemistry, 5th ed.; Elvers, B., Hawkins, S., Schultz, G., Eds.; VCH: Weinheim,
Basel, Cambridge, New York, NY, 1990; Vol. A16, p 487; (b) Bertelson, R. C.
Spiropyrans In. Organic Photochromic and Thermochromic Compounds; Crano, J.
C., Guglielmetti, R. J., Eds.; Plenum: New York, NY, London, 1999; Vol. 1, p 11; (c)
Colorants for Non-textile Applications; Freeman, H. S., Peters, A. T., Eds.; Elsevier:
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p 636; (d) Lee, H.; Mason, C.; Achilefu, S. J. Org. Chem. 2006, 71, 7862; (e) De-
ligeorgiev, T.; Vasilev, A.; Drexhage, K.-H. Dyes Pigm. 2007, 74, 320.
d
15.5 (2-CH3), 23.9 (2ꢂ3-CH3),
50.2 (C-3), 57.9 (CH2), 116.3, 125.6, 132.1, 133.4, 143.0, 143.5 (AreC),
170.9 (CO2H), 203.3 (Nþ]C). IR (KBr, cmꢀ1): nOH¼3436, nC]O¼1634,
nBF4¼1053, 768. Anal. Calcd for C13H16BF4NO2.H2O: C, 48.33; H, 5.62;
N, 4.34. Found: C, 47.93; H, 5.46; N, 4.67.
2. Degutis, J. A.; Sackus, A. A.; Urbonavicius, A. G. Khim. Geterotsikl. Soedin. 1985,
933; Chem. Abstr. 1985, 103, 160443.
4.7. Procedure for the preparation of N-hydroxy-2-(2,3,3-
trimethyl-2,3-dihydro-1H-indol-1-yl)acetamide (12)
3. Wang, B.; Fan, J.; Sun, S.; Wang, L.; Song, B.; Peng, X. Dyes Pigments 2010, 85, 43.
4. (a) Yamamoto, S.; Taniguchi, T. JP 62242686,1987; Chem. Abstr.1988,108, 229708;
(b) Feiler, L., Raimann, T., PCT Int. Appl. WO 2009/141237 A1, 2009; (c) Marty-
ꢀ
ꢀ
_
naitis, V.; Sackus, A.; Berg, U. J. Heterocycl. Chem. 2002, 39,1123; (d) Kleiziene, N.;
To a solution of compound 3a (200 mg, 0.8 mmol) in glacial acetic
acid (2 mL), sodium borohydride (98.8 mg, 2.6 mmol) was added in
portions and the mixture was stirred at ambient temperature for 3 h.
The reaction mixture was poured into water (5 mL), the solutionwas
neutralized with sodium carbonate to pH 9 and extracted with Et2O
(3ꢂ5 mL). The combined organic extracts were washed with brine
(3 mL), dried over Na2SO4 and filtered. The solvent was evaporated
under reduced pressure and the residue was chromatographed on
a silica gel column with hexane/EtOAc (1:1 v/v) as eluent to yield
compound 12 (165 mg, 88%) as white crystals, mp 119e120 ꢁC. 1H
ꢀ
ꢀ
ꢀ
_
Amankaviciene, V.; Berg, U.; Schicktanz, C.; Schlothauer, K.; Sackus, A. Monatsh.
Chem. 2006, 137, 1109.
5. (a) Psaar, H.; Raue, R., Ger. Offen. 36 22 009 A1, 1988. Chem. Abstr. 1988, 108,
169175; (b) Sackus, A.; Amankaviciene, V.; Martynaitis, V. Chem. Heterocycl.
_
Compd. 2000, 36, 663.
ꢀ
ꢀ ꢁ _
ꢀ
6. Dumciute, J.; Martynaitis, V.; Holzer, W.; Mangelinckx, S.; De Kimpe, N.; Sackus,
A. Tetrahedron 2006, 62, 3309.
7. Mhaske, S. B.;Argade, N. P. Tetrahedron2006, 62, 9787 and references cited therein.
8. Agrawal, Y. K.; Sharma, K. R. Talanta 2005, 97, 112.
9. (a) Codd, R. Coord. Chem. Rev. 2008, 252, 1387; (b) Korner, M.; Tibes, U. Prog.
Med. Chem. 2008, 46, 205.
€
10. Petit, S.; Duroc, Y.; Larue, V.; Giglione, C.; Leon, C.; Soulama, C.; Denis, A.;
Dardel, F.; Meinel, T.; Artaud, I. ChemMedChem 2009, 4, 261.
11. (a) Hosseini, S. H.; Entezami, A. A. J. Appl. Polym. Sci. 2003, 90, 63; (b) Hosseini,
S. H.; Entezami, A. Eur. Polym. J. 1995, 31, 635.
NMR (300 MHz, CDCl3):
d
1.11 (s, 3H, 3-CH3), 1.26 (d, J¼6.6 Hz, 3H,
CHCH3), 1.35 (s, 3H, 3-CH3), 3.15 (q, J¼6.6 Hz, CHCH3), 3.74 (s, CH2),
6.50e7.17 (4H, m, AreH), 9.21 (br s, 1H, NH or OH), 9.46 (br s, NH or
ꢀ
ꢀ
12. Rajic, Z.; Perkovic, I.; Butula, I.; Zorc, B.; Hadjipavlou-Litina, D.; Pontiki, E.;
Pepeljnjak, S.; Kosalec, I. J. Enzyme Inhib. Med. Chem. 2009, 24, 1179.
13. (a) Escobar, C. A.; Kluge, M.; Sicker, D. Tetrahedron Lett. 1997, 38,1017; (b) Tanaka,
K.; Matuso, K.; Nakanishi, A.; Kataoka, Y.; Takase, K.; Setsuo, O. Chem. Pharm. Bull.
1988, 36, 2323; (c) Misra, R. N.; Botti, C. M.; Haslanger, M. F.; Engebrecht, J. R.;
Mahoney, E. M.; Ciosek, C. P., Jr. Bioorg. Med. Chem. Lett. 1991, 1, 295.
14. Jencks, W. P.; Gilchrist, M. J. Am. Chem. Soc. 1964, 86, 5616.
OH). 13C NMR (75 MHz, CDCl3):
d 12.9 (CH3), 23.5 (CH3), 25.8 (CH3),
43.1 (C-3), 51.9 (CH2), 72.2 (C-2), 108.4, 120.8, 122.4, 127.9, 139.5,
150.2, 168.6 (C]O). IR (KBr, cmꢀ1): nOH, NH¼3203, nC]O¼1656. MS
(ESþ) m/z (%): 257 (MþNaþ, 60). Anal. Calcd for C13H18N2O2: C, 66.64;
H, 7.74; N, 11.96. Found: C, 66.86; H, 7.77; N, 11.53.
15. (a) Reddy, A. S.; Kumar, M. S.; Reddy, G. R. Tetrahedron Lett. 2000, 41, 6285; (b)
Boukhris, S.; Souzi, A.; Robert, A. Tetrahedron Lett. 1998, 39, 6281; (c) Riva, E.;
Gagliardi, S.; Mazzoni, C.; Passarela, D.; Rencurosi, A.; Vigo, D.; Martinelli, M. J.
Org. Chem. 2009, 74, 3540; (d) Massaro, A.; Mordini, A.; Reginatto, G.; Russo, F.;
Taddei, M. Synthesis 2007, 3201.
4.8. Procedure for the preparation of 1,3,9,9,9a-pentamethyl-
9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one (15)
16. Gal’bershtam, M. A.; Przhiyalgovskaya, N. M.; Khrolova, O. R.; Lazarenko, I. B.;
Bobyleva, G. K.; Suvorov, N. N. Chem. Heterocycl. Compd. 1977, 13, 1309.
17. (a) Vasilevsky, S. F.; Mshvidobadze, E. V.; Elguero, J. Heterocycles 2002, 57, 2255;
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18. Braun, S.; Kalinowski, H.-O.; Berger, S. 150 and More Basic NMR Experiments;
Wiley-VCH: Weinheim, 1998.
n-BuLi (3 mL, 4.8 mmol,1.6 M in hexane) was added to a solution of
compound 13 (920 mg, 4 mmol) inTHF (13 mL) under argon at ꢀ78ꢁC.
After stirring for 1 h, a solution of methyl iodide (681 mg, 4.8 mmol) in
dry THF (8 mL) was added dropwise over 20 min, and the mixture
allowed to reach ambient temperature. After 3 h, the reaction mixture
was quenched with an ammonium chloride solution (10%, 25 mL) and
extracted with EtOAc (2ꢂ15 mL). The combined organic extracts were
washedwithwater(15mL), driedoverNa2SO4, filteredandthesolvent
was evaporated under reduced pressure. The residue was chromato-
graphedonasilicagelcolumnwithhexane/EtOAc(9:1v/v)aseluentto
give compound 15 (495mg, 51%)as acolourless oil.1HNMR(300 MHz,
19. The CCDC deposition number of 1-hydroxy-9,9,9a-trimethyl-9,9a-dihydro-1H-imi-
dazo[1,2-a]indol-2(3H)-one 3a is 772457; formula: C13H16N2O2; unit cell parame-
ters: a 7.39860 (10), b 18.9176 (2), c 9.3134 (5),
b 108.3289 (11), space group P21/a.
20. Politzer, P.; Murray, J. S. Structural analysis of hydroxylamines, oximes and
hydroxamic acids: trends and patterns In The Chemistry of Hydroxylamines,
Oximes and Hydroxamic Acids; Rappoport, Z., Liebman, J. F., Eds.; John Wiley:
2009; Part 1, pp 29e52.
21. (a) Vystorop, I. V.; Lyssenko, K. A.; Kostyanovsky, R. G. Mendeleev Commun.
2002, 12, 85e87; (b) Vystorop, I. V.; Lyssenko, K. A.; Voznesensky, V. N.; Lo-
dygina, V. P.; Kostyanovsky, R. G. Mendeleev Commun. 2002, 12, 193.
CDCl3):
J¼6.9 Hz, 3H, CH3), 2.95 (s, 3H, CH3), 3.78 (q, J¼6.9 Hz, 1H, CHCH3),
6.82e7.18 (m, 4H, AreH). 13C NMR (75 MHz, CDCl3):
21.6, 22.2, 24.1,
d 1.01 (s, 3H, CH3),1.426 (s, 3H, CH3),1.429 (s, 3H, CH3),1.56 (d,
€
€
22. Boese, R.; Niederprum, N.; Blaser, D.; Antipin, M. Y.; Mallinson, P. R. J. Phys.
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35. The CCDC deposition number of 1-carboxymethyl-2,3,3-trimethyl-3H-indolium
tetrafluoroborate monohydrate 11 is 804,508; formula C13H18B1F4N1O3; unit
27. Maldaner, A. O.; Pilli, R. A. Tetrahedron 1999, 55, 13321.
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methyl-3H-indolium perchlorate 8a is 804507; formula C13H17Cl1N2O6 unit cell
cell parameters: a 7.5325 (4), b 23.7452 (12), c 9.0242 (5),
b 103.093 (4), space
group P21/c.
parameters: a 10.1033 (2), b 11.7548 (2), c 13.3390 (3),
a
93.4872 (8),
b
97.
36. Gribble, G. W.; Nutaitis, C. F. Org. Prep. Proced. Int. 1985, 17, 317.
5743(8),
g
96.1956(8), space group Pꢀ1.
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