Iodoamination of Alkenyl Sulfonamides by Potassium Iodide and Hydrogen Peroxide in Aqueous Medium

Article abstract of DOI:10.1002/hlca.201900088

A procedure for the iodoamination of unfunctionalized olefins tethered to a tosyl-protected NH-group has been developed. The combined use of KI and H₂O₂ in aqueous medium was effective for the preparation of iodomethyl-substituted ni

Full text of DOI:10.1002/hlca.201900088

HELVETICA
chimica acta
Accepted Article
Title: Iodoamination of Alkenyl Sulfonamides by Potassium Iodide and
Hydrogen Peroxide in Aqueous Medium
Authors: Gianluigi Broggini, Sabrina Giofrè, Roberto Sala, Egle Maria
Beccalli, and Leonardo Lo Presti
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10.1002/hlca.201900088
Helvetica Chimica Acta
HELVETICA
Iodoamination of Alkenyl Sulfonamides by Potassium Iodide and Hydrogen
Peroxide in Aqueous Medium
Sabrina Giofrè,a Roberto Sala,b Egle Maria Beccalli,a Leonardo Lo Presti,c and Gianluigi Brogginib*
a DISFARM, Sezione di Chimica Generale e Organica “A. Marchesini”, Università degli Studi di Milano, Via Venezian 21, 20133, Milano (Italy)
b Dipartimento di Scienza e Alta Tecnologia, Università degli Studi dell’Insubria, Via Valleggio 9, 22100, Como (Italy)
c Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, 20133, Milano (Italy)
Phone : (+39)-031-238-6443, e-mail: gianluigi.broggini@uninsubria.it
Dedication ((optional))
Abstract A procedure for the iodoamination of unfunctionalized olefins tethered to a tosyl-protected NH-group has been developed. The combined use
of KI and H2O2 in aqueous medium was effective for the preparation of iodomethyl-substituted nitrogen-containing heterocycles. The selective exo-trig
iodocyclization provided 1,2-bifunctional 5-, 6-, and 7-membered cyclic skeletons.
Keywords Cyclization • amination • nitrogen heterocycles • synthetic methods • sulfonamides
antitumor, anti-infective, and anti-inflammatory agents feature
Introduction
iodomethyl substituted nitrogen-containing heterocycles (Figure 1).[25-26]
The development of efficient synthetic protocols which allow the
formation of more than one bond in a single step plays a central role in
organic synthesis. Recently, haloamination of carbon-carbon double
bond involving an intramolecular carbon-nitrogen bond formation
received great attention as fruitful methodology for the synthesis of
nitrogen-containing heterocycles.[1-3] The usefulness of heterocycles
containing
a vicinal haloamine moiety as versatile synthetic
intermediates[4-7] or as potential medicinal agents[8,9] is well established.
Among the alkene halocyclizations, iodoamination reactions
represent a powerful tool for the preparation of heterocycles suitable for
further introduction of functionalities.[10,11] The formation of a carbon-
iodine bond provides high added value to the process as proven by the
multi-faceted conversions which can undergo. While the most efficient
procedures for the access to vicinal chloro- and bromoamines are based
on transition metal-catalyzed reactions, direct formation of vicinal
iodoamines from aminoalkenes can be typically realized by initial
activation of the carbon-carbon double bond with different sources of
electrophile. Molecular iodine and N-iodosuccinimide (NIS) have been
widely used with amide-type substrates (Scheme 1a)[12-15] as well as with
alkenyl imidates (Scheme 1b).[16-18] Alternatively, KI in the presence of a
hypervalent iodine derivatives (Scheme 1c)[19] or a transition metal-
catalyst (Scheme 1d)[20-21] were proven to be effective for this goal. Also
NaI, combined with MnI2 as catalyst, has been proven a useful source of
iodine for iodoamination of unfunctionalized olefins (Scheme 1e).[22-23] It
is worth noting also the iodocyclization of alkenyl carbamates
performed with Bu4NI as iodine source with NaNO2 as catalyst and
molecular oxygen as oxidant.[24]
The importance of the development of a mild and easy synthesis
of vicinal iodoamine moieties is also due to their role as core scaffolds in
various structures of bioactive compounds. In particular, some
Scheme 1. Synthetic procedure for aminoiodination
1
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Following our previous investigations on heterocyclization reactions in
domino processes,[27-30] we focused our attention on the search of
alternative conditions for intramolecular amination reactions combined
with iodine functionalization (Scheme 1f). Herein we report selected
mild conditions relying on the use of KI as iodine source and H2O2 as
oxidant agent which act in water at room temperature providing
iodomethyl-substituted heterocycles. Although it is known that H2O2
has been used combined to tetrabutylammonium iodide to promote an
iodine source. Using molecular iodine in O2 atmosphere combined with
benzoquinone as further oxidant in acetonitrile, no formation of 2a was
observed and carbamate 1a was completely recovered (Table 1, entry 9).
Also MnO2 was tested as additive in the reaction mixture under oxygen
atmosphere but 2a was achieved in low yield (Table 1, entry 10).
Intriguingly, a consistent improvement of the outcome of the reaction
was detected when H2O2 was used as the sole oxidant in the presence of
KI and CH3CN as the solvent. These conditions determined a neat
conversion of 1a, providing the desired iodoamination product in 79%
yield (Table 1, entry 11). Use of DMF or dioxane led to a remarkable
decrease of the yield (Table 1, entries 12 and 13), while water associated
to DMSO or CH3CN as a co-solvent was gratifyingly proven to be a good
medium to obtain the complete conversion of the substrate into 2a in
mild conditions (Table 1, entries 14 and 15). Working in the conditions of
Table 1, entry 14, the crude mixture resulted cleaner than the
corresponding reaction carried out with I2 or NIS as iodine source.
Besides, the product obtained might be collected through an easy
filtration, due to its lower solubility in the DMSO/H2O mixture compared
to the starting material.
Table 1. Optimization of the reaction conditions.
Figure 1. Selected bioactive vicinal iodoamine derivatives
amination reaction,[31] to the best of our knowledge the possibility to
perform iodoamination reactions by the use of KI/H2O2 is unknown in
the literature.
Entry
Iodine
source
Oxidant
Solvent[a]
Time
(h)
2a[b]
(% yield)
52
1
I2
-
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
30
18
24
4
2
NIS
NIS
I2
-
29[c]
Results and Discussion
3[d]
4
CuCl2 (5 mol%), O2
49[c]
[e]
PIFA
-
O-Allyl-N-tosylcarbamate (1a) was investigated in preliminary
experiments aimed to explore new conditions for the feasibility of the
iodoamination reaction. Various combinations of iodine sources and
oxidant agents in different solvents used to afford the oxazolidinone
[e]
5
NIS
KI
PIFA
6
-
6
PIFA
3
81
68
73
-
7
KI
PIDA
8
8
KI
PhI(mcba)2
20
48
48
product 2a are collected in Table 1.
A stoichiometric amount of
9
KI
BQ (20 mol%), O2
molecular iodine or NIS in acetonitrile at room temperature furnished
the iodoamination product in unsatisfactory yields in a complex crude
mixture, in the latter case also due to the formation of the O-(2,3-
diiodopropyl)-N-tosyl-carbamate (Table 1, entries 1 and 2). The same
acyclic diiodinated compound was obtained as by-product when the
reaction was carried out in the presence of NIS and CuCl2 as the oxidant
in oxygen atmosphere (Table 1, entry 3). A iodocyclizative process was
observed when I2 and NIS were combined with PIFA, although the
product resulted in the 3-unsubstituted 4-iodomethyloxazolidinone,
isolated in both cases in moderate yields (Table 1, entries 4 and 5).
Conversely, the use of PIFA was effective if used with KI as iodine source,
providing 2a in 81% yield (Table 1, entry 6).
10
KI
MnO2 (20 mol%),
31
O2
11[f]
12[f]
13[f]
14[f]
15[f]
KI
KI
KI
KI
KI
H2O2
H2O2
H2O2
H2O2
H2O2
CH3CN
24
24
24
24
24
79
32
54
78
67
DMF
Dioxane
H2O/ DMSO[g]
H2O/CH3CN[h]
[a] The reactions were carried out at room temperature unless otherwise stated. [b]
Yields of purified products. [c] O-(2,3-Diiodopropyl)-N-tosyl-carbamate has been
[d]
isolated in 57% yield (entry 2) and 37% yield (entry 3).
The reaction was
3-Unsubstituted 4-
[e]
performed in CH3CN at reflux under O2 atmosphere.
iodomethyl-oxazolidin-2-one has been isolated in 54% yield (entry 4) and 43%
yield (entry 5). [f] The reaction was carried out at room temperature using a 30%
solution of H2O2 in water. [g] In 3:1 ratio. [h] In 2:1 ratio.
Other hypervalent iodine derivatives such as PIDA and PhI(mcba)2
were a good choice as promoter to afford 2a, although with a slight
decrease in yield (Table 1, entries 7 and 8). Following these preliminary
results, we focused on other conditions based on the presence of KI as
The result obtained with KI/H2O2 in water as solvent at room
temperature prompted us to explore the substrate scope of the
2
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iodoamination reaction in the conditions of Table 1, entry 19. Initially,
variously substituted alkenyl carbamates were envisaged and the results
of the iodocyclization reactions are reported in Table 2. The presence of
substituents on the allylic moiety is compatible with reaction conditions,
as demonstrated by the formation of compounds 2b-h, although a mild
heating in some cases was required. Compounds 2b and 2c were
obtained as a mixture of cis/trans diastereoisomers, easily separated and
fully characterized.
Figure 2. Molecular structure of the (R,R) enantiomer of 2f at room temperature,
as derived from single crystal X-ray diffraction. The methyl of the tosyl group is
rotationally disordered with site occupation factors of 0.64(7) and 0.36(7). Thermal
ellipsoids are drawn at the 30% probability level. Configurational descriptors of the
stereogenic centres are also shown.
The (R*,R*)-configuration of
a representative iodo-derivative
arising from O-allyl-carbamates mono-substituted at terminal position
[
A
was confirmed by X-ray analysis of compound 2f (Figure 2), ] achieved
by iodocyclization of the O-pent-2-enyl carbamate in the (Z)-
configuration. The O-2-cyclohexenyl-N-tosyl-carbamate furnished
exclusively the bicyclic oxazolidinone 2i in 66% yield. The reaction
conditions are also suitable for the iodoamination of O-alk-3-enyl
carbamates, which provided the 1,3-oxazin-2-one products 2j and 2k.
Interestingly, the treatment of the optically active carbamate 3
with H2O2 and KI in H2O/DMSO 1:3 at 40 °C resulted selectively in an
exo-cyclization, providing the spiro-compound 4 as the sole product
(Scheme 2).
Table 2. Reaction of iodoamination of alkenyl carbamates
.
Scheme 2. Iodoamination of the optically active carbamate 3
[a] Starting from a mixture of (E/Z)-1e. [b] Starting from (Z)-1f. [c] Starting from (E)-
1g.
[A] CCDC 1868155 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/structures.
Scheme 3. Selective formation of the sole diastereoisomer (-)-4.
3
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The stereoselective reaction path is due to the difference arisen
interest from the synthetic point of view for the application of this
procedure to alkenyl ureas.
from the torsional strain of the two plausible transition states having a
substituent on the pseudo equatorial position (Scheme 3).[32-33] The
stability of the chair-like transition state (from TS-A) rather than the
twist-boat state (from TS-B) afforded only the trans-diaxial addition
product (-)-4.
The configuration was unambiguously assigned by X-ray diffraction
[B]
analysis (Figure 3).
Scheme 5. Iodoamination reactions of allyl ureas
Figure 3. Molecular structure of 4 at room temperature, as derived from single
crystal X-ray diffraction. Thermal ellipsoids are drawn at the 30% probability level.
Configurational descriptors of the stereogenic centres are also shown.
Further extension of the reaction scope was attempted taking into
account other alkenyl sulphonamides. The iodomethyl-substituted
heterocyclic products, obtained by reaction with KI and H2O2 using
H2O/DMSO in a ratio depending on the solubility of the substrates, are
collected in Table 3.
Based on the observed results and literature data,[10,11] a plausible
mechanism for the iodocyclization is shown in Scheme
4 taking
carbamate 1a as example. The I+ species generated in situ from KI and
H2O2 suggested the formation of the electrophilic iodinated
intermediate A,[34-41] from which the anti-attack by the nucleophilic
tosylamino group afforded the 4-iodomethyl oxazolidinone product.
Table 3. Reaction of iodoamination of alkenyl tosylamines
Scheme 4. Proposed iodoamination reaction mechanism
The use of H2O2 and KI for the iodocyclization of N-allyl-N’-tosylureas
resulted in a different outcome of the reaction depending on the
substituent on the nitrogen atom. If the phenyl-substituted urea 5a
provided the 4-iodomethyl-imidazolidinone 6a as the major product,
the N-allyl-N-methyl-urea 5b followed mainly
a iodoalkoxylation
process giving the 2-imino-oxazolidine 6b in 52% yield (Scheme 5). In
both cases, minor products were detected in the crude mixtures,
specifically arising from iodoalkoxylation (imino-oxazolidine 7a from 5a)
and iodoamination (imidazolidinone 7b from 5b) reactions. The
possibility of C-O vs C-N bond formation in intramolecular reactions of
secondary ureas is well known in literature.[42-44] However, the low
selectivity achieved in cyclization of compounds 5a,b decreases the
N-Allyl 2-tosylamino-benzamides, already used by our group for the
synthesis of benzodiazepine scaffolds,[45] were proven compatible with
the iodoamination process, giving the 2-iodomethyl-substituted 1,2,3,4-
tetrahydro-benzodiazepin-5-one derivatives 8a-d in 63-74% yield.
Satisfyingly, this procedure also represents a valuable alternative for the
[B] CCDC 1868135 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/structures.
4
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synthesis of these compounds, previously reported in the literature by
displacement with KI of the first-formed chloromethyl derivative.[46] The
iodocyclization conditions were found effective also for the conversion
of the 1-allyl-indole-2-N-tosylcarboxamide into the iodomethyl-
substituted pyrazino[1,2-a]indole 9. It is noteworthy the reluctance of
these substrates to afford haloamination processes in palladium-
catalyzed reactions,[47] as further proof of the fruitfulness of the KI/H2O2
system. Finally, we explored the behaviour of 2-allyl-N-tosylanilines,
already successfully undergone to iodoamination in palladium-catalyzed
conditions.[21] Treatment of these substrates with the standard
iodocyclization conditions provided the iodo-indolines 10a-c, although
in moderate yields.
organic phase was dried over Na2SO4, filtered and evaporated under
reduced pressure. The purification by flash silica gel column
chromatography afforded the corresponding products.
4-(Iodomethyl)-3-tosyloxazolidin-2-one (2a). Compound 2a was
prepared according to the general procedure (H2O/DMSO 3:1, 30h, room
temperature) and isolated as white solid (yield 78%) after flash column
chromatography (hexane:EtOAc 3:1). 1H NMR (400 MHz, CDCl3) δ 7.90
(d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 4.54-4.44 (m, 1H), 4.36 (t, J =
8.8 Hz, 1H), 4.09 (dd, J = 9.1, 3.9 Hz, 1H), 3.60 (dd, J = 10.3, 2.3 Hz, 1H),
3.49-3.28 (m, 1H), 2.39 (s, 3H). The data are in good agreement with
those reported in the literature.[20]
Conclusions
Cis-4-(Iodomethyl)-5-methyl-3-tosyloxazolidin-2-one
(cis-2b).
Compound cis-2b was prepared according to the general procedure
(H2O/DMSO 2.5:1, 30h, room temperature) and isolated as white solid
(yield 45%) after flash column chromatography (hexane:EtOAc 2:1). IR:
In summary, we have developed an efficient iodoamination procedure
on alkenes bearing a secondary sulphonamide group based on the use of
KI/H2O2 system. The current methodology allows to achieve easily
different kind of iodomethyl-substituted nitrogen containing
heterocycles by totally selective exo-cyclization which involves
halogenation and the formation of an intramolecular C-N bond. This
iodoamination reaction proceeds smoothly in water needing the
minimum amount of DMSO as co-solvent to solubilize the substrates.
1
3428, 2975, 1778, 1359, 1163, 1135, 819, 666, 594, 572, 541 cm-1. H NMR
(300 MHz, CDCl3) δ 8.00 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 4.91-
4.79 (m, 1H), 4.54 (td, J = 7.2, 2.2 Hz, 1H), 3.58-3.40 (m, 2H), 2.48 (s, 3H),
1.61 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 151.2 (s), 145.9 (s), 134.
7 (s), 129.9 (d), 128.7 (d), 75.0 (d), 59.3 (d), 21.8 (q), 13.5 (q), -0.5 (t). MS:
(ESI) m/z 418.05 [M+Na+]. Anal. calcd for C12H14NIO4S: C, 36.47; H, 3.57;
N, 3.54. Found: C, 36.69; H, 3.32; N, 3.77.
Experimental Section
Analytical Instruments
Trans-4-(Iodomethyl)-5-methyl-3-tosyloxazolidin-2-one (trans-2b).
Compound trans-2b was prepared according to the general procedure
(H2O/DMSO 2.5:1, 30h, room temperature) and isolated as white solid
(yield 22%) after flash column chromatography (hexane:EtOAc 2:1). M.p.
146-147 °C. IR: 3435, 2984, 1785, 1595, 1359, 1166, 1131 1088, 816, 665,
Melting points were determined in a Stuart Scientific melting point
apparatus in open capillary tubes and are uncorrected. Chemicals were
obtained from Sigma Aldrich and used without further purification.
HPLC analyses were carried out on a Kromasil 5-AmyCoat column (4.6
mm i.d. × 250 mm, 5 μm, AkzoNobel). ESI mass spectra were recorded
on a LCQ Advantage spectrometer from Thermo Finningan and a LCQ
Fleet spectrometer from Thermo Scientific. The NMR spectroscopic
experiments were carried out either on a Bruker AVANCE 400 (400 and
101 MHz for 1H and 13C, respectively), on a Varian OXFORD 300 MHz
(300 and 75 MHz for 1H and 13C, respectively), or on a Bruker Avance 300
MHz spectrometers (300 and 75 MHz for 1H and 13C, respectively).
Optical rotations were measured on a Perkin–Elmer 343 polarimeter at
20 °C (concentration in g/100 mL). Chemical shifts δ are given in ppm
relative to the CHCl3 internal standard, and the coupling constants J are
reported in Hertz (Hz).
1
596, 568, 539 cm-1. H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.2 Hz, 2H),
7.30 (d, J = 8.1 Hz, 2H), 4.36 (dd, J = 6.3, 3.0 Hz, 1H), 4.02 (dt, J = 8.9, 2.7
Hz, 1H), 3.57 (dd, J = 10.3, 2.6 Hz, 1H), 3.31 (t, J = 9.7 Hz, 1H), 2.39 (s, 3H),
1.31 (d, J = 6.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 148.0 (s), 145.0 (s),
134.6 (s), 129.9 (d), 128.5 (d), 77.3 (d), 62.8 (d), 21.7 (q), 21.1 (q), 6.5 (t).
MS: (ESI) m/z 418.12 [M+Na+]. Anal. calcd for C12H14NIO4S: C, 36.47; H,
3.57; N, 3.54. Found: C, 36.31; H, 3.80; N, 3.72.
Cis-4-(Iodomethyl)-5-propyl-3-tosyloxazolidin-2-one
(cis-2c).
Compound cis-2c was prepared according to the general procedure
(H2O/DMSO 1:1, 24h, 40 °C) and isolated as white solid (yield 28%) after
flash column chromatography (hexane:EtOAc 5:1 to 2:1). M.p.: 130-131°
C. IR: 3435, 2973, 1788, 1366, 1160, 657, 560 cm-1. 1H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 4.70-4.54 (m, 1H),
4.55-4.39 (m, 1H), 3.51-3.40 (m, 2H), 2.39 (s, 3H), 2.04-1.98 (m, 1H), 1.85-
1.79 (m, 1H), 1.80-1.46 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 151.4 (s), 145.0 (s), 135.0 (s), 130.0 (d), 128.9 (d), 78.8 (d), 59.1
(d), 29.6 (t), 21.9 (q), 19.3 (t), 13.8 (q), -0.0 (t). MS: (ESI) m/z 424.82 [M+],
General Procedure for the Aminoiodination Reaction. To a solution
of the appropriate olefins (1 equiv.) in a mixture of DMSO and water
(0.1M), potassium iodide (2 equiv.) was added at room temperature,
followed by the addition of a solution of 30% H2O2 (1.1 equiv) in water.
The reaction was monitored by TLC. Then, the reaction mixture was
quenched with Na2S2O3 (1M), and ethyl acetate was added. The organic
layer was separated and washed with brine (6 x 15 mL). Afterwards, the
5
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446.54 [M+Na+]. Anal. calcd for C14H18NIO4S: C, 39.73; H, 4.29; N, 3.31.
Found: C, 39.65; H, 4.08; N, 3.59.
4-(1-Iodobutyl)-3-tosyloxazolidin-2-one (2g). Compound 2g was
prepared according to the general procedure (H2O/DMSO 1:1, 24h,
40 °C) and isolated as white solid (yield 64%) after flash column
chromatography (hexane:EtOAc 4:1). M.p. 136-137 °C. IR: 3439, 2965,
Trans-4-(Iodomethyl)-5-propyl-3-tosyloxazolidin-2-one
(trans-2c).
Compound trans-2c was prepared according to the general procedure
(H2O/DMSO 1:1, 24h, 40 °C) and isolated as white solid (yield 32%) after
flash column chromatography hexane:EtOAc 5:1 to 2:1). M.p. 118-119 °C.
IR: 3437, 2969, 1786, 1361, 1158, 655, 563 cm-1. 1H NMR (300 MHz, CDCl3)
δ 7.97 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 4.39-4.24 (m, 1H), 4.15
(dt, J = 8.8, 2.8 Hz, 1H), 3.64 (dd, J = 10.3, 2.8 Hz, 1H), 3.42 (dd, J = 10.2,
8.8 Hz, 1H), 2.48 (s, 3H), 1.74-1.27 (m, 4H), 0.95 (t, J = 7.3 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ 145.93 (s), 134.6 (s), 129.9 (d), 128.5 (d), 80.4 (d),
61.2 (d), 36.0 (t), 21.7 (q), 17.3 (d), 13.5 (q), 7.0 (t). MS: (ESI) m/z 424.82
[M+], 446.54 [M+Na+]. Anal. calcd for C14H18NIO4S: C, 39.73; H, 4.29; N,
3.31. Found: C, 39.46; H, 4.55; N, 3.04.
1
1784, 1352, 1121, 645, 565 cm-1. H NMR (400 MHz, CDCl3) δ 7.92 (d, J =
8.2 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 4.73-4.56 (m, 1H), 4.32 (t, J = 9.0 Hz,
1H), 4.16 (dd, J = 9.0, 3.8 Hz, 1H), 4.09-3.98 (m, 1H), 2.39 (s, 3H), 1.73-
1.28 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 151.6 (s),
145.8 (s), 134.6 (s), 129.7 (d), 128.8 (d), 66.6 (t), 60.1 (d), 38.6 (d), 37.3 (t),
22.7 (t), 21.7 (q), 13.1 (q). MS: (ESI) m/z 446.21 [M+Na+]. Anal. calcd for
C14H18NIO4S: C, 39.73; H, 4.29; N, 3.31. Found: C, 39.56; H, 4.47; N, 3.06.
4-(2-Iodopropan-2-yl)-3-tosyloxazolidin-2-one (2h). Compound 2h
was prepared according to the general procedure (H2O/DMSO 1:2, 30h,
room temperature) and isolated as white solid (yield 55%) after flash
chromatography (hexane:EtOAc 2.5:1). M.p. 156-160 °C (decomp.). IR:
3396, 2921, 1783, 1165, 1160, 665, 554, 538 cm-1. 1H NMR (300 MHz,
CDCl3) δ 7.95 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 4.79 (dd, J = 8.0,
1.6 Hz, 1H), 4.63 (dd, J = 9.9, 1.6 Hz, 1H), 4.38 (dd, J = 9.7, 7.9 Hz, 1H),
2.48 (s, 3H), 2.16 (s, 3H), 1.89 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 153.2,
145.9, 134.7, 129.8, 128.5, 69.8, 67.0, 48.9, 35.4, 30.0, 21.7. MS: (ESI) m/z
432,24 [M+Na+]. Anal. calcd for C13H16NIO4S: C, 38.15; H, 3.94; N, 3.42.
Found: C, 38.21; H, 3.72; N, 3.59.
4-(Iodomethyl)-5,5-dimethyl-3-tosyloxazolidin-2-one
(2d).
Compound 2d was prepared according to the general procedure
(H2O/DMSO 2:1, 30h, room temperature) and isolated as white solid
(yield 56%) after flash chromatography (hexane:EtOAc 3:1). 1H NMR
(300 MHz, CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 4.17
(dd, J = 7.6, 1.9 Hz, 1H), 3.59-3.41 (m, 2H), 2.46 (s, 3H), 1.61 (s, 3H), 1.39 (s,
3H). The data are in good agreement with those reported in the
literature.[24]
4-(1-Iodopropyl)-3-tosyloxazolidin-2-one (2e). Compound 2e was
prepared according to the general procedure (H2O/DMSO 2.5:1, 30h,
room temperature) and isolated as white solid (yield 67%) after flash
column chromatography (hexane:EtOAc 2:1). M.p. 164-165 °C. IR: 2998,
4-Iodo-3-tosylhexahydrobenzo[d]oxazol-2(3H)-one (2i). Compound 2i
was prepared according to the general procedure (H2O/DMSO 1:1.5, 30h,
room temperature) and isolated as white solid (yield 66%) after flash
chromatography (hexane:EtOAc 3:1). M.p.: 171-172 °C. IR: 3294, 2940,
1787, 1175, 1163, 671, 558, 541 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J
= 8.2 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 5.00 (dd, J = 8.0, 3.9 Hz, 1H), 4.77
(dd, J = 11.1, 6.2 Hz, 1H), 4.67 (dd, J = 6.5, 3.6 Hz, 1H), 2.48 (s, 3H), 2.28 –
1.58 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 145.9 (s), 129.8 (d), 128.6 (d),
74.2 (d), 63.3 (d), 28.9 (t), 25.6 (d), 25.1 (t), 21.7 (q), 18.1 (t). MS: (ESI) m/z
444.32 [M+Na+]. Anal. calcd for C14H16NIO4S: C, 39.92; H, 3.83; N, 3.33.
Found: C, 40.13; H, 3.55; N, 3.24.
1
1781, 1602, 1346, 1174, 1126 1075, 810, 603, 575, 549 cm-1. H NMR (400
MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 4.81-4.62
(m, 1H), 4.33 (t, J = 9.0 Hz, 1H), 4.14 (dd, J = 9.0, 3.7 Hz, 1H), 3.90 (dq, J =
6.6, 3.1 Hz, 1H), 2.39 (s, 3H), 1.77 (d, J = 7.2 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 151.6 (s), 145.9 (s), 134.6 (s), 129.8 (d), 128.8 (d), 66.4 (t), 61.2
(d), 29.2 (d), 23.1 (q), 21.7 (q). MS: (ESI) m/z 418.26 [M+Na+]. Anal. calcd
for C12H14NIO4S: C, 36.47; H, 3.57; N, 3.54. Found: C, 36.61; H, 3.30; N,
3.69.
4-(Iodomethyl)-3-tosyl-1,3-oxazinan-2-one (2j). Compound 2j was
prepared according to the general procedure (H2O/DMSO 3:1, 30h, room
temperature) and isolated as white solid (yield 74%) after flash
chromatography (hexane:EtOAc 2:1). M.p.: 127-128 °C. IR: 3324, 1722,
1358, 1271, 1170, 1143, 669, 612, 542, 533 cm-1. 1H NMR (400 MHz, CDCl3)
δ 7.84 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 4.75-4.57 (m, 1H), 4.33-
4.14 (m, 2H), 3.69 (dd, J = 10.1, 3.0 Hz, 1H), 3.24 (t, J = 10.6 Hz, 1H), 2.53-
2.42 (m, 1H), 2.36 (s, 3H), 2.22-2.06 (m, 1H). 13C NMR (101 MHz, CDCl3) δ
148.0 (s), 145.4 (s), 135.2 (s), 129.5 (d), 129.1 (d), 63.9 (t), 55.4 (d), 26.0 (t),
21.7 (q), 5.3 (t). MS: (ESI) m/z 418.51 [M+Na+]. Anal. calcd for
C12H14NIO4S: C, 36.47; H, 3.57; N, 3.54. Found: C, 36.41; H, 3.75; N, 3.39.
4-(1-Iodopropyl)-3-tosyloxazolidin-2-one (2f). Compound 2f was
prepared according to the general procedure (H2O/DMSO 2:1, 30h, room
temperature) and isolated as white solid (yield 66%) after flash column
chromatography (hexane:EtOAc 1:1). M.p. 146-146 °C. IR: 3435, 2971,
2873, 2850, 1784, 1369, 1356, 1175, 1164, 1116, 668, 596, 540 cm-1. 1H
NMR (300 MHz, CDCl3) δ 7.97 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H),
5.02-4.95 (m, 1H), 4.60-4.50 (m, 1H), 4.48-4.36 (m, 2H), 2.48 (s, 3H),
1.62-1.45 (m, 2H), 1.01 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
152.6 (s), 146.5 (s), 134.8 (s), 130.3 (d), 128.7 (d), 66.8 (t), 61.0 (d), 37.5 (d),
24.1 (t), 22.1 (q), 14.6 (q). MS: (ESI) m/z 432.38 [M+Na+]. Anal. calcd for
C13H16NIO4S: C, 38.15; H, 3.94; N, 3.42. Found: C, 37.98; H, 4.17; N, 3.15.
6
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4-(Iodomethyl)-4-methyl-3-tosyl-1,3-oxazinan-2-one (2k). Compound
2k was prepared according to the general procedure (H2O/DMSO 1.5:1,
30h, room temperature) and isolated as colorless oil (yield 68%) after
flash chromatography (hexane:EtOAc 4:1). IR: 2936, 1755, 1342, 1176,
667, 562, 546 cm-1.1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.1 Hz, 2H),
7.30 (d, J = 8.2 Hz, 2H), 4.30 (d, J = 10.4 Hz, 1H), 4.23-4.15 (m, 2H), 3.89 (d,
J = 10.4 Hz, 1H), 2.57-2.45 (m, 1H), 2.42 (s, 3H), 2.11-1.96 (m, 4H). 13C
NMR (101 MHz, CDCl3) δ 149.3, 144.9, 136.6, 129.4, 129.1, 64.0, 62.6,
38.3, 25.8, 21.6, 13.0. MS: (ESI) m/z 432.45 [M+Na+]. Anal. calcd for
C13H16NIO4S: C, 38.15; H, 3.94; N, 3.42. Found: C, 37.99; H, 4.13; N, 3.53.
1H), 3.37-3.22 (m, 3H), 2.96 (s, 3H), 2.41 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 157.6 (s), 142.8 (s), 140.3 (s), 129.4 (d), 127.6 (d), 77.1 (d), 53.5 (t), 32.1
(q), 21.9 (q), 5.1 (t). MS: (ESI) m/z 417.22 [M+Na+]. Anal. calcd for
C12H15N2IO3S: C, 36.56; H, 3.84; N, 7.11. Found: C, 36.29; H, 4.12; N, 6.91.
2-(Iodomethyl)-4-methyl-1-tosyl-1,2,3,4-tetrahydro-5H-
benzo[e][1,4]diazepin-5-one (8a). Compound 8a was prepared
according to the general procedure (H2O/DMSO 1.5:1, 20h, 60 °C) and
isolated as white solid (yield 71%) after flash chromatography
(hexane:EtOAc 1.5:1). M.p. 156-156 °C. IR: 3074, 1670, 1382, 1157, 1145,
1
1049, 712, 667 cm-1. H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 7.2 Hz, 1H),
(5S,6R,8S)-6-Iodo-8-(prop-1-en-2-yl)-1-tosyl-3-oxa-1-
7.60-7.38 (m, 5H), 7.27 (d, J = 7.7 Hz, 2H), 4.72-4.33 (m, 1H), 3.75-3.45 (m,
2H), 3.28-2.93 (m, 2H), 2.62 (s, 3H), 2.43 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 167.5 (s), 144.1 (s), 135.3 (s), 134.4 (s), 133.6 (d), 132.3 (s), 131.9 (d),
130.1 (d), 129.9 (d), 129.5 (d), 127.1 (d), 61.5 (d), 52.8 (t), 34.2 (q), 21.6 (q),
4.0 (t). MS: (ESI) m/z 471,22 [M+Na+]. Anal. calcd for C18H19N2IO3S: C,
45.97; H, 4.07; N, 5.96. Found: C, 45.94; H, 4.23; N, 6.19.
azaspiro[4.5]decan-2-one (4). Compound 4 was prepared according to
the general procedure (H2O/DMSO 1:3, 24h, 40 °C) and isolated as white
solid (yield 63%) after flash chromatography (hexane:EtOAc 3:1). M.p.:
160-164 °C (decomp.). IR: 3358, 3261, 2959, 2922, 1785, 1188, 1168, 1084,
1
667, 562, 545 cm-1. H NMR (300 MHz, CDCl3) δ 8.06 (d, J = 8.4 Hz, 2H),
7.35 (d, J = 8.1 Hz, 2H), 5.46 (dd, J = 13.6, 4.1 Hz, 1H), 5.17 (s, 1H), 5.01 (s,
1H), 4.48 (d, J = 8.3 Hz, 1H), 4.31 (d, J = 8.7 Hz, 1H), 3.03 (td, J = 13.8, 3.2
Hz, 1H), 2.93-2.82 (m, 1H), 2.46 (s, 3H), 2.33-1.99 (m, 4H), 1.83 (s, 3H),
1.71-1.56 (m, 1H). 13C NMR (300 MHz, CDCl3) δ 151.0 (s), 145.5 (s), 143.1
(s), 135.1 (s), 129.7 (d), 129.2 (d), 112.7 (t), 71.5 (t), 70.0 (s), 40.5 (d), 39.2
(t), 34.2 (d), 30.5 (t), 24.6 (t), 22.5 (q), 21.7 (q). MS: (ESI) m/z 498,23 [M]+.
[α]D20: -17 (c: 0.1 in CHCl3). Anal. calcd for C18H22NIO4S: C, 45.48; H, 4.67;
N, 2.95. Found: C, 45.44; H, 4.89; N, 3.11.
4-Cyclohexyl-2-(iodomethyl)-1-tosyl-1,2,3,4-tetrahydro-5H-
benzo[e][1,4]diazepin-5-one (8b). Compound 8b was prepared
according to the general procedure (H2O/DMSO 1:5, 30h, 50 °C) and
isolated as white solid (yield 68%) after flash chromatography
(hexane:EtOAc 7:3). M.p. = 158–159 °C. IR = 2924, 1640, 1347, 1157, 1139,
1
1055, 710, 662 cm-1. H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8 Hz, 1H),
7.47-7.38 (m, 5H), 7.17 (d, J = 8 Hz, 2H), 4.16-4.09 (m, 1H), 3.84-3.78 (m,
1H), 3.69 (dd, J = 15.5Hz, 4.5Hz, 1H), 3.53 (dd, J = 9.9 Hz, 3.7 Hz, 1H), 2.97
(t, J = 10.1 Hz, 1H), 2.73 (dd, J = 15.4, 11.9 Hz, 1H), 2.34 (s, 3H), 1.74-0.81
(m, 10H). 13C NMR (101 MHz, CDCl3): δ 167.5 (s), 144.1 (s), 135.7 (s), 135.1
(s), 132.9 (d), 132.3 (s), 131.6 (d), 130.5 (d), 129.7 (d), 129.2 (d), 127.7 (d),
64.0 (d), 53.0 (d), 45.6 (t), 30.4 (t), 30.1 (t), 25.7 (t), 25.3 (t), 25.3 (t), 21.5
(q), 4.0 (t). MS: (ESI) m/z 561.45 [M+Na+]. Anal. calcd for C23H27N2IO3S: C,
51.30; H, 5.05; N, 5.20. Found: C, 51.07; H, 5.28; N, 4.97.
4-(Iodomethyl)-1-phenyl-3-tosylimidazolidin-2-one (6a). Compound
6a was prepared according to the general procedure (H2O/DMSO 1:1,
30h, room temperature) and isolated as pale yellow solid (yield 54%)
after flash chromatography (hexane:EtOAc 2.5:1). M.p. 148-149 °C. IR:
3023, 2958, 1716, 1599, 1504, 1359, 1170, 1131, 751, 666, 592, 554 cm-1. 1H
NMR (300 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, 2H), 7.53-7.43 (m, 2H), 7.35 (t,
J = 8.0 Hz, 4H), 7.14 (t, J = 7.4 Hz, 1H), 4.54 (tt, J = 8.8, 3.2 Hz, 1H), 4.09 (t,
J = 9.4 Hz, 1H), 3.78 (dd, J = 10.2, 2.7 Hz, 1H), 3.68 (dd, J = 9.6, 3.7 Hz, 1H),
3.54 (dd, J = 10.2, 8.4 Hz, 1H). 7.54-7.44 (m, 2H), 7.41-7.32 (m, 4H), 7.14 (t,
J = 7.4 Hz, 1H), 4.72-4.41 (m, 1H), 4.09 (t, J = 9.4 Hz, 1H), 3.73 (ddd, J =
29.8, 9.9, 3.2 Hz, 1H), 3.54 (dd, J = 10.2, 8.4 Hz, 1H), 2.46 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 151.1 (s), 145.2 (s), 137.9 (s), 135.5 (s), 129.7 (d), 129.0
(d), 128.5 (d), 124.6 (d), 118.9 (d), 52.9 (d), 49.6 (t), 21.6 (q), 9.3 (t). MS:
(ESI) m/z 479.20 [M+Na+]. Anal. calcd for C17H17N2IO3S: C, 44.75; H, 3.76;
N, 6.14. Found: C, 44.97; H, 3.50; N, 5.88.
2-(Iodomethyl)-4-phenyl-1-tosyl-1,2,3,4-tetrahydro-5H-
benzo[e][1,4]diazepin-5-one (8c). Compound 8c was prepared
according to the general procedure (H2O/DMSO 1:5, 30h, 50 °C) and
isolated as white solid (yield 63%) after flash chromatography
(hexane:EtOAc 4:1). M.p.: 87–88 °C. IR = 1653, 1398, 1350, 1170, 1087,
1
1050, 743, 717. H NMR (400MHz, CDCl3): δ 7.68 (d, J = 7.4 Hz, 1H), 7.55-
7.42 (m, 5H), 7.21-7.14 (m, 5H), 6.59 (d, J = 7.5 Hz, 2H), 4.46-4.40 (m, 1H),
4.02 (dd, J = 15.1, 4.3Hz, 1H), 3.60-3.35 (m, 2H), 3.11 (t, J = 9.8 Hz, 1H),
2.33 (s, 3H). 13C NMR (101MHz, CDCl3): δ 157.3 (s), 144.3 (s), 141.4 (s),
135.9 (s), 134.8 (s), 133.4 (d), 132.5 (s), 132.0 (d), 130.5 (d), 130.0 (d), 129.4
(d), 128.0 (d), 127.6 (d), 126.8 (d), 125.3 (d), 62.0 (d), 54.3 (t), 21.5 (q), 4.2
(t). MS: (ESI) m/z 555.23 [M+Na+]. Anal. calcd for C23H21N2IO3S: C, 51.89;
H, 3.98; N, 5.26. Found: C, 52.01; H, 3.81; N, 5.45.
(Z)-N-(5-(Iodomethyl)-3-methyloxazolidin-2-ylidene)-4-
methylbenzenesulfonamide (6b). Compound 6b was prepared
according to the general procedure (H2O/DMSO 2:1, 30h, room
temperature) and isolated as white solid (yield 52%) after flash
chromatography (hexane:EtOAc 1:1). M.p. 120-121 °C. IR: 2920, 1728,
1
1358, 1172, 1140, 666, 590 cm-1. H NMR (300 MHz, CDCl3) δ 7.87 (d, J =
2-(Iodomethyl)-4-methyl-8-nitro-1-tosyl-1,2,3,4-tetrahydro-5H-
benzo[e][1,4]diazepin-5-one (8d). Compound 8d was prepared
8.3 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 5.00-4.55 (m, 1H), 3.79 (t, J = 9.2 Hz,
7
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10.1002/hlca.201900088
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according to the general procedure (H2O/DMSO 2:1, 24h, 60 °C) and
isolated as pale yellow solid (yield 74%) after flash chromatography
(hexane:EtOAc 1:1). M.p. 85-86 °C. IR: 2921, 1654, 1334, 1155, 1111, 709,
666, 583, 571 cm-1. 1H NMR (300 MHz, CDCl3) δ 8.42 (d, J = 2.1 Hz, 1H),
8.30 (dd, J = 8.5, 2.2 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 8.3 Hz,
2H), 7.32-7.22 (m, 2H), 4.66-4.28 (m, 1H), 3.66-3.48 (m, 2H), 3.28-3.07 (m,
2H), 2.64 (s, 3H), 2.43 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 144.8 (s), 140.1
(s), 134.7 (s), 133.8 (s), 131.2 (d), 130.1 (d), 129.0 (d), 127.1 (d), 123.9 (d),
61.3 (d), 52.8 (t), 34.3 (q), 21.6 (q), 4.1 (t). MS: (ESI) m/z 538.43[M+Na+].
Anal. calcd for C18H18N3IO5S: C, 41.95; H, 3.52; N, 8.15. Found: C, 42.08;
H, 3.43; N, 7.96.
J = 7.5 Hz, 1H), 4.48-4.37 (m, 1H), 3.36 (dd, J = 9.8, 5.1 Hz, 1H), 2.98 (t, J =
9.9 Hz, 1H), 2.45 (s, 3H), 2.38 (s, 3H), 2.31 (s, 3H), 2.12-1.98 (m, 2H). The
data are in good agreement with those reported in the literature.[20]
General procedure for the X-ray diffraction analysis. Single-crystal X-ray
diffraction experiments were carried out on a Bruker AXS three-circle
diffractometer equipped with an Apex II CCD area detector. Data were
collected using graphite-monochromated Mo K radiation (=0.71073
Å) at a nominal X-rays power of 50 kV x 30 mA. A 100 % complete full
sphere of reflections was recorded up to a maximum resolution of 0.77 Å,
resulting in 3578 (compound 2f) and 4460 (ompound 4) independent
structure factor amplitudes. The latter were reduced with the SAINT+
software[48] and corrected for absorption using the empirical procedure
implemented in SADABS.[49] The structures were solved by either
iterative charge-flipping methods implemented in SUPERFLIP[50]
(compound 2f) or by direct methods (SIR92).[51] Structure refinements
were carried out in the independent atom approximation with the least
squares algorithm implemented in shelxl.[52] Molecular drawings were
plotted with Diamond 3.0k (©1997–2014 Crystal Impact GbR, Bonn,
Germany).
3-(Iodomethyl)-2-tosyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (9).
Compound
9 was prepared according to the general procedure
(H2O/DMSO 1:5, 6h, room temperature) and isolated as white solid
(yield 67%) after flash chromatography (hexane:EtOAc 4:1). M.p. 173-
174 °C. IR: 3435, 2922, 1690, 1536, 1346, 1163, 742, 715, 556 cm-1. 1H NMR
(300 MHz, CDCl3) δ 8.06 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.2 Hz, 1H), 7.46-
7.33 (m, 5H), 7.26-7.13 (m, 1H), 5.37-5.25 (m, 1H), 5.13 (d, J = 13.2 Hz, 1H),
4.33 (dd, J = 12.8, 3.0 Hz, 1H), 3.62-3.49 (m, 1H), 3.17 (dd, J = 11.6, 10.3 Hz,
1H), 2.46 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 156.3 (s), 145.5 (s), 137.3 (s),
135.8 (s), 129.6 (d), 129.0 (d), 127.3 (s), 126.4 (d), 126.1 (s), 123.2 (d),
121.6 (d), 110.0 (d), 56.9 (d), 42.8 (t), 21.7 (q), 2.8 (t). MS: (ESI) m/z 481.25
[M+], 503.38 [M+Na+]. Anal. calcd for C19H17N2IO3S: C, 47.51; H, 3.57; N,
5.83. Found: C, 47.59; H, 3.80; N, 5.62.
X-ray-quality crystals of the compound 2f (prismatic habit, colorless)
were grown by slow evaporation ( 10 hrs) from a 1:1 mixture of hexane
and CH2Cl2 at room temperature. The specimen used for the X-ray
diffraction experiment was cut from a larger agglomerate and polished
by mechanical ablation in a drop of perfluorinated oil. It showed
pleochroism under polarized light (from colourless to dark grey). 2f is
chiral and crystallizes in the monoclinic centric space group P21/n as a
racemate, with one molecule per asymmetric unit and absolute
configurations (S,S) or (R,R). The oxazolidin-2-one ring is slightly
distorted toward a half-chair conformation. Unit cell (Å, deg, Å3), as
estimated from 9987 intense reflections with 4.7  2  56.2 deg: a =
7.8801(2), b = 17.1890(5), c = 11.5884(3),  = 96.156(1), V = 1560.6(1).
X-ray quality crystals (prismatic habit, colorless) were grown by slow
2-(Iodomethyl)-1-tosylindoline (10a). Compound 10a was prepared
according to the general procedure (H2O/DMSO 1:1, 24h, 60 ° C) and
isolated as pale yellow solid (yield 58%) after flash chromatography
(hexane:EtOAc 10:1). 1H NMR (400 MHz, CDCl3) δ = 7.57 (d, J = 8.1 Hz,
1H), 7.48 (d, J = 8.1 Hz, 2H), 7.20-7.07 (m, 3H), 7.00-6.93 (m, 2H), 4.30-
4.24 (m, 1H), 3.58 (dd, J = 9.7, 3.4 Hz, 1H), 3.18 (t, J = 9.9 Hz, 1H), 2.86 (dd,
J = 16.7, 9.3 Hz, 1H), 2.76 (dd, J = 16.7, 3.0 Hz, 1H), 2.27 (s, 3H). The data
are in good agreement with those reported in the literature.[18]
evaporation (
6 hrs) from a 1:1 hexane:CH2Cl2 mixture at room
temperature. The sample chosen for the X-ray analysis was cut from a
larger agglomerate and polished by mechanical ablation in a drop of
perfluorinated oil. It showed pleochroism under polarized light (from
colourless to dark grey). The compound is chiral and crystallizes in the
orthorhombic acentric space group P212121 as a pure enantiomer, with
one molecule per asymmetric unit. The presence of sulphur and iodine
anomalous scatterers allow to secure the absolute molecular
configuration, with a Flack parameter[53] as low as 0.02(2) by classical fit
to all intensities (Figure 3). The saturated six-membered ring assumes an
almost perfect chair conformation, while the oxazolidin-2-one ring,
analogously to compound 2f, adopts a slightly distorted half-chair
conformation. Unit cell (Å, Å3), as estimated from 8060 intense
reflections with 5.3  2  47.2 deg: a = 8.1577(2), b = 11.8874(2), c =
20.0540(4), V = 1944.7(1).
5-Chloro-2-(iodomethyl)-1-tosylindoline (10b). Compound 10b was
prepared according to the general procedure (H2O/DMSO 1:1.2, 20h,
40 °C) and isolated as white solid (yield 62%) after flash
chromatography (hexane:EtOAc 10:1). 1H NMR (300 MHz, CDCl3) δ =
7.58-7.53 (m, 3H), 7.23-7.16 (m, 3H), 7.03 (s, 1H), 4.36 − 4.30 (m, 1H), 3.63
(dd, J = 9.7, 3.3 Hz, 1H), 3.26 (t, J = 9.9 Hz, 1H), 2.89-2.82 (m, 2H), 2.37 (s,
3H). The data are in good agreement with those reported in the
literature.[18]
2-(Iodomethyl)-6,7-dimethyl-1-tosylindoline (10c). Compound 10c
was prepared according to the general procedure (H2O/DMSO 1:2.5, 20h,
60 °C) and isolated as pale yellow solid (yield 51%) after flash
chromatography (hexane:EtOAc 12:1). 1H NMR (300 MHz, CDCl3) δ 7.31
(d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 6.96 (t, J = 6.9 Hz, 2H), 6.77 (d,
8
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Trifluoromethylated Homoallylic N-Acylhydrazines: Metal-free Synthesis
of CF3-Substituted Pyrazolines’, J. Org. Chem. 2018, 83, 939-950.
Acknowledgements
[16] S. Knapp, K. E. Rodriques, A. T. Levorse, R. M. Omaf, ‘A Procedure for
“Iodolactamization”’, Tetrahedron Lett. 1985, 26, 1803-1806.
Università degli Studi dell’Insubria and Università degli Studi di Milano
are acknowledged for financial support.
[17]
A. Bongini, G. Cardillo, M. Orena, S. Sandri, C. Tomasini, ‘Factors Affecting
the Regioselection of Allylic Imidate Iodocyclization’, J. Org. Chem. 1986,
51, 4905-4910.
Author Contribution Statement
[18] C. S. Brindle, C. S. Yeung, E. N. Jacobsen, ‘Chiral β-Iodoamines by Urea-
Catalysed Iodocyclization of Trichloroacetimidates’, Chem. Sci. 2013, 4,
2100-2104.
G. B. and E. M. B. designed the project. S. G. and R. S. performed the
experiments. XRD data was acquired and analyzed by L. L. P. All authors
contributed to writing the manuscript.
[19] G. Q. Liu, Y. M. Li, ‘Regioselective (Diacetoxyiodo)benzene-Promoted
Halocyclization of Unfunctionalized Olefins’, J. Org. Chem. 2014, 79, 10094-
10109.
References
[1]
S. R. Chemler, M. T. Bovino, ‘Catalytic Aminohalogenation of Alkenes and
Alkynes’, ACS Catal. 2013, 3, 1076-1091.
[20] M. T. Bovino, S. R. Chemler, ‘Catalytic Enantioselective Alkene
Aminohalogenation/Cyclization Involving Atom Transfer’, Angew. Chem.,
Int. Ed. 2012, 51, 3923-3927.
[2]
C. K. Tan, Y. Y. Yeung, ‘Recent Advances in Stereoselective
Bromofunctionalization of Alkenes using N-Bromoamide Reagents’, Chem.
Commun. 2013, 49, 7985-7996.
[21] L. Chen, X. Luo, Y. Li, ‘Palladium-Catalyzed Intramolecular
Aminoiodination of Alkenes Using Molecular Oxygen as Oxidant’, Monatsh.
Chem. 2017, 148, 957-961.
[3]
[4]
[5]
E. M. G. Broggini, T. Borelli, S. Giofré A. Mazza, ‘Intramolecular Oxidative
Palladium-Catalyzed Amination Involving Double C–H Functionalization of
Unactivated Olefins’, Synthesis 2017, 49, 2803- 2818.
[22] H. Sun, B. Cui, G.-Q. Liu, Y.-M. Li, ‘MnI2-Catalysed Regioselective
Intramolecular Iodoamination of Unfunctionalized Olefins’, Tetrahedron
2016, 72, 7170-7178.
G. Q. Liu, W. Li, Y. M. Li, ‘A New Method for Intramolecular
Chloroamination of Unfunctionalized Olefins’, Adv. Synth. Catal. 2013, 355,
395-402.
[23] H. Sun, B. Cui, L. Duan, Y.-M. Li, ‘Intramolecular Aminoalkoxylation of
Unfunctionalized Olefins via Intramolecular Iodoamination and Aziridinium
Ion Ring-Opening Sequence’, Org. Lett. 2017, 19, 1520-1523.
[24] H. Liu, Y. Pan, C. Tan, ‘Sodium Nitrite (NaNO2) Catalysed Iodo-cyclisation
of Alkenes and Alkynes using Molecular Oxygen’, Tetrahedron Lett. 2008,
49, 4424-4426.
M. R. Manzoni, T. P. Zabawa, D. Khasi, S. R. Chemler, ‘Palladium(II)-
Catalyzed Intramolecular Aminobromination and Aminochlorination of
Olefins’, Organometallics 2004, 23, 5618-5621.
[6]
[7]
D. H. Horning, J. M. Muchowski, ‘Intramolecular Bromination. Part I’, Can. J.
Chem. 1974, 52, 1321- 1330.
[25] M. Hashimoto, M. Matsumoto, K. Yamada, S. Terashima, ‘Synthetic
Studies of Carzinophilin. Part 4: Chemical and Biological Properties of
Carzinophilin Analogues’, Tetrahedron 2003, 59, 3089-3097.
[26] I. Pérez-Castro, O. Caamaňo, F. Fernàndez, M.D. Garcìa, C. Lopez, E. De
Clercq, ‘Synthesis of 4-Substituted-1,2,3-triazole Carbanucleoside
Analogues of Ribavirin via Click chemistry’, Org. Biomol. Chem. 2007, 5,
3805-3813.
W. Li, G.-Q. Liu, B. Cui, L. Zhang, T.-T. Li, L. Li, L. Duan, Y.-M. Li ‘Transition
Metal-Free Iodine-Promoted Haloamination of Unfunctionalized Olefins’,
RSC Adv. 2014, 4, 13509-13513.
[8]
[9]
J. Qiu, R. B. Silverman, ‘A New Class of Conformationally Rigid Analogues
of 4-Amino-5-halopentanoic Acids, Potent Inactivators of γ-Aminobutyric
Acid Aminotransferase’, J. Med. Chem. 2000, 43, 706-720.
K. Pors, S. D. Shnyder, P. H. Teesdale-Spittle, J. A. Hartley, M. Zloh, M.
Searcey, L. H. Patterson, ‘Synthesis of DNA-Directed Pyrrolidinyl and
Piperidinyl Confined Alkylating Chloroalkylaminoanthraquinones: Potential
for Development of Tumor-Selective N-Oxides’, J. Med. Chem. 2006, 49,
7013-7023.
[27] S. Gazzola, E. M. Beccalli, T. Borelli, C. Castellano, D. Diamante, G.
Broggini, ‘Selective 7-endo-Cyclization of 3-Aza-5-alkenols through
Oxidative Pd(II)-Catalyzed Olefin Oxyarylation’, Synlett 2018, 29, 503-508.
[28] G. Broggini, E. M. Beccalli, T. Borelli, F. Brusa, S. Gazzola, A. Mazza, ‘Intra-
Intermolecular Palladium-Catalyzed Domino Reactions of Glycine
Allylamides for the Synthesis of Diversely Functionalized Piperazinones’,
Eur. J. Org. Chem. 2015, 4261-4268.
[10] A. F. French, S. Bissmire, T. Wirth, ‘Iodine Electrophiles in Stereoselective
Reactions: Recent Developments and Synthetic Applications’, Chem. Soc.
Rev. 2004, 33, 354-362.
[29] G. Broggini, V. Barbera, E. M. Beccalli, U. Chiacchio, A. Fasana, S. Galli, S.
[11] P. Mizar, T. Wirth, ‘Iodoaminations of Alkenes’, Synthesis 2017, 49, 981-986.
[12] O. Kitagawa, N. Kikuchi, T. Hanano, K. Aoki, T. Yamazaki, M. Okada, T.
Taguchi, ‘A Mild and Highly Chemoselective α-Iodination of N-Allylic
Carboxamides and Lactams’, J. Org. Chem. 1995, 60, 7161-7165.
Gazzola,
‘Selective
Intramolecular
Palladium(II)‐Catalyzed
Aminooxygenation vs. Diamination of Alkenylureas: Efficient Microwave‐
Assisted Reactions to Bicyclic Piperazinones’, Adv. Synth. Catal. 2013, 355,
1640-1648.
[13]
M. Fujita, O. Kitagawa, T. Suzuki, T. Taguchi, ‘Regiocontrolled
Iodoaminocyclization Reaction of an Ambident Nucleophile Mediated by
Basic Metallic Reagent’, J. Org. Chem. 1997, 62, 7330-7335.
[30] E. Borsini, G. Broggini, A. Fasana, S. Galli, M. Khansaa, U. Piarulli, M.
Rigamonti, ‘Intramolecular Palladium‐Catalyzed Aminocarboxylation of
Olefins as a Direct Route to Bicyclic Oxazolidinones’, Adv. Synth. Catal.
2011, 353, 985-994.
[14] O. Kitagawa, T. Suzuki, T. Taguchi, ‘t-BuOK-Mediated Iodoaziridination
Reaction of N-Allylic Tosylamide Derivatives’, J. Org. Chem. 1998, 63, 4842-
4845.
[31]
T. Froehr, C. P. Sindlinger, U. Kloeckner, P. Finkbeiner, B. J. Nachtsheim,
‘Benzoxazoles The First Example of an Iodide-Catalyzed Oxidative
Amination of Heteroarenes’, Org. Lett. 2011, 13, 3754-3757.
–
[15] Y. Wang, K.-F. Wang, Y. Su, Z. Yang, L. Wen, L. Liu, J. Wang, D. Huang, Y.
Hu,
‘Cascade
Oxidation/Halogenoaminocyclization
Reaction
of
[32] A. Fürst, P. A. Plattner, ‘2α, 3α‐ und 2β, 3β‐Oxido‐chlolestane;
Konfiguration der 2‐Oxy‐cholestane’ Helv. Chim. Acta 1949, 32, 275-283.
9
This article is protected by copyright. All rights reserved.

10.1002/hlca.201900088
Helvetica Chimica Acta
HELVETICA
[33]
G. Bellucci, G. Berti, G. Ingrosso, A. Vatteroni, G. Conti, R. Ambrosetti,
[51] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, ‘Completion and
Refinement of Crystal Structures with SIR92’, J. Appl. Crystallogr. 1993, 26,
343-350.
‘Influence of Substituents in the 3-Position of Cyclohexene Oxides on the
Rates of their Reactions with Hydrogen Chloride in Low Polarity Aprotic
Solvents’, J. Chem. Soc., Perkin Trans. 2 1978, 627-632.
[52] G. M. Sheldrick, ‘SHELXT – Integrated Space-group and Crystal-structure
Determination’, Acta Crystallogr. 2015, 71, 3-8.
[34] G. Li, L. Huang, J. Xu, W. Sun, J. Xie, L. Hong, R. Wang, ‘Sodium
Iodide/Hydrogen Peroxide-Mediated Oxidation/Lactonization for the
Construction of Spirocyclic Oxindole-Lactones’, Adv. Synth. Catal. 2016,
358, 2873-2877.
[53] H. D. Flack., ‘On Enantiomorph-polarity Estimation’, Acta Crystallogr. 1983,
A39, 876-881.
[35] A. Yoshimura, C. Zhu, K. R. Middleton, A. D. Todora, B. J. Kastern, A. V.
Maskaev, V. V. Zhdankin, ‘Hypoiodite Mediated Synthesis of Isoxazolines
from Aldoximes and Alkenes Using Catalytic KI and Oxone as the Terminal
Oxidant’, Chem. Commun. 2013 49, 4800-4802.
[36] V. K. Yadav, V. P. Srivastava, L. D. S. Yadav, ‘ Iodide Catalyzed Synthesis of
2-Aminobenzoxazoles via Oxidative Cyclodesulfurization of Phenolic
Thioureas with Hydrogen Peroxide’, Tetrahedron Lett. 2018, 59, 252-255.
[37]
M. Uyanik, H. Okamoto, T. Yasui, K. Ishihara, ‘Quaternary Ammonium
(Hypo)iodite Catalysis for Enantioselective Oxidative Cycloetherification’,
Science 2010, 328, 1376-1379.
[38] C. Fortin, S. Khanniche, D. Khiri, V. Fèvre-Nollet, P. Lebègue, F. Cousin, I.
Černušàk, F. Louis, ‘Reactivity of Hydrogen Peroxide with Br and I Atoms’, J.
Phys. Chem. 2018, 122, 1053-1063.
[39] T. K. Achar, S. Maiti, P. Mal, ‘PIDA-I2 Mediated Direct Vicinal
Difunctionalization of Olefins: Iodoazidazion, iodoetherification and
iodoacyloxylation’, Org. Biomol. Chem. 2016, 14, 4654.
[40] K. B. Hong, J. N. Johnston, ‘Alkene Diamination Using Electron-Rich
Amines: Hypervalent Iodine-Promoted Inter/Intramolecular C-N Bond
Formation’, Org. Lett. 2014, 16, 3804-3807.
[41] Y.-T. Gao, X.-Y. Jin, Q. Liu, A.-D. Liu, L. Cheng, D. Wang, ‘Iodide/H2O2
Catalyzed Intramolecular Oxidative Amination for the Synthesis of 3,2’-
Pyrrolidinyl Spirooxindoles’, Molecules 2018, 23, 2265.
[42] S. Gazzola, E. M. Beccalli, T. Borelli, C. Castellano, M. A. Chiacchio, D.
Diamante, G. Broggini, ‘Copper(II)-Catalyzed Alkoxyhalogenation of
Alkynyl Ureas and Amides as
a Route to Haloalkylidene-Substituted
Heterocycles’, J. Org. Chem. 2015, 80, 7226-7234.
[43] K. Muniz, A. Iglesias, Y. Fang, ‘Platinum-Catalysed Aerobic 1,2-
Aminooxygenation of Alkenes’, Chem. Commun. 2009, 5591-5593.
[44] A. Gimeno, A. B. Cuenca, M. Médio-Simon, G. Asensio, ‘Gold(I)‐Catalyzed
Reactions of 1‐(ortho‐Alkynylaryl)ureas: Highly Selective Heterocyclization
and Synthesis of Mixed N,O‐Acetals’, Adv. Synth, Catal. 2014, 356, 229-236.
[45] E. M. Beccalli, G. Broggini, G. Paladino, A. Penoni, C. Zoni, Regioselective
Formation of Six- and Seven-Membered Ring by Intramolecular Pd-
Catalyzed Amination of N-Allyl-anthranilamides, J. Org. Chem. 2004, 69,
5627-5630.
[46] A. D. Manick, F. Berhal, G. Prestat, ‘Synthesis of Six- and Seven-Membered
Chloromethyl-Substituted Heterocycles via Palladium-Catalyzed Amino-
and Oxychlorination’, Synthesis 2016, 48, 3719-3729.
[47]
G. Abbiati, E. M. Beccalli, G. Broggini, M. Martinelli, G. Paladino, ‘Pd-
Catalyzed Cyclization of 1-Allyl-2-indolecarboxamides by Intramolecular
Amidation of Unactivated Ethylenic Bond’, Synlett 2006, 73-76.
[48] Bruker AXS Inc., SAINT+, Madison, Wisconsin, USA, 2012.
[49] Bruker AXS Inc., SADABS, Madison, Wisconsin, USA, 2001.
[50] L. Palatinus, G. Chapuis, ‘SUPERFLIP
– A Computer Program for the
Solution of Crystal Structures by Charge Flipping in Arbitrary Dimensions’,
J. Appl. Crystallogr. 2007, 40, 786-790.
10
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