S-(3-Chloro-2-oxo-propyl)-O-ethyl xanthate: A linchpin radical coupling agent for the synthesis of heterocyclic and polycyclic compounds

Article abstract of DOI:10.1039/b514509k

The preparation and use of S-(3-chloro-2-oxo-propyl)-O-ethyl xanthate to directly introduce an α-chloroketone motif is described, along with applications for the synthesis of heterocyclic and polycyclic structures. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b514509k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
S-(3-Chloro-2-oxo-propyl)-O-ethyl xanthate: a linchpin radical coupling
agent for the synthesis of heterocyclic and polycyclic compounds
Olga Bergeot, Camilla Corsi, Myriem El Qacemi and Samir Z. Zard*
Received 12th October 2005, Accepted 14th November 2005
First published as an Advance Article on the web 5th December 2005
DOI: 10.1039/b514509k
The preparation and use of S-(3-chloro-2-oxo-propyl)-O-ethyl xanthate to directly introduce an
a-chloroketone motif is described, along with applications for the synthesis of heterocyclic and
polycyclic structures.
Introduction
a-Haloketones, and a-chloroketones in particular, are key start-
ing materials for numerous named classical syntheses of het-
eroaromatic compounds such as pyrroles, thiazoles, imidazoles,
furans (Benary-Feist, Hantzsch reactions)1 in addition to being
useful and versatile general synthetic intermediates. A variety
of methods exist for their regiospecific formation including the
traditional direct halogenation of the parent ketone.2 In more
recent approaches, a-haloketones have been obtained from the
corresponding vinyl halides by the action of NCS, NBS or
NIS in aqueous acetonitrile3 or by treatment with an aqueous
sodium hypochlorite solution in an acetic acid–acetone mixture.4
A conceptually different route involves the reaction of N-methoxy-
N-methylchloroacetamide with an organometallic reagent5 or,
as in the case of the synthesis of 19- and 20-fluororetinal,
by reaction of the corresponding N-methoxy-N-methylamide
and chloroiodomethane in the presence of methyllithium.6 In
yet another approach, disubstituted internal olefins were effi-
ciently converted into a-chloroketones by reaction with chromic
anhydride–chlorotrimethylsilane in carbon tetrachloride.7
We were attracted by the synthetic importance of this func-
tionality and its wide use in the field of medicinal chemistry
Scheme 1 Radical addition of 1 to an olefin, in the presence of lauroyl
peroxide (DLP). (In• = initiating radical).
for the synthesis of biologically active substances. Therefore,
we explored the possibility of introducing this motif using the
xanthate (dithiocarbonate) radical transfer we have developed
recently.8 In general, a-chloroketones are generated at the stage
in the synthesis at which they are needed, since their high
reactivity as electrophiles usually precludes carrying them over
several synthetic operations. It seemed that the tin-free radical
chemistry based on xanthates would be compatible with such a
functional group and would allow the creation of one or more
carbon–carbon bonds in its presence. The fact that the radical
process takes place in a neutral medium should limit ionic side
reactions of the a-chloroketone, and the absence of tin (or silicon)
centred radicals should eliminate unwanted but otherwise well
precedented abstraction of the chlorine atom.
of this enterprise. Reagent 1 had to be stable under the reaction
conditions and its preparation had to be practical. The presence in
the same molecule and in close proximity of a strong electrophile
and a sulfur based, potentially nucleophilic, group was worrying
and, as will become clear later in the discussion, we were fortunate
that the decomposition of xanthate 1 was a little slower than the
radical addition process. The product xanthate 3 also had to be
stable to allow isolation or the implementation of another radical
sequence.
Results and discussion
The simplest approach for the synthesis of xanthate 1 was by
displacing one chlorine atom from commercially available 1,3-
dichloroacetone 4 with potassium O-ethyl xanthate salt in acetone
(Scheme 2). Various experimental conditions, such as different
temperatures and numbers of equivalents, were explored in order
to avoid the undesired formation of the bis-xanthate 5. In a
preliminary study, it was concluded that the selective formation
of 1 could be achieved by performing the reaction in excess of
dichloroacetone (3 equivalents) and at very low temperature.
Our approach, outlined in Scheme 1, involves the synthesis of
a xanthate such as 1 and its addition to various olefins according
to the now accepted radical chain mechanism. Several potential
problems could be identified from the outset and affect the success
Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytechnique,
91128, Palaiseau, France. E-mail: zard@poly.polytechnique.fr; Fax: +33
169 333851; Tel: +33 169 334872
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Table 1 Radical addition of impure xanthate 1 on various olefins
Entry
1
Olefin
Addition product
Scheme 2 Preparation of xanthate 1.
2
3
4
5
Unfortunately, after numerous attempts, no practical purifica-
tion of the crude mixture could be achieved and fractional recrys-
tallisations revealed the lability of the product 1 which slowly de-
composed upon heating. We therefore decided to use the xanthate
as a crude mixture still contaminated by dichloroketone 4. We
hoped that the latter would not interfere with the radical step and
that purification would be easier at the product stage. The initial
radical additions were thus performed using an impure reagent.
Later in the project, a simple solution was found for the synthesis
of 1 and resulted in improved yields in many cases (vide infra).
The feasibility of the radical sequence was examined using a
number of different olefins. The results of the radical additions,
using an excess of the olefins, are collected in Table 1. Octene, vinyl
pivalate, and allyl silane gave high yields of the expected adducts
7a,c,d (entries 1, 3, and 4). The reaction with phenyl vinyl sulfone
proceeded poorly (entry 2), presumably because both olefin and
the radical are electrophilic in character resulting in lower reac-
tivity. Finally, radical additions of the novel xanthate to various
N-allyl anilides 6e–h furnished the desired adducts in syntheti-
cally useful yields. These preliminary experiments, despite being
imperfect in that they were carried out using an impure reagent,
answered nevertheless one main concern and that is that xanthate
1 was sufficiently stable to allow the radical addition to proceed
unimpeded. They also demonstrated the possibility of creating a
new C–C bond in the presence of the highly reactive chloroketone.
At this stage a better procedure for the synthesis of 1 was found.
It consisted of simply using water as the solvent in the displacement
step. The dichloroacetone was added to a solution of potassium
O-ethyl xanthate salt in water at near 0 ◦C. The desired mono-
xanthate 1 is highly insoluble in water and precipitated out. This
physically prevented it from reacting further to give the unwanted
bis-xanthate 5. The mono-xanthate 1 formed in this manner was
simply filtered and dried; it was sufficiently pure for our purposes.
We could now significantly improve the radical addition process,
as will be seen shortly. Furthermore, a ready access to large
amounts of good quality xanthate allowed us to better study its
thermal stability. We thus found that heating the xanthate alone
in chlorobenzene resulted in the formation of a cyclic derivative 8
as the main product (Scheme 3). The slow thermal generation of
a In this case, pure xanthate was used for the radical addition.
this derivative consumes the xanthate in a non productive manner
during the reactions and causes a lowering in the yield, even if
it does not interfere with the radical addition itself. Surprisingly,
compound 8, which represents an interesting building block, has
not been described in the literature as far as we can tell.
We repeated some of the experiments displayed in Table 1. We
thus used the higher purity xanthate in slight excess and the olefin
as the limiting reagent. In this manner, the yield of adducts 7g–h
were greatly improved (Scheme 4).
In addition to simplicity, cheapness, absence of heavy metals for
the generation of radicals, ease of scale up, and the possibility
of working under quite concentrated conditions, the starting
xanthate can be used without further purification.
Also, this approach has numerous synthetically useful features;
in fact, the addition products (7) could be utilised as starting
points for multiple radical sequences and for the synthesis of
Scheme 3 Thermal rearrangement of xanthate 1.
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group, followed by an addition to vinyl pivalate, furnished addition
products of type 11e–h, where the carbon bearing both the
pivaloxy and xanthate group is at the oxidation level of an
aldehyde. In particular, in our case, the intermediates 11e–h are
1,4-ketoaldehyde equivalents and therefore able to undergo Paal–
Knorr12,13 reactions. In fact, as previously reported,14 reaction of
vinyl pivalate adducts with different primary amines or ammonia
in the presence of para-toluenesulfonic acid leads to the corre-
sponding pyrroles. Intermediates 11e–h were therefore treated with
cyclopropylamine, 4-methoxybenzylamine and cyclohexylamine
to afford pyrroles 12f–h in good yield. Unsubstituted pyrrole 12e
could be prepared by using excess of ammonia and ammonium
acetate, in dioxane at room temperature (Scheme 5). However, it is
important to state that the pyrroles proved to be somewhat unsta-
ble when exposed to air giving rise to highly coloured side products.
The chemistry of these different chloroketones could then be
further exploited by performing Hantzsch15 reactions for the
synthesis of thiazoles, by condensing a-halo carbonyl compounds
with thioamides.16,17 Thiazoles have also been prepared from
amino nitrile16c or from amino thiols and carbonyl compounds18
and by other procedures that are less important due to either the
limited availability of starting materials and/or lack of overall
generality.16c
Scheme 4 Optimisation of radical additions.
heterocyclic structures. Thus, upon further exposure of 7e–h to
a stoichiometric amount of the peroxide, the radical formed can
now cyclise onto the aromatic ring9,10 forming indolines (9e–h) in
good yield (Scheme 5), or azaindolines as has been described in a
previous paper.11
In our case, it was possible to synthesise in few steps rather
complicated structures that would not be easily accessible by other
more classical routes. In fact, after attempting various conditions
for the reactions, the condensation was optimised by refluxing
the mixture in chlorobenzene with anhydrous magnesium sulfate.
As depicted in Scheme 6, the Hantzsch reaction using 7c in the
presence of N-acetylthiourea furnished compound 13 in good
yield where, as stated above, the carbon bearing the pivalate group
is at the oxidation level of an aldehyde, and therefore could then
undergo a variety of reactions.
Scheme 6 Hantzsch reaction on compound 7c.
When the same methodology was extended to the chloro in-
doline derivative 9f with N-acetylthiourea 14 or thionicotinamide
15, new heterocycles were isolated and characterised (Scheme 7).
Nevertheless, all these yields remain unoptimised, and there is
certainly room for further improvement.
Model studies toward natural product syntheses
In addition to the preparation of various heterocycles, the two-
dimensional nature of the starting dichloroketone allows us
to construct complex polycyclic molecules using the xanthate
technology. An interesting example is the preparation of an
octahydronaphthalen-2-one in a three-step sequence starting from
the commercially available b-(−)-pinene (Scheme 8). The first
addition of xanthate 1 to the external double bond is immediately
followed by the fragmentation to produce a tertiary xanthate. This
sequence also generates a suitably located double bond which can
be submitted to a new radical addition. This was achieved by
Scheme 5 Sequence of radical additions to synthesise pyrroles through
Paal–Knorr condensations.
Further transformations could then be performed using indo-
lines (9e–h). Displacement of the chlorine atom by the xanthate
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Scheme 7 Hantzsch reactions with compound 9f.
Scheme 9 Perhydrohistrionicotoxin retrosynthesis (Pn = pentyl).
enging azaspirocyclic framework of these substances have prom-
pted considerable synthetic interest over the last few decades.21
Taking advantage of a two-directional approach, which offers
the possibility of substantially reducing the number of chemical
operations required to synthesise complex target molecules of
biological and pharmaceutical interest, we explored first the
formal synthesis of perhydrohistrionicotoxin.
Our retrosynthesis of a known intermediate for perhydrohistrio-
nicotoxin22 is shown in Scheme 9. We envisioned the azaspirocyclic
core of 19 to be constructed through an intramolecular Mannich
reaction of the diketo compound 20.23 The requisite linear com-
pound 20 could be secured through a sequence of radical reduction
and deprotection followed by oxidation of xanthate 21, which in
turn could be constructed through our key disconnection. The
linear compound could then arise from xanthate 1, following two
successive intermolecular radical additions to olefins 22 and 23.
The synthesis of allylamine 22 was performed as illustrated in
Scheme 10. Amidoalkyl sulfones are known to be synthetic equiv-
alents of N-acyl imines toward the addition of organometallic
reagents.24 Amidopentyl sulfone 24, envisioned as a precursor of
allylamine 22, was easily prepared by reaction of benzylcarbamate
with hexanal and sodium benzenesulfinate, in the presence of
formic acid. Sulfone 24 is particularly convenient because it is
a stable solid that can be recovered from the reaction mixture by
simple filtration and purified by crystallisation. Vinylmagnesium
bromide reacted smoothly with sulfone 24 at low temperature
in THF, affording in good yield the corresponding N-protected
allylamine 22.
Scheme 8 Radical cascade starting from b-(−)-pinene.
substituting the chlorine atom by a xanthate group. The second
radical addition then provides compound 18 in good yield, and
as only one isomer. Spectral analysis indicated it to possess the
cis-decalin backbone, in accord with precedent in this area.19
nicely functionalised bicyclic compound is rapidly constructed by
this short sequence; it contains two xanthate groups that can be
further modified by radical or ionic reactions. This approach holds
promise for the synthesis of various terpene structures.
Another way of using the title xanthate 1 is illustrated by
preliminary studies toward (−)-histrionicotoxin (HTX)20 and its
hydrogenation product, the nonnatural perhydrohistrionicotoxin
(Scheme 9). In combination with the parent compound’s low abun-
dance in nature, the remarkable biological activity and the chall-
A
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Conclusions
In conclusion, the present methodology can be clearly extended
to numerous examples. To summarise, the new reagent 1, readily
obtained from cheap starting materials, furnishes an alternative
route to the existing methods for the synthesis of a-chloroketones
and, in an simple manner, allows the selective synthesis of
heterocycles in good yield as well as complex structures which
can be used as templates for the synthesis of natural products
belonging to various families.
Experimental
Commercial reagents were used as received, without further
purification. Anhydrous magnesium sulfate was used for drying
organic extracts, and all volatiles were removed under reduced
pressure. All reaction mixtures and column eluents were mon-
itored by TLC using commercial aluminium backed thin layer
chromatography (TLC) plates (Merck Kieselgel 60 F254). The
plates were observed under UV light at 254 nm and subsequently
revealed using a vanillin or anisaldehyde-based stain. Flash
chromatography were performed using SDS Silica Gel 60 C.C.
40–63 and a small layer of basic alumina was placed on top
of the silica to remove any lauric acid present. Melting points
were determined using a Reichert microscope apparatus. IR
spectra were recorded on a Perkin-Elmer 1600 Fourier Transform
spectrometer. 1H and 13C NMR spectra were recorded on a
Bruker AMX400 instrument (at 400 and 100 MHz respectively);
chemical shifts are given in ppm using tetramethylsilane as a
reference and coupling constants are given in hertz. Mass spectra
were recorded on an HP 5989B and on a Q-TOF MS or JEOL
JMS-GCmate II mass spectrometer for HRMS. Petrol refers
to light petroleum ether (PE), bp 40–60 ◦C. The addition of
dilauroyl peroxide (DLP), after degassing the solution for 20 min,
was performed portionwise as 5 mol% every 90 min for the
radical additions and as 20 mol% every hour for the cyclisation
steps, until complete disappearance of the starting material was
observed. N-Allyl-N-(4-chloro-phenyl)acetamide, N-allyl-N-(4-
bromo-phenyl)acetamide, N-allyl-N-(4-fluoro-phenyl)acetamide
and N-allyl-N-(4-methoxy-phenyl)methanesulfonamide were pre-
pared by a simple two step procedure; firstly, protection of the
corresponding p-substituted aniline using acetyl or mesyl chloride
was performed, followed by reaction with allyl bromide in the
presence of sodium hydroxide or potassium carbonate. All pyrrole
derivatives proved to be unstable when exposed to air, and
consequently their immediate characterisation was required.
Scheme 10 Synthesis of intermediate 28.
With all the precursors in hand, we were now set to carry
out the two-directional radical additions. The first intermolecular
addition of xanthate 1 to olefin 23 was carried out in refluxing
DCE, using a small amount of lauroyl peroxide. Once the addition
was complete, it was followed without purification by nucleophilic
substitution of the chlorine atom with the xanthate salt in acetone.
This sequence resulted in the isolation of compound 25, bearing
two xanthate groups, in 98% overall yield. The difference in
stability of the two radicals corresponding to the two xanthates
in 25 was deemed to be sufficient to conduct the second radical
intermolecular addition on protected allylamine 22 in a clean
manner. Indeed, when xanthate 25 was treated under the same
conditions with 22, adduct 26 was obtained in good yield.
Following this sequence, removal of the xanthate groups was
achieved using a tributyltin hydride reduction, providing the linear
compound 27 in 70% yield. Subsequent saponification of the
acetate group under weakly basic conditions and oxidation of the
resulting alcohol with PCC furnished diketo compound 28 in 74%
yield for the two steps. Unfortunately, initial efforts to perform
the intramolecular Mannich reaction have not been successful so
far. Experiments are ongoing in the laboratory to achieve the last
steps as well as to develop an asymmetric version of this formal
synthesis.
N-Allyl-N-(4-methoxy-phenyl)methanesulfonamide 6e9
White crystals, mp 42 ◦C (from EtOH), mmax (CCl4)/cm−1 3094m,
3013m, 2963s, 2931s, 2256m, 1606s, 1512s, 1344s, 1250s, 1156m,
1031m; dH (400 MHz; CDCl3) 2.90 (3H, s, SO2CH3), 3.81 (3H, s,
OCH3), 4.23 (2H, d, J 6.1, NCH2), 5.13 (1H, d, J 9.9, CH2CH),
5.15 (1H, d, J 15.9, CH2CH), 5.84 (1H, m, CHCH2), 6.90 (2H, d,
J 9.0, ArH), 7.25 (2H, d, J 9.0, ArH); dC (100 MHz; CDCl3) 38.1
(SO2CH3), 54.1 (NCH2), 55.6 (OCH3), 114.7 (2 × ArCH), 119.2
(CH2CH), 129.3 (ArC), 130.2 (2 × ArCH), 133.1 (CHCH2), 159.3
(ArC); m/z (CI, NH3) 259 (MNH4 , 100%), 242 (MH+, 48), 164
+
(46).
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N-Allyl-N-(4-chloro-phenyl)acetamide 6f25
of the starting material. The crude mixture was concentrated in
vacuo and the residue was purified by column chromatography
(PE–AcOEt, 95 : 5) to give 7a as yellow oil (0.520 g, 89%), mmax
White crystals, mp 42–43 ◦C (from EtOH), mmax (CCl4)/cm−1
=
3083m, 3013m, 2985s, 2925s, 1667s (C O), 1592w, 1549m, 1495s,
(CCl4)/cm−1 2957s, 2930s, 2857m, 1722s (C O), 1455w, 1367w,
=
1381s, 1279s, 1230s, 1094s, 1016s; dH (400 MHz; CDCl3) 1.82
(3H, s, CH3), 4.23 (2H, d, J 6.5, NCH2), 4.99–5.08 (2H, m,
CH2CH), 5.80 (1H, m, CHCH2), 7.07 (2H, d, J 8.2, ArH), 7.33
(2H, d, J 8.2, ArH); dC (100 MHz; CDCl3) 22.6 (CH3), 51.9
(NCH2), 118.1 (CH2CH), 129.4 (2 × ArCH), 129.8 (2 × ArCH),
1216s, 1119m, 1052s; dH (400 MHz; CDCl3) 0.88 (3H, t, J 7.0,
CH3), 1.22–1.34 (6H, m, CH2), 1.35–1.49 (2H, m, CH2), 1.43 (3H,
t, J 7.0, OCH2CH3), 1.66 (2H, q, J 7.04, CH2), 1.86 (1H, m, CH2),
2.13 (1H, m, CH2), 2.66–2.84 (2H, m, CH2), 3.75 (1H, m, CHS),
4.1 (2H, s, CH2Cl), 4.64 (2H, q, J 7.0, OCH2CH3); dC (100 MHz;
CDCl3) 13.9 (CH3), 14.2 (CH3), 22.7 (CH2), 26.9 (CH2), 28.1
(CH2), 29.1 (CH2), 31.7 (CH2), 34.7 (CH2), 37.0 (CH2), 48.3
=
132.8 (CHCH2), 133.5 (ArC), 141.3 (ArC), 169.6 (C O); m/z (CI,
NH3) 210 (MH+, 100%).
=
=
(CH2), 51.0 (CHS), 70.1 (OCH2), 202.0 (C O), 214.7 (C S); m/z
N-Allyl-N-(4-bromo-phenyl)acetamide 6g25
(CI, NH3) 341 (MNH3 , 25%), 324 (M+, 100); HRMS, Found:
+
MH+, 325.1180. C14H26ClO2S2 requires MH+, 325.1160.
White crystals, mp 43–44 ◦C (from EtOH), mmax (CCl4)/cm−1
=
3083m, 3013m, 2986m, 2925m, 1668s (C O), 1586m, 1488s, 1431s,
Dithiocarbonic acid (1-benzenesulfonyl-5-chloro-4-oxo-pentyl)
ester ethyl ester 7b
1385s, 1278s, 1231s, 1141m, 1071s, 1013s; dH (400 MHz; CDCl3)
1.86 (3H, s, CH3), 4.22 (2H, d, J 6.5, NCH2), 5.03–5.13 (2H,
m, CH2CH), 5.84 (1H, m, CHCH2), 7.04 (2H, d, J 8.8, ArH),
7.53 (2H, d, J 8.8, ArH); dC (100 MHz; CDCl3) 22.3 (CH3), 51.9
(NCH2), 118.2 (CH2CH), 121.7 (ArC), 129.1 (2 × ArCH), 132.8
Treatment of the xanthate 1 (0.561 g, 2.65 mmol) with phenyl
vinyl sulfone (0.890 g, 5.29 mmol) in DCE (3 ml), furnished after
addition of DLP (0.105 g, 0.26 mmol) a crude mixture which was
concentrated in vacuo and purified by column chromatography
(PE–AcOEt, 60 : 40). Compound 7b was obtained as a yellow
oil (0.357 g, 35%), mmax (CCl4)/cm−1 3069w, 2983w, 2899w, 1724s
=
(2 × ArCH and CHCH2), 141.9 (ArC), 169.7 (C O); m/z (CI,
NH3) 254 (M+, 100%).
N-Allyl-N-(4-fluoro-phenyl)acetamide 6h
=
(C O), 1447m, 1327s, 1240s, 1153s, 1046s; dH (400 MHz; CDCl3)
White crystals, mp 77–78 ◦C (from EtOH), mmax (CCl4)/cm−1
1.33 (3H, t, J 7.3, OCH2CH3), 2.18 (1H, m, CH2), 2.67 (1H,
m, CH2), 2.79–3.02 (2H, m, CH2), 4.08 (2H, s, CH2Cl), 4.38–
4.57 (2H, m, OCH2CH3), 5.30 (1H, m, CHS), 7.51–7.58 (2H, m,
ArH), 7.66 (1H, m, ArH), 7.95 (2H, d, J 7.3, ArH); dC (100 MHz;
CDCl3) 13.6 (CH3), 21.9 (CH2), 35.9 (CH2), 48.0 (CH2), 70.8
(CHS), 71.7 (OCH2), 129.4 (2 × ArCH), 129.8 (2 × ArCH), 134.3
=
3082w, 3050w, 2985w, 2924w, 1668s (C O), 1509s, 1431s, 1385s,
1296s, 1278s, 1239s, 1220s, 1152m, 1091m, 1013w; dH (400 MHz;
CDCl3) 1.86 (3H, s, CH3), 4.27 (2H, d, J 6.2, NCH2), 5.09 (2H, dd,
J 12.0, 18.5, CH2CH), 5.85 (1H, m, CHCH2), 7.08–7.18 (4H, m,
ArH); dC (100 MHz; CDCl3) 22.6 (CH3), 52.0 (NCH2), 116.4 (d,
=
=
(ArCH), 136.5 (ArC), 200.7 (C O), 209.1 (C S); m/z (CI, NH3)
J
C–F 23, 2 × ArCH), 118.1 (CH2CH), 129.9 (d, JC–F 8, 2 × ArCH),
397 (MNH4 , 100%), 239 (20); HRMS, Found: MNa+, 402.9862,
+
132.9 (CH2CH), 158.8 (ArC), 161.8 (d, JC–F 246, ArC), 170.0
C14H17ClNaO4S3 requires MNa+, 402.9875.
+
+
=
(C O); m/z (CI, NH3) 194 (MH , 100%); HRMS, Found: M ,
193.0900. C11H12ONF requires M, 193.0902.
2,2-Dimethyl-propionic acid 5-chloro-1-
ethoxythiocarbonylsulfanyl-4-oxo-pentyl ester 7c
Dithiocarbonic acid (3-chloro-2-oxo-propyl) ester ethyl ester 1
After the addition of DLP (0.08 g, 0.192 mmol), the reaction
between 1 (1 g, 2.58 mmol) and vinyl pivalate 6c (0.662 g,
5.17 mmol) in refluxing DCE (2.5 ml) furnished a crude mixture
which was concentrated in vacuo and purified by column chro-
matography (PE–AcOEt, 95 : 5). Compound 7c was obtained as
a yellow oil (0.750 g, 85%), mmax (CCl4)/cm−1 2976s, 2933s, 2905m,
To a solution of potassium O-ethyl xanthate (1.21 g, 7.54 mmol)
in water (10 mL), under argon at 0 ◦C, was added portionwise
1,3-dichloro-propan-2-one (957 mg, 7.53 mmol, 0.99 eq.). The
solution was stirred for 1 h at 0 ◦C and then filtered. The solid
was then washed with water and dried to give compound 1 in 72%
yield as a white solid.
Recrystallisations gave white crystals, mp 49–50 ◦C (from PE–
AcOEt), mmax (CCl4)/cm−1 2987s, 2939s, 2899m, 1738s, 1365m,
1232s, 1113s, 1058s; dH (400 MHz; CDCl3) 1.43 (3H, t, J 7.1,
CH3), 4.15 (2H, s, CH2), 4.32 (2H, s, CH2), 4.64 (2H, q, J 7.1,
CH2CH3); dC (100 MHz; CDCl3) 13.7 (CH3), 42.8 (CH2), 47.9
=
1731s (C O), 1479s, 1397m, 1367m, 1279m, 1222s, 1128m, 1053s;
dH (400 MHz; CDCl3) 1.18 (9H, s, CH3), 1.40 (3H, t, J 7.0,
OCH2CH3), 2.15–2.36 (2H, m, CH2), 2.70–2.78 (2H, m, CH2),
4.09 (2H, s, CH2Cl), 4.55–4.68 (2H, m, OCH2CH3), 6.59 (1H, t,
J 6.75, CHS); dC (100 MHz; CDCl3) 13.6 (CH3), 26.9 (3 × CH3),
27.9 (CH2), 35.2 (CH2), 39.5 (C), 48.0 (CH2), 70.1 (OCH2), 79.7
=
=
(CH2), 71.2 (OCH2), 195.7 (C O), 212.8 (C S); m/z (CI, NH3)
213 (MH+, 100%); HRMS, Found: M+, 211.9733. C6H9ClO2S2
requires M, 211.9732.
=
=
=
(CHS), 176.8 (C O), 200.8 (C O), 209.8 (C S); m/z (CI, NH3)
357 (MNH3 , 30%), 239 (100), 207 (20), 135 (50); HRMS, Found:
+
MNa+, 363.0495, C13H21ClNaO4S2 requires MNa+, 363.0468.
Dithiocarbonic acid [1-(4-chloro-3-oxo-butyl)-heptyl] ester ethyl
ester 7a
Dithiocarbonic acid (5-chloro-4-oxo-1-
trimethylsilanylmethyl-pentyl) ester ethyl ester 7d
Xanthate 1 (0.689 g, 1.79 mmol) and 1-octene (0.401 g, 3.58 mmol)
were dissolved in DCE (2 ml) and the resulting solution refluxed
under nitrogen for 15 min. DLP (53 mg, 0.13 mmol) was then
added. Heating was continued until the complete consumption
Allyl trimethylsilane 6d (0.591 g, 5.17 mmol) and 1 (1 g, 2.58 mmol)
in DCE (2.5 ml) were reacted in the presence of DLP (0.08 g,
0.192 mmol). Concentration in vacuo of the reaction mixture
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afforded an oil which was purified by column chromatography
purified by column chromatography (PE–Et2O, 40 : 60) affording
(PE–AcOEt, 95 : 5), to give 7d as a yellow oil (0.650 g, 77%), mmax
7g as a yellow oil (507 mg, 91%), mmax (CCl4)/cm−1 2984m, 2935m,
(CCl4)/cm−1 2952s, 1736s (C O), 1403m, 1366m, 1214s, 1111s,
1721s (C O), 1670s (C O), 1550m, 1487s, 1435m, 1387m, 1286m,
1222s, 1112m, 1052s; dH (400 MHz; CDCl3) 1.31 (3H, t, J 7.1,
OCH2CH3), 1.79 (1H, m, CH2), 1.86 (3H, s, CH3), 2.26 (1H, m,
CH2), 2.79 (2H, t, J 6.9, CH2), 3.69 (1H, dd, J 13.6, 6.6, CH2),
3.78 (1H, m, CHS), 4.08 (2H, s, CH2Cl), 4.22 (1H, dd, J 13.6,
8.4, CH2), 4.54 (2H, q, J 7.1, OCH2CH3), 7.17 (2H, d, J 8.6,
ArH), 7.59 (2H, d, J 8.6, ArH); dC (100 MHz; CDCl3) 13.5 (CH3),
22.6 (CH3), 24.6 (CH2), 36.2 (CH2), 48.1 (CH2), 48.2 (CH), 51.0
(CH2), 70.2 (CH2), 122.0 (ArC), 129.9 (2 × ArCH), 132.9 (2 ×
=
=
=
1052s; dH (400 MHz; CDCl3) 0.08 (9H, s, Si(CH3)3), 0.90–1.18
(2H, m, CH2Si), 1.42 (3H, t, J 7.0, OCH2CH3), 1.85 (1H, m, CH2),
2.17 (1H, m, CH2), 2.62–2.86 (2H, m, CH2), 3.88 (1H, m, CHS),
4.08 (2H, s, CH2Cl), 4.56–4.70 (2H, m, OCH2CH3); dC (100 MHz;
CDCl3) −0.8 (Si(CH3)3), 13.7 (CH3), 23.6 (CH2), 30.6 (CH2), 36.7
=
(CH2), 48.0 (CHS), 48.2 (CH2), 69.8 (OCH2), 201.8 (C O), 214.3
+
+
=
(C S); m/z (CI, NH3) 343 (MNH3 , 10%), 326 (M , 10), 205 (70),
92 (100).
=
=
=
ArCH), 141.2 (ArC), 170.5 (C O), 201.6 (C O), 212.8 (C S);
m/z (CI, NH3) 486 (20%), 484 (MNH4 , 15), 469 (100), 467 (MH+,
+
Dithiocarbonic acid (5-chloro-1-{[methanesulfonyl-(4-
75); HRMS, Found: MH+, 465.9916. C17H22BrClNO3S2 requires
methoxyphenyl)-amino]-methyl}-4-oxo-pentyl) ester ethyl ester 7e
MH+, 465.9913.
To a refluxing solution of 6e (300 mg, 1.25 mmol) and 1 (132 mg,
0.62 mmol) in DCE (2 ml), was added DLP (49 mg, 0.12 mmol).
The crude mixture was concentrated in vacuo then purified by
column chromatography (EP–Et2O, 30 : 70) to give compound 7e
as a white foam (230 mg, 81%), mmax (CCl4)/cm−1 2934m, 1723m
Dithiocarbonic acid (1-{[acetyl-(4-fluorophenyl)-amino]-
methyl}-5-chloro-4-oxo-pentyl) ester ethyl ester 7h
To a refluxing solution of 1 (670 mg, 3.16 mmol) and 6h (303 mg,
1.57 mmol) in DCE (2 ml) was added DLP (170 mg, 0.43 mmol).
The crude mixture was then concentrated in vacuo and the residue
was purified by column chromatography (PE–Et2O, 50 : 50).
Compound 7h was isolated as a yellow oil (504 mg, 80%), mmax
=
(C O), 1509s, 1353s, 1250s, 1222s, 1158s, 1052s; dH (400 MHz;
CDCl3) 1.31 (3H, t, J 7.3, OCH2CH3), 1.87 (1H, m, CH2), 2.37
(1H, m, CH2), 2.62–2.89 (2H, m, CH2), 2.89 (3H, s, CH3), 3.66
(1H, m, CHS), 3.83 (3H, s, OCH3), 3.78–3.96 (2H, m, CH2), 4.07
(2H, s, CH2Cl), 4.55 (2H, q, J 7.3, OCH2CH3), 6.94 (2H, d, J 8.8,
ArH), 7.29 (2H, d, J 8.8, ArH); dC (100 MHz; CDCl3) 13.6 (CH3),
24.0 (CH2), 36.3 (CH2), 37.1 (CH3), 48.0 (CH2), 48.2 (CH), 53.5
(CH2), 55.5 (CH3), 70.3 (CH2), 114.8 (2 × ArCH), 130.1 (2 ×
(CCl4)/cm−1 2984w, 2934w, 1721m (C O), 1669s (C O), 1510s,
1389m, 1289m, 1223s, 1112m, 1052s; dH (400 MHz; CDCl3) 1.31
(3H, t, J 7.1, OCH2CH3), 1.77 (1H, m, CH2), 1.84 (3H, s, CH3),
2.20 (1H, m, CH2), 2.80 (2H, t, J 6.9, CH2), 3.67 (1H, dd, J 13.6,
6.5, CH2), 3.75 (1H, m, CHS), 4.09 (2H, d, J 2.0, CH2Cl), 4.16 (1H,
dd, J 13.6, 8.6, CH2), 4.47 (2H, qd, J 7.1, 2.1, OCH2CH3), 7.14
(2H, t, J 8.5, ArH), 7.27 (2H, dd, J 8.6, 4.9, ArH); dC (100 MHz;
CDCl3) 13.7 (CH3), 22.8 (CH3), 24.8 (CH2), 36.4 (CH2), 48.3
(CH), 48.4 (CH2), 51.3 (CH2), 70.3 (CH2), 116.8 (d, JC–F 23, 2 ×
ArCH), 130.1 (d, JC–F 9, 2 × ArCH), 138.4 (ArC), 162.0 (d, JC–F
=
=
=
=
ArCH), 130.7 (ArC), 159.5 (ArC), 201.4 (C O), 212.4 (C S);
m/z (CI, NH3) 472 (MNH4 , 100%), 455 (MH+, 20), 374 (74), 348
+
(25), 253 (22); HRMS, Found: MH+, 454.0581, C17H25ClNO5S3
requires MH+, 454.0583.
Dithiocarbonic acid (1-{[acetyl-(4-chlorophenyl)-amino]-
methyl}-5-chloro-4-oxo-pentyl) ester ethyl ester 7f
=
=
=
247, ArC), 171.0 (NC O), 201.8 (C O), 213.1 (C S); m/z (CI,
NH3) 426 (12%), 424 (MNH4 , 15), 407 (MH+, 50), 405 (100);
+
6f (1.02 g, 4.88 mmol) and 1 (0.684 g, 3.21 mmol) were refluxed in
DCE (5 ml) before adding DLP (0.256 g, 0.64 mmol). The crude
mixture was then concentrated in vacuo and purified by column
chromatography (PE–AcOEt, 50 : 50). Compound 7f was isolated
as a yellow oil (0.740 g, 55%), mmax (CCl4)/cm−1 2936w, 1720m
HRMS, Found: MH+, 406.0708, C17H22ClFNO3S2 requires MH+,
406.0714.
[1,3]Dithiane-2,5-dione 8
=
=
(C O), 1670s (C O), 1491s, 1388m, 1286m, 1222s, 1112m, 1053s;
dH (400 MHz; CDCl3) 1.31 (3H, t, J 7.2, OCH2CH3), 1.82 (1H,
m, CH2), 1.86 (3H, s, CH3), 2.26 (1H, m, CH2), 2.79 (2H, t, J
6.4, CH2), 3.69 (1H, dd, J 13.6, 6.4, CH2), 3.78 (1H, m, CHS),
4.08 (2H, s, CH2Cl), 4.22 (1H, dd, J 13.6, 8.0, CH2), 4.54 (2H, q,
J 7.2, OCH2CH3), 7.22 (2H, d, J 8.4, ArH), 7.43 (2H, d, J 8.4,
ArH); dC (100 MHz; CDCl3) 13.6 (CH3), 22.8 (CH3), 24.9 (CH2),
36.4 (CH2), 48.3 (CH2), 48.4 (CH), 51.2 (CH2), 70.3 (CH2), 129.8
Compound 8 was prepared by refluxing a solution of compound
1 (538 mg, 2.53 mmol) in chlorobenzene (25 mL) for 10 hours.
The solvent was then removed in vacuo. The crude residue was
purified by flash column chromatography (PE–AcOEt, 10 : 0 to
8 : 2), to give compound 8 in 50% yield as white crystals (190 mg,
◦
50%), mp 47–50 C (from heptane–AcOEt), mmax (CH2Cl2)/cm−1
=
=
2924m, 1728s (C O), 1648s (C O), 1389 s, 1239 m; dH (400 MHz;
CDCl3), 3.87 (4H, s, CH2); dC (100 MHz; CDCl3) 39.8 (2 × CH2),
+
=
=
(2 × ArCH), 130.1 (2 × ArCH), 134.2 (ArC), 140.9 (ArC), 170.8
190.5 (C O), 198.1 (C O); m/z, HRMS, Found: M , 147.9653,
(C O), 201.8 (C O), 213.0 (C S); m/z (CI, NH3) 440 (MNH4 ,
25%), 423 (MH+, 100), 300 (23); HRMS, Found: MH+, 422.0418,
C17H22Cl2NO3S2 requires MH+, 422.0406.
C14H16BrClNO2 requires M+, 147.9652.
+
=
=
=
1-Chloro-4-(1-methanesulfonyl-5-methoxy-2,3-dihydro-
1H-indol-3-yl)-butan-2-one 9e
Dithiocarbonic acid (1-{[acetyl-(4-bromophenyl)-amino]-
methyl}-5-chloro-4-oxo-pentyl) ester ethyl ester 7g
To a refluxing solution of 7e (0.298 g, 0.66 mmol) in 1,2-
dichloroethane (7 ml), was added DLP (0.262 g, 0.66 mmol). The
crude mixture was concentrated in vacuo and purified by column
chromatography (EP–AcOEt, 60 : 40) to give compound 9e as
a white solid (0.118 g, 54%), mp 81–83 ◦C (from PE–AcOEt),
To a refluxing solution of 6g (303 mg, 1.19 mmol) and xanthate
1 (500 mg, 2.36 mmol) in DCE (2 ml) was added DLP (183 mg,
0.46 mmol). Concentration in vacuo gave a crude oil which was
284 | Org. Biomol. Chem., 2006, 4, 278–290
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mmax (CCl4)/cm−1 2928m, 1723m (C O), 1549s, 1488m, 1361m,
concentrated in vacuo and purified by column chromatography to
=
◦
1249m, 1165m; dH (400 MHz; CDCl3), 1.88 (1H, dddd, J 14.4,
8.4, 8.4, 6.0, CH2), 2.14 (1H, m, CH2), 2.60–2.78 (2H, m, CH2),
2.83 (3H, s, CH3), 3.40 (1H, m, CH), 3.62 (1H, dd, J 10.0, 5.9,
NCH2), 3.78 (3H, s, OCH3), 4.01 (1H, t, J 10.0, NCH2), 4.08
(2H, s, CH2Cl), 6.74–6.77 (2H, m, ArH), 7.31 (1H, dd, J 7.6, 2,
ArH); dC (100 MHz; CDCl3) 28.0 (CH2), 33.8 (CH), 36.2 (CH2),
39.2 (CH3), 48.1 (CH2), 55.7 (CH3), 56.1 (CH2), 111.0 (ArCH),
give 9h as a white solid (0.295 g, 60%), mp 80–81 C (from PE–
AcOEt), mmax (CH2Cl2)/cm−1 2935w, 1737m, 1720m (C O), 1659s
=
=
(C O), 1609m, 1485s, 1402s, 1282s, 1263s, 1249s; dH (400 MHz;
CDCl3), 1.89 (1H, m, CH2), 2.07 (1H, m, CH2), 2.18 (3H, s, CH3),
2.60–2.66 (2H, m, CH2), 3.42 (1H, m, CH), 3.68 (1H, dd, J 10.2,
5.5, NCH2), 4.05 (2H, s, CH2Cl), 4.13 (1H, t, J 10.0, NCH2), 6.83–
6.89 (2H, m, ArH), 8.12 (1H, dd, J 8.8, 4.9, ArH); dC (100 MHz;
CDCl3) 23.9 (CH3), 28.2 (CH2), 36.0 (CH2), 38.9 (CH), 48.0
(CH2), 54.8 (CH2), 111.1 (d, JC–F 24, ArCH), 114.3 (d, JC–F 22,
ArCH), 117.7 (d, JC–F 8, ArCH), 135.6 (d, JC–F 8, ArCH), 138.7
113.3 (ArCH), 114.6 (ArCH), 135.1 (ArC), 135.5 (ArC), 156.7
+
=
(ArC), 201.8 (C O); m/z (CI, NH3) 348 (MNH4 , 100%), 330
(M+, 35), 253 (60), 161 (20); HRMS, Found: MH+, 332.0731,
C14H19ClNO4S requires MH+, 322.0723.
(ArC), 159.2 (d, JC–F 243, ArC), 168.3 (C O), 201.7 (C O); m/z
=
=
(CI, NH3) 301 (MNH4 , 17%), 284 (MH+, 100); HRMS, Found:
+
MH+, 284.0847, C14H16ClFNO2 requires MH+, 284.0854.
4-(1-Acetyl-5-chloro-2,3-dihydro-1H-indol-3-yl)-1-chloro-butan-2-
one 9f
Dithiocarbonic acid ethyl ester [4-(1-methanesulfonyl-
5-methoxy-2,3-dihydro-1H-indol-3-yl)-2-oxo-butyl] ester 10e
In the same manner described above, 7f (1.08 g, 2.6 mmol) was
dissolved in DCE (26 ml) and DLP (1.02 g, 2.6 mmol) was added
until consumption of all starting material. After concentration in
vacuo, the crude mixture was purified by column chromatography
(PE–AcOEt, 80 : 20) to give 9f as a white solid (0.570 g, 66%),
mp 135–137 ◦C (from AcOEt), mmax (CCl4)/cm−1 2980w, 2930w,
To a solution of 9e (0.200 g, 0.6 mmol) in acetone (20 ml) was
added portionwise ethylxanthic acid potassium salt (0.106 g,
0.66 mmol) and the reaction was stirred at room temperature
for 2 h. The solvent was then evaporated in vacuo and DCM
(30 ml) was added to the crude mixture and washed with water
(20 ml). After separation, the organic layer was dried over MgSO4;
evaporation furnished a crude oil which was purified by column
chromatography (PE–Et2O, 1 : 5) to give 10e as a colourless oil
=
=
1724m (C O), 1672s (C O), 1478s, 1392s; dH (400 MHz; CDCl3),
1.90 (1H, m, CH2), 2.08 (1H, m, CH2), 2.19 (3H, s, CH3), 2.60–
2.68 (2H, m, CH2), 3.42 (1H, m, CH), 3.68 (1H, dd, J 10.5, 5.5,
NCH2), 4.06 (2H, s, CH2Cl), 4.15 (1H, t, J 10.0, NCH2), 7.11
(1H, br s, ArH), 7.15 (1H, dd, J 8.6, 2.1, ArH), 8.10 (1H, d, J
8.6, ArH); dC (100 MHz; CDCl3) 24.1 (CH3), 28.4 (CH2), 36.2
(CH2), 38.9 (CH), 48.2 (CH2), 54.8 (CH2), 118.0 (ArCH), 124.1
(0.202 g, 81%), mmax (CCl4)/cm−1 2940w, 2837w, 1718m (C O),
=
=
1607m (C O), 1488s, 1348s, 1227s, 1161s, 1049s; dH (400 MHz;
CDCl3), 1.42 (3H, t, J 7.2, OCH2CH3), 1.86 (1H, m, CH2), 2.16
(1H, m, CH2), 2.64–2.79 (2H, m, CH2), 2.83 (3H, s, CH3), 3.38
(1H, m, CH), 3.61 (1H, dd, J 10.4, 6.0, NCH2), 3.79 (3H, s,
OCH3), 3.99 (2H, s, CH2S), 4.02 (1H, m, NCH2), 4.64 (2H, q, J 7.2,
OCH2CH3), 6.75 (1H, d, J 8.8, ArH), 6.78 (1H, s, ArH), 7.31 (1H,
d, J 8.8, ArH); dC (100 MHz; CDCl3) 13.6 (CH3), 28.0 (CH2), 33.7
(CH3), 38.4 (CH2), 39.1 (CH), 45.2 (CH2), 55.6 (CH3), 56.1 (CH2),
71.1 (CH2), 111.8 (ArCH), 113.2 (ArCH), 114.5 (ArCH), 135.0
(ArCH), 128.1 (ArCH), 128.6 (ArC), 135.7 (ArC), 141.4 (ArC),
+
=
=
168.7 (C O), 201.8 (C O); m/z (CI, NH3) 318 (MNH3 , 10%),
316 (15), 301 (M+, 75), 299 (100); HRMS, Found: MH+, 300.0543,
C14H16Cl2NO2 requires MH+, 300.0558.
4-(1-Acetyl-5-bromo-2,3-dihydro-1H-indol-3-yl)-1-chloro-butan-2-
one 9g
=
=
(ArC), 135.6 (ArC), 156.7 (ArC), 202.4 (C O), 213.4 (C S);
To a refluxing solution of 7g (0.800 g, 1.71 mmol) in DCE
(17 ml), was added DLP (0.818 g, 2.05 mmol). The crude
mixture was concentrated in vacuo and then purified by column
chromatography (PE–AcOEt, 30 : 20): compound 9g was isolated
as a white solid (0.400 g, 68%), mp 140–142 ◦C (from AcOEt), mmax
m/z (CI, NH3) 435 (MNH4 , 100%), 418 (MH+, 88), 338 (40), 252
+
(35); HRMS, Found: 418.0782 MH+, C17H24NO5S3 requires MH+,
418.0817.
(CCl4)/cm−1 2919m, 2359m, 1724m (C O), 1673s (C O), 1477s,
1391s, 1335m, 1256m; dH (400 MHz; CDCl3), 1.91 (1H, m, CH2),
2.09 (1H, m, CH2), 2.21 (3H, s, CH3), 2.63–2.68 (2H, m, CH2),
3.44 (1H, m, CH), 3.69 (1H, dd, J 10.4, 5.5, NCH2), 4.07 (2H, s,
CH2Cl), 4.16 (1H, t, J 9.7, NCH2), 7.27 (1H, br s, ArH), 7.32
(1H, dd, J 8.6, 1.9, ArH), 8.07 (1H, d, J 8.6, ArH); dC (100 MHz;
CDCl3) 24.1 (CH3), 28.3 (CH2), 36.1 (CH2), 38.8 (CH), 48.0
(CH2), 54.7 (CH2), 116.0 (ArC), 118.3 (ArCH), 126.9 (ArCH),
=
=
Dithiocarbonic acid [4-(1-acetyl-5-chloro-2,3-dihydro-1H-
indol-3-yl)-2-oxo-butyl] ester ethyl ester 10f
To a solution of 9f (0.427 g, 1.42 mmol) in acetone (20 ml) was
added portionwise a solution of ethylxanthic acid potassium salt
(0.251 g, 1.56 mmol) in acetone (6 ml). After stirring for 2 h at room
temperature, the crude mixture was evaporated, diluted with DCM
(40 ml) and washed with water (20 ml). The organic layer was dried
over MgSO4 and evaporated in vacuo. The residue was purified by
column chromatography (Et2O) to give comp◦ound 10f as ivory
coloured needles (0.485 g, 88%), mp 131–132 C (from AcOEt),
=
131.1 (ArCH), 136.0 (ArC), 141.8 (ArC), 168.7 (C O), 201.7
+
+
=
(C O); m/z (CI, NH3) 362 (MNH3 , 25%), 360 (18), 345 (M ,
100), 343 (75); HRMS, Found: MH+, 344.0037, C14H16BrClNO2
requires MH+, 344.0053.
mmax (CH2Cl2)/cm−1 2929m, 2837m, 1728w (C O), 1663m (C O),
1604m, 1478m, 1396m, 1338m, 1242m, 1018s; dH (400 MHz;
CDCl3) 1.41 (3H, t, J 7.1, OCH2CH3), 1.90 (1H, m, CH2), 2.10
(1H, m, CH2), 2.20 (3H, s, CH3), 2.65–2.69 (2H, m, CH2), 3.43
(1H, m, CH), 3.69 (1H, dd, J 10.4, 5.6, NCH2), 3.97 (2H, s, CH2S),
4.15 (1H, t, J 10.0, NCH2), 4.62 (2H, q, J 7.1, OCH2CH3), 7.12
(1H, br s, ArH), 7.16 (1H, dd, J 8.6, 2.0, ArH), 8.11 (1H, d, J 8.6,
=
=
4-(1-Acetyl-5-fluoro-2,3-dihydro-1H-indol-3-yl)-1-chloro-butan-2-
one 9h
To a refluxing solution of 7h (0.712 g, 1.75 mmol) in DCE (17 ml)
was added DLP (0.839 g, 2.1 mmol). The crude mixture was then
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ArH); dC (100 MHz; CDCl3) 13.8 (CH3), 24.2 (CH3), 28.4 (CH2),
38.4 (CH2), 38.9 (CH), 45.4 (CH2), 55.0 (CH2), 71.2 (CH2), 117.9
(ArCH), 124.2 (ArCH), 128.1 (ArCH), 128.6 (ArC), 136.0 (ArC),
2,2-Dimethyl-propionic acid 1-ethoxythiocarbonylsulfanyl-
6-(1-methanesulfonyl-5-methoxy-2,3-dihydro-1H-indol-
3-yl)-4-oxo-hexyl ester 11e
=
=
=
141.4 (ArC), 168.7 (C O), 202.5 (C O), 213.6 (C S); m/z (CI,
To a refluxing solution of 10e (0.073 g, 0.175 mmol) and vinyl
pivalate (0.045 g, 0.35 mmol) in DCE (1 ml) was added DLP
(0.024 g, 0.06 mmol). The crude mixture was concentrated in vacuo
and column chromatography (PE–Et2O, 1 : 2) gave compound
11e as a yellow oil (0.061 g, 64%), mmax (CCl4)/cm−1 2957m,
NH3) 402 (MNH3 , 10%), 387 (50), 385 (M+, 100); HRMS, Found:
+
386.0649 MH+, C17H21ClNO3S2 requires MH+, 386.0651.
Dithiocarbonic acid [4-(1-acetyl-5-bromo-2,3-dihydro-1H-
indol-3-yl)-2-oxo-butyl] ester ethyl ester 10g
=
2928s, 1723s (C O), 1488m, 1360s, 1228s, 1164s, 1111w, 1051s;
dH (400 MHz; CDCl3) 1.20 (9H, s, CH3), 1.42 (3H, t, J 7.0,
OCH2CH3), 1.50–1.91 (2H, m, CH2), 2.05–2.33 (2H, m, CH2),
2.36–2.62 (2H, m, CH2), 2.83 (3H, s, CH3), 3.38 (1H, m, CH),
3.59 (1H, m, NCH2), 3.78 (3H, s, OCH3), 3.01 (1H, m, NCH2),
4.56–4.70 (2H, m, OCH2CH3), 6.58 (1H, t, J 6.8, CHS), 6.73–6.76
(2H, m, ArH), 7.30 (1H, d, J 8.5, ArH); dC (100 MHz; CDCl3) 13.6
(CH3), 26.9 (3 × CH3), 27.9 (CH2), 28.33 (CH2), 29.6 (CH2), 33.7
(CH), 38.1 (CH2), 39.2 (C), 39.3 (SCH3), 55.7 (OCH3), 56.2 (CH2),
70.2 (OCH2), 80.0 (CHS), 110.9 (ArCH), 113.2 (ArCH), 114.6
To a solution of 9g (0.384 g, 1.11 mmol) in acetone (20 ml)
was added portionwise ethylxanthic acid potassium salt (0.197 g,
1.23 mmol). The reaction was stirred at room temperature
for 4 h before evaporation of the solvent. The crude mixture
was then dissolved in DCM (40 ml) and washed with water
(20 ml); after separation, the organic layer was dried over MgSO4.
Evaporation in vacuo furnished a residue which was purified
by column chromatography (Et2O) to give compound 10g as a
white solid (0.473 g, quant.), mp 117–118 ◦C (from AcOEt), mmax
=
(ArCH), 135.1 (ArC), 135.8 (ArC), 156.7 (ArC), 176.8 (C O),
(CH2Cl2)/cm−1 1727w (C O), 1663s (C O), 1592w, 1477s, 1394s,
1233s, 1113m, 1049s; dH (400 MHz; CDCl3) 1.43 (3H, t, J 7.0,
OCH2CH3), 1.92 (1H, m, CH2), 2.12 (1H, m, CH2), 2.22 (3H, s,
CH3), 2.66–2.71 (2H, m, CH2), 3.44 (1H, m, CH), 3.70 (1H, dd, J
10.3, 5.5, NCH2), 3.99 (2H, s, CH2S), 4.16 (1H, t, J 10.0, NCH2),
4.65 (2H, q, J 7.0, OCH2CH3), 7.27 (1H, br s, ArH), 7.33 (1H,
d, J 8.6, ArH), 8.09 (1H, d, J 8.6, ArH); dC (100 MHz; CDCl3)
13.8 (CH3), 24.2 (CH3), 28.5 (CH2), 38.3 (CH2), 38.9 (CH), 45.3
(CH2), 54.9 (CH2), 71.2 (CH2), 116.1 (ArC), 118.4 (ArCH), 127.0
+
=
=
=
=
207.3 (C O), 210.0 (C S); m/z (CI, NH3) 563 (MNH4 , 90%),
546 (MH+, 20), 443 (60), 338 (55), 243 (51), 152 (30); HRMS,
Found: M+, 545.1583. C24H35O7NS3 requires M, 545.1575.
2,2-Dimethyl-propionic acid 6-(1-acetyl-5-chloro-2,3-dihydro-1H-
indol-3-yl)-1-ethoxythiocarbonylsulfanyl-4-oxo-hexyl ester 11f
To a refluxing solution of 10f (0.150 g, 0.39 mmol) and vinyl
pivalate (0.100 g, 0.78 mmol) in DCE (1 ml), DLP (0.012 g,
0.03 mmol) was added. The crude mixture was then concentrated
in vacuo and purified by flash chromatography (PE–AcOEt, 60 :
40) to give compound 11f as a yellow oil (0.165 g, 82%), mmax
=
(ArCH), 131.0 (ArCH), 136.3 (ArC), 141.9 (ArC), 168.7 (C O),
+
=
=
202.4 (C O), 213.6 (C S); m/z (CI, NH3) 450 (MNH4 , 10%),
448 (10), 433 (MH+), 431 (90); HRMS, Found: M+, 429.0068.
C17H20O3NS2Br requires M, 429.0068.
(CCl4)/cm−1 2977m, 2934m, 1723s (C O), 1674s (C O), 1479s,
1392s, 1333w, 1230m, 1136m, 1110w, 1051m, 1031m; dH (400 MHz;
CDCl3) 1.20 (9H, s, CH3), 1.41 (3H, t, J 7.2, OCH2CH3), 1.88 (1H,
m, CH2), 2.08 (1H, m, CH2), 2.15–2.30 (2H, m, CH2), 2.22 (3H, s,
CH3), 2.41–2.48 (2H, m, CH2), 2.51–2.56 (2H, m, CH2), 3.44 (1H,
m, CH), 3.70 (1H, m, NCH2), 4.17 (1H, m, NCH2), 4.58–4.67 (2H,
m, OCH2CH3), 6.58 (1H, dt, J 6.4, 1.6, CHS), 7.12 (1H, s, ArH),
7.18 (1H, d, J 8.4, ArH), 8.13 (1H, d, J 8.4, ArH); dC (100 MHz;
CDCl3) 13.8 (CH3), 24.2 (CH3) 27.1 (3 × CH3), 28.0 (CH2), 28.5
(CH2), 38.3 (2 × CH2), 39.1 (CH), 39.2 (C), 55.0 (NCH2), 70.4
(OCH2), 80.2 (CHS), 114.9 (ArC), 118.0 (ArCH), 124.2 (ArCH),
=
=
Dithiocarbonic acid [4-(1-acetyl-5-fluoro-2,3-dihydro-1H-indol-
3-yl)-2-oxo-butyl] ester ethyl ester 10h
9h (0.295 g, 1.04 mmol) was dissolved in acetone (20 ml) and
ethylxanthic acid potassium salt (0.183 g, 1.14 mmol), was added
portionwise. The reaction mixture was stirred at room temperature
for 4 h and then concentrated in vacuo. The crude solid was
dissolved in DCM (40 ml) and washed with water (20 ml);
after separation, drying over MgSO4 and evaporation, column
chromatography (EP–Et2O, 1 : 3) gave compound 10h as a white
solid (0.321 g, 84%), mp 109–110 ◦C (from PE–AcOEt), mmax
=
128.2 (ArCH), 128.6 (ArC), 136.0 (ArC), 168.7 (C O), 177.0
+
=
=
=
(C O), 207.4 (C O), 210.2 (C S); m/z (CI, NH3) 577 (MNH3 ,
20%), 575 (17), 560 (M+, 85), 558 (80); HRMS, Found: 514.1454
MH+, C24H33ClNO5S2 requires MH+, 514.1489.
(CH2Cl2)/cm−1 2937m, 1718m (C O), 1659s (C O), 1609m,
1485s, 1401s, 1359w, 1340w, 1221s, 1114s, 1049s; dH (400 MHz;
CDCl3) 1.40 (3H, t, J 7.1, OCH2CH3), 1.90 (1H, m, CH2), 2.07
(1H, m, CH2), 2.19 (3H, s, CH3), 2.64–2.69 (2H, m, CH2), 3.42
(1H, m, CH), 3.69 (1H, dd, J 10.4, 5.6, NCH2), 3.97 (2H, s, CH2S),
4.15 (1H, t, J 10.0, NCH2), 4.61 (2H, q, J 7.1, OCH2CH3), 6.85–
6.90 (2H, m, ArH), 8.14 (1H, dd, J 8.5, 4.9, ArH); dC (100 MHz;
CDCl3) 13.6 (CH3), 23.9 (CH3), 28.4 (CH2), 38.2 (CH2), 38.9
(CH), 45.2 (CH2), 54.9 (CH2), 71.0 (CH2), 111.1 (d, JC–F 24,
ArCH), 114.2 (d, JC–F 23, ArCH), 117.7 (d, JC–F 8, ArCH), 135.9
=
=
2,2-Dimethyl-propionic acid 6-(1-acetyl-5-bromo-2,3-dihydro-1H-
indol-3-yl)-1-ethoxythiocarbonylsulfanyl-4-oxo-hexyl ester 11g
To a refluxing solution of 10g (0.150 g, 0.35 mmol) and vinyl
pivalate (0.09 g, 0.70 mmol) in DCE (1 ml) was added DLP
(0.020 g, 0.051 mmol). The mixture was then concentrated in
vacuo and purified by column chromatography (PE–Et2O, 10 :
30); compound 11g was isolated as a yellow oil (0.230 g, 73%), mmax
=
=
=
(ArC), 138.8 (ArC), 159.2 (d, JC–F 241, ArC), 168.2 (C O), 202.3
(CCl4)/cm−1 2957s, 2932s, 1720s (C O), 1666s (C O), 1592m,
1477s, 1392s, 1334s, 1232s, 1135s, 1112s, 1045s; dH (400 MHz;
CDCl3) 1.18 (9H, s, CH3), 1.40 (3H, t, J 6.5, OCH2CH3), 1.85
(1H, m, CH2), 2.05 (1H, m, CH2), 2.11–2.32 (2H, m, CH2), 2.20
+
+
=
=
(C O), 213.5 (C S); m/z (CI, NH3) 386 (MNH3 , 10%), 369 (M ,
100), 337 (25); HRMS, Found: 370.0963 MH+, C17H20FNO3S2
requires MH+, 370.0947.
286 | Org. Biomol. Chem., 2006, 4, 278–290
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(3H, s, CH3), 2.40–2.48 (2H, m, CH2), 2.48–2.58 (2H, m, CH2),
3.43 (1H, m, CH), 3.68 (1H, m, CH2), 4.15 (1H, m, CH2), 4.58–
4.64 (2H, m, OCH2CH3), 6.75 (1H, td, J 6.5, 2.0, CHS), 7.25 (1H,
br s, ArH), 7.30 (1H, dd, J 8.5, J 1.8 ArH), 8.06 (1H, d, J 8.5,
ArH); dC (100 MHz; CDCl3) 13.6 (CH3), 24.0 (CH3), 26.9 (3 ×
CH3), 28.3 (CH2), 28.4 (CH2), 38.1 (CH2), 38.8 (CH2), 38.9 (CH),
39.1 (C), 54.7 (CH2), 70.2 (OCH2), 80.0 (SCH), 115.9 (ArC), 118.3
(ArCH), 126.9 (ArCH), 130.9 (ArCH), 136.3 (ArC), 141.8 (ArC),
1-{5-Chloro-3-[2-(1-cyclopropyl-1H-pyrrol-2-yl)-ethyl]-2,3-
dihydro-1H-indol-1-yl}-ethanone 12f
A solution of 11f (0.088 g, 0.17 mmol), p-toluenesulfonic acid
monohydrate (0.032 g, 0.17 mmol) and cyclopropylamine (0.01 g,
0.17 mmol) in dioxane (1 ml) was refluxed for 1 h. Additional
cyclopropylamine (0.01 g, 0.17 mmol) was then added and the
reaction was refluxed for a further 90 min. Evaporation of the
solvent in vacuo furnished a crude oil which was purified by column
chromatography (PE–AcOEt, 50 : 50) to give compound 12f as a
colourless oil (0.039 g, 70%); mmax (CCl4)/cm−1 2980w, 2923w, 1674s
=
=
=
=
168.6 (C O), 176.8 (C O), 207.2 (C O), 210.0 (C S); m/z (CI,
NH3) 515 (MH+, 28%), 413 (M-OCOtBu, 95), 290 (50); HRMS,
Found: 558.0989 MH+, C24H33BrNO5S2 requires MH+, 558.0984.
=
(C O), 1478s, 1391s, 1332w, 1256w; dH (400 MHz; CDCl3) 0.87–
0.99 (4H, m, CH2), 1.96 (1H, m, CH2), 2.17 (1H, m, CH2), 2.22
(3H, s, CH3) 2.72–2.86 (2H, m, CH2), 3.10 (1H, m, CH), 3.50 (1H,
m, NCH2), 3.72 (1H, m, CH), 4.19 (1H, t, J 9.4, NCH2), 5.89 (1H,
m, ArH), 6.02 (1H, t, J 3.2, ArH), 6.61 (1H, m, ArH), 7.15 (1H, s,
ArH), 7.18 (1H, dd, J 8.2, 2.0, ArH), 8.15 (1H, d, J 8.2, ArH);
dC (100 MHz; CDCl3) 6.7 (2 × CH2), 23.8 (CH2), 24.2 (CH3),
28.0 (CH), 34.0 (CH2), 39.7 (CH), 55.1 (CH2), 106.2 (ArCH),
106.6 (ArCH), 118.0 (ArCH), 120.7 (ArCH), 125.4 (ArCH), 127.9
2,2-Dimethyl-propionic acid 6-(1-acetyl-5-fluoro-2,3-dihydro-1H-
indol-3-yl)-1-ethoxythiocarbonylsulfanyl-4-oxo-hexyl ester 11h
To a refluxing solution of 10h (0.148 g, 0.40 mmol) and vinyl
pivalate (0.102 g, 0.80 mmol) in DCE (1 ml) was added DLP
(0.024 g, 0.06 mmol). The crude mixture was concentrated in
vacuo and then purified by column chromatography (EP–AcOEt,
50 : 50) to give compound 11h as a yellow oil (0.150 g, 75%),
(ArCH), 128.6 (ArC), 133.5 (ArC), 136.8 (ArC), 141.4 (ArC),
mmax (CCl4)/cm−1 2979m, 2935w, 1739s (C O), 1670s (C O),
1609w, 1485s, 1397s, 1370s, 1235s, 1136m, 1110w, 1050m, 1031m;
dH (400 MHz; CDCl3) 1.19 (9H, s, CH3), 1.40 (3H, t, J 7.1,
OCH2CH3), 1.88 (1H, m, CH2), 2.07 (1H, m, CH2), 2.15–2.30
(2H, m, CH2), 2.21 (3H, s, CH3), 2.42–2.49 (2H, m, CH2), 2.51–
2.57 (2H, m, CH2), 3.44 (1H, m, CH), 3.69 (1H, ddd, J 10.0,
5.2, 2.4, NCH2), 4.17 (1H, dt, J 10.0, 4.4, NCH2), 4.55–4.68
(2H, m, OCH2CH3), 6.58 (1H, dt, J 6.8, 2.0, CHS), 6.84–6.92
(2H, m, ArH), 8.15 (1H, dd, J 8.8, 4.8, ArH); dC (100 MHz;
CDCl3) 13.7 (CH3), 24.1 (CH3), 27.0 (3 × CH3), 28.0 (CH2), 28.4
(CH2), 38.3 (2 × CH2), 39.1 (CH), 39.6 (C), 55.1 (CH2), 70.4,
(OCH2), 80.2 (SCH), 111.2 (d, JC–F 24, ArCH), 114.4 (d, JC–F 22,
ArCH), 117.9 (d, JC–F 8, ArCH), 136.0 (ArC), 138.9 (ArC), 159.4
+
=
=
=
168.7 (C O); m/z (CI, NH3) 328 (M , 100%).
1-(5-Bromo-3-{2-[1-(4-methoxybenzyl)-1H-pyrrol-2-yl]-ethyl}-
2,3-dihydro-1H-indol-1-yl)-ethanone 12g
To a solution of 11g (0.081 g, 0.140 mmol) in dioxane (1 ml), were
added p-toluenesulfonic acid monohydrate (0.028 g, 0.14 mmol)
and 4-methoxybenzyl amine (0.023 g, 0.168 mmol). The reaction
was refluxed under nitrogen for 30 min. Further amine was
introduced (0.019 g, 0.140 mmol) and the reaction mixture was
refluxed for 30 min before evaporating the solvent in vacuo.
Column chromatography (PE–Et2O, 1 : 10) afforded compound
12g as a yellow oil (0.046 g, 72%); mmax (CCl4)/cm−1 2933s, 2836w,
=
1672s (C O), 1513s, 1477s, 1466s, 1391s, 1353w, 1333s, 1250s,
=
=
=
(d, JC–F 241, ArC), 168.4 (C O), 176.9 (C O), 207.3 (C O),
+
1174m, 1040m; dH (400 MHz; CDCl3) 1.74 (1H, m, CH2), 1.96
(1H, m, CH2), 2.15 (3H, s, CH3), 2.53 (2H, t, J 8.2, CH2), 3.35
(1H, m, CH), 3.52 (1H, m, CH2), 3.80 (3H, s, OCH3), 3.99 (1H,
t, J 9.9, CH2), 4.97 (2H, s, NCH2), 5.99 (1H, br m, ArH), 6.15
(1H, t, J 3.2, ArH), 6.69 (1H, br t, J 2.0, ArH), 6.81–6.98 (4H, m,
ArH), 7.10 (1H, s, ArH), 7.30 (1H, dd, J 8.5, 2.0, ArH), 8.06 (1H,
d, J 8.5, ArH); dC (100 MHz; CDCl3) 23.3 (CH2), 24.0 (CH3), 34.1
(CH2), 39.1 (CH), 50.0 (CH2), 54.7 (NCH2), 55.3 (OCH3), 106.5
(ArCH), 107.1 (ArCH), 114.2 (2 × ArCH), 115.9 (ArC), 118.2
(ArCH), 121.5 (ArCH), 126.8 (ArCH), 127.5 (2 × ArCH), 130.2
=
210.1 (C S); m/z (CI, NH3) 498 (MH , 20%), 395 (90); HRMS,
Found: 498.1758 MH+, C24H33FNO5S2 requires MH+, 498.1784.
1-Methanesulfonyl-5-methoxy-3-[2-(1H-pyrrol-2-yl)-ethyl]-2,3-
dihydro-1H-indole 12e
To a solution of 11e (0.077 g, 0.141 mmol) in dioxane (2 ml),
were added ammonium acetate (0.109 g, 1.41 mmol) followed by
a 33% solution of ammonia (0.048 g, 2.82 mmol). The reaction
was stirred at room temperature for 12 h and then the solvent
was evaporated in vacuo. The residue was purified by column
chromatography (PE–Et2O, 1 : 2) to give compound 12e as a yellow
oil (0.030 g, 66%); mmax (CCl4)/cm−1 3409m (NH), 2934m, 2855w,
1487s, 1360s, 1235m, 1038m, 1164s, 1038s; dH (400 MHz; CDCl3)
1.89 (1H, m, CH2), 2.16 (1H, m, CH2), 2.72 (2H, m, CH2), 2.83
(3H, s, CH3), 3.34 (1H, m, CH), 3.61–3.68 (2H, m, NCH2), 3.79
(3H, s, OCH3), 4.06 (1H, t, J 9.1, NCH2), 5.97 (1H, m, ArH),
6.15 (1H, m, ArH), 6.71 (1H, m, ArH), 6.74 (1H, m, ArH), 6.76
(1H, s, ArCH), 7.32 (1H, d, J 8.5, ArCH), 8.0 (1H, br s, NH);
dC (100 MHz; CDCl3) 25.0 (CH2), 33.8 (CH3), 34.4 (CH2), 39.7
(CH), 55.7 (OCH3), 56.4 (CH2), 105.4 (ArCH), 108.5 (ArCH),
111.0 (ArCH), 112.9 (ArCH), 114.6 (ArCH), 116.7 (ArCH), 130.8
(ArC), 135.1 (ArC), 136.4 (ArC), 156.7 (ArC); m/z (CI, NH3) 321
(MH+, 100%).
(ArC), 130.7 (ArCH), 131.3 (ArC), 136.8 (ArC), 141.7 (ArC),
+
=
158.8 (ArC), 168.6 (C O); m/z (CI, NH3) 456 (MH , 100%),
(453, 100).
1-{3-[2-(1-Cyclohexyl-1H-pyrrol-2-yl)-ethyl]-5-fluoro-2,3-dihydro-
1H-indol-1-yl}-ethanone 12h
A solution of 11h (0.139 g, 0.28 mmol), p-toluenesulfonic acid
monohydrate (0.053 g, 0.28 mmol) and cyclohexylamine (0.083 g,
0.84 mmol) in dioxane (2 ml) was refluxed for 30 min. Additional
cyclohexylamine (0.083 g, 0.84 mmol) was then added and the
reaction was refluxed for a further 30 min. Evaporation of the
solvent in vacuo furnished a crude oil which was purified by column
chromatography (PE–AcOEt, 70 : 30) to give compound 12h as
a yellow oil (0.042 g, 42%); mmax (CCl4)/cm−1 2936s, 2857w, 1670s
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=
(C O), 1609w, 1485s, 1451w, 1397s, 1282w, 1262w; dH (400 MHz;
MgSO4, was refluxed for 3 days. The solvent was then removed
in vacuo and the crude was purified by column chromatography
(Et2O). Compound 15 was obtained as a brown solid (0.250 g,
78%) mp 122–124 ◦C (from AcOEt), mmax (CCl4)/cm−1 2926w,
CDCl3) 1.17–1.31 (2H, m, CH2), 1.32–1.48 (2H, m, CH2), 1.70–
1.54 (2H, m, CH2), 1.92–2.00 (5H, m, CH2), 2.12 (1H, m, CH2),
2.20 (3H, s, CH3), 2.57–2.74 (2H, m, CH2), 3.48 (1H, m, CH),
3.62–3.79 (2H, m, NCH2 and CH), 4.17 (1H, t, J 9.9, NCH2),
5.90 (1H, br m, ArH), 6.11 (1H, t, J 3.2, ArH), 6.72 (1H, t, J 1.86,
ArH), 6.83–6.98 (2H, m, ArH), 8.18 (1H, m, ArH); dC (100 MHz;
CDCl3) 23.6 (CH2), 24.0 (CH3), 25.5 (CH2), 26.1 (2 × CH2), 34.7
(CH2), 34.8 (2 × CH2), 39.7 (CH), 55.0 (CH), 55.1 (CH2), 105.5
(ArCH), 107.0 (ArCH), 111.1 (d, JC–F 22, ArCH), 114.2 (d, JC–F
22, ArCH), 116.6 (ArCH), 117.8 (ArCH), 130.5 (ArC), 137.9 (d,
=
=
1674s (C O), 1479s, 1392s, 1331w, 1256w; dH (400 MHz; CDCl3)
2.06 (1H, m, CH2), 2.22 (3H, s, CH3), 2.29 (1H, m, CH2), 2.93
(2H, t, J 7.9, CH2), 3.51 (1H, m, CH), 3.79 (1H, m, CH2), 4.22
(1H, t, J 10.0, CH2), 7.00 (1H, s, ArH), 7.13–7.20 (2H, m, ArH),
7.39 (1H, m, ArH), 8.14 (1H, d, J 8.2, ArH), 8.23 (1H, d, J
8.2, ArH), 8.66 (1H, d, J 4.7, ArH), 9.16 (1H, br s, ArH); dC
(100 MHz; CDCl3) 23.8 (CH3), 28.3 (CH2), 34.3 (CH2), 39.0
(CH), 54.7 (CH2), 114.0 (ArCH), 117.5 (ArCH), 123.4 (ArCH),
123.8 (ArCH), 127.6 (ArCH), 128.2 (ArC), 129.3 (ArC), 133.3
J
C–F 209, ArC), 158.2 (ArC), 160.6 (ArC), 168.4 (C O); m/z (CI,
NH3) 354 (M+, 100%).
(ArCH), 136.1 (ArC), 141.0 (ArC), 147.3 (ArCH), 150.4 (ArCH),
+
=
157.2 (ArC), 164.1 (ArC), 168.3 (C O); m/z (CI, NH3) 385 (M ,
2,2-Dimethyl-propionic acid 3-(2-acetylamino-thiazol-4-yl)-1-
ethoxythiocarbonylsulfanyl-propyl ester 13
33%), 383 (100); HRMS; Found: MH+, 384.0939, C20H19ClN3OS
requires MH+, 384.0937.
A solution of 7c (0.216 g, 0.63 mmol) and N-acetylthiourea
(0.150 g, 1.27 mmol) in chlorobenzene (15 ml) was refluxed
for 16 h in the presence of MgSO4. The solvent was then
evaporated in vacuo and the crude mixture was purified by column
chromatography (PE–Et2O, 50 : 50) to give compound 13 as
a colourless oil (0.140 g, 55%); mmax (neat)/cm−1 3195w, 2973s,
Dithiocarbonic acid {4-[(S)-4-(1-ethoxythiocarbonylsulfanyl-1-
methyl-ethyl)-cyclohex-1-enyl]-2-oxo-butyl} ester ethyl ester 17
A solution of b-(−)-pinene (1.5 mL, 9.53 mmol, 2.0 eq.) and
xanthate 1 (1.01 g, 4.68 mmol, 1 eq.) in 1,2-dichloroethane (5 mL)
under argon was refluxed for 15 min before the addition of DLP
(90 mg, 0.22 mmol, 0.05 eq.). The solution was then refluxed for
an additional hour and DLP (40 mg, 0.10 mmol, 0.02 eq.) was
added. The solution was refluxed for a further hour before being
cooled to rt. The solvent was evaporated in vacuo and the residue
was dissolved in acetone (45 mL). The solution was stirred at rt
under argon for 15 min before the addition of potassium O-ethyl
xanthate (1.06 g, 6.62 mmol, 1.4 eq.). The solution was stirred at
rt for 1 h then acetone was evaporated in vacuo. The residue was
then washed with water, extracted with dichloromethane, dried
over sodium sulfate and concentrated in vacuo. The residue was
purified by flash column chromatography (PE–Et2O, 10 : 0 to 9 : 1)
to give compound 17 (1.718 g, 84%) yield as a yellow oil, elemental
analysis, Found: C, 52.65; H, 6.98. C19H30S4O3 requires C, 52.50;
=
=
2871m, 1737s (C O), 1694s (C O), 1519s, 1283s, 1223s, 1135s,
1050s; dH (400 MHz; CDCl3) 1.19 (9H, s, CH3), 1.39 (3H, t, J 7.0,
OCH2CH3), 2.24 (3H, s, CH3), 2.23–2.37 (2H, m, CH2), 2.78 (2H,
t, J 7.9, CH2), 4.55–4.67 (2H, m, CH2), 6.60 (1H, s, CH), 6.66
(1H, t, J 6.5, CHS), 9.98 (1H, br s, NH); dC (100 MHz; CDCl3)
13.6 (CH3), 23.2 (CH3), 26.9 (3 × CH3), 27.3 (CH2), 33.3 (CH2),
38.8 (C), 70.2 (CH2), 80.2 (CH), 108.3 (ArCH), 149.1 (ArC),
=
=
=
158.0 (ArC), 167.7 (C O), 176.9 (C O), 210.1 (C S); m/z (CI,
NH3) 404 (M+, 100%), 302 (66), 283 (20); HRMS, Found: MH+,
405.0964, C16H25N2O4S3 requires MH+, 405.0976.
N-{4-[2-(1-Acetyl-5-chloro-2,3-dihydro-1H-indol-3-yl)-ethyl]-
thiazol-2-yl)-acetamide} 14
A mixture of 9f (0.150 g, 0.5 mmol), N-acetylthiourea (0.118 g,
1 mmol) and MgSO4 in chlorobenzene (10 ml) was refluxed for
24 h. The solvent was then evaporated in vacuo and the crude was
purified by column chromatography (Et2O) to give compound 14
as a white solid (0.146 g, 80%), mp 219–220 ◦C (from DCM),
H, 6.96%; mmax (CCl4)/cm−1 2924w, 1715s (C O), 1442s, 1366s,
=
=
1231s (C S), 1148s, 1112s, 1038s (CS), 1002s, 914s; dH (400 MHz;
CDCl3) 1.29 (1H, m, CH), 1.43 (3H, t, J 7.1, CH3), 1.46 (3H, t, J
7.1, CH3), 1.48 (6H, s, CH3), 1.93–1.85 (1H, m, CH2), 1.89 (4H,
m, CH2), 2.16 (1H, m, CH2), 2.28 (2H, t, J 7.4, CH2), 2.72 (2H, t, J
7.4, CH2), 4.01 (2H, s, CH2), 4.64 (2H, q, J 7.1, OCH2), 4.69 (2H,
mmax (CCl4)/cm−1 3180s (NH), 2977w, 2980w, 1703s (C O), 1674s
=
=
(C O), 1535s, 1479s, 1392s, 1282m, 1119w; dH (400 MHz; CDCl3)
=
q, J 7.1, OCH2), 5.40 (1H, d, J 4.0, C CH); dC (100 MHz; CDCl3)
1.90 (1H, m, CH2), 2.11 (1H, m, CH2), 2.19 (3H, s, CH3), 2.25
(3H, s, CH3), 2.72 (2H, t, J 7.6, CH2), 3.37 (1H, m, CH), 3.67
(1H, m, CH2), 4.12 (1H, m, CH2), 6.58 (1H, s, ArH), 7.08 (1H, s,
ArH), 7.12 (1H, dd, J 8.8, 2.0, ArH), 8.1 (1H, d, J 8.8, ArH), 10.0
(1H, br s, NH); dC (100 MHz; CDCl3) 23.1 (CH3), 24.0 (CH3),
28.4 (CH2), 34.3 (CH2), 39.1 (CH), 54.9 (CH2), 108.2 (ArCH),
117.8 (ArCH), 124.0 (ArCH), 127.8 (ArCH), 128.4 (ArC), 136.5
13.7 (CH3), 13.8 (CH3), 24.5 (CH2), 24.7 (CH3), 25.1 (CH3), 27.0
(CH2), 29.5 (CH2), 30.9 (CH2), 40.1 (CH2), 42.6 (CH), 45.4 (CH2),
59.0 (C), 69.4 (OCH2), 70.8 (OCH2), 120.9 (CH), 135.8 (C), 202.8
+
=
=
=
(C O), 213.3 (C S), 214.2 (C S); m/z (CI, NH3) 313 (M -122,
100%).
=
(ArC), 141.1 (ArC), 150.0 (ArC), 158.0 (ArC), 167.8 (C O), 168.8
Dithiocarbonic acid [(2S,4aS,8aS)-2-(1-ethoxythiocarbonyl-
sulfanyl-1-methyl-ethyl)-7-oxo-octahydro-naphthalen-4a-yl] ester
ethyl ester 18
+
=
(C O); m/z (CI, NH3) 366 (M , 33%), 363 (100); HRMS, Found:
MH+, 364.0886, C17H19ClN3O2S requires MH+, 364.0887.
A solution of xanthate 17 (521 mg, 1.20 mmol) in 1,2-
dichloroethane (12 mL) under argon, was refluxed for 15 min
before the addition of DLP (32 mg, 0.08 mmol, 0.07 eq.). The
solution was then refluxed and portions of DLP (total 106 mg,
0.27 mmol, 0.22 eq.) were added every hour. The solvent was then
1-{5-Chloro-3-[2-(2-pyridin-3-yl-thiazol-4-yl)-ethyl]-2,3-dihydro-
1H-indol-1-yl}-ethanone 15
A suspension of 9f (0.250 g, 0.83 mmol) and thionicotinamide
(0.230 g, 1.66 mmol) in chlorobenzene (20 ml) in the presence of
288 | Org. Biomol. Chem., 2006, 4, 278–290
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=
(CH CH2), 128.0 (ArCH), 128.1 (2 × ArCH), 128.5 (2 × ArCH),
evaporated in vacuo and the residue was purified by flash column
chromatography (PE–Et2O, 10 : 0 to 75 : 25) to give compound 18
(341 mg, 65%) as yellow crystals, mp 101–105 ◦C (from heptane–
ethyl acetate) as a single diastereomer, elemental analysis, Found:
C, 52.53; H, 6.85. C19H30S4O3 requires C, 52.50; H, 6.96%; mmax
=
=
136.7 (ArC), 138.9 (CH CH2), 155.9 (C O); m/z (CI, NH3) 262
(MH+, 100%); HRMS, Found: M+, 261.1721. C16H23O2N requires
M, 261.1728.
(CH2Cl2)/cm−1 2942w, 2868w, 1715s (C O), 1455s, 1387s, 1367s,
Acetic acid 2,6-bis(ethoxythiocarbonylsulfanyl)-5-oxo-1-
pentyl-hexyl ester 25
=
1225s, 1148s, 1113s, 1036s, 1002s, 912s; dH (400 MHz; CDCl3) 1.42
(3H, t, J 7.1, CH3), 1.44 (3H, t, J 7.1, CH3), 1.45 (3H, s, CH3),
1.48 (3H, s, CH3), 1.54 (1H, dd, J 2.2, J 14.1, CH), 1.72 (1H, m,
CH), 1.96–1.87 (2H, m, CH2), 2.23–2.10 (3H, m, CH2), 2.36–2.27
(2H, m, CH2), 2.72–2.43 (5H, m, CH2), 4.70–4.60 (4H, m, OCH2);
dC (100 MHz; CDCl3) 13.7 (CH3), 14.0 (CH3), 23.4 (CH2), 24.9
(2 × CH3), 28.5 (CH2), 28.7 (CH2), 36.6 (CH2), 37.7 (CH2), 38.2
(CH), 39.7 (CH), 43.1 (CH2), 58.4 (C), 58.5 (C), 69.3 (OCH2),
A solution of 3-acetoxy-oct-1-yne (1.83 g, 10.8 mmol, 1.4 eq.) and
xanthate 1 (1.67 g, 7.9 mmol, 1 eq.) in 1,2-dichloroethane (8 mL)
under argon was refluxed for 15 min before the addition of DLP
(157 mg, 0.39 mmol, 0.05 eq.). The solution was then refluxed for
an additional hour and DLP (80 mg, 0.20 mmol, 0.02 eq.) was
added. The solution was refluxed for a further hour before being
cooled to rt. The solvent was evaporated in vacuo and the residue
was dissolved in acetone (70 mL). The solution was stirred at rt
under argon for 15 min before the addition of potassium O-ethyl
xanthate (1.39 g, 8.61 mmol, 1.1 eq.). The solution was stirred at
rt for 1 h then acetone was evaporated in vacuo. The residue was
then washed with water, extracted with dichloromethane, dried
over sodium sulfate and concentrated in vacuo. The residue was
purified by flash column chromatography (PE–Et2O, 10 : 0 to 9 :
1) to give compound 25 as a yellow oil (3.140 g, 98%, mixture
of diastereomers), elemental analysis, Found: C, 48.67; H, 6.99.
C19H32O5S4 requires C, 48.69; H, 6.88%; mmax (CaF2)/cm−1 2930w,
=
=
=
69.7 (OCH2), 209.8 (C O), 212.0 (C S), 213.5 (C S); m/z (CI,
NH3) 435 (MH+, 100%).
(1-Benzenesulfonyl-hexyl)carbamic acid benzyl ester 24
To a solution of benzylcarbamate (1.51 g, 10.0 mmol, 1 eq.) in wa-
ter (10 mL) and THF (4 mL) was added sodium benzenesulfinate
(1.64 g, 10.0 mmol, 1 eq.), hexanal (1.3 mL, 10.1 mmol, 1.1 eq.)
and formic acid (2.4 mL, 63.6 mmol, 6.4 eq.). The solution was
stirred at rt overnight. The mixture was then filtered to collect a
white precipitate. The solid was washed with water and dried.
It was then dissolved in dichloromethane, dried over sodium
sulfate and concentrated in vacuo to give compound 24 as white
crystals (3.158 g, 84%), mp 123–127 ◦C (from hexane–AcOEt), mmax
=
=
2855w, 1732s (C O), 1454s, 1372s, 1232s (C S), 1147s, 1111s,
1048s (CS), 856s; dH (400 MHz; CDCl3) 0.93 (3H, m, CH3), 1.29–
1.25 (5H, m, CH2), 1.45–1.40 (6H, m, CH3), 1.68–1.57 (3H, m,
CH2), 1.82 (1H, m, CH2), 2.06 and 2.04 (3H, s, CH3), 2.12 (1H,
m, CH2), 2.88–2.72 (2H, m, CH2), 3.98–3.96 (2H, m, SCH2),
4.02 (1H, m, CH), 4.69–4.61 (4H, m, OCH2), 5.18–5.11 (1H, m,
OCH); dC (100 MHz; CDCl3) 13.8 (2 × CH3), 14.0 (CH3), 21.1
(21.0) (CH3), 23.0 (22.5) (CH2), 25.3 (25.2) (CH2), 25.9 (CH2),
31.6 (31.5) (CH2), 32.0 (CH2), 39.1 (39.0) (CH2), 45.5 (CH2), 53.9
(53.5) (CHS), 70.9 (70.7) (2 × OCH2), 75.4 (75.2) (OCH), 170.6
(CH2Cl2)/cm−1 3414w, 2959w, 2931w, 2862w, 1732s (C O), 1507s,
=
1308s, 1217s, 1145s, 1083s, 1046s; dH (400 MHz; CDCl3) 0.90 (3H,
t, J 6.8, CH3), 1.52–1.31 (6H, m, CH2), 1.75 (1H, m, CH2), 2.25
(1H, m, CH2), 4.92–4.82 (3H, m, NCH and OCH2), 5.43 (1H, d, J
10.6, NH), 7.20–7.09 (2H, m, ArCH), 7.36–7.33 (3H, m, ArCH),
7.45–7.41 (2H, m, ArCH), 7.59 (1H, t, J 7.5, ArCH), 7.88 (2H,
d, J 7.5, ArCH); dC (100 MHz; CDCl3) 14.0 (CH3), 22.4 (CH2),
25.0 (CH2), 26.4 (CH2), 31.2 (CH2), 67.4 (OCH2), 71.5 (NCH),
128.2 (2 × ArCH), 128.4 (ArCH), 128.6 (2 × ArCH), 129.0 (2 ×
=
=
=
(170.5) (C O), 202.4 (202.3) (C O), 213.4 (C S), 214.1 (213.9)
(C S); m/z (CI, NH3) 469 (MH , 100%).
+
=
ArCH), 129.3 (2 × ArCH), 134.0 (ArCH), 135.7 (ArC), 136.7
+
Acetic acid 9-benzyloxycarbonylamino-2,8-bis(ethoxythio-
carbonylsulfanyl)-5-oxo-1-pentyl-tetradecyl ester 26
=
(ArC), 155.0 (C O); m/z (CI, NH3) 376 (MH , 100%); HRMS,
Found: M+, 375.1507. C20H25O4NS requires M, 375.1504.
A solution of xanthate 25 (710 mg, 1.51 mmol) and olefine 22
(783 mg, 3.0 mmol, 2 eq.) in 1,2-dichloroethane (2 mL) under
argon was refluxed for 15 min before the addition of DLP
(45 mg, 0.11 mmol, 0.07 eq.). The solution was refluxed under
argon and DLP (115 mg, 0.29 mmol, 0.26 eq.) was added in
portions (2.5 mol% every 90 min) until the disappearance of the
starting material. After evaporation of the solvent and purification
by flash column chromatography (PE–Et2O, 10 : 0 to 7 : 3),
compound 26 was obtained as a yellow oil (715 mg, 65%, mixture
of diasteromers); mmax (CaF2)/cm−1 3336w, 2955w, 2902w, 2858w,
(1-Vinyl-hexyl)carbamic acid benzyl ester 22
To a solution of compound 24 (768 mg, 2.0 mmol) in dry THF
(15 mL) under argon, was added at −20 ◦C a solution of vinyl
magnesium bromide (1 mol L−1 in THF) (4.3 mL, 4.3 mmol,
2.1 eq.) and the solution was stirred at 0 ◦C for 1 h. Saturated
aqueous NH4Cl was then added to quench the reaction and
the mixture was neutralised with saturated aqueous Na2CO3,
extracted with dichloromethane, dried over sodium sulfate and
concentrated in vacuo. The residue was purified by flash column
chromatography (PE–Et2O, 10 : 0 to 9 : 1) to give compound 22
as a colourless oil (469 mg, 88%), mmax (CaF2)/cm−1 3324w, 2955w,
=
=
1731s (C O), 1714s (C O), 1520s, 1504s, 1454s, 1372s, 1222s
=
(C S), 1111s, 1048s (CS), 911s; dH (400 MHz; CDCl3) 0.92–0.86
=
2931w, 2858w, 1714s (C O), 1694s, 1538s, 1505s, 1336s, 1245s,
(6H, m, CH3), 1.36–1.21 (16H, m, CH2), 1.45–1.39 (6H, m, CH3),
1.84–1.57 (5H, m, CH2), 2.07 (2.04) (3H, s, CH3), 2.18–1.09 (2H,
m, CH2), 2.65–2.51 (3H, m, CH2), 4.06–3.92 (2H, m, SCH), 4.68–
4.56 (4H, m, CH2 and CH), 5.17–5.06 (3H, m, CH and CH2),
7.38–7.30 (5H, m, ArCH); dC (100 MHz; CDCl3) 13.8 (2 × CH3),
14.0 (2 × CH3), 21.1 (21.0) (CH3), 22.6 (2 × CH2), 25.3 (CH2), 25.8
(CH2), 31.3 (CH2), 31.6 (CH2), 31.7 (3 × CH2), 31.9 (CH2), 33.6
1112s, 1072s, 1037s, 992s, 919s; dH (400 MHz; CDCl3) 0.89 (3H,
t, J 6.6, CH3), 1.53–1.30 (8H, m, CH2), 4.18 (1H, br s, NCH),
=
4.78 (1H, br s, NH), 5.19–5.09 (4H, m, CH CH2 and OCH2),
=
5.77 (1H, ddd, J 5.7, J 10.3, J 17.1, CH CH2), 7.37–7.31 (5H,
m, ArCH); dC (100 MHz; CDCl3) 14.1 (CH3), 22.6 (CH2), 25.4
(CH2), 31.6 (CH2), 35.1 (CH2), 53.4 (NCH), 66.7 (OCH2), 114.6
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(CH2), 40.0 (CH2), 54.4 (54.1) (CH), 54.7 (CH), 56.2 (CH), 66.9
(66.8) (OCH2), 70.6 (70.5) (2 × OCH2), 75.4 (75.2) (OCH), 128.0
(2 × ArCH), 128.1 (ArCH), 128.6 (2 × ArCH), 136.5 (ArC), 156.4
Acknowledgements
We wish to thank Dr J. Cassayre and Dr Joachim Blanz for the
HRMS performed at Syngenta (Basel).
=
=
=
(156.1) (C O), 170.6 (170.5) (C O), 208.6 (208.4) (C O), 214.0
+
=
=
(C S), 214.2 (C S); HRMS, Found: M , 729.2875. C35H55O7NS4
requires M, 729.2861.
References
1 A. W. Erian, S. M. Sherif and H. M. Gaber, Molecules, 2003, 8, 793.
2 N. De Kimpe and R. Verhe´, The Chemistry of a-Haloketones, a-
Haloaldehydes and a-Haloimines, ed. S. Patai, Wiley, NY, 1988.
3 H. E. Morton and R. M. Leanna, Tetrahedron Lett., 1993, 23, 4481.
4 M. P. VanBraunt, R. O. Ambenge and S. M. Weinreb, J. Org. Chem.,
2003, 68, 3323.
Acetic acid 9-benzyloxycarbonylamino-5-oxo-1-pentyl-tetradecyl
ester 27
A solution of xanthate 26 (327 mg, 0.45 mmol) in toluene (5 mL)
under argon was refluxed for 15 min before the addition of
tributyltin hydride (0.34 mL, 1.26 mmol, 2.8 eq.) and AIBN
(14 mg, 0.08 mmol, 0.19 eq.). The solution was heated at 100 ◦C
under argon for 90 min then AIBN was added again (14 mg,
0.08 mmol, 0.19 eq.). After 30 min of reflux, the solution was
cooled to rt and the solvent was removed in vacuo. The crude
residue was purified by flash column chromatography (pentane–
Et2O, 10 : 0 to 6 : 4), to give compound 27 as a colourless oil
(153 mg, 70%); mmax (CaF2)/cm−1 3335w, 2937w, 2858w, 1739s
5 R. Tillyer, L. F. Frey, D. M. Tschaen and U.-H. Dolling, Synlett, 1996,
226.
6 M. Groesbeck and S. O. Smith, J. Org. Chem., 1997, 62, 3638.
7 J. G. Lee and D. S. Ha, Tetrahedron Lett., 1989, 30, 193.
8 (a) For general reviews on the xanthate transfer, see: S. Z. Zard, Angew.
Chem., Int. Ed. Engl., 1997, 36, 672; (b) S. Z. Zard, in Radicals in Organic
Synthesis, ed. P. Renaud and M. P. Sibi, Wiley-VCH, Weinheim, 2001,
vol. 1, p. 90.
9 T. Ly, B. Quiclet-Sire, B. Sortais and S. Z. Zard, Tetrahedron Lett., 1999,
40, 2533.
10 T. Kaoudi, B. Quiclet-Sire, S. Seguin and S. Z. Zard, Angew. Chem.,
Int. Ed., 2000, 39, 731.
11 E. Bacque´, M. El Qacemi and S. Z. Zard, Org. Lett., 2004, 21, 3671.
12 (a) A. Jones and G. P. Bean, The Chemistry of Pyrroles, Academic
Press, London, 1977; (b) A. Jones, Pyrroles, Wiley, NY, 1990; (c) L. N.
Sobenina, A. I. Mikhaleva and B. A. Trofimov, Russ. Chem. Rev. (Engl.
Transl.), 1989, 58, 163.
13 For some recent applications of the Paal–Knorr reaction see: (a) B. M.
Trost and G. A. Doherty, J. Am. Chem. Soc., 2000, 122, 3801; (b) A. C.
Cunha, L. O. R. Pereira, M. C. B. V. De Souza and V. F. Ferreira,
Synth. Commun., 2000, 3215; (c) R. Ballini, L. Barboni, G. Bosica and
M. Petrini, Synlett, 2000, 391; (d) T. N. Danks, Tetrahedron Lett., 1999,
40, 3957.
=
=
(C O), 1694s (C O), 1531s, 1455s, 1375s, 1247s, 1025s; dH
(400 MHz; CDCl3) 0.92–0.86 (6H, m, CH3), 1.64–1.26 (24H, m,
CH2), 2.03 (3H, s, CH3), 2.46–2.30 (4H, m, CH2), 3.59 (1H, m,
NCH), 4.57 (1H, m, NH), 4.84 (1H, m, OCH), 5.11–5.05 (2H, m,
OCH2), 7.35–7.27 (5H, m, CHar); dC (100 MHz; CDCl3) 14.1 (2 ×
CH3), 19.4 (CH2), 19.9 (CH2), 21.3 (CH3), 22.6 (CH2), 22.6 (CH2),
25.0 (CH2), 25.5 (CH2), 31.7 (CH2), 31.8 (CH2), 33.5 (CH2), 34.0
(CH2), 34.8 (CH2), 35.4 (CH2), 42.3 (CH2), 42.4 (CH2), 51.1 (CH),
66.6 (OCH2), 73.9 (OCH), 128.1 (ArCH), 128.0 (2 × ArCH),
=
=
128.6 (2 × ArCH), 136.8 (ArC), 156.2 (C O), 171.0 (C O), 210.5
+
+
14 B. Quiclet-Sire, L. Quintero, G. Sanchez-Jimenez and S. Z. Zard,
Synlett, 2003, 1, 75.
=
(C O); m/z (CI, NH3) 490 (MH , 100%); HRMS, Found: M ,
489.3461. C29H47O5N requires M, 489.3454.
15 A. Hantzsch and J. H. Weber, Ber. Dtsch. Chem. Ges., 1887, 20, 3118.
16 (a) M. W. Bredenkamp, C. W. Holzapfel and W. J. Van Zyl, Synth.
Commun., 1990, 20, 2235; (b) U. Schmdit, R. Utz, A. Lieberknecht,
H. Griesser, B. Potzolli, J. Bahr, K. Wagner and P. Fischer, Synthesis,
1987, 233; (c) J. V. Metzger, in Comprehensive Heterocyclic Chemistry,
ed. A. R. Katritzky and C. W. Rees, Wiley, NY, 1984, vol. 6, p. 235.
17 For some applications of the Hantzsch reaction see: (a) T. J. Miller, H. D.
Farquar, A. Sheybani, C. E. Tallini, A. S. Saurage, F. R. Fronczek and
R. P. Hammer, Org. Lett., 2002, 4, 877; (b) C. J. Moody and M. C.
Bagley, J. Chem. Soc., Perkin Trans. 1, 1998, 601; (c) A. R. Katritzky,
J. Chen and Z. Yang, J. Org. Chem., 1995, 60, 5638; (d) S. E. Bramley,
V. Dupplin, D. G. C. Goberdhan and G. D. Meakins, J. Chem. Soc.,
Perkin Trans. 1, 1987, 639.
18 Y. Hamada, K. Kohda and T. Shioiri, Tetrahedron Lett., 1984, 25, 5303.
19 V. Singh, S. R. Iyer and S. Pal, Tetrahedron, 2005, 61, 9197.
20 First isolation of histrionicotoxin: J. W. Daly, I. Karle, C. W. Myers, T.
Tokuyama, J. A. Waters and B. Witkop, Proc. Natl. Acad. Sci. USA,
1971, 68, 1870.
21 For recent leading references to histrionicotoxins and perhydrohistri-
onicotoxin syntheses, see: (a) S. Kim, H. Ko, T. Lee and D. Kim, J. Org.
Chem., 2005, 70, 5756; (b) R. A. Stockman, A. Sinclair, L. G. Arini,
P. Szeto and D. L. Hugues, J. Org. Chem., 2004, 69, 1598; (c) M. J.
McLaughlin, R. P. Hsung, K. P. Cole, J. M. Hahn and J. Wang, Org.
Lett., 2002, 4, 2017; (d) F. A. Luzzio and R. W. Fitch, J. Org. Chem.,
1999, 64, 5485.
(5,9-Dioxo-1-pentyl-tetradecyl)carbamic acid benzyl ester 28
To a solution of compound 27 (120 mg, 0.24 mmol) in methanol
(4 mL) was added potassium carbonate (80 mg, 0.58 mmol) and
the solution was stirred at rt for 2 d. The solution was then filtered
and the solvent was evaporated in vacuo. The crude residue was
then dissolved in dichloromethane (5 mL) and to this solution PCC
was added (90 mg, 0.42 mmol, 1.7 eq.). The solution was stirred
at rt for 4 h before being filtered through celite. The solvent was
evaporated in vacuo and the crude mixture was purified by flash
column chromatography (silica gel, pentane–diethyl ether, 10 : 0
to 1 : 1), to give compound 28 as white crystals (81 mg, 74% over
2 steps), mp 83–88 ◦C (from heptane–AcOEt); elemental analysis,
Found: C, 72.29; H, 9.59. C27H43NO4 requires C, 72.77; H, 9.73%;
mmax (CH2Cl2)/cm−1 3409w, 2957w, 2932w, 1716w (C O), 1511s,
=
1454s, 1220s, 1096s; dH (400 MHz; CDCl3) 0.90–0.85 (6H, m,
CH3), 1.67–1.21 (21H, m, CH2), 1.85–1.78 (2H, m, CH2), 2.36
(3H, d, J 7.6, CH2), 2.41 (2H, t, J 7.1, CH2), 3.60 (1H, m, NCH),
4.56 (1H, br d, J 9.1, NH), 5.13–5.02 (2H, m, OCH2), 7.35–7.28
(5H, m, CHar); dC (100 MHz; CDCl3) 14.0 (CH3), 14.1 (CH3),
17.8 (CH2), 19.8 (CH2), 22.5 (CH2), 22.6 (CH2), 23.6 (CH2),
25.6 (CH2), 31.5 (CH2), 31.8 (CH2), 34.7 (CH2), 35.4 (CH2), 41.6
(CH2), 41.7 (CH2), 42.3 (CH2), 42.8 (CH2), 51.1 (NCH), 66.6
(OCH2), 128.1 (ArCH), 128.1 (2 × ArCH), 128.6 (2 × ArCH),
22 (a) D. L. Comins, Y.-M. Zhang and X. Zheng, Chem. Commun., 1998,
2509; (b) J. D. Winkler and P. M. Hershberger, J. Am. Chem. Soc., 1989,
13, 4852.
23 For a related synthetic strategy, see: E. J. Corey and R. D. Balanson,
Heterocycles, 1976, 5, 445.
24 T. Mecozzi and M. J. Petrini, J. Org. Chem., 1999, 64, 8970 and
references cited therein.
25 S. Krompiec, M. Pigulla, W. Szczepankiewicz, T. Bieg, N. Kuznik, K.
Leszczynska-Sejda, M. Kubicki and T. Borowiak, Tetrahedron Lett.,
2001, 42, 7095.
=
=
=
136.8 (ArC), 156.2 (C O), 210.5 (C O), 210.9 (C O); m/z (CI,
NH3) 446 (MH+, 100%).
290 | Org. Biomol. Chem., 2006, 4, 278–290
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