Formation of N-heterocycles by the reaction of thiols with glyoxamides: Exploring a connective Pummerer-type cyclisation

Article abstract of DOI:10.1039/b816608k

The reaction of thiols with glyoxamides provides a convenient method for the generation of thionium ions and the initiation of Pummerer-type reactions. When the glyoxamides contain tethered aromatic nucleophiles, N-heterocycles are formed by a thionium ion cyclisation. The scope and mechanism of the connective Pummerer-type process has been investigated using a range of thiols, Lewis acids and both mono- and bis-glyoxamides. The utility of the process has been illustrated in a synthesis of the indoloquinoline natural product, neocryptolepine. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b816608k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Formation of N-heterocycles by the reaction of thiols with glyoxamides:
exploring a connective Pummerer-type cyclisation†
Marc Miller,a Johannes C. Vogel,a William Tsang,a Andrew Merritb and David J. Procter*a
Received 22nd September 2008, Accepted 31st October 2008
First published as an Advance Article on the web 12th December 2008
DOI: 10.1039/b816608k
The reaction of thiols with glyoxamides provides a convenient method for the generation of thionium
ions and the initiation of Pummerer-type reactions. When the glyoxamides contain tethered aromatic
nucleophiles, N-heterocycles are formed by a thionium ion cyclisation. The scope and mechanism of the
connective Pummerer-type process has been investigated using a range of thiols, Lewis acids and both
mono- and bis-glyoxamides. The utility of the process has been illustrated in a synthesis of the
indoloquinoline natural product, neocryptolepine.
a hemithioacetal that upon activation, for example, by acylation,
generates a thionium ion. The connective route to thionium ions
Introduction
Pummerer reactions,1 involving nucleophilic additions to thio-
has several advantages over its traditional counterpart: the process
nium ions, are a useful tool for the synthesis of heterocyclic
utilises widely available thiol and aldehyde starting materials,
compounds.2 We have recently developed a fluorous approach to
negating the need to prepare sulfoxide or sulfide starting materials
N-heterocycles that utilises a Pummerer-type process to introduce
(sulfides are essentially prepared in situ). In addition, the properties
the fluorous tag and construct the heterocyclic scaffold in a single
or structural features of the thiol and aldehyde substituents are
step,3 thus a higher synthetic return is gained from the introduction
united in a single synthetic operation, with concomitant addition
of a nucleophile. Reactive aldehydes such as glyoxylates4 and
glyoxamides3 are ideal substrates and the use of an internal
nucleophile allows heterocycles to be constructed.3 Attractively,
the residual organosulfanyl group can impart specific properties
to the Pummerer adducts or can be used as a synthetic handle for
further manipulation.
of a phase tag. The cyclative–capture step involves the reaction
of a fluorous thiol with glyoxamide substrates in a ‘connective’
Pummerer-type reaction.3 The classical Pummerer reaction of
sulfoxides and the connective Pummerer reaction are compared
in Scheme 1.
Here we report in full5 our studies on the potential of this
new Pummerer-type process for the synthesis of heterocycles.
Our studies have concentrated on the mechanism of the cycli-
sation, the role of the thiol component, the Lewis acid, and
the feasibility of two–directional Pummerer cyclisations to form
extended heterocyclic systems. The products of the Pummerer-
type cyclisations possess heterocyclic motifs that are widespread
amongst natural products and compounds of pharmaceutical
significance. A concise synthesis of the indoloquinoline natural
product neocryptolepine has been carried out to illustrate the
utility of the connective Pummerer-type cyclisation.
Scheme 1 Comparison of the Pummerer reaction of sulfoxides and a
Results and discussion
connective Pummerer-type reaction.
Generality and mechanism of the connective Pummerer-type
cyclisation
In the classical Pummerer reaction, sulfoxides are activated by
acylation of the sulfoxide oxygen. Elimination then generates a
thionium ion that is trapped by an external or internal nucleophile.
In the connective variant, thiol addition to an aldehyde generates
We began by examining the reaction of functionalised alkyl and
aryl thiols with glyoxamides 9–12 derived from secondary anilines
containing neutral, electron-withdrawing and electron-releasing
substituents. The glyoxamides were prepared from secondary
anilines 1–4 using the approach of Bartlett et al.:6 coupling with
acetoxyacetic acid gave amides 5–8 that were deprotected and
oxidised under Swern conditions (Scheme 2).7 The purification
of intermediates by column chromatography was typically not
required. Glyoxamides 9–12 were isolated as a mixture of aldehyde
aSchool of Chemistry, Oxford Road, The University of Manchester, Manch-
ester, UK M13 9PL. E-mail: david.j.procter@manchester.ac.uk
bGlaxoSmithKline, Gunnelswood Rd., Stevenage, UK SG1 2NY
† Electronic Supplementary Information (ESI) available: Additional ex-
perimental procedures and characterisation data. See http://dx.doi.org/
10.1039/b816608k/
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Table 1 Reaction of thiols with glyoxamides derived from secondary
anilinesa
Scheme 2 Synthesis of glyoxamides from anilines.
and the corresponding hydrate8 and were used without further
purification (vide infra).
Pummerer-type cyclisations were carried out by stirring thiol
with glyoxamide, followed by addition of trifluoroacetic anhydride
(TFAA), then BF3·OEt2. Omitting either TFAA or the Lewis acid
led to the observation of hemithioacetal or trifluoroacetylated
hemithioacetal intermediates (vide infra). We have found that at
least two equivalents of BF3·OEt2 and four equivalents of TFAA
are required before a significant degree of cyclisation is seen
(Table 1).
A preliminary survey of other Lewis acids showed that Sc(OTf)3
gave comparable results to BF3·OEt2 when used in the cyclisa-
tion, while Yb(OTf)3 also promoted the Pummerer-type reaction
but gave lower yields. Reaction conditions involving the use
of Sc(OTf)3 provide a useful, milder alternative to the use of
BF3·OEt2. In all cases, the connective Pummerer-type cyclisation
occurred to give the corresponding oxindole products in moderate
to good isolated yields (over two steps) indicating that the process
is compatible with thiols bearing a range of functional groups
(aryl rings, ester, bromide, amino and hydroxyl groups). The
reaction of 11 with thiols derived from cysteine proceeded to give
the expected products 22a and 22b (Table 1). Milder conditions
using Sc(OTf)3 were required for the cyclisation of Fmoc-protected
cysteine methyl ester. The use of cysteine derivatives in connective
Pummerer reactions suggest that the process could form the basis
of a method for chemical ligation:9 hemithioacetal formation
through the reaction of a carbonyl compound, or a masked
derivative, with a cysteine residue could be followed by cyclisation
to make the attachment permanent.
a RSH (1 eq), TFAA (9 eq), BF3·OEt2 (4 eq), CH2Cl2. b Yields are for 2
steps as glyoxamides are not purified. c 1 : 1 mixture of diastereoisomers.
d RSH (1 eq), TFAA (6 eq), Sc(OTf)3 (2 eq), CH2Cl2.
as a 1 : 1 mixture of diastereoisomers (Scheme 3). In this case,
higher yields were obtained when the crude glyoxamide was dried
in the manner described above.
Functionalised thiols can also be used in connective
Pummerer-type cyclisations with glyoxamide substrates derived
from phenethylamines. For example, glyoxamide 29 under-
went cyclisation upon treatment with ethylthioglycolate or
6-hydroxyhexanethiol to give 30 and 31, respectively, in good
overall yield (Scheme 4).
We have also examined the feasibility of a connective, Pummerer
process that is catalytic in Lewis acid. Varying the amount
of Sc(OTf)3 used in the reaction between glyoxamide 11 and
ethylthioglycolate showed that the yield of 21 decreases as the
loading of Lewis acid is reduced, although significant conversion
is still seen when sub-stoichiometric amounts of Lewis acid are
used. ‘Drying’ of the glyoxamide (vide supra) proved necessary
when using lower quantities of Lewis acid to prevent the formation
of the hydroxyoxindole by-product 32 (Scheme 5).
A complementary approach to glyoxamide substrates involves
the N-arylation of amines. For example, N-arylation of (S)-a-
methylbenzylamine 2510 and coupling with acetoxyacetic acid gave
amide 26 that upon deprotection and Swern oxidation7 gave 27.
Consistent with our previous observations, glyoxamide 27 was
obtained as a mixture of hydrate and aldehyde, as evident from
the complex 1H NMR of crude 27. After moderate heating under
1
vacuum, the H NMR of glyoxamide 27 simplified and could be
assigned. Pummerer-type cyclisation of 27 with ethylthioglycolate,
TFAA and Sc(OTf)3 gave oxindole 28 in 64% yield (over 2 steps)
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give a hydroxyoxindole on treatment with BF3·OEt2. To investigate
the importance of hemithioacetal formation in the cyclisations,
a cross-over experiment was conducted: glyoxamides 9 and 11
were stirred with ethylthioglycolate and 6-hydroxyhexanethiol,
respectively, in separate reaction flasks. After 18 h, hemithioacetal
formation was complete by TLC and the two solutions were mixed.
After 2 h, TFAA and then BF3·OEt2 were added to complete
the cyclisation process. Oxindoles 14 (68%) and 19 (80%) were
1
isolated with no cross-over products observed in the crude H
NMR (Scheme 6).
Scheme 3 N-Arylation in an approach to glyoxamide substrates.
Scheme 4 Functionalised thiols in the synthesis of benzazepinones.
Scheme
6
Investigating the mechanism of the Pummerer-type
cyclisations.
This experiment confirms that equilibria between thiols and
glyoxamides lie well over to the side of the hemithioacetal as
no thiol-exchange is observed upon mixing. In addition, the
lack of cross-over products would appear to rule out alternative
mechanisms involving breakdown of hemithioacetals and addition
of thiols to the 3-position of oxindoles formed by cyclisations
of ‘free’ glyoxamides. Our current understanding of the reaction
mechanism therefore remains consistent with that proposed in
Scheme 1: hemithioacetal formation, activation of the hemithioac-
etal intermediate by trifluoroacetylation, elimination to give a
thionium ion, and intramolecular addition of a nucleophile.
Scheme 5 The use of sub-stoichiometric amounts of Lewis acid in the
connective Pummerer-type cyclisation.
The connective Pummerer-type cyclisations of bis-glyoxamides
We have also examined the reaction of bis-1,3-glyoxamides
and bis-1,4-glyoxamides with thiols. Bis-1,3-glyoxamides 39–41
were conveniently prepared, in two-directional fashion, from
diaminobenzenes 33–35 (Scheme 7).
Although the overall yields for the two-directional Pummerer-
type cyclisations of bis-glyoxamides are somewhat lower than
We have carried out preliminary studies to probe the mech-
anism of the Pummerer-type cyclisations. As previously stated,
omitting either TFAA or the Lewis acid led to the observation
of hemithioacetal or trifluoroacetylated hemithioacetal interme-
diates. Only electron-rich glyoxamide 12 underwent cyclisation to
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Table 3 Connective Pummerer cyclisations of a 1,4 bis-glyoxamidea,b
RSH
Isolated yieldb
Product
linear : bentc,d
PhSH
55%
54%
48
49
>5 : 1
5 : 1
61%
55%
50
51
~3 : 1
>5 : 1
57%
52
2 : 1
a See Table 1 for reagents and conditions. b Yields are for 2 steps as
glyoxamides are not purified. c Regioisomeric ratios are obtained from
1H NMR. d Each regioisomer is a 1 : 1 mixture of diastereoisomers.
Scheme 7 Two-directional synthesis of bis-glyoxamide substrates.
(approximately 2 : 1 to >5 : 1). The use of bulkier thiols such
as thiophenol and p-bromobenzylthiol gave more linear isomer
presumably due to unfavourable steric interactions involved in
the formation of the bent isomers. Both the linear and bent
regioisomers were obtained as ~1 : 1 mixtures of cis and trans di-
astereoisomers. In most cases regioisomeric bis-oxindole products
could be separated by chromatography (e.g. 52) or recrystallisation
(e.g. 49) (Table 3).
those obtained with simple glyoxamides, the expected products are
obtained in acceptable yields and good purity. To the best of our
knowledge these represent the first examples of two–directional
thionium ion cyclisations (Table 2 and Table 3). In the case of bis-
1,3-glyoxamides, the oxindole products were obtained as single,
linear regioisomers and inseparable ~1 : 1 mixtures of cis and trans
diastereoisomers.
The analogous reactions of a 1,4-bis-glyoxamide proceeded
to give oxindoles with the linear regioisomers predominating
The symmetry present in the linear and bent isomers of 48–
52 does not allow the isomers to be distinguished by NMR. The
nature of the isomers obtained from the cyclisation of bis-1,4-
glyoxamides was determined by the following experiments: after
the isolation of the major pair of isomers from the reactions to
Table 2 Connective Pummerer cyclisations of bis-1,3-glyoxamidesa,b
11
form 51 and 52, independent treatment of each mixture with SmI2
gave a single product 53 in good yield after reductive removal of the
sulfanyl groups12 (Scheme 8). Thus, the major isomer pairings from
each reaction are diastereoisomers and the major isomer pairs for
51 and 52 belong to the same regioisomeric family. The identity of
the major regioisomers was confirmed by partial SmI2 reduction
of 52 to break the symmetry and provide 54. The presence of two
singlets in the 1H NMR spectrum for the aromatic protons in 54
confirmed the major products of cyclisation to be linear isomers
(Scheme 8).
R2SH
R1
Isolated yieldb
Product
BnSH
PhSH
n-Pr
n-Pr
n-Pr
51%
47%
45%
42c
43c
44c
Application in a synthesis of neocryptolepine
n-Pr
56%
45c
We have utilised the connective Pummerer-type cyclisation in a
synthesis of the indoloquinoline natural product neocryptolepine
65. Neocryptolepine was isolated from Cryptolepis sanguinolenta13
and has been shown to display cytotoxicity through the inhibi-
tion of DNA topoisomerase II activity.14 Neocryptolepine and
its analogues have also been shown to be sequence-selective
BnSH
PhSH
Bn
Bn
62%
45%
46c
47c
a See Table 1 for reagents and conditions. b Yields are for 2 steps as
glyoxamides are not purified. c 1 : 1 to 1 : 1.5 mixture of diastereoisomers.
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Scheme
8 Determining the regioselectivity of the cyclisation of
1,4-bis-glyoxamides.
DNA intercalators.15 Our synthesis began with the protection
of phenylamine with the 2-phenylsulfonylethyl (PSE) group16
(phenylvinylsulfone, MeOH, MW 20 min, 76%) and straightfor-
ward conversion of 55 to the corresponding hydroxyamide 57.
After oxidation to the glyoxamide, the connective Pummerer-
type cyclisation was carried out by treatment with the fluorous
thiol C8F17CH2CH2SH, under our standard conditions, to give
59 in 67% after two steps. As the resultant oxindole contains a
fluorous tag, conventional chromatography can be avoided and
fluorous solid-phase extraction (FSPE)17 can be used for rapid
purification, as we have previously shown.3 Alkylation of the
oxindole skeleton with 2-nitrobenzylbromide is facilitated by the
alkylsulfanyl group introduced in the Pummerer-type cyclisation
and gave 61 in 75% after FSPE. Sequential reductive removal
of the fluorous tag18 and nitro group reduction, using SmI2,
according to our recently reported procedure,3d and cyclisation
with acid, gave 63 in 83% yield. Finally, one-pot removal of the PSE
group and N-methylation gave neocryptolepine 65 in 69% yield
(Scheme 9).
Scheme 9 Synthesis of neocryptolepine and an analogue (PSE =
CH2CH2SO2Ph).
studies, we have varied the thiol and glyoxamide components and
also the choice of Lewis acid, and have made observations regard-
ing the mechanism of the process. We have utilised the connective
Pummerer-type cyclisation in a synthesis of the indolquinoline ring
system and the natural product neocryptolepine. We continue to
explore the utility of the connective Pummerer process.
Experimental
General Procedure A for the connective Pummerer cyclisation
reactions
Our route to neocryptolepine illustrates the utility of the
connective Pummerer-type cyclisation of substrates having a
protecting group on nitrogen. The route to the indoloquinoline
ring system can easily be modified to allow analogues of the natural
product to be prepared for biological evaluation, for example, the
approach has been used to convert protected 4-methylphenylamine
56 to neocryptolepine analogue 66.
1-Methyl-3-phenylsulfanyl-1,3-dihydroindol-2-one 1319
To a solution of 9 (105 mg, 0.64 mmol, 1 eq) in CH2Cl2 (10 ml) was
added thiophenol (66 ml, 0.64 mmol, 1 eq) at room temperature.
After 18 h, TFAA (823 ml, 5.82 mmol, 9 eq) was added. After a
further 1 h, BF3·OEt2 (398 ml, 3.20 mmol, 5 eq) was added. After
1 h, the reaction was quenched with aqueous NaHCO3 (25 ml),
the organic layer was washed with aqueous NaHCO3 (2 ¥ 20 ml),
dried (MgSO4), filtered and concentrated in vacuo to give an orange
oil. Purification by column chromatography using 30% EtOAc in
petroleum ether as eluant, gave 13 (103 mg, 0.40 mmol, 63% from
hydroxyamide, 2 steps) as an oil. dH (500 MHz, CDCl3) 2.85 (3H, s,
NCH3), 4.39 (1H, s, CHS), 6.47 (1H, d, J = 7.8 Hz, ArH), 6.90
(1H, t, J = 7.8 Hz, ArH), 7.00 (2H, t, J = 7.8 Hz, 2 ¥ ArH),
7.05–7.10 (3H, m, 3 ¥ ArH) and 7.19–7.22 (2H, m, 2 ¥ ArH).
dC (75 MHz, CDCl3) 26.5 (CH3), 49.4 (CHS), 108.3 (ArCH),
123.0 (ArCH), 125.5 (ArCH), 126.5 (ArCH), 128.8 (ArCH), 128.9
Conclusions
We have begun to assess the scope of a connective Pummerer-type
process in which thionium ions are generated by the coupling of
thiols with reactive aldehydes. The use of glyoxamides bearing an
aromatic nucleophile as the reactive aldehyde component, allows
N-heterocycles to be prepared by intramolecular additions to the
thionium ion. Extension of this method has allowed us to carry
out the first, two-directional Pummerer cyclisations. During our
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(ArCH), 129.3 (ArCH), 131.2 (ArC), 129.9 (ArC), 133.9 (ArCH),
General procedure B for the Pummerer-type cyclisation to
give benzazepinones
134.4 (ArCH), 144.2 (ArC) and 174.6 (C O). nmax/(cm-1) 3054,
=
+
=
2916, 1697 (C O), 1465, 1350, 1085 and 725. m/z (EI mode) 255
1-(Ethoxycarbonylmethoxysulfanyl)-3,4-methylenedioxy-3-propyl-
1,3,4,5-tetrahydro-benzo[d]azepin-2-one 30
(M+, 24%), 218 (14%), 146 (100%), 118 (10%) and 91 (6%). m/z
(M + H) 256.0783, C15H14NOS requires 256.0791.
To a stirred solution of glyoxamide 29 (69 mg, 0.26 mmol, 1 eq)
in CH2Cl2 (3 ml) was added ethylthioglycolate (29 ml, 0.26 mmol,
1 eq) and the reaction mixture stirred at room temperature for 18 h.
TFAA (335 ml, 2.37 mmol, 9 eq) was added followed by BF3·OEt2
(162 ml, 1.32 mmol, 5 eq) after a further 1 h. After 1 h, the reaction
was quenched with aqueous saturated NaHCO3 (5 ml), and the
organic layer washed with aqueous saturated NaHCO3 (2 ¥ 5 ml).
The organic layer was dried (Na2SO4), filtered and concentrated in
vacuo. Purification by column chromatography using 15% EtOAc
in petroleum ether as eluant gave 30 (61 mg, 0.17 mmol, 65% from
hydroxyamide, 2 steps) as a yellow oil. dH (500 MHz, CDCl3) 0.84
(3H, t, J = 7.6 Hz, CH3), 1.24 (3H, t, J = 7.1 Hz, CH3), 1.50–1.57
(2H, m, CH2CH2N), 2.90–2.99 (2H, m, CH2), 3.19–3.27 (2H, m,
1H of CH3CH2CH2N and 1H of NCH2CH2ArC), 3.27 (1H, d, J =
16.0 Hz, 1H of CH2S), 3.41–3.47 (1H, m, 1H of CH3CH2CH2N),
3.55 (1H, d, J = 16.0 Hz, 1H of CH2S), 4.16 (2H, q, J = 7.1 Hz,
CH2CH3), 4.45–4.51 (1H, m, 1H of NCH2CH2ArC), 4.86 (1H, s,
CHS), 5.84 (1H, d, J = 1.25 Hz, 1H of OCH2O), 5.86 (1H, d,
J = 1.25 Hz, 1H of OCH2O), 6.44 (1H, s, ArCH) and 6.73 (1H, s,
ArCH). dC (125 MHz, CDCl3) 11.3 (CH3), 14.2 (CH3), 21.2 (CH2),
33.8 (CH2), 34.5 (CH2S), 45.7 (CH2N), 50.3 (CH2N), 55.5 (CHS),
61.6 (CH2CH3), 101.3 (CH2), 109.7 (ArCH), 111.6 (ArCH), 124.7
Pummerer-type cyclisation with Fmoc-protected cysteine derivative
using Sc(OTf)3-2-(9H-fluoren-9-ylmethoxycarbonylamino)-
3-(5-fluoro-2-oxo-1-propyl-2,3-dihydro-1H-indol-3-ylsulfanyl)-
propionic acid methyl ester 22b
To a solution of glyoxamide 11 (70 mg, 0.33 mmol, 1 eq) in CH2Cl2
(3 ml) was added 2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-
mercaptopropionic acid methyl ester (116 mg, 0.33 mmol, 1 eq)
at room temperature. After 18 h, TFAA (284 ml, 2.00 mmol,
6 eq) was added and, after a further 1 h, Sc(OTf)3 (329 mg,
0.67 mmol, 2 eq) was added. After 1 h, the reaction was quenched
with NaHCO3 (15 ml) and CH2Cl2 (15 ml) added, the organic
layer was washed with NaHCO3(aq) (2 ¥ 15 ml), dried (Na2SO4),
filtered and concentrated in vacuo to give a clear oil. Purification
by column chromatography using 30% EtOAc in petroleum ether
as eluant to give 22b (93 mg, 0.17 mmol, 53% from hydroxyamide,
2 steps) as a clear oil (1 : 1 mixture of diastereoisomers). [a]D
=
8.0 (c = 1.75, CH2Cl2). dH (500 MHz, CDCl3) 0.84 (3H, t, J =
7.3 Hz, CH3), 0.88 (3H, t, J = 7.3 Hz, CH3), 1.56–1.63 (4H, m,
2 ¥ CH2), 2.89 (1H, d, J = 7.3 and 13.9 Hz, 1H of CH2CHS
one isomer), 2.97 (1H, d, J = 4.1 and 14.2 Hz, 1H of CH2CHS
one isomer), 3.34 (1H, d, J = 4.1 and 14.2 Hz, 1H of CH2CHS one
isomer), 3.39 (1H, d, J = 6 and 14.2 Hz, 1H of CH2CHS one
=
(ArC), 131.2 (ArC), 146.6 (ArC), 147.7 (ArC), 169.1 (C O amide)
and 169.8 (C O ester). nmax/(cm-1) 2864, 2920, 1733, 1643, 1504,
=
=
isomer), 3.54–3.60 (4H, m, 2 ¥ CH2N), 3.69 (3H, s, CH3OC O
1486, 1386, 1268, 1226, 1153, 1036 and 867. m/z (ES+ mode)
388 ((M + Na)+ 100%) and 366 ((M + H)+ 23%). m/z (M + Na)
388.1184, C18H23NNaO5S requires 388.1189.
=
one isomer), 3.69 (3H, s, CH3OC O one isomer), 4.12–4.19 (2H,
=
m, 2 ¥ CHCH2OC O), 4.22 (1H, s, CHS one isomer), 4.25–4.35
=
(5H, m, 2 ¥ C OOCH2CH and CHS one isomer), 4.57–4.64 (2H,
m, 2 ¥ CHCH2S), 6.00 (1H, d, J = 7.9 Hz, 1 ¥ NH one isomer),
6.64–6.68, (2H, m, 2 ¥ ArH both isomers), 6.72 (1H, d, J = 8.5 Hz,
1 ¥ NH one isomer), 6.89–6.93 (2H, m, 2 ¥ ArH both isomers),
6.98–7.06 (2H, m, 2 ¥ ArH both isomers), 7.16–7.23 (4H, m, 4 ¥
ArH both isomers), 7.27–7.32 (4H, m, 4 ¥ ArH both isomers),
7.54–7.58 (4H, m, 4 ¥ ArH both isomers) and 7.63–7.67 (4H,
m, 4 ¥ ArH both isomers). dC (125 MHz, CDCl3) 11.3 (CH3),
11.4 (CH3), 20.7 (CH2 one isomer), 20.7 (CH2), 32.5 (CH2S), 32.9
(CH2S), 42.0 (CH2N), 42.1 (CH2N), 44.1 (CHS), 45.4 (CHS),
General procedure C for the two-directional Pummerer-type
cyclisations of bis-glyoxamides
3,5-Bis-benzylsulfanyl-1,7-dipropyl-5,7-dihydro-1H,
3H-pyrrolo[3,2-f ] indole-2,6-dione 42
To a stirred solution of bis-glyoxamide 39 (90 mg, 0.30 mmol,
1 eq) in CH2Cl2 (4 ml) was added benzyl thiol (70 ml, 0.60 mmol,
2.0 eq) and the reaction stirred at room temperature for 18 h.
TFAA (761 ml, 5.27 mmol, 18 eq) was added and after a further
1 h, BF3·Et2O (410 ml, 2.93 mmol, 10 eq) was also added.
After stirring for 1 h, the reaction was quenched with NaHCO3
(20 ml), the organic layer was washed with NaHCO3 (2 ¥ 30 ml),
dried (MgSO4), filtered and concentrated in vacuo. Purification by
column chromatography using 30% EtOAc in petroleum ether as
eluant gave 42 (769 mg, 0.15 mmol, 51% from bis-hydroxyamide,
2 steps) as a dark oil (1 : 1 mixture of diastereoisomers). dH
(500 MHz, CDCl3) 0.92 (6H, t, J = 7.4 Hz, 2 ¥ CH3), 1.60–1.66
(4H, m, 2 ¥ CH2), 3.53–3.58 (4H, m, 2 ¥ NCH2), 3.65 (1H, d, J =
13.2 Hz, 1H of CH2S), 3.69 (1H, d, J = 13.1 Hz, 1H of CH2S),
4.01 (1H, s, CHS), 4.03 (1H, s, CHS), 4.13 (1H, d, J = 13.2 Hz,
1H of CH2S), 4.14 (1H, d, J = 13.1 Hz, 1H of CH2S), 6.14 (1H, s,
ArH) and 7.14–7.31 (11H, m, 1H of ArH and 10H of benzyl
groups). dC (75 MHz, CDCl3) 11.7 (2 ¥ CH3), 21.2 (2 ¥ CH2),
34.6 (2 ¥ CH2S), 42.1 (2 ¥ CH2N), 43.0 (2 ¥ CHS), 91.0 (ArCH),
118.9 (2 ¥ ArC), 122.5 (2 ¥ ArCH), 127.5 (ArCH), 127.6 (ArCH),
=
=
47.1 (CHCH2OC O), 47.2 (CHCH2OC O), 52.8 (CH3O), 52.9
=
(CH3O), 53.4 (CHCH2S), 54.5 (CHCH2S), 67.1 (C OOCH2CH),
=
67.3 (C OOCH2CH), 109.2 (ArCH, d, J = 8.8 Hz), 109.3 (ArCH,
d, J = 8.8 Hz), 113.4 (ArCH, d, J = 25 Hz), 113.6 (ArCH,
d, J = 25 Hz), 115.7 (ArCH, d, J = 23.75 Hz), 115.8 (ArCH,
d, J = 23.75 Hz), 119.9 (2 ¥ ArCH), 120.0 (2 ¥ ArCH), 125.2
(2 ¥ ArCH), 125.3 (2 ¥ ArCH), 127.0 (ArCH), 127.1 (ArCH),
127.1 (ArCH), 127.2 (ArCH), 127.3 (ArCH), 127.4 (ArCH), 127.7
(ArCH), 127.7 (ArCH), 139.0 (ArC), 139.5 (ArC), 141.3 (ArC),
141.3 (ArC), 143.7 (ArC), 143.9 (ArC), 144.0 (2 ¥ ArC), 156.1
(2 ¥ ArC), 159.2 (ArCF, d, J = 240 Hz), 159.2 (ArCF, d, J =
=
=
=
=
240 Hz), 170.9 (C O amide), 171.0 (C O amide), 175.4 (C O
ester) and 175.4 (C O ester). nmax/(cm-1) 3337, 3064, 2962, 1717
=
(C O), 1612, 1489, 1452, 1342, 1266, 1135, 1051 and 815. m/z
(ES+ mode) 607 (22%), 571 ((M + Na)+ 100%), 566 (40%) and
+
549 (14%). m/z (M + NH4 ) 566.2121, C30H33FN3O5S requires
566.2119.
594 | Org. Biomol. Chem., 2009, 7, 589–597
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128.7 (2 ¥ ArCH), 128.8 (2 ¥ ArCH), 129.5 (2 ¥ ArCH), 129.6
n
max/(cm-1) 2930, 2858, 1699, 1475, 1348, 1241, 1211, 1150, 1087
(ArCH), 137.5 (ArC), 137.6 (ArC), 144.8 (ArC), 144.9 (ArC) and
and 956. m/z (ES+ mode) 857 (M + Na, 100%). m/z (M + Na)
857.2061, C32H35F17N2NaO2S requires 857.2040.
-1
=
=
176.3 (2 ¥ C O). nmax/(cm ) 3410, 3061, 2966, 1714 (C O), 1614,
1487, 1372, 1208 and 1129. m/z (EI+ mode) 516 (M+, 7%), 393
(16%), 124 (8%), 91 (100%), 77 (16%) and 65 (43%). m/z (M + H)
517.1978, C30H33N2O2S2 requires 517.1987.
1-(2-Benzenesulfonylethyl)-3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
heptadecafluorodecylsulfanyl)-1,3-dihydroindol-2-one 59
To a solution of oxalyl chloride (0.66 ml, 7.56 mmol, 1.1 eq) in
CH2Cl2 (25 ml) was added DMSO (0.98 ml, 13.7 mmol, 2 eq) at
-78 ◦C. After 10 min, 57 (2.19 g, 6.87 mmol, 1 eq.) in CH2Cl2
(25 ml) was added. After a further 1 h, Et3N (4.79 ml, 34.0 mmol,
5 eq) was added and the reaction was allowed to warm to room
temperature. After 3.5 h, NaHCO3 (50 ml) was added to the
reaction mixture and the organic layer was extracted with CH2Cl2
(3 ¥ 50 ml), then the organic layers were dried (MgSO4) and
concentrated in vacuo to give the crude glyoxamide, which was
used without further purification.
To the crude glyoxamide in CH2Cl2 (75 ml) was added
3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluoro-decane-1-
thiol (1.41 ml, 4.81 mmol, 0.7 eq) and the reaction stirred for 18 h at
room temperature. Trifluoroacetic anhydride (8.73 ml, 61.8 mmol,
9 eq) was added, stirred for 1 h, then BF3·OEt2 (4.24 ml, 34.3 mmol,
5 eq) was added and the reaction mixture was left for 3 h. The
reaction mixture was quenched with NaHCO3 (70 ml), extracted
with CH2Cl2 (3 ¥ 50 ml), and the organic layers dried (Na2SO4)
and concentrated in vacuo. The crude mixture was purified using
FSPE to give 59 as a white solid (2.52 g, 3.23 mmol, 67% over 2
steps). Mp 81–83 ◦C (recrystallised from MeOH). dH (400 MHz,
CDCl3) 2.32–2.44 (2H, m, CH2C8F17), 2.77–2.84 (1H, m, SCHH),
2.93–3.00 (1H, m, SCHH), 3.42–3.49 (1H, m, NCHH), 3.53–3.60
General procedure D for the removal of the organosulfanyl groups
using SmI2
1,5-Dihexyl-5,7-dihydro-1H,3H-pyrrolo[2,3-f ]indole-2,6-dione 53
from 52
To a stirred solution of 52 (95 mg, 0.07 mmol, 1eq) in THF (6 ml)
was added SmI2 (3.10 ml of a 0.1 M solution in THF, 4.4 eq) at
room temperature. After 14 h, the reaction mixture was opened
to air and aqueous saturated NaHCO3 (15 ml) was added. The
aqueous layer was extracted with EtOAc (3 ¥ 20 ml), the organic
layer dried (Na2SO4) and concentrated in vacuo. Purification by
column chromatography using 40% EtOAc in petroleum ether as
eluant gave 53 (19 mg, 0.05 mmol, 74%) as a grey solid. Mp 149.3–
151.2 ◦C (recrystallised from EtOAc and petroleum ether). dH
(500 MHz, CDCl3) 0.80–0.83 (6H, m, 2 ¥ CH3), 1.18–1.31 (12H,
m, 2 ¥ CH2CH2CH2CH3), 1.57–1.60 (4H, m, 2 ¥ NCH2CH2), 3.48
=
(4H, s, 2 ¥ (C O)CH2), 3.61 (4H, t, J = 7.4 Hz, 2 ¥ NCH2) and 6.71
(2H, s, 2 ¥ ArH). dC (75 MHz, CDCl3) 14.3 (2 ¥ CH3), 22.8 (2 ¥
CH2), 26.9 (2 ¥ CH2), 27.7 (2 ¥ NCH2CH2), 31.7 (2 ¥ CH2), 36.6
=
(2 ¥ (C O)CH2), 40.4 (2 ¥ NCH2), 106.0 (2 ¥ ArCH), 124.2 (2 ¥
ArC), 140.0 (2 ¥ ArC) and 174.6 (2 ¥ C O). nmax/(cm-1) (CH2Cl2
=
=
evaporated film) 2952, 2929, 2854, 1710 (C O), 1676, 1478, 1360
and 1128. m/z (CI+ mode) 357 (M+, 100%), 251 (17%), 242 (20%),
210 (20%), 138 (40%), 122 (25%) and 110 (15%). m/z (M + H)
357.2547, C22H33N2O2 requires 357.2537.
=
(1H, m, NCHH), 4.11–4.16 (3H, m, CH2SO2 and CHC O), 6.93
(1H, d, J = 8.3 Hz, ArCH), 7.13 (1H, dt, J = 7.5 and 1.2 Hz,
ArCH), 7.34–7.38 (2H, ArCH), 7.53–7.57 (2H, m, ArCH), 7.67
(1H, tt, J = 7.6 and 1.3 Hz, ArCH), 7.88–7.91 (2H, m, ArCH).
dC (100 MHz, CDCl3) 21.2 (CH2), 31.8 (CH2C8F17), 34.4 (SCH2),
Removal of a single organosulfanyl group using SmI2
=
44.5 (CHC O), 52.3 (NCH2), 108.7 (ArCH), 123.5 (ArCH), 124.9
3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluoro-
decylsulfanyl)1,5-dihexyl-5,7-dihydro-1H,3H-pyrrolo[2,3-f ]-
indole-2,6-dione 54
(ArC), 125.5 (ArCH), 127.9 (2 ¥ ArCH), 129.4 (2 ¥ ArCH),
129.7 (ArCH), 134.1 (ArCH), 138.7 (ArCSO2), 142.0 (ArCN),
175.0 (C O). nmax/cm-1 3443 (OH), 3062, 2961, 1716 (C O), 1612,
=
=
+
=
To a stirred solution of 52 (90 mg, 0.07 mmol, 1 eq) in THF
(5 ml) was added SmI2 (0.70 ml of a 0.1 M solution in THF, 1 eq)
at room temperature. After 5 min, the reaction was quenched
with air and aqueous saturated NaHCO3 (20 ml) added to the
reaction mixture. The aqueous layer was extracted with EtOAc
(3 ¥ 15 ml), the organic layers dried (Na2SO4), and concentrated in
vacuo. Purification by column chromatography using 20% EtOAc
in petroleum ether as eluant gave recovered 52 (17 mg, 0.01 mmol,
18%), 54 (25 mg, 0.03 mmol, 43%) as a yellow oil and 53 (3 mg,
0.009 mmol, 11%). For 54: dH (500 MHz, CDCl3) 0.81 (3H, t, J =
7.2 Hz, CH3), 0.82 (3H, t, J = 7.2 Hz, CH3), 1.21–1.33 (12H, m,
2 ¥ CH2CH2CH2CH3), 1.51–1.61 (4H, m, 2 ¥ CH2 CH2N), 2.32–
2.41 (2H, m, CH2CF2), 2.72–2.78 (1H, m, 1H of CH2S), 2.87–2.93
1487, 1467, 1359, 1306, 1086 (S O). m/z(ES mode) 802 ((M +
Na)+, 100%), 797 (30%), 441 (15%), 197 (20%), 151 (30%), 101
(20%). m/z (M + Na)+ 802.0349, C26H18F17NNaO3S2 requires
802.0343.
1-(2-Benzenesulfonylethyl)-3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
heptadecafluorodecylsulfanyl)-3-(2-nitrobenzyl)-1,3-dihydroindol-
2-one 61
To a solution of 59 (0.69 g, 0.86 mmol, 1 eq) in DMF (15 ml) was
added K2CO3 (0.60 g, 4.43 mmol, 5 eq) and 2-nitrobenzyl bromide
(0.57 g, 2.66 mmol, 3 eq) at room temperature and the reaction
mixture was allowed to stir for 18 h. H2O (15 ml) was added and
the mixture extracted with Et2O (3 ¥ 15 ml). The organic layer was
washed with H2O (5 ¥ 15 ml), dried (Na2SO4) and concentrated in
vacuo. The crude mixture was purified using FSPE to give 61 as a
clear, viscous oil (0.60 g, 0.66 mmol, 75%). dH (400 MHz, CDCl3)
2.05–2.13 (2H, m, CH2C8F17), 2.55–2.62 (2H, m, CH2SO2), 2.90–
2.97 (1H, m, SCHH), 3.06–3.14 (1H, m, SCHH), 3.64 (1H, d, J =
13.9 Hz, CHHAr), 3.76–3.84 (1H, m, CHHN), 3.91–3.99 (1H,
=
(1H, m, 1H of CH2S), 3.49 (2H, s, CH2C O), 3.55–3.70 (4H,
m, 2 ¥ CH2N), 4.26 (1H, s, CHS), 6.74 (1H, s, ArCH) and 6.81
(1H, s, ArCH). dC (125 MHz, CDCl3) 14.0 (CH3), 14.0 (CH3), 20.9
(2 ¥ CH2), 22.5 (CH2), 22.6 (CH2), 26.6 (CH2), 27.4 (CH2), 29.7
(CH2), 31.5 (CH2CF2), 36.8 (CH2), 40.3 (CH2N), 40.5 (CH2N),
45.2 (CHS), 106.1 (ArCH), 106.2 (ArCH), 124.5 (ArC), 125.8
=
=
(ArC), 138.5 (ArC), 140.4 (ArC), 174.1 (C O) and 174.3 (C O).
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m, CHHN), 4.02 (1H, d, J = 13.9 Hz, CHHAr), 6.66 (1H, d,
J = 7.8 Hz, ArCH), 7.05 (1H, dt, J = 7.5 and 1.0 Hz, ArCH),
7.13 (1H, dd, J = 7.6 and 1.0 Hz, ArCH), 7.19–7.26 (3H, m, 3 ¥
ArCH), 7.34 (1H, dt, J = 7.6 and 1.2 Hz, ArCH), 7.54–7.55 (3H,
m, 3 ¥ ArCH), 7.64–7.69 (1H, m, ArCH), 7.87–7.89 (2H, m, 2 ¥
ArCH). dC (100 MHz, CDCl3) 20.0 (CH2SO2), 31.0 (CH2C8F17),
33.8 (NCH2), 37.6 (CH2Ar), 52.3 (SCH2), 55.0 (C), 108.4 (ArCH),
124.1 (ArCH), 124.9 (ArCH), 125.0 (ArCH), 127.4 (ArC), 128.0
(2 ¥ ArCH), 128.5 (ArCH), 129.2 (ArC), 129.6 (2 ¥ ArCH),
130.0 (ArCH), 132.4 (ArCH), 133.5 (ArCH), 134.3 (ArCH), 138.5
(400 MHz, CDCl3) 7.24–7.30 (1H, m, ArCH), 7.46–7.56 (3H, m,
3 ¥ ArCH), 7.70–7.75 (1H, m, ArCH), 7.98 (1H, d, J = 8.5 Hz,
ArCH), 8.11 (1H, d, J = 8.3 Hz, ArCH), 8.27 (1H, d, J = 7.5 Hz,
ArCH), 9.06 (1H, s, ArCH), 11.7 (1H, s, NH). dC (75 MHz,
CDCl3) 110.9 (ArCH), 117.9 (ArC), 119.7 (ArCH), 120.3 (ArC),
121.8 (ArCH), 122.7 (ArCH), 123.7 (ArC), 127.0 (ArCH), 127.5
(ArCH), 128.2 (2 ¥ ArCH), 128.6 (ArCH), 141.5 (ArC), 144.4
(ArC), 152.9 (ArC). m/z (ES+ mode) 219 ((M + H)+, 10%), 179
(100%), 101 (40%).
(ArC), 140.6 (ArC), 149.8 (ArC), 175.5 (C O). nmax/cm-1 2395,
Neocryptolepine 6513,20,21
=
+
=
=
1716 (C O), 1682, 1651, 1560, 1505, 1086 (S O). m/z (ES mode)
937 ((M + Na)+, 10%), 179 (50%), 142.2 (50%). m/z (M + Na)+
937.0669 C33H23F17N2NaO5S2 requires 937.0660.
11H-10,11-Diazabenzo[b]fluorene (0.017 g, 0.078 mmol, 1 eq) was
suspended in THF (0.5 ml) and methyl iodide was added (0.034 ml,
0.54 mmol, 7 eq). The reaction was heated under reflux for 18 h
and then concentrated in vacuo. The crude mixture was dissolved
in CH2Cl2 (3 ml), NaHCO3 (3 ml) was added and the organic
layer extracted with CH2Cl2 (3 ¥ 3 ml). The combined organic
layers were dried (Na2SO4), concentrated in vacuo and purified by
column chromatography using 80% EtOAc in petroleum ether as
eluant to give 65 as an orange solid (0.013 g, 0.054 mmol, 70%).
(Analytic◦al data was in agreement with the literature.)13,20,21 Mp
112–114 C (recrystallised from hexane). dH (400 MHz, CDCl3)
4.32 (3H, s, Me), 7.15–7.20 (1H, m, ArCH), 7.38–7.42 (1H, m,
ArCH), 7.49 (1H, t, J = 7.6 Hz, ArCH), 7.70 (1H, d, J = 7.9 Hz,
ArCH), 7.72 (2H, apparent d, J = 3.9 Hz, 2 ¥ ArCH), 7.95 (1H,
d, J = 7.6 Hz, ArCH), 8.00 (1H, d, J = 7.6 Hz, ArCH), 8.49
(1H, s, ArCH). dC (75 MHz, CDCl3) 32.1 (Me), 113.2 (ArCH),
116.6 (ArCH), 118.9 (ArCH), 119.9 (ArC), 120.0 (ArCH), 121.0
(ArCH), 122.9 (ArC), 127.1 (ArC), 127.2 (ArCH), 128.3 (ArCH),
129.0 (ArCH), 129.5 (ArCH), 135.9 (ArC), 154.0 (ArC), 155.0
(ArC). m/z (ES+ mode) 233 ((M + H)+, 40%), 218 (100%), 107
(90%). m/z 233.1069, C16H13N2 requires 233.1073.
11-(2-Benzenesulfonylethyl)-11H-10,11-diaza-benzo[b]fluorene 63
To a solution of SmI2 in THF (31.0 ml, 0.1 M, 3.10 mmol, 9 eq) was
added a degassed solution of 61 (0.31 g, 0.34 mmol, 1 eq) in THF
(3 ml) and MeOH (1.5 ml). The solution was allowed to stir for
4 h and then exposed to air. Saturated, aqueous Na2S2O3 (30 ml)
was added, the aqueous layer extracted with Et2O (3 ¥ 30 ml), and
the combined organic layers dried (Na2SO4) and concentrated in
vacuo. Purification by column chromatography using 50% EtOAc
in petroleum ether as eluant gave the aniline intermediate which
was then directly dissolved in a MeOH : AcOH (1 : 1) mix (20 ml)
and heated to 100 ◦C for 18 h. K2CO3 was added to the mixture
until basic pH was reached, the organic layer was extracted with
EtOAc (3 ¥ 20 ml), the combined organic layers dried (Na2SO4)
and concentrated in vacuo. The crude mixture was purified by
column chromatography using 20% EtOAc in petroleum ether as
eluant to◦give 63 as a white solid (0.11 g, 0.25 mmol, 82%). Mp
103–105 C (recrystallised from MeOH). dH (400 MHz, CDCl3)
3.98 (2H, t, J = 7.0 Hz, SCH2), 4.89 (2H, t, J = 7.0 Hz, NCH2),
7.13–7.17 (2H, m, 2 ¥ ArCH), 7.20 (1H, dt, J = 7.2 and 1.0 Hz,
ArCH), 7.31–7.39 (3H, m, 3 ¥ ArCH), 7.48 (1H, ddd, J = 8.3, 7.6
and 1.3 Hz, ArCH), 7.59–7.64 (3H, m, 3 ¥ ArCH), 7.85 (1H, dd,
J = 8.0 and 1.5 Hz, ArCH), 7.92–7.94 (2H, m, 2 ¥ ArCH), 8.44
(1H, s, ArCH). dC (100 MHz, CDCl3) 35.9 (NCH2), 53.0 (SCH2),
108.9 (ArCH), 118.0 (ArC), 120.5 (ArCH), 120.6 (ArC), 121.5
(ArCH), 123.3 (ArCH), 124.3 (ArC), 127.3 (ArCH), 127.4 (2 ¥
ArCH), 127.6 (ArCH), 128.3 (ArCH), 128.4 (ArCH), 128.8 (2 ¥
ArCH), 129.0 (ArCH), 133.4 (ArCH), 138.7 (ArC), 141.3 (ArC),
146.5 (ArC), 151.8 (ArC). nmax/cm-1 3334 br, 1650, 1556, 1505,
1455, 1417, 1259, 1123. m/z (ES+ mode) 409 ((M + Na)+, 100%),
284 (20%). m/z (M + Na)+ 409.0981 C23H18N2NaO2S requires
409.0969.
Acknowledgements
We thank GlaxoSmithKline for a CASE award (M. M.),
Novartis (J. V.) and the University of Manchester for funding.
We thank Christopher Knox for preliminary studies towards
neocryptolepine, and Dr Rebecca Butler of Novartis for helpful
discussions.
Notes and references
1 R. Pummerer, Chem. Ber., 1909, 42, 2282.
2 (a) For recent reviews on the Pummerer reaction, see: S. Akai and Y.
Kita, Top. Curr. Chem., 2007, 274, 35; (b) K. S. Feldman, Tetrahedron,
2006, 62, 5003; (c) S. K. Bur and A. Padwa, Chem. Rev., 2004, 104,
2401.
3 (a) L. A. McAllister, R. A. McCormick, S. Brand and D. J. Procter,
Angew. Chem., Int. Ed., 2005, 44, 452; (b) R. A. McCormick, K. M.
James, N. Willetts and D. J. Procter, QSAR Comb. Sci., 2006, 25, 709;
(c) L. A. McAllister, R. A. McCormick, K. M. James, S. Brand, N.
Willetts and D. J. Procter, Chem.–Eur. J., 2007, 13, 1032; (d) K. M.
James, N. Willetts and D. J. Procter, Org. Lett., 2008, 10, 1203;
(e) We have used thionium ions formed in this way in dearomatising
spirocyclisations, see: C. Ovens, N. G. Martin and D. J. Procter, Org.
Lett., 2008, 10, 1441.
4 For thiol addition to glyoxalates, see: J. Milton, S. Brand,
M. F. Jones and C. M. Rayner, Tetrahedron Lett., 1995, 36,
6961.
5 (a) M. Miller, W. Tsang, A. Merritt and D. J. Procter, Chem. Commun.,
2007, 498.
11H-10,11-Diazabenzo[b]fluorene20
Compound 63 (0.10 g, 0.26 mmol, 1 eq) was suspended in
THF (3 ml) and potassium tert-butoxide (0.09 g, 0.79 mmol,
3 eq) was added. The reaction was allowed to stir for 4 h. H2O
(5 ml) was added, the organic layer was extracted with EtOAc
(3 ¥ 5 ml), the combined organic layers dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by column
chromatography using 5% MeOH in CH2Cl2 as eluant to give 11H-
10,11-diazabenzo[b]fluorene as a brown solid (0.056 g, 0.26 mmol,
98%). (Analytical data was in agreement with the literature.)20 dH
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6 M. A. Marx, A.-L. Grillot, C. T. Louer, K. A. Beaver and P. A. Bartlett,
J. Am. Chem. Soc., 1997, 119, 6153.
7 K. Omura and D. Swern, Tetrahedron, 1978, 34, 1651.
8 K. R. Henery-Logan and C. G. Chen, Tetrahedron Lett., 1973, 14,
1103.
9 P. F. van Swieten, M. A. Leeuwenburgh, B. M. Kessler and H. S.
Overkleeft, Org. Biomol. Chem., 2005, 3, 20.
14 (a) W. Peczynska-Czoch, F. Pognan, L. Kaczmarek and J. Boratynski,
J. Med. Chem., 1994, 37, 3503; (b) L. Dassonneville, A. Lansiaux, A.
Wattelet, N. Wattez, C. Mahieu, S. Van Miert, L. Pieters and C. Bailly,
Eur. J. Pharm., 2000, 409, 9.
15 J. Osiadacz, J. Majka, K. Czarnecki, W. Peczynska-Czoch, J.
Zakrzewska-Czerw´ınska, L. Kaczmarek and W. A. Sokalski, Bioorg.
Med. Chem., 2000, 8, 937.
10 D. Ma, Q. Cai and H. Zhang, Org. Lett., 2003, 5, 2453.
11 (a) For recent reviews on the use of SmI2, see: D. J. Edmonds, D.
Johnston and D. J. Procter, Chem. Rev., 2004, 104, 3371; (b) H. B.
Kagan, Tetrahedron, 2003, 59, 10351; (c) P. G. Steel, J. Chem. Soc.,
Perkin Trans. 1, 2001, 2727.
12 (a) L. A. McAllister, S. Brand, R. de Gentile and D. J. Procter, Chem.
Commun., 2003, 2380; (b) K. L. Turner, T. M. Baker, S. Islam, D. J.
Procter and M. Stefaniak, Org. Lett., 2006, 8, 329; (c) L. A. McAllister,
K. L. Turner, S. Brand, M. Stefaniak and D. J. Procter, J. Org. Chem.,
2006, 71, 6497.
16 D. DiPietro, R. M. Borzilleri and S. M. Weinreb, J. Org. Chem., 1994,
59, 5856.
17 (a) For recent reviews; see: D. P. Curran, in Handbook of Fluorous
Chemistry, ed. J. A. Gladysz, D. P. Curran, I. T. Horva´th, Wiley-VCH,
Weinheim, 2004; (b) W. Zhang, Tetrahedron, 2003, 59, 4475.
18 For a review of sulfur linkers in phase tag-assisted synthesis, see: L. A.
McAllister, R. A. McCormick and D. J. Procter, Tetrahedron, 2005, 61,
11527.
19 W. B. Motherwell, M. F. Greaney, J. J. Edmunds and J. W. Steed,
J. Chem. Soc., Perkin Trans. 1, 2002, 2816.
13 K. Cimanga, T. De Bruyne, L. Pieters, M. Claeys and A. Vlietinck,
Tetrahedron Lett., 1996, 37, 1703.
20 T.-L. Ho and D.-G. Jou, Helv. Chim. Acta, 2002, 85, 3823.
21 P. Molina, P. M. Fresneda and S. Delgado, Synthesis, 1999, 326.
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The Royal Society of Chemistry 2009
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©