A fluorous, pummerer cyclative-capture strategy for the synthesis of N-heterocycles

Article abstract of DOI:10.1002/chem.200601429

A fluorous, cyclative-capture strategy based on a new Pummerer cyclization process allows rapid access to tagged, heterocyclic frameworks. Convenient modification of the fluorous, heterocyclic scaffolds by using a variety of approaches including Pd-catalyzed cross-couplings is possible. Traceless, reductive cleavage of the fluorous-phase tag or oxidative cleavage and further elaboration, completes a strategy for the high-throughput, fluorous-phase synthesis of a diverse range of N-heterocycles.

Full text of DOI:10.1002/chem.200601429

FULL PAPER
DOI: 10.1002/chem.200601429
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Chem. Eur. J. 2007, 13, 1032 – 1046

FULL PAPER
A Fluorous, Pummerer Cyclative-Capture Strategy for the Synthesis
of N-Heterocycles
Laura A. McAllister,[a] Rosemary A. McCormick,[a] Karen M. James,[b] Stephen Brand,[c]
Nigel Willetts,[d] and David J. Procter*[b]
Abstract: A fluorous, cyclative-capture strategy based on a new Pummerer cycliza-
tion process allows rapid access to tagged, heterocyclic frameworks. Convenient
modification of the fluorous, heterocyclic scaffolds by using a variety of ap-
proaches including Pd-catalyzed cross-couplings is possible. Traceless, reductive
cleavage of the fluorous-phase tag or oxidative cleavage and further elaboration,
completes a strategy for the high-throughput, fluorous-phase synthesis of a diverse
range of N-heterocycles.
Keywords: fluorous-phase synthe-
sis · heterocycles · organic synthesis ·
Pummerer reaction · samarium
Introduction
tag.[3] In recent years, thanks largely to the efforts of Curran
and co-workers, fluorous-phase synthesis has emerged as an
important tool for synthetic chemists.[4] Fluorous-phase syn-
thesis has several advantages over solid-phase synthesis, but
arguably the most important is the ability to monitor reac-
tions by using conventional analytical methods, such as
TLC, HPLC, IR, and NMR.[4] We envisaged that the combi-
nation of fluorous-phase techniques with versatile, sequen-
tial processes that achieve multiple synthetic objectives in a
single operation could lead to efficient routes to important
compound classes. Here we report in full our studies on the
development and evaluation of a fluorous, Pummerer cycla-
tive-capture strategy for the synthesis of N-heterocycles.[5]
Nitrogen-containing, heterocyclic organic compounds in the
form of biologically active drugs or agents play an important
role in the pharmaceutical and agrochemical industries.[1]
The development of new strategies for the assembly of col-
lections of heterocyclic compounds in a rapid and efficient
high-throughput manner is therefore a key activity in syn-
thetic chemistry.[2]
The use of phase tags to facilitate the purification of inter-
mediates during multistep sequences is a common strategy
in synthesis. Whereas solid-phase synthesis involves the use
of insoluble polymers as phase tags, fluorous-phase synthesis
uses a soluble perfluoroalkyl group in place of the polymer
Results and Discussion
[a] Dr. L. A. McAllister, R. A. McCormick
The Pummerer reaction[6] has evolved into a useful tool for
the synthesis of heterocyclic compounds.[7] We have recently
reported a solid-phase approach to oxindoles utilising the
Pummerer cyclization of substrates attached to resin via an
“enabling” sulfur atom.[8] The approach is limited by the
synthetic sequence required to access the immobilized heter-
ocyclic framework (immobilization/oxidation/cyclization). A
more general limitation, common to many solid-phase pro-
cesses, arises from the considerable investment required to
optimize solid-phase sequences due to difficulties monitor-
ing transformations.[9] The work described here was borne
from a need to address these issues and has led to the devel-
opment of a sequential, fluorous process involving a Pum-
merer cyclative-capture step.
Department of Chemistry, The Joseph Black Building
The University of Glasgow, Glasgow G12 8QQ (Scotland)
[b] K. M. James, Dr. D. J. Procter
The School of Chemistry, The University of Manchester
Oxford Road M13 9 PL (UK)
Fax : (+44)161-275-4939
E-mail: David.J.Procter@manchester.ac.uk
[c] Dr. S. Brand
Celltech R&D, 216Bath Road, Slough
Berkshire SL1 4EN (UK)
[d] N. Willetts
Syngenta, Jealottꢁs Hill International Research Centre
Bracknell, Berkshire RG42 6EY (UK)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2007, 13, 1032 – 1046ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. J. Procter et al.
Pummerer cyclative capture: Our approach is based on the
addition of thiols to glyoxamides 1. The resultant hemithioa-
cetals are at the correct oxidation level for activation and
Pummerer cyclization. This constitutes a new, general strat-
egy for generating thionium ions and triggering Pummerer
cyclizations.[10] The use of a thiol containing a phase tag
leads to cyclative capture of the substrate. The choice of a
fluorous thiol[11] allows reactions to be monitored conven-
iently whilst allowing phase-tag assisted purification at each
stage of the process.[3,4] Our approach constitutes the first
example of fluorous, cyclative capture and utilises a fluo-
rous-phase scavenging reagent in a novel manner. Upon
completion of the sequence, the fluorous-phase tag can be
removed in a traceless manner to give a potentially diverse
collection of product heterocycles (Scheme 1).
bered heterocycles (entries 8–17), electronic activation of
the aromatic ring leads to higher yields of product. In con-
trast, the formation of oxindoles (entries 1–7) proceeds effi-
ciently with neutral, electron-deficient and -rich substrates.
Several nitrogen protecting groups, for example, Bn, p-me-
thoxybenzyl (PMB) and 2-phenylsulfonyl ethyl (PSE) have
been shown to be compatible with the reaction conditions
for cyclative capture, thus allowing access to heterocycles
bearing free NH groups.
Developing conditions for the removal of the fluorous tag:
Identifying effective conditions for the efficient removal of
the fluorous tag is crucial to our approach. We decided to
use simple, unmodified, tagged-heterocycles as model sub-
strates to help develop and optimize methods for the remov-
al of the fluorous tag. These conditions would then be used
to access more complex systems in a library synthesis.
We began by examining reductive methods for the “trace-
less” removal of the fluorous tag. A number of electron-
transfer reagents are known to reduce a-heteroatom-substi-
tuted carbonyl compounds to the parent carbonyl com-
pound.[14] By using a range of model tagged substrates, it
[15]
was found that reduction with SmI2 resulted in the clean
removal of the fluorous tag (Figure 1). We have previously
utilised this process in the cleavage of oxygen and sulfur-
linker systems for solid-phase synthesis.[8,16] No additives are
required to activate SmI2,[17] due to the reactive nature of
the carbon–sulfur linkage to the fluorous tag present in our
systems.
Alternative cleavage methods were investigated for use
with the fluorous-phase approach. In particular, we wished
to develop a complimentary oxidative method for the cleav-
age of the sulfur linker. Again, unmodified, tagged heterocy-
cles were used as model substrates. We began by focusing
on the removal of the fluorous tag from oxindole 7 by oxi-
dative cleavage of the sulfur linker by using a Pummerer
process.[18] Selective oxidation of 7 by using BØguØꢁs H2O2-
hexafluoroisopropanol (HFIP) system gave sulfoxide 19,
with no over oxidation.[19] Pummerer cleavage was then car-
ried out by using TFAA to give indoline-1,2-dione 20 in
moderate yield (Scheme 2). We subsequently found that the
Pummerer, oxidative cleavage of 7 could be carried out in a
Scheme 1. Fluorous, Pummerer cyclative-capture strategy (RF =fluorous
alkyl).
single step with ceric(iv) ammonium nitrate (Ce
(NO3)6, CAN), giving 20 in quantitative yield (Scheme 2).[20]
The oxidative removal of the fluorous tag worked well for
ACHTREUNG(NH4)2-
AHCTREUNG
Treatment of readily accessible glyoxamide[12] starting ma-
terials
with
1H,1H,2H,2H-perfluorodecane-1-thiol
a range of tagged oxindoles (Figure 1), giving the expected
1,2-dicarbonyl products in high yield after purification with
FSPE. Interestingly, in the reaction of benzazepinone 15
with CAN, the fluorous tag can be removed in the presence
of the PMB protecting group to give dihydrobenzazepine-
1,2-dione 21 (Figure 1). The only side product from this re-
action is the alternative benzylic oxidation product 22; how-
ever, as this still contains a fluorous tag it is readily removed
from the product mixture during FSPE. FSPE proved effec-
tive in removing the fluorous byproduct after both reductive
and oxidative cleavage, the desired products eluting in the
non-fluorous fraction.
(C8F17CH2CH2SH) results in capture of the substrate
through hemithioacetal formation. In the same reaction pot,
activation (TFAA) and treatment with BF3·OEt2 gave the
product heterocycle in good isolated yield after rapid purifi-
cation by using fluorous-solid-phase extraction (FSPE).[13]
The fluorous-phase, Pummerer cyclative capture of a range
of glyoxamides is shown in Table 1.
Oxindoles (entries 1–7), tetrahydroisoquinolinones (en-
tries 8–10) and tetrahydrobenzazepinones (entries 11–17)
can be prepared by straightforward variation of the glyoxa-
mide substrate. For the formation of six and seven-mem-
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Chem. Eur. J. 2007, 13, 1032 – 1046

Synthesis of N-Heterocycles
FULL PAPER
Table 1. Fluorous, Pummerer cyclative-capture of glyoxamides.[a]
acylation reactions, at either the
sulfide or sulfone oxidation
states. For example, adducts
23[5] and 24 were prepared by
Michael addition while the fluo-
rous oxindole, tetrahydroisoqui-
nolinone and tetrahydrobenza-
zepinone derivatives 25, 26,
28[5] and 29[5] were formed by
alkylation. Ester 27[5] was pre-
pared by O-acylation followed
by DMAP-catalysed rearrange-
ment.[21] In all cases, excess re-
agent can be used to drive reac-
tions to completion as purifica-
tion after each modification
step can be conveniently car-
ried out by using FSPE
(Scheme 3).
Entry
Glyoxamide
Tagged heterocycle[b]
Product Isolated yield [%][c]
1
2
3
65[5]
2
54
3 R=nPr
4 R=PSE
4
5
75[5][d]
55[d]
5 X=Cl, R=Me
6 X=Br, R=nPr
7 X=F, R =Me
6
7
8
79[5]
85[5]
80[5]
Palladium-catalysed
cou-
plings[22] are amongst the most
powerful reactions for library
synthesis and such processes
must be accommodated in any
new high-throughput synthetic
strategy. The transformations il-
lustrated in Scheme 4 show the
compatibility of the linker
system with palladium-cata-
lysed cross-coupling technolo-
gies. For example, sequences to
prepare alkynes 30[5] and 31[5]
include sulfone-assisted alkyla-
tion and Sonagashira cross-cou-
pling.[22,23] Tagged 5-bromooxin-
doles 32[5] and 35[5] readily un-
dergo Suzuki–Miyaura cross-
coupling[22,24] with aryl and het-
eroaryl boronic acids to give
33,[5] 34[5] and 36.[5] Hartwig–
8 X,Y,Z=H, R=Me
9 X=OMe, X,Z=H,
R=nPr
10 X,Y,Z=OMe,
R=n-pentyl
9
10
45[5]
51[5][e]
11
60[5]
11
12
76[5][f]
12 R=n-pentyl
13 R=Bn
14 R=PMB
15 R=PSE
16R =allyl
13
14
15
16
17
98[5]
80
77
100
60
17
18
82[5]
[a] Conditions: C8F17CH2CH2SH, CH2Cl2, 18 h then trifluoroacetic anhydride, 1 h then BF3·OEt2, 1 h see Ex-
perimental Section for details. [b] RF =C8F17CH2CH2. [c] Isolated yield for 2 steps. [d] 5:1 and [e] ꢀ1:1 mixture
of isomers. [f] ꢀ2:1 mixture of isomers. Major isomers shown.
Buchwald
amination[22]
of
tagged substrates was also pos-
sible by using phosphine ligand
37[25] and microwave (MW) as-
sistance.[26] For example, cou-
pling of 32 and 26 with different
With efficient methods for the reductive and oxidative re-
moval of the fluorous tag in place, we next examined the
versatility of the fluorous-tagged heterocycles as frameworks
for library synthesis.
amines gave the expected adducts 38–40 in good yield.
Again, purification after each modification step can be con-
veniently carried out by using FSPE (Scheme 4).
Removal of the fluorous tag: As already illustrated for un-
modified systems (Figure 1), the fluorous tag can be reduc-
tively removed from elaborated heterocyclic systems by
treatment with SmI2. For the cleavage of the linker at the
sulfone oxidation state, the fluorous component is lost to
the aqueous layer during work up and no purification is re-
quired. Cleavage reactions at the sulfide oxidation state can
Elaboration of tagged heterocycles: The Pummerer cycla-
tive-capture process allows convenient access to fluorous-
tagged heterocyclic frameworks. These tagged heterocycles
are versatile scaffolds that can be modified in a variety of
ways. In particular, the sulfur linkage to the fluorous tag can
be used to facilitate elaboration, that is, in alkylation and
Chem. Eur. J. 2007, 13, 1032 – 1046ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. J. Procter et al.
As previously discussed, oxi-
dative cleavage of the sulfide
linker releases heterocycles
bearing a 1,2-dicarbonyl motif
(Figure 1). These compounds
are versatile substrates for the
introduction of structural diver-
sity. After cleavage and FSPE
to remove the fluorous byprod-
uct, modification of the re-
leased heterocycle can be car-
ried out. For example, oxidative
cleavage of tagged oxindoles 7
and 8, FSPE and condensation
with 1,2-phenyldiamine, gave 54
and 55,[27] while fluorination
with diethylaminosulfur trifluor-
ide (DAST) gave difluorooxin-
doles[28] 56 and 57 (Scheme 5).
Similarly, after cleavage of
the tag from 8 and FSPE, treat-
ment of the crude indoline-1,2-
dione with varying amounts of
2-thienyllithium led to the cor-
responding mono- and bisaddi-
tion products,[29] 58 and 59
(Scheme 6). Finally, a Bucher-
er–Bergs reaction[30] was used
to convert the crude indoline-
1,2-dione to spirohydantoin 60.
Finally, we have carried out
preliminary investigations into
the development of sequential
Figure 1. Products from the reductive and oxidative removal of the fluorous tag (RF =C8F17CH2CH2).
tag-cleavage/cyclization
pro-
cesses. For example, tagged ox-
indole 61 was prepared and the fluorous tag cleaved with
SmI2. We were pleased to find that the intermediate SmIII
enolate formed on cleavage of the tag underwent intramo-
lecular alkylation to give the expected spirocycle 62 in good
yield (Scheme 7). We were intrigued by the isolation of in-
dolocarbazole 63 as the only byproduct from the reaction.
On changing the order of addition, 63 was isolated as the
major product. We believe 63 was formed after reductive
cleavage of the tag by the intramolecular Barbier addition
of a benzylic samarium to the oxindole carbonyl followed by
dehydration and aromatization. Thus, by changing the order
of addition of SmI2, the mode of sequential tag-cleavage/
cyclization can be controlled to access two very different
heterocyclic systems (Scheme 7).
Scheme 2. Optimizing an oxidative method for removal of the fluorous
tag. a) 30% H2O2, H2O, HFIP/CH2Cl2, 99%; b) TFAA, NEt3, EtOH,
THF, 55%; c) CAN, MeCN, H2O, 100%. RF =C8F17CH2CH2; HFIP=
hexafluoroisopropanol; TFAA=trifluoroacetic anhydride; CAN=ceric
ammonium nitrate.
Conclusion
be readily purified by using FSPE. Figure 2 shows the di-
verse range of products accessible from the cyclative-capture
approach and modification, coupled with reductive cleavage
of the fluorous tag.
This report describes the development of a new strategy for
the high-throughput, fluorous-phase synthesis of N-hetero-
cycle libraries. The sequence involves several key features:
1) a new Pummerer process used in a fluorous, cyclative-
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Chem. Eur. J. 2007, 13, 1032 – 1046

Synthesis of N-Heterocycles
FULL PAPER
In a typical FSPE separation, a crude
product mixture containing tagged and
non-tagged organic compounds was
loaded onto the fluorous silica by
using a minimum amount of organic
solvent (less than 20% of silica gel
volume). Elution with a fluorophobic
solvent mix, such as 80% MeCN/H2O,
removes non-fluorinated compounds
from the column. The column was
then eluted with a fluorophilic solvent,
such as MeCN, which removes tagged
compounds from the column. The flu-
orous silica gel could often be reused.
General procedure A for the cyclative
capture of glyoxamide: Details for
general procedure A can be found in
reference [5].
3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
Heptadecafluorodecylsulfanyl)-1-
methyl-1,3-dihydroindole-2-one
(3):
General procedure A was followed as
described in reference [5]. Thus, treat-
ment of crude N-methyl-2-oxo-N-phe-
nylacetamide with C8F17CH2CH2SH
(0.15 mL, 0.5265 mmol, 0.7 equiv),
TFAA (0.96mL, 6.77 mmol, 9 equiv)
and BF3·OEt2 (0.46mL, 3.76mmol,
5 equiv) and purification by fluorous
Scheme 3. Elaboration of fluorous-tagged heterocyclic frameworks—modification a to sulfur. a) NaOMe,
MeOH, methylacrylate, 18 h, 71%; b) NaOMe, MeOH, divinylsulfone, RT, 18 h, 87%; c) mCPBA, CH2Cl2,
4 h, 90%; d) K2CO3, DMF, ethyl bromoacetate, 408C, 93%; e) K2CO3, DMF, prenyl bromide, 408C, 82%;
f) methylchloroformate, CH2Cl2, NEt3, RT, 3 h; g) 30 mol% DMAP, toluene, 708C, 3 h, 60% for two steps;
h) NaH, THF/DMF, 808C, 18 h, allyl bromide, 77%; i) LHMDS, THF, À788C, 7 h, BnBr, 85%. RF =
C8F17CH2CH2; mCPBA=meta-chloroperbenzoic acid; DMAP=4-dimethylaminopyridine; LHMDS=lithium
hexamethyl disilazide.
chromatography gave
3
(0.179 g,
0.286mmol, 54%) as a light-brown oil.
1H NMR (300 MHz, CDCl3): d=7.34–
7.43 (2H, m; 2”ArH), 7.14 (1H, t, J=
6.0 Hz; ArH), 6.87 (1H, d; J=6.0 Hz;
ArH), 4.36(1H, s; C H), 3.25 (3H, s;
CH3), 2.96–3.05 (1H, m; 1H of CH2),
2.80–2.90 (1H, m; 1H of CH2), 2.35–2.53 ppm (2H, m; CH2); 13C NMR
(75 MHz, CDCl3): d=175.1 (C=O), 144.2 (ArC), 129.6(Ar CH), 125.3
(ArC), 125.2 (ArCH), 123.2 (ArCH), 108.5 (ArCH), 45.0 (CH), 32.1 (t,
J=22.0 Hz; CH2), 26.4 (CH3), 21.2 ppm (CH2); IR (ATR): n˜ =1705 (C=
O), 1611, 1470, 1348, 1199, 1134, 941 cmÀ1; MS (ES+ mode): m/z (%):
648 [M+Na]+ (83), 643 (23), 381 (13); HRMS: m/z: calcd for
C19H16ON2F17S: 643.0706; found: 643.0703 [M+NH4]+.
capture strategy for rapid access to tagged, heterocyclic
frameworks, 2) modification of the fluorous, heterocyclic
scaffolds by using a variety of approaches including Pd-cata-
lyzed cross-couplings and 3) traceless reductive or oxidative
removal of the fluorous-phase tag. The overall sequence
allows a diverse range of pharmaceutically interesting N-
heterocyclic systems to be accessed.
1-(2-Benzenesulfonylethyl)-3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptade-
cafluorodecylsulfanyl)-6-methoxy-1,3-dihydroindol-2-one (5): General
procedure A was followed as described in reference [5]. Thus, treatment
of
N-(2-benzenesulfonylethyl)-N-(3-methoxyphenyl)-2-oxoacetamide
Experimental Section
(0.47 g, 1.35 mmol, 1 equiv) with C8F17CH2CH2SH (1.58 mL, 5.39 mmol,
4 equiv), TFAA (1.80 mL, 12.12 mmol, 9 equiv) and BF3·OEt2 (0.85 mL,
6.74 mmol, 5 equiv) and purification by using fluorous silica (eluting with
80% MeCN/H2O then MeCN) and then on silica (eluting with 30%
EtOAc/petroleum ether (40–608C)) gave 5 (0.60 g, 0.74 mmol, 55%) as a
pale-yellow solid and as a 5:1 mixture of regioisomers.
General considerations: All experiments were performed under an at-
mosphere of Ar or N2 and anhydrous solvents, unless stated otherwise.
Oven-dried glassware was used in the reactions. THF was distilled from
sodium/benzophenone, CH2Cl2 was distilled from CaH2, Et2O was distil-
led from CaH2, and iPrNH2 was distilled from CaH2. Et3N was distilled
from CaH2 and stored over KOH under Ar/N2. DMSO was distilled from
CaH2 and stored over molecular sieves and under Ar/N2.
1H and 13C NMR spectra were recorded on a Fourier transform spec-
trometer, with chemical shift values being reported in ppm relative to re-
sidual chloroform (dH =7.27 or dC =77.2 ppm) as an internal standard
unless otherwise stated. NMR signals were assigned by using DEPT-135,
HMQC and COSY spectra. All coupling constants (J) are reported in
Hertz (Hz). RF =C8F17. Perfluorinated carbon atoms are not observed in
the 13C NMR spectra. Mass spectra and microanalyses were recorded at
the University of Glasgow and the University of Manchester. IR spectra
were recorded by using a FTIR spectrometer. Column chromatography
was carried out with silica gel 60 and fluorous silica. Aluminium-backed
plates precoated with silica gel 60 (UV254) were used for TLC and were
visualised by UV or staining with alkali KMnO4.
Major isomer: 1H NMR (400 MHz, CDCl3): d=7.84–7.82 (2H, m; ArH),
7.62–7.58 (1H, m; ArH), 7.51–7.47 (2H, m; ArH), 7.16(1H, d, J=
8.4 Hz; ArH), 6.54 (1H, dd, J=8.2, 2.2 Hz; ArH), 6.44 (1H, d, 2.2;
ArH), 4.05 (1H, s; CHS), 4.02 (2H, t; J=7.0 Hz; NCH2), 3.78 (3H, s;
CH3O), 3.50–3.43 (1H, m; 1H of NCH2CH2), 3.40–3.33 (1H, m; 1H of
NCH2CH2), 2.92–2.85 (1H, m; 1H of CH2CH2RF), 2.76–2.68 (1H, m; 1H
of CH2CH2RF), 2.38–2.23 ppm (2H, m; CH2RF); 13C NMR (100 MHz,
CDCl3): d=175.7 (C=O), 161.3 (ArCOMe), 143.3 (ArC), 138.7 (ArC),
134.2 (ArCH), 129.5 (2”ArCH), 127.9 (2”ArCH), 126.2 (ArCH), 116.3
(ArC), 107.8 (ArCH), 96.5 (ArCH), 55.7 (CH3O), 52.4 (NCH2CH2), 44.2
(CHS), 34.3 (NCH2), 31.8 ppm (t, J=21.5 Hz; CH2RF), 21.2
(CH2CH2RF); IR (KBr): n˜ =2966, 1720, 1628 (C=O), 1504, 1450, 1377,
1315, 1219 cmÀ1; MS (FAB mode, NOBA, NaI): m/z (%): 832 [M+Na]+
(100), 71 (17), 330 (58); HRMS: m/z: calcd for C27H20O4NF17S2Na:
832.0460; found: 832.0463 [M+Na]+.
Chem. Eur. J. 2007, 13, 1032 – 1046ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1037

D. J. Procter et al.
5.99 mmol, 5 equiv) and purification by using fluorous silica (eluting with
80% MeCN/H2O then MeCN) gave 14 (0.53 g, 0.67 mmol, 80%) as a
yellow solid. 1H NMR (400 MHz, CDCl3): d=7.28–7.19 (5H, s; ArH),
6.59 (1H, s; ArH), 6.41 (1H, s; ArH), 4.82 (1H, d, J=14.8 Hz; 1H of
NCH2), 4.79 (1H, s; CHS), 4.67–4.57 (1H, m; 1H of ring CH2N), 4.40
(1H, d, J=14.8; 1H of NCH2), 3.80 (3H, s; CH3O), 3.75 (3H, s; CH3O),
3.28–3.23 (1H, m; 1H of ring CH2N), 3.03–2.79 (4H, m; CH2CH2RF and
ring CH2CH2N), 2.49–2.42 ppm (2H, m; CH2RF); 13C NMR (100 MHz,
CDCl3): d=169.9 (C=O), 148.9 (ArCOMe), 147.7 (ArCOMe), 137.3
(ArC), 131.3 (ArC), 128.7 (2”ArCH), 128.1 (2”ArCH), 127.7 (ArCH),
123.1 (ArC), 114.6(Ar CH), 112.9 (ArCH), 56.0 (CH3O), 55.9 (CH3O),
55.9 (CHS), 51.4 (NCH2), 44.8 (ring CH2N), 32.9 (ring CH2CH2N), 31.6
F
F
À
(t, J=21.8 Hz; CH2R ), 24.4 ppm (CH2CH2R ); IR (KBr): n˜ =2936(C
H), 1633 (C=O), 1519, 1438, 1365, 1243, 1196, 1146, 1118 cmÀ1; MS (EI
mode): m/z (%): 789 [M]+ (12), 155 (11), 164 (12), 282 (100), 283 (20),
310 (24), 311 (27); HRMS: m/z: calcd for C29H24O3NF17S: 789.1205;
found: 789.1208 [M]+.
1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecylsulfanyl)-7,8-di-
methoxy-3-(4-methoxybenzyl)-1,3,4,5-tetrahydrobenzo[d]azepin-2-one
(15): General procedure A was followed as described in reference [5].
Thus, treatment of N-[2-(3,4-dimethoxyphenyl)ethyl]-N-(4-methoxyben-
zyl)-2-oxoacetamide (0.56g, 1.57 mmol, 1 equiv) with C 8F17CH2CH2SH
(0.32 mL, 1.10 mmol, 0.7 equiv), TFAA (2.09 mL, 14.1 mmol, 9 equiv)
and BF3·OEt2 (0.99 mL, 7.84 mmol, 5 equiv) and purification by using flu-
orous silica (eluting with 80% MeCN/H2O then MeCN) gave 15 (0.69 g,
0.85 mmol, 77%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d=7.17
(2H, d; J=8.4; ArH), 6.79 (2H, d, J=8.8; ArH), 6.59 (1H, s; ArH), 6.41
(1H, s; ArH), 4.78 (1H, s; CHS), 4.70 (1H, d, J=14.4; 1H of NCH2),
4.62–4.55 (1H, m; 1H of ring CH2N), 4.38 (1H, d, J=14.4; 1H of
NCH2), 3.80 (3H, s; CH3O), 3.76(3H, s; C H3O), 3.73 (3H, s; CH3O),
3.29–3.23 (1H, m; 1H of ring CH2N), 3.02–2.80 (4H, m; CH2CH2RF and
ring CH2CH2N), 2.54–2.37 ppm (2H, m; CH2RF); 13C NMR (100 MHz,
CDCl3): d=169.7 (C=O), 159.1 (ArCOMe), 148.8 (ArCOMe), 147.6
(ArCOMe), 129.9 (ArC), 129.5 (2”ArCH), 129.3 (ArC), 123.1 (ArC),
114.6(Ar CH), 114.1 (2”ArCH), 112.9 (ArCH), 56.0 (2”CH3O and
CHS), 55.2 (CH3O), 50.8 (NCH2), 44.5 (ring CH2N), 33.0 (ring
CH2CH2N), 31.6(t, J=22.1; CH2RF), 24.4 ppm (CH2CH2RF); IR (KBr):
n˜ =2933, 1635 (C=O), 1516, 1471, 1363, 1246, 1204, 1150, 1119,
1038 cmÀ1; MS (FAB mode, NOBA, NaI): m/z (%): 842 (45) [M+Na]+,
70 (17), 121 (100), 192 (13), 312 (74), 363 (12), 599 (10); HRMS: m/z:
calcd for C30H26O4NF17SNa: 842.1209; found: 842.1207 [M+Na]+.
3-(2-Benzenesulfonylethyl)-1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptade-
cafluorodecylsulfanyl)-7,8-dimethoxy-1,3,4,5-tetrahydrobenzo[d]azepin-2-
one (16): General procedure A was followed as described in refer-
ence [5]. Thus, treatment of N-(2-benzenesulfonylethyl)-N-[2-(3,4-dime-
thoxyphenyl)ethyl]-2-oxoacetamide (0.39 g, 0.96mmol, 1 equiv) with
C8F17CH2CH2SH (0.20 mL, 0.67 mmol, 0.7 equiv), TFAA (1.27 mL,
8.60 mmol, 9 equiv) and BF3·OEt2 (0.61 mL, 4.78 mmol, 5 equiv) and pu-
rification by using fluorous silica (eluting with 80% MeCN/H2O then
MeCN) gave 16 (0.58 g, 0.67 mmol, 100%) as a cream solid. 1H NMR
(400 MHz, CDCl3): d=7.94–7.92 (2H, m; ArH), 7.70–7.67 (1H, m;
ArH), 7.61–7.57 (2H, m; ArH), 6.64 (1H, s; ArH), 6.57 (1H, s; ArH),
4.90–4.83 (1H, m; 1H of ring CH2N), 4.75 (1H, s; CHS), 4.05–3.98 (1H,
m; 1H of NCH2), 3.87 (3H, s; CH3O), 3.86(3H, s; C H3O), 3.80–3.73
(1H, m; 1H of NCH2), 3.57–3.48 (2H, m; 1H of ring CH2N and 1H of
NCH2CH2), 3.40–3.33 (1H, m; 1H of NCH2CH2), 3.18–2.88 (4H, m; ring
CH2CH2N and CH2CH2RF), 2.64–2.40 ppm (2H, m; CH2RF); 13C NMR
(100 MHz, CDCl3): d=170.0 (C=O), 149.0 (ArCOMe), 147.8 (ArCOMe),
139.3 (ArC), 134.0 (ArCH), 129.6(Ar C), 129.4 (2”ArCH), 127.8 (2”
ArCH), 122.7 (ArC), 114.4 (ArCH), 113.1 (ArCH), 55.9 (CH3O), 55.9
(CH3O), 55.5 (CHS), 54.2 (NCH2CH2), 47.4 (ring CH2N), 43.9 (NCH2),
33.1 (ring CH2CH2N), 31.4 (t, J=21.9; CH2RF), 24.2 ppm (CH2CH2RF);
IR (KBr): n˜ =3074, 3005, 2976, 2955, 2927, 2838, 1648 (C=O), 1611,
1521, 1482, 1469 cmÀ1; MS (FAB mode, NOBA, NaI): m/z (%): 890 (97)
[M+Na]+, 199 (11), 218 (13), 360 (71); HRMS: m/z: calcd for
C30H26O5NF17S2Na: 890.0879; found: 890.0876[ M+Na]+.
Scheme 4. Elaboration of fluorous-tagged heterocycles—Pd-catalyzed
modifications. a) mCPBA, CH2Cl2, RT, 2 h; b) K2CO3, MeI, DMF, 408C,
2 h; c) Pd
methylsilylacetylene (CuI 20 mol%), 44 and 60% overall, respectively;
d) Pd(PPh3)4 (20 mol%), Na2CO3, H2O, dioxane, 808C, 3.5 h, ArB(OH)2;
e) Pd(OAc)2 (4 mol%), 37 (8 mol%), morpholine or N-methylpiperazine
ACHTREUNG(PPh3)4 (20 mol%), NEt3, 808C, 18 h, propargyl alcohol or tri-
ACHTREUNG
ACHTREUNG
or piperidine, Cs2CO3, toluene, MW (1208C), 2 h, 73% (38), 69% (39),
68% (40). RF =C8F17CH2CH2.
3-Benzyl-1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecylsulfan-
yl)-7,8-dimethoxy-1,3,4,5-tetrahydrobenzo[d]azepin-2-one (14): General
procedure A was followed as described in reference [5]. Thus, treatment
of N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-oxoacetamide (0.39 g,
1.20 mmol, 1 equiv) with C8F17CH2CH2SH (0.25 mL, 0.84 mmol,
0.7 equiv), TFAA (1.60 mL, 10.8 mmol, 9 equiv) and BF3·OEt2 (0.76mL,
3-Allyl-1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecylsulfan-
yl)-7,8-dimethoxy-1,3,4,5-tetrahydrobenzo[d]azepin-2-one (17): General
1038
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1032 – 1046

Synthesis of N-Heterocycles
FULL PAPER
procedure A was followed as described
in reference [5]. Thus, treatment of N-
allyl-N-[2-(3,4-dimethoxyphenyl)eth-
yl]-2-oxoacetamide (0.21 g, 0.76mmol,
1 equiv)
(0.16mL,
with
0.53 mmol,
C8F17CH2CH2SH
0.7 equiv),
TFAA (1.01 mL, 6.81 mmol, 9 equiv)
and BF3·OEt2 (0.48 mL, 3.79 mmol,
5 equiv) and purification by using fluo-
rous silica (eluting with 80% MeCN/
H2O then MeCN) and then silica
(eluting with 30% EtOAc/petroleum
ether (40–60)) gave 17 (0.23 g,
0.32 mmol, 60%) as
a white solid.
1H NMR (400 MHz, CDCl3): d=6.58
(1H, s; ArH), 6.46 (1H, s; ArH),
5.80–5.70 (1H, m; CH=CH2), 5.20–
5.12 (2H, m; CH=CH2), 4.72 (1H, s;
CHS), 4.67–4.60 (1H, m; 1H of ring
CH2N), 4.21 (1H, dd, J=15.2, 5.6Hz;
1H of NCH2), 3.84 (1H, dd; J=15.2,
5.6Hz; 1H of NC H2), 3.80 (3H, s;
CH3O), 3.77 (3H, s; CH3O), 3.28–3.22
(1H, m; 1H of ring CH2N), 3.03–2.85
(4H, m; CH2CH2RF and ring
CH2CH2N), 2.53–2.38 ppm (2H, m;
CH2RF); 13C NMR (100 MHz, CDCl3):
d=169.5 (C=O), 148.9 (ArCOMe),
147.7 (ArCOMe), 133.0 (CH=CH2),
129.9 (ArC), 123.2 (ArC), 117.6(CH =
CH2), 114.7 (ArCH), 113.0 (ArCH),
56.0 (CHS), 55.9 (CH3O), 55.9
(CH3O), 50.7 (NCH2), 44.7 (ring
CH2N), 33.1 (ring CH2CH2N), 31.7 (t,
Figure 2. Products of the reductive removal of the fluorous tag from decorated heterocyclic scaffolds. [a] Ob-
tained as a 1:1 mixture of tautomers by NMR spectroscopy.
J=22.0;
CH2RF),
24.4 ppm
(CH2CH2RF); IR (KBr): n˜ =3066,
3010, 2965, 2936, 2911, 2853, 2835,
2255, 1649 (C=O), 1634, 1519 cmÀ1
;
MS (FAB mode, NOBA, NaI): m/z
(%): 762 (100) [M+Na]+, 71 (11), 178
(10), 232 (88), 260 (65); HRMS: m/z:
calcd for C25H22O3NF17SNa: 762.0947;
found: 762.0945 [M+Na]+.
Scheme 5. Sequential-oxidative-cleavage modification. a) CeACHTER(UNG NH4)2ACHRTEU(GN NO3)6, MeCN/H2O, FSPE; b) 1,2-diamino-
benzene, AcOH, D, 20 min, 89% for 54, 90% for 55; c) DAST, CH2Cl2, RT, 82% for 56, 77% for 57. RF =
C8F17CH2CH2; FSPE=fluorous solid-phase extraction; DAST=diethylaminosulfur trifluoride.
3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
Heptadecafluorodecylsulfanyl)-3-[2-(2-
methoxyethanesulfonyl)ethyl]-1-
methyl-1,3-dihydroindol-2-one
(24):
NaOMe (0.04 mL, 25% wt solution in
MeOH, 0.364 mmol, 2.5 equiv) and di-
vinyl sulfone (0.02 mL, 0.189 mmol, 1.3 equiv) were added to a solution
of 3 (0.091 g, 0.145 mmol, 1 equiv) in methanol (7 mL) at room tempera-
ture. The reaction was allowed to stir at room temperature for 19 h. The
reaction was then quenched with saturated aqueous NH4Cl (5 mL) and
the aqueous layer was extracted with CH2Cl2 (3”10 mL). The organic
layer was then dried (MgSO4), filtered and concentrated in vacuo to give
the crude product as a brown oil. Purification by fluorous chromatogra-
phy gave 24 (0.098 g, 0.126mmol, 87%) as
a
brown oil. 1H NMR
(300 MHz, CDCl3): d=7.27–7.35 (2H, m; 2”ArH), 7.11 (1H, t, J=
6.0 Hz; ArH), 6.85 (1H, d, J=6.0 Hz; ArH), 3.69 (2H, t, J=6.0 Hz;
CH2), 3.25 (3H, s; CH3), 3.20 (3H, s; CH3), 3.09–3.12 (2H, m; CH2),
2.90–3.01 (2H, m; CH2), 2.75–2.42 (4H, m; 2”CH2), 2.04–2.22 ppm (2H,
m; CH2); 13C NMR (75 MHz, CDCl3): d=175.4 (C=O), 143.1 (ArC),
130.2 (ArCH), 127.7 (ArC), 124.3 (ArCH), 123.7 (ArCH), 108.9 (ArCH),
66.1 (CH2), 59.1 (CH3), 53.4 (CH2), 52.8 (SCC=O), 50.5 (CH2), 31.6(t,
J=21 Hz; CH2), 28.5 (CH2), 26.6 (CH3), 19.9 ppm (CH2); IR (ATR): n=
2924, 1713, 1611, 1466, 1344, 1198 cmÀ1; MS (ES+ mode): m/z (%): 798
(100) [M+Na]+, 653 (18), 574 (14), 374 (24); HRMS: m/z: calcd for
C24H26O4N2F17S2: 793.1057; found: 793.1054 [M+NH4]+.
Scheme 6. Sequential-oxidative-cleavage
ACHTREUNG
modification.
a) CeACHTRE(UNG NH4)2-
RT, 74%; c) 2-thienyllithium (3 equiv), THF, 08C to RT, 69%; d) KCN,
(NH4)2CO3, MeOH, RT to 708C, 56%. RF =C8F17CH2CH2.
Chem. Eur. J. 2007, 13, 1032 – 1046ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1039

D. J. Procter et al.
(%): 854 (91) [M+Na]+, 851 (23),
813(15), 776(20); HRMS: m/z: calcd
for C26H23O3NBrF17NaS: 854.0205;
found: 854.0203 [M+Na]+.
General Procedure B—Pd-catalysed
Hartwig–Buchwald aminations
3-Benzyl-3-
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hep-
tadecafluorodecane-1-sulfonyl)-5-mor-
pholin-4-yl-1-propyl-1,3-dihydroindol-
2-one
(38):
3-Benzyl-5-bromo-3-
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hep-
tadecafluoro-decane-1-sulfonyl)-1-
propyl-1,3-dihydroindol-2-one
(32)
(0.043 g, 0.050 mmol, 1 equiv), Pd-
A
(0.0004 g,
X-Phos
0.0019 mmol,
(0.0019 g,
Scheme 7. Sequential tag-cleavage/cyclization. a) mCPBA, CH2Cl2, 4 h, 90%; b) K2CO3, a,a’-dibromo-o-
xylene, DMF, 408C, 4 h, 83%; c) SmI2 (syringe pump addition of SmI2 to substrate), THF, RT; d) SmI2 (syringe
pump addition of substrate to SmI2), THF, RT; RF =C8F17CH2CH2.
0.08 equiv),
Cs2CO3
(0.078 g, 0.240 mmol, 4.8 equiv) and
morpholine (0.010 mL, 0.10 mmol,
2 equiv) were added to a microwave
vial equipped with a magnetic stirrer
[5-Bromo-3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecane-1-
and sealed. Toluene (0.8 mL) was injected into the vial and the reaction
underwent microwave irradiation for 2 h at 1208C. The reaction vessel
was then allowed to cool to room temperature before diluting with ethyl
acetate (6mL). The solution was filtered through a plug of Celite and
concentrated in vacuo to give the crude product. Purification by flash
chromatography using 40% ethyl acetate in petroleum ether gave 38
(0.031 g, 0.036mmol, 73%) as a yellow oil. 1H NMR (400 MHz, CDCl3):
d=7.26(1H, d, J=2.0 Hz; ArH), 7.02–6.94 (3H, m; 3”ArH), 6.82 (2H,
dd, J=2.0, 7.6Hz; 2”Ar H), 6.78 (1H, d, J=7.6Hz; Ar H), 6.50 (1H, d,
J=8.4 Hz; ArH), 3.83–3.79 (4H, m; 2”CH2), 3.79–3.74 (1H, m; 1H from
CH2), 3.65 (1H, d, J=12.6Hz; 1H from C H2), 3.54 (1H, d, J=12.6Hz;
1H from CH2), 3.43–3.50 (1H, m; 1H from CH2), 3.24–3.38 (2H, m; 2”
1H from CH2S), 3.09–3.02 (4H, m; 2”CH2), 2.51–2.64 (2H, m; CH2),
1.22–1.31 (2H, m; CH2), 0.59 ppm (3H, t, J=7.6Hz; C H3); 13C NMR
(100 MHz, CDCl3): d=169.4 (C=O), 132.3 (ArC), 130.3 (2”ArCH),
128.3 (2”ArCH), 127.7 (2”ArC), 121.5 (ArC), 118.6(Ar CH), 116.4
(ArCH), 109.6(2”Ar CH), 75.4 (CCH2Ph), 67.0 (2”CH2O), 50.7 (2”
CH2N), 42.3 (CH2), 40.9 (CH2), 37.4 (CH2), 23.9 (CH2), 20.5 (CH2),
11.3 ppm (CH3); IR (ATR): n˜ =2920, 2337, 1706(C =O), 1598, 1501,
1448, 1196, 941 cmÀ1; MS (ES+ mode): m/z (%): 883 (100) [M+Na]+, 798
(40), 622 (17), 515 (59), 492 (22), 290 (9), 105 (19); HRMS: m/z: calcd
for C32H29O4N2F17NaS: 883.1469; found: 883.1480 [M+Na]+.
sulfonyl)-2-oxo-1-propyl-2,3-dihydro-1H-indole-3-yl]acetic acid ethyl
ester (25): Ethylbromoacetate (0.15 mL, 1.31 mmol, 5 equiv) and K2CO3
(0.181 g, 1.31 mmol, 5 equiv) were added to a solution of 5-bromo-3-
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecane-1-sulfonyl)-1-
propyl-1,3-dihydroindole-2-one (7) (0.20 g, 0.263 mmol, 1 equiv) in DMF
(6mL) and the reaction was heated to 40 8C. The reaction was left to stir
for 2 h. Ethyl acetate (5 mL) was added to the reaction mixture and the
organic layer washed with water (3”5 mL), dried (MgSO4), filtered and
concentrated in vacuo to give a crude orange solid. The crude product
was purified by fluorous chromatography to give 25 (0.208 g, 0.245 mmol,
93%) as an orange oil. 1H NMR (300 MHz, CDCl3): d= 7.59–7.65 (2H,
m; 2”ArH), 6.87 (1H, d, J=9.0 Hz; ArH), 4.08–3.95 (2H, m; CH2),
3.87–3.76(2H, m; 1H of SC H2 and 1H of NCH2), 3.74–3.67 (1H, m; 1H
of NCH2), 3.49 (1H, app. d, J=15.0 Hz; 1H of CH2CO2Et), 3.56(1H,
app. d, J=15.0 Hz; 1H of CH2CO2Et), 3.38–3.28 (1H, m; 1H of SCH2),
2.75–2.60 (2H, m; CH2), 1.84–1.75 (2H, m; CH2), 1.13 (3H, t, J=6.0 Hz;
CH3), 1.04 ppm (3H, t, J=9.0 Hz; CH3); 13C NMR (75 MHz, CDCl3): d=
170.0 (C=O), 167.0 (C=O), 144.5 (ArC), 134.4 (ArCH), 129.0 (ArCH),
122.5 (ArC), 116.0 (ArC), 110.8 (ArCH), 71.1 (CSO2), 61.9 (OCH2), 42.9
(NCH2), 40.5 (SCH2), 36.0 (CH2), 23.8 (t, J=21.7 Hz; CH2), 20.7 (CH2),
14.0 (CH3), 11.4 ppm (CH3); IR (ATR): n˜ =1719 (C=O), 1605 (C=O),
1474, 1334, 1197, 1126, 957 cmÀ1; MS (ES+ mode): m/z (%): 872 (100)
[M+Na]+, 794 (37), 278 (23), 110 (22), 105 (26); HRMS: m/z: calcd for
C25H25O5N2BrF17S: 867.0391; found: 867.0392 [M+NH4]+.
3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecane-1-sulfonyl)-3-
(3-methylbut-2-enyl)-5-(4-methylpiperazin-1-yl)-1-propyl-1,3-dihydroin-
dol-2-one (39): General procedure B was followed. Thus, treatment of 26
5-Bromo-3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecane-1-
(0.047 g, 0.057 mmol, 1 equiv) with PdCAHTRE(UNG OAc)2 (0.0005 g, 0.0023 mmol,
sulfonyl)-3-(3-methylbut-2-enyl)-1-propyl-1,3-dihydroindol-2-one
(26):
0.04 equiv), X-Phos (0.0022 g, 0.0045 mmol, 0.08 equiv), Cs2CO3 (0.089 g,
0.27 mmol, 4.8 equiv) and N-methylpiperazine (0.010 mL, 0.11 mmol,
2 equiv) and purification by fluorous chromatography gave 39 (0.033 g,
0.039 mmol, 69%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d=7.23
(1H, d, J=2.4 Hz; ArCH), 6.96 (1H, dd, J=2.4, 8.4 Hz; ArCH), 6.80
(1H, d, J=8.4 Hz; ArCH), 4.61 (1H, t, J=6.4 Hz; CH), 3.81–3.71 (2H,
m; 2”1H from 2”CH2), 3.64–3.57 (1H, m; 1H from CH2), 3.34–3.41
(1H, m; 1H from CH2), 3.19 (4H, app. t, J=5.0 Hz; 2”CH2), 3.16–3.14
(1H, m; 1H from CH2), 3.06–3.01 (1H, m; 1H from CH2), 2.64 (4H, app.
t, J=5.0 Hz; 2”CH2), 2.40 (3H, s; CH3), 1.86(2H, m; C H2), 1.67 (2H,
app. q, J=7.2 Hz; CH2), 1.60 (3H, s; CH3), 1.52 (3H, s; CH3), 0.93 ppm
(3H, t; J=7.2 Hz; CH3); 13C NMR (100 MHz, CDCl3): d=169.8 (C=O),
K2CO3 (0.292 g, 2.11 mmol, 5 equiv) and prenyl bromide (0.240 mL,
2.11 mmol, 5 equiv) were added to a solution of 7 (0.323 g, 0.422 mmol,
1 equiv) in DMF (9 mL) at room temperature. The reaction was then
heated to 408C and allowed to stir for 2 h. Ethyl acetate (12 mL) was
added to the reaction mixture and the organic layer was separated,
washed with water (3”10 mL), dried (MgSO4), filtered and concentrated
in vacuo to give a crude orange solid. The crude product was purified by
fluorous chromatography to give 26 (0.288 g, 0.346mmol, 82%) as a
light-brown solid. 1H NMR (500 MHz, CDCl3): d=0.75 (3H, t, J=
7.4 Hz; CH3), 1.35 (3H, s; CH3), 1.43 (3H, s; CH3), 1.48–1.53 (2H, m;
CH2), 2.49–2.52 (2H, m; CH2), 2.89–2.90 (1H, m; 1H from CH2), 2.97–
3.00 (1H, m; 1H from CH2), 3.22–3.30 (1H, m; 1H from CH2), 3.44–3.46
(1H, m; 1H from CH2), 3.56–3.60 (1H, m; 1H from CH2), 3.67–3.75
(1H, m; 1H from CH2), 4.41–4.44 (1H, m; CH=), 6.62–6.64 (1H, m;
ArH), 7.36–7.37 (1H, m; ArH), 7.54 ppm (1H, s; ArH); 13C NMR
(75 MHz, CDCl3): d=11.3 (CH3), 18.5 (CH3), 20.8 (CH2), 24.1 (CH2),
26.0 (CH3), 30.8 (CH2), 40.8 (CH2), 42.6( CH2), 74.1 (CCH2CH=), 110.7
148.0 (ArCH), 138.1 (ArCH), 137.2 (ArCH), 121.8 (=CACHTREU(GN CH3)2), 118.2
(ArCH), 116.2 (ArCH), 114.1 (CH=), 109.3 (ArCH), 74.0 (CCH2CH=),
55.0 (2”CH2), 50.0 (2”CH2), 46.0 (CH3), 42.2 (CH2), 40.6( CH2), 30.4
(CH2), 25.7 (CH3), 23.9 (CH2), 20.6( CH2), 18.3 (CH3), 11.1 ppm (CH3);
IR (ATR): n˜ =2938, 1710 (C=O), 1456, 1352, 1185 cmÀ1 MS (ES+
;
mode): m/z (%): 874 (17) [M+Na]+, 852 (100) [M]+, 510 (4), 129 (7),
105 ppm (15); HRMS: m/z: calcd for C31H35O3N3F17S: 852.2122; found:
852.2116[ M+H]+.
(ArCH), 113.7 (CH=), 116.2 (ArCH), 123.1 (CACHTREU(GN CH3)2), 129.8 (ArCH),
134.0 (ArCH), 139.1 (ArC), 143.7 (ArC), 170.2 ppm (C=O); IR (ATR):
n˜ =2938, 1714 (C=O), 1466, 1342, 1137, 519 cmÀ1; MS (ES+ mode): m/z
1040
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1032 – 1046

Synthesis of N-Heterocycles
FULL PAPER
3-Benzyl-3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecane-1-
sulfonyl)-5-piperidin-1-yl-1-propyl-1,3-dihydroindol-2-one (40): General
procedure B was followed. Thus, treatment of 32 (0.042 g, 0.050 mmol;
(CH2CO), 108.7 (d, J=7.9 Hz; ArCH), 112.9 (d, J=24.8 Hz; ArCH),
114.4 (d, J=23.1 Hz; ArCH), 126.4 (d, J=9.1 Hz; ArC), 138.5 (ArCN),
159.5 (d, J=238.6Hz; Ar CF), 175.0 (C=O); IR (ATR): n˜ =1695 (C=O),
1621, 1494, 1348, 1222, 1133 cmÀ1; MS (EI+ mode): m/z (%): 165 (100)
1 equiv) with PdACHTREUNG(OAc)2 (0.0004 g, 0.0019 mmol, 0.04 equiv), X-Phos
(0.0019 g, 0.0039 mmol, 0.08 equiv), Cs2CO3 (0.078 g, 0.24 mmol,
4.8 equiv) and piperidine (0.010 mL, 0.10 mmol, 2 equiv) and purification
by fluorous chromatography gave 40 (0.029 g, 0.034 mmol, 68%) as a
yellow oil. 1H NMR (300 MHz, CDCl3): d=7.38 (1H, s; ArCH), 7.09–
7.05 (3H, m; 3”ArCH), 6.94–6.89 (3H, m; 3”ArCH), 6.57 (1H, d, J=
8.2 Hz; ArCH), 3.85–3.79 (1H, m; 1H of CH2), 3.74 (1H, d, J=12.7 Hz;
1H of CH2), 3.64 (1H, d, J=12.7 Hz; 1H of CH2), 3.58–3.52 (1H, m; 1H
of CH2), 3.45–3.38 (1H, m; 1H of CH2), 3.39–3.32 (1H, m; 1H of CH2),
3.16–3.08 (4H, m; 2”CH2), 2.76–2.56 (2H, m; CH2), 1.78–1.74 (4H, m;
2”CH2), 1.62–1.57 (2H, m; CH2), 1.39–1.31 (2H, m; CH2), 0.68 ppm
(3H, t, J=7.4 Hz; CH3); 13C NMR (75 MHz, CDCl3): d=169.3 (C=O),
149.5 (ArC), 137.0 (ArC), 132.4 (ArC), 130.3 (2”ArCH), 128.4 (ArCH),
128.3 (ArCH), 127.6(Ar CH), 121.2 (ArC), 119.4 (ArCH), 117.1 (ArCH),
[M]+, 150 (10), 136(99), 109 (20), 96(10); HRMS:
C9H8NOF: 165.1670; found: 165.1676 [M]+.
m/z: calcd for
2-Methyl-1,4-dihydro-2H-isoquinolin-3-one:[33] General procedure C was
followed. Thus, treatment of 4-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptade-
cafluorodecylsulfanyl)-2-methyl-1,2-dihydroisoquinolin-3(4H)one
(9)
(153 mg, 0.24 mmol, 1 equiv) in THF (5 mL) with SmI2 (6.0 mL of a 0.1m
solution in THF, 0.60 mmol, 2.5 equiv) and purification by using fluorous
silica gel gave the title compound (39 mg, 0.18 mmol, 74%) as a yellow
oil. 1H NMR (400 MHz, CDCl3): d=3.05 (3H, s; NCH3), 3.55 (2H, s;
CH2N), 4.43 (2H, s; CH2CO), 7.08–7.10 (2H, m; 2”ArH), 7.14–7.24 ppm
(2H, m; 2”ArH); 13C NMR (100 MHz, CDCl3): d=34.8 (CH3), 37.9
(CH2N), 53.3 (CH2CO), 125.4 (ArCH), 126.9 (ArCH), 127.7 (ArCH),
127.9 (ArCH), 131.3 (ArC), 132.6(Ar C), 169.2 (C=O); IR (ATR): n˜ =
3033, 2922, 1632 (C=O), 1493, 1457, 1401, 1088 cmÀ1; MS (EI+ mode):
m/z (%): 161 (14) [M]+, 118 (10), 104 (22), 85 (100), 83 (100), 47 (46);
HRMS: m/z: calcd for C10H11NO: 161.0841; found: 161.0841 [M]+.
À
109.5 (ArCH), 75.3 (C C=O), 52.2 (CH2), 52.1 (CH2), 42.3 (CH2), 40.9
(CH2), 37.3 (CH2), 26.0 (CH2), 26.0 (CH2), 24.3 (CH2), 24.2 (t, J=
15.0 Hz; CH2), 20.5 (CH2), 11.2 ppm (CH3); IR (ATR): n˜ =2936, 1708
(C=O), 1498, 1332, 1210 cmÀ1; MS (ES+ mode): m/z (%): 881 (100)
[M+Na]+, 798 (8), 512 (3), 393 (4), 349 (13), 305 (21), 261 (12), 217 ppm
(8); HRMS: m/z: calcd for C33H31O3N2F17NaS: 881.1676; found: 881.1677
[M+Na]+.
3,4-Methylenedioxy-3-(3-methyl-butyl)-1,3,4,5-tetrahydrobenzo[d]azepin-
2-one: General procedure
C was followed. Thus, treatment of 1-
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluoro-decylsulfanyl)-3,4-
methylenedioxy-3-(3-methyl-butyl)-1,3,4,5-tetrahydrobenzo[d]azepin-2-
one (18) (0.10 g, 0.13 mmol, 1 equiv) with SmI2 (2.93 mL, 0.1m in THF,
0.29 mmol, 2.2 equiv) and concentration in vacuo gave the title com-
General Procedure C—the reductive cleavage of the fluorous tag
[3,2,1-ij]quinolin-2(4H)one:[31] SmI2 (4.5 mL of a
5,6-Dihydro-1H-pyrroloACHTREUNG
0.1m solution in THF, 0.45 mmol, 2.5 equiv) was added to a solution of 1-
pound (0.04 g, 0.14 mmol, 99%) as a
dark-yellow oil. 1H NMR
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecylsulfanyl)-5,6-dihy-
dro-1H-pyrroloACHTREUNG[3,2,1-ij]quinolin-2(4H)-one (2) (118 mg, 0.18 mmol,
(400 MHz, CDCl3): d=6.62 (1H, s; ArH), 6.57 (1H, s; ArH), 5.92 (2H,
s; OCH2O), 3.78 (2H, s; CH2C(O)), 3.69–3.66 (2H, t, J=6.1 Hz; ring
CH2N), 3.45–3.42 (2H, t; J=7.8 Hz; NCH2), 3.06–3.03 (2H, t, J=6.0 Hz;
1 equiv) in THF (5 mL) and the reaction was allowed to stir at room tem-
perature for 24 h. NaHCO3 (10 mL) was added to the reaction and the
aqueous layer was extracted with EtOAc (2”10 mL). The combined or-
ganic layers were dried (MgSO4) and concentrated in vacuo. The crude
product mixture was purified by fluorous chromatography to give the
title compound (27 mg, 0.16mmol, 87%) as a white solid. 1H NMR
(400 MHz, CDCl3): d=2.00–2.06(2H, app. pentet, J=5.9 Hz; CH2), 2.79
(2H, t, J=6.1 Hz; ArCH2), 3.52 (2H, s; CH2CO), 3.74 (2H, t, J=5.9 Hz;
CH2N), 6.95 (1H, t, J=7.8 Hz; ArH), 7.05 (1H, d, J=7.7 Hz; ArH),
7.09 ppm (1H, d, J=7.3 Hz; ArH); 13C NMR (100 MHz, CDCl3): d=21.6
(CH2), 24.8 (CH2), 36.9 (CH2), 39.9 (CH2), 120.5 (ArC), 122.1 (ArCH),
122.5 (ArCH), 123.6(Ar C), 126.9 (ArCH), 141.5 (ArC), 174.5 ppm (C=
O); IR (ATR): n˜ =3041, 2924, 1691 (C=O), 1600, 1479, 1345 cmÀ1; MS
(EI+ mode): m/z (%): 173 (100) [M]+, 144 (67), 117 (15), 83 (65), 47
(13); HRMS: m/z: calcd for C11H11NO: 173.0841; found: 173.0840 [M]+.
ring CH2CH2N), 1.63–1.53 (1H, m; CH
ACHTREUNG
NCH2CH2), 0.94–0.93 ppm (6H, d, J=6.6 Hz; CHAHCTREUNG
(100 MHz, CDCl3): d=171.7 (C=O), 147.1 (ArCO), 146.4 (ArCO), 129.3
(ArC), 125.2 (ArC), 111.2 (ArCH), 110.1 (ArCH), 101.4 (OCH2O), 46.8
(ring CH2N), 45.9 (NCH2), 43.3 (CH2C(O)), 37.4 (NCH2CH2), 33.3 (ring
CH2CH2N), 26.4 (CHACHTREUGN(CH3)2), 23.0 ppm (2”CH3 of CHACHTRE(UGN CH3)2); IR
(ATR): n˜ =2952, 2251, 2063, 1651 (C=O), 1505, 1484, 1224, 1038, 909,
858 cmÀ1; MS (EI mode): m/z (%): 275 (88) [M]+, 42 (10), 77 (10), 84
(35), 86(22), 89 (13), 91 (11), 103 (15), 131 (13), 147 (23), 148 (99), 149
(58), 161 (21), 162 (44), 176 (15), 190 (58), 204 (18), 205 (44), 219 (60),
260 (22), 176 (17); HRMS: m/z: calcd for C16H21O3N: 275.1521; found:
275.1520 [M]+.
7,8-Dimethoxy-3-pentyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one: General
procedure
C
was
followed.
Thus,
treatment
of
1-
5-Bromo-1-propyl-1,3-dihydroindol-2-one: General procedure C was fol-
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecylsulfanyl)-7,8-di-
lowed. Thus, treatment of
(10 mL) with SmI2 (10 mL of
7
(292 mg, 0.40 mmol, 1 equiv) in THF
0.1m solution in THF, 1.0 mmol,
methoxy-3-pentyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one (13) (0.20 g,
0.26mmol, 1 equiv) in THF (4 mL) with SmI 2 (5.72 mL, 0.1m in THF,
0.57 mmol, 2.2 equiv) and concentration in vacuo gave the title com-
pound (0.06g, 0.22 mmol, 84%) as a cream solid. 1H NMR (400 MHz,
CDCl3): d=6.53 (1H, s; ArH), 6.49 (1H, s; ArH), 3.77 (3H, s; CH3O),
3.76(3H, s; C H3O), 3.73 (2H, s; CH2C(O)), 3.65–3.62 (2H, t, J=6.0 Hz;
ring CH2N), 3.35–3.31 (2H, t, J=7.6Hz; NC H2), 2.98–2.95 (2H, t, J=
5.9 Hz; ring CH2CH2N), 1.52–1.45 (2H, m; NCH2CH2), 1.31–1.15 (4H,
m; CH2CH2CH3, CH2CH2CH3), 0.83–0.79 ppm (3H, t, J=7.0 Hz;
CH2CH3); 13C NMR (100 MHz, CDCl3): d=170.9 (C=O), 146.8
(ArCOMe), 146.1 (ArCOMe), 126.5 (ArC), 122.6(Ar C), 113.0 (ArCH),
112.1 (ArCH), 54.9 (CH3O), 54.9 (CH3O), 45.9 (NCH2), 45.3 (ring
CH2N), 41.7 (CH2C(O)), 31.4 (ring CH2CH2N), 28.7 (CH2CH2CH3), 27.0
(NCH2CH2), 21.5 (CH2CH2CH3), 13.0 ppm (CH2CH3); IR (ATR): n˜ =
3001, 2954, 2927, 2858, 2359, 2025, 1959, 1643 (C=O), 1606, 1522, 1485,
1458, 1421 cmÀ1; MS (EI mode): m/z (%): 291 (98) [M]+, 83 (33), 85
(22), 121 (13), 163 (12), 164 (81), 165 (48), 178 (53), 206 (58), 221 (55),
235 (11), 291 (98), 292 (18); HRMS: m/z: calcd for C17H25O3N: 291.1834;
found: 291.1837 [M]+.
a
2.5 equiv) and purification by using fluorous silica gave 5-bromo-1-
propyl-1,3-dihydro-indol-2-one (57 mg, 0.22 mmol, 57%) as a white solid.
1H NMR (400 MHz, CDCl3): d=0.89 (3H, t, J=7.4 Hz; CH3), 1.57–1.66
(2H, m; CH2), 3.45 (2H, s; CH2CO), 3.58 (2H, t, J=7.4 Hz; CH2N), 6.63
(1H, d, J=8.2 Hz; ArH), 7.30–7.33 ppm (2H, overlapping doublet and
singlet; 2”ArH); 13C NMR (100 MHz, CDCl3): d=11.8 (CH3), 21.1
(CH2), 36.0 (CH2CO), 42.1 (CH2N), 110.1 (ArCH), 115.1 (ArC), 127.0
(ArC), 128.0 (ArCH), 131.0 (ArCH), 144.2 (ArC), 174.7 ppm (C=O); IR
(ATR): n˜ =2965, 2935, 2877, 1695 (C=O), 1606, 1484, 1342, 1105 cmÀ1
MS (EI+ mode): m/z (%): 253 (56) [M]+, 224 (25), 196(25), 117 (100),
;
84 (56), 47 (12); HRMS: m/z: calcd for C11H12ONBr: 253.0102; found:
253.0101 [M]+.
5-Fluoro-1-methyl-1,3-dihydroindol-2-one:[32] General procedure C was
followed. Thus, treatment of 5-fluoro-3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
heptadecafluorodecylsulfanyl)-1-methyl-1,3-dihydroindol-2-one
(170 mg, 0.26mmol, 1 equiv) in THF (3 mL) with SmI 2 (6.5 mL of a 0.1m
solution in THF, 0.65 mmol, 2.5 equiv) and purification by fluorous chro-
matography gave the title compound (31 mg, 0.19 mmol, 71%) as an
orange oil. 1H NMR (400 MHz, CDCl3): d=3.13 (3H, s; CH3N), 3.45
(2H, s; CH2CO), 6.65 (1H, dd, J=8.4, 4.4 Hz; ArH), 6.89–6.94 ppm (2H,
m; 2”ArH); 13C NMR (100 MHz, CDCl3): d= 26.7 (CH3N), 36.4
(8)
3-Benzyl-7,8-dimethoxy-1,3,4,5-tetrahydrobenzo[d]azepin-2-one:[34] Gen-
eral procedure C was followed. Thus, treatment of 14 (0.12 g, 0.14 mmol,
1 equiv) with SmI2 (6.34 mL, 0.1m solution in THF, 0.63 mmol, 4.4 equiv)
and purification by using fluorous silica (eluting with 80% MeCN/H2O
Chem. Eur. J. 2007, 13, 1032 – 1046ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1041

D. J. Procter et al.
then MeCN) gave 3-benzyl-7,8-dimethoxy-1,3,4,5-tetrahydrobenzo[d]aze-
pin-2-one (41 mg, 0.13 mmol, 92%) as
yellow solid: 1H NMR
(33), 207 (10), 88 (15), 74 (38); HRMS: m/z: calcd for C15H19O3NBr:
340.0543; found: 340.0545 [M]+.
a
(400 MHz, CDCl3): d=7.33–7.18 (5H, m; ArH), 6.58 (1H, s; ArH), 6.44
(1H, s; ArH), 4.58 (2H, s; NCH2), 3.84 (2H, s; CH2C(O)), 3.79 (3H, s;
CH3O), 3.75 (3H, s; CH3O), 3.59 (2H, t, J=6.0 Hz; ring CH2N),
2.83 ppm (2H, t, J=6.0 Hz; CH2CH2N); 13C NMR (100 MHz, CDCl3):
d=172.3 (C=O), 147.9 (ArCOMe), 147.2 (ArCOMe), 137.6(Ar C), 128.7
(2”ArCH), 128.2 (2”ArCH), 127.6(Ar C), 127.5 (ArCH), 123.4 (ArC),
113.9 (ArCH), 113.0 (ArCH), 55.9 (2”CH3O), 49.7 (NCH2), 45.7 (ring
CH2N), 42.6( CH2C(O)), 31.9 ppm (ring CH2CH2N); IR (neat): n˜ =2935
3-Benzyl-5-morpholin-4-yl-1-propyl-1,3-dihydroindol-2-one (52): General
procedure C was followed. Thus, treatment of 38 (0.072 g, 0.084 mmol,
1 equiv) in THF (2.5 mL) with SmI2 (2.1 mL, 0.1m solution in THF,
0.21 mmol, 2.5 equiv) and purification by flash chromatography (50%
ethyl acetate in petroleum ether) gave 52 (0.024 g, 0.069 mmol, 82%) as
1
a brown oil. H NMR (300 MHz, CDCl3): d=7.23–7.16(3H, m; 3”Ar H),
7.13–7.10 (2H, m; 2”ArH), 6.72 (1H, dd, J=3.0, 9.0 Hz; ArH), 6.62
(1H, d, J=9.0 Hz; ArH), 6.31 (1H, d, J=3.0 Hz; ArH), 3.77 (4H, t, J=
6.0 Hz; 2”CH2), 3.67–3.57 (2H, m; 2”1H of CH2), 3.51–3.42 (2H, m;
1H of CH2 + CH), 2.90–2.87 (4H, m; 2”CH2), 2.85–2.78 (1H, m; 1H of
CH2), 1.54 (2H, app. q, J=6.0 Hz; CH2), 0.82 (3H, t, J=6.0 Hz; CH3);
13C NMR (75 MHz, CDCl3): d=176.8 (C=O), 147.2 (ArC), 138.2 (ArC),
137.6(Ar C), 129.9 (ArCH), 129.8 (ArCH), 129.7 (ArC), 128.5 (ArCH),
128.4 (ArCH), 126.8 (ArCH), 115.7 (ArCH), 114.9 (ArCH), 108.6
(ArCH), 67.2 (CH2), 67.1 (CH2), 50.9 (CH2), 50.8 (CH2), 47.5 (CH), 41.7
(CH2), 37.1 (CH2), 20.9 (CH2), 11.5 ppm (CH3); IR (ATR): n˜ =1694 (C=
O), 1596, 1481, 1359, 1211, 1111, 934 cmÀ1; MS (CI+ mode): m/z (%):
351 (100) [M]+, 166 (23), 108 (17), 91 (27), 79 (12), 69 (9), 58 (16);
HRMS: m/z: calcd for C22H26O2N2: 350.1989; found: 350.1992 [M]+.
À1
À
(C H), 1640 (C=O), 1517, 1486, 1448, 1420, 1355, 1257, 1243, 1218 cm
;
MS (EI mode): m/z (%): 311 (99) [M]+, 91 (38), 121 (13), 164 (57), 220
(50), 312 (22); HRMS: m/z: calcd for C19H21O3N: 311.1521; found:
311.1523 [M]+.
5,6,7-Trimethoxy-2-pentyl-1,4-dihydro-2H-isoquinolin-3-one:
procedure was followed. Thus, treatment
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecylsulfanyl)-5,6,7-tri-
methoxy-2-pentyl-1,4-dihydro-2H-isoquinolin-3-one (11) (0.10 g,
General
C
of 4-
0.13 mmol, 1 equiv) with SmI2 (8.37 mL, 0.1m in THF, 0.84 mmol,
6.6 equiv) and purification by using flash chromatography on silica (elut-
ing with CH2Cl2 then 50% EtOAc/petroleum ether (40–608C)) gave the
a
brown oil. 1H NMR
3-(3-Methylbut-2-enyl)-5-(4-methylpiperazin-1-yl)-1-propyl-1,3-dihydroin-
dol-2-one (53): General procedure C was followed. Thus, treatment of 39
(0.068 g, 0.079 mmol, 1 equiv) in THF (3 mL) with SmI2 (1.7 mL, 0.1m so-
lution in THF, 0.17 mmol, 2.2 equiv) and purification by column chroma-
tography using (20% ethyl acetate in petroleum ether) gave 53 (0.022 g,
0.064 mmol, 80%) as a light-brown oil. 1H NMR (500 MHz, CDCl3): d=
6.82 (1H, d, J=2.0 Hz; ArH), 6.69 (1H, dd, J=2.0, 8.4 Hz; ArH), 6.58
(1H, d, J=8.4 Hz; ArH), 4.92 (1H, t, J=7.3 Hz; CH), 3.58–3.54 (1H, m;
1H of CH2), 3.44–3.40 (1H, m; 1H of CH2), 3.27–3.25 (1H, m; 1H of
CH), 3.00 (4H, app. t, J=4.8 Hz; 2”CH2), 2.51 (4H, app. t, J=4.8 Hz;
2”CH2), 2.47–2.43 (2H, m; 1H of CH2CH=), 2.26(3H, s; C H3N), 1.53
(2H, app. q, J=7.4 Hz; CH2), 1.50 (3H, s; CH3), 1.43 (3H, s; CH3),
0.78 ppm (3H, t, J=7.4 Hz; CH3); 13C NMR (75 MHz, CDCl3): d=177.4
(C=O), 147.4 (ArC), 137.8 (ArC), 134.7 (ArC), 130.4 (=C), 119.9 (CH=
), 116.1 (ArCH), 114.8 (ArCH), 108.4 (ArCH), 55.4 (CH2), 55.3 (CH2),
50.8 (CH2), 50.7 (CH2), 46.2 (CH3), 46.1 (CH2), 41.6( CH2), 29.6( CH),
26.0 (CH3), 21.0 (CH2), 18.3 (CH3), 11.4 ppm (CH3); IR (ATR): n˜ =2931,
2798, 1697 (C=O), 1449, 1359, 1212 cmÀ1; MS (CI+ mode): m/z (%): 342
(100) [M]+, 274 (22), 152 (8), 101 (37), 97 (17), 74 (15), 70 (26), 58 (43);
HRMS: m/z: calcd for C21H32ON3: 342.2545; found 342.2540.
title compound (0.03 g, 0.09 mmol, 73%) as
(400 MHz, CDCl3): d=6.40 (1H, s; ArH), 4.36(2H, s; ring C H2N), 3.81
(3H, s; CH3O), 3.79 (3H, s; CH3O), 3.78 (3H, s; CH3O), 3.46(4H, brs;
CH2C(O), NCH2), 1.54 (2H, brs; NCH2CH2), 1.26(4H, brs;
CH2CH2CH3, CH2CH2CH3), 0.85–0.82 ppm (3H, t, J=6.6 Hz; CH2CH3);
13C NMR (100 MHz, CDCl3): d=168.8 (C=O), 152.8 (ArCOMe), 150.7
(ArCOMe), 141.6(Ar COMe), 126.9 (ArC), 118.7 (ArC), 104.5 (ArCH),
61.3 (CH3O), 61.2 (CH3O), 56.6 (CH3O), 51.4 (ring CH2N), 47.4
(CH2C(O)), 31.7 (NCH2), 29.5 (CH2CH2CH3), 27.4 (NCH2CH2), 22.9
(CH2CH3), 14.4 ppm (CH2CH3); IR (ATR): n˜ =2932, 2859, 2235, 2035,
1647 (C=O), 1491, 1465, 1415, 1353, 1311, 1270 cmÀ1; MS (EI mode): m/z
(%): 307 (99) [M]+, 84 (55), 86(35), 179 (25), 181 (12), 194 (42), 195
(17), 206(14), 221 (14), 222 (31), 236(14), 237 (25), 251 (13), 276(13),
292 (13), 306(37), 308 (20); HRMS: m/z: calcd for C17H25O4N: 307.1784;
found: 307.1781 [M]+.
3-[2-(2-Methoxyethanesulfonyl)ethyl]-1-methyl-1,3-dihydroindol-2-one
(43): General procedure C was followed. Thus, treatment of 24 (0.115 g,
0.148 mmol, 1 equiv) in THF (4.5 mL) with SmI2 (3.7 mL, 0.1m solution
in THF, 0.371 mmol, 3.7 mL) and purification by fluorous chromatogra-
phy gave 43 (0.044 g, 0.148 mmol, 100%) as a yellow oil. 1H NMR
(300 MHz, CDCl3): d=7.44–7.31 (2H, m; 2”ArH), 7.19–7.10 (1H, m;
ArH), 6.90 (1H, t, J=6.0 Hz; ArH), 3.83 (2H, t, J=6.0 Hz; CH2), 3.65–
3.57 (1H, m; CH), 3.38 (3H, s; CH3), 3.22–2.32 (7H, m; CH3, 2”CH2),
2.62–2.52 (1H, m; 1H of CH2), 2.43–2.28 ppm (1H, m; 1H of CH2);
13C NMR (300 MHz, CDCl3): d=176.6 (C=O), 144.4 (ArC), 128.7
(ArCH), 127.4 (ArC), 124.1 (ArCH), 122.9 (ArCH), 108.4 (ArCH), 66.1
(CH2), 59.1 (CH3), 53.5 (CH2), 51.3 (CH2), 43.7 (CH), 26.4 (CH3),
5-Bromo-3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecane-1-
sulfinyl)-1-propyl-1,3-dihydroindol-2-one
(19):
H2O2
(0.050 mL,
0.435 mmol, 4 equiv) was added to a solution of 7 (0.080 g, 0.109 mmol,
1 equiv) in HFIP (1 mL) and CH2Cl2 (0.5 mL) was added at room tem-
perature. The reaction was allowed to stir at room temperature for 2 h
before quenching with aqueous saturated Na2SO3 (1 mL) and the aque-
ous layer was extracted with CH2Cl2 (3”5 mL). The organic layer was
then dried (MgSO4), filtered and concentrated in vacuo to give 19
(0.081 g, 0.108 mmol, 99%) as an orange solid which was used without
further purification. 1H NMR (500 MHz, CDCl3): d=7.66–7.63 (1H, m;
ArH), 7.49 (1H, s; ArH), 6.66 (1H, d, J=8.4 Hz; ArH), 4.69 (1H, s;
CH), 3.67–3.57 (2H, m; CH2), 2.95–2.66 (2H, m; CH2), 2.49–2.28 (2H,
m; CH2), 1.66–1.60 (2H, m; CH2), 0.93–0.86ppm (3H, m; C H3);
13C NMR (125 MHz, CDCl3): d=174.3 (C=O), 142.5 (ArC), 132.3
(ArCH), 128.5 (ArCH), 127.3 (ArC), 115.4 (ArC), 110.1 (ArCH), 44.6
(CH), 42.0 (CH2), 31.0 (CH2), 29.7 (CH2), 20.6( CH2), 11.3 ppm (CH3);
IR (ATR): n˜ =3071, 2955, 1721 (C=O), 1589, 1430, 1329, 1177,
1103 cmÀ1; MS (ESÀ mode) m/z (%): 748 (100) [M]+, 746(85), 559 (50),
527 (53), 479 (30), 304 (29), 269 (37), 248 (49), 212 (41), 203 (28), 127
(37); HRMS: m/z: calcd for C21H16O2NBrF17S: 747.9808; found: 747.9813
[M+H]+.
23.3 ppm (CH2). IR (ATR): n˜ =1707 (C=O), 1613, 1470, 1296, 1111 cmÀ1
;
MS (CI+ mode): m/z (%): 298 (100) [M]+, 173 (26), 160 (8); HRMS:
m/z: calcd for C14H20O4NS: 298.1108; found: 298.1108 [M+H]+.
(5-Bromo-2-oxo-1-propyl-2,3-dihydro-1H-indol-3-yl)acetic acid ethyl
ester (44): General procedure C was followed. Thus, treatment of 25
(0.23 g, 0.28 mmol, 1 equiv) in THF (7 mL) with SmI2 (6.1 mL, 0.1m solu-
tion in THF, 0.61 mmol, 2.2 equiv) and purification by flash chromatogra-
phy using 30% ethyl acetate in petroleum ether gave 44 (0.058 g,
0.17 mmol, 73% (based on recovered starting material)) as a brown oil.
1H NMR (300 MHz, CDCl3): d=0.96(3H, t, J=9.0 Hz; CH3), 1.22 (3H,
t, J=6.0 Hz; CH3), 1.64–1.76 (2H, m; CH2), 2.80 (1H, dd, J=9.0,
18.0 Hz; 1H of CH2), 3.07 (1H, dd, J=6.0, 18.0 Hz; 1H of CH2), 3.66
(2H, t, J=9.0 Hz; CH2), 3.75 (1H, dd, J=6.0, 18.0 Hz; CH), 4.09–4.20
(2H, m; CH2), 6.73 (1H, d, J=9.0 Hz; ArH), 7.38–7.41 ppm (2H, m; 2”
ArH); 13C NMR (75 MHz, CDCl3): d=11.5 (CH3), 14.2 (CH3), 20.7
(CH2), 34.9 (CH2), 41.9 (CH), 41.9 (CH2), 61.2 (CH2), 109.8 (ArCH),
115.0 (ArC), 127.4 (ArCH), 130.5 (ArC), 131.1 (ArCH), 143.1 (ArCH),
170.9 (C=O), 176.2 ppm (C=O); IR (ATR): n˜ =2972, 1720 (C=O), 1605,
1474, 1348, 1199 cmÀ1; MS (CI+ mode): m/z (%): 340 (100) [M]+, 26 2
5-Bromo-1-propyl-1H-indol-2,3-dione (20)[35] from 19: TFAA (0.030 mL,
0.216mmol, 2 equiv) was added to a solution of 19 (0.081 g, 0.108 mmol,
1 equiv) in THF (2 mL) at 08C and the reaction was stirred at 08C for
2.5 h. NEt3 (1.5 mL, 0.011 mmol, 0.1 equiv) and ethanol (0.010 mL,
0.238 mmol, 2.2 equiv) were then added to the reaction at 08C and the
reaction was stirred at room temperature for 4.5 h. After this time, the
1042
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1032 – 1046

Synthesis of N-Heterocycles
FULL PAPER
reaction mixture was quenched with aqueous saturated NaHCO3 (10 mL)
and the aqueous layer extracted with CH2Cl2 (3”15 mL). The organic
layer was then washed with aqueous saturated NaHCO3 (2”10 mL),
dried (MgSO4), filtered and concentrated in vacuo to give the crude
product. Purification by fluorous chromatography gave 20 (0.016g,
0.060 mmol, 55%) as a dark-orange solid. 1H NMR (500 MHz, CDCl3):
d=0.87 (3H, t, J=7.4 Hz; CH3), 1.57–1.65 (2H, m; CH2), 3.58 (2H, t, J=
7.3 Hz; CH2N), 6.75 (1H, d, J=8.4 Hz; ArH), 7.52 (1H, d, J=2.0 Hz;
ArH), 7.58 ppm (1H, dd, J=2.0, 8.4 Hz; ArH); 13C NMR (300 MHz,
CDCl3): d=11.6( CH3), 20.8 (CH2), 42.2 (CH2N), 112.3 (ArCH), 116.6
(ArC), 118.9 (ArC), 128.3 (ArCH), 140.8 (ArCH), 150.1 (ArC), 157.7
(C=O), 182.8 ppm (C=O); IR (ATR): n˜ =3456, 2966, 2931, 1733, 1601,
1462, 1432, 1329, 1179, 698, 581 cmÀ1; MS (EI+ mode): m/z (%): 267 (48)
[M]+, 209 (28), 102 (21), 74 (100), 69 (20), 62 (86), 56 (72), 49 (62), 41
(92); HRMS: m/z: calcd for C11H14O2N2Br: 285.0238; found: 285.1233
[M]+.
6-Methoxy-1-propyl-1H-indole-2,3-dione: General procedure D was fol-
lowed. Thus, treatment of 3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadeca-
fluorodecylsulfanyl)-6-methoxy-1-propyl-1,3-dihydroindole-2-one
(4)
(0.281 g, 0.411 mmol, 1 equiv) in MeCN (10 mL) and water (1.2 mL) with
CAN (0.686 g, 1.232 mmol, 3 equiv) and purification by fluorous chroma-
tography gave the title compound (0.062 g, 0.283 mmol, 70%) as an
orange solid. 1H NMR (500 MHz, CDCl3): d=7.46(1H, d, J=8.4 Hz;
ArH), 6.41 (1H, dd, J=2.1, 8.4 Hz; ArH), 6.24 (1H, d, J=2.1 Hz; ArH),
3.80 (3H, s; OCH3), 3.52 (2H, t, J=7.4 Hz; CH2), 1.62–1.56 (2H, m;
CH2), 0.86ppm (3H, t, J=7.4 Hz; CH3); 13C NMR (75 MHz, CDCl3): d=
181.2 (C=O), 168.4 (C=O), 159.8 (ArC), 153.7 (ArC), 128.2 (ArCH),
111.5 (ArCH), 107.6(Ar CH), 97.7 (ArCH), 56.3 (OCH3), 41.9 (CH2),
20.9 (CH2), 11.5 ppm (CH3); IR (ATR): n˜ =2940, 1721 (C=O), 1597 (C=
O), 1358, 1211, 1096cm À1
;
MS (CI+ mode): m/z (%): 237 (50)
[M+NH4]+, 220 (42), 206(100), 190 (17), 176(5), 96(13), 58 (12);
HRMS: m/z: calcd for C12H17O3N2: 237.1234; found: 237.1238 [M+NH4]+
.
General Procedure D—CAN oxidative cleavage of the fluorous tag
1-Methyl-1H-indole-2,3-dione:[36] CAN (0.377 g, 0.666 mmol, 3 eq) was
added to a solution of 3 (0.139 g, 0.222 mmol, 1 equiv) in MeCN (5 mL)
and water (0.6mL) at room temperature. The reaction was allowed to
stir at room temperature for 15 h. The reaction mixture was then washed
with H2O (10 mL) and brine (10 mL) and the aqueous layer was extract-
ed with ethyl acetate (3”10 mL). The organic layer was then dried
(MgSO4), filtered and concentrated in vacuo to give the crude product as
an orange solid which was purified by fluorous chromatography to give
the title compound (0.036g, 0.223 mmol, 100%) as an orange solid.
1H NMR (500 MHz, CDCl3): d=7.56–7.52 (2H, m; 2”ArH), 7.06(1H, t,
J=6.9 Hz; ArH), 6.83 (1H, d, J=7.9 Hz; ArH), 3.19 ppm (3H, s;
NCH3); 13C NMR (75 MHz, CDCl3): d=183.5 (C=O), 158.4 (C=O), 151.6
(ArC), 138.6(Ar CH), 125.5 (ArCH), 124.0 (ArCH), 117.6(Ar C), 110.1
(ArCH), 26.4 ppm (CH3); IR (ATR): n˜ =1713 (C=O), 1589 (C=O), 1450,
1324, 1087, 847, 754 cmÀ1; MS (EI+ mode): m/z (%): 179 (49) [M+NH4]+
, 164 (70), 162 (40), 148 (69), 136 (30), 121 (30), 108 (35), 94 (72), 78 (51),
69 (30), 60 (100), 58 (51), 44 (50); HRMS: m/z: calcd for C33H11O2N2:
179.0815; found: 179.0811 [M+NH4]+.
7,8-Dimethoxy-3-(4-methoxybenzyl)-4,5-dihydro-3H-benzo[d]azepine-
1,2-dione (21) and 1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluoro-
decylsulfanyl)-5-hydroxy-7,8-dimethoxy-3-(4-methoxy-benzyl)-1,3,4,5-tet-
rahydrobenzo[d]azepin-2-one (22): General procedure D was followed.
Thus, treatment of 15 (0.15 g, 0.18 mmol, 1 equiv) in MeCN (9 mL) and
H2O (1 mL) with CAN (0.30 g, 0.55 mmol, 3 equiv) and purification by
using fluorous silica (eluting with 80% MeCN/H2O then MeCN) gave 21
(42 mg, 0.12 mmol, 65%) as a brown oil. 1H NMR (400 MHz, CDCl3):
d=7.23–7.19 (3H, m; ArH), 6.82 (2H, d, J=8.8 Hz; ArH), 6.51 (1H, s;
ArH), 4.59 (2H, s; NCH2), 3.84 (3H, s; CH3O), 3.83 (3H, s; CH3O), 3.75
(3H, s; CH3O), 3.56–3.54 (2H, m; ring CH2N), 2.88–2.86ppm (2H, m;
CH2CH2N); 13C NMR (100 MHz, CDCl3): d=193.2 (C=O), 167.1 (C=O),
159.4 (ArCOMe), 153.3 (ArCOMe), 148.0 (ArCOMe), 135.6(Ar C),
130.0 (2”ArCH), 128.3 (ArC), 126.7 (ArC), 114.3 (2”ArCH), 111.9
(ArCH), 111.9 (ArCH), 56.1 (CH3O), 56.1 (CH3O), 55.3 (CH3O), 48.7
(NCH2), 45.2 (ring CH2N), 33.8 ppm (ring CH2CH2N); IR (neat): n˜ =
À1
À
2935 (C H), 2837, 1657 (C=O), 1599, 1514, 1463, 1442, 1418, 1402 cm
;
MS (EI mode): m/z (%): 355 (55) [M]+, 121 (100), 122 (10), 190 (18),
191 (10), 234 (25), 356(12); HRMS: m/z: calcd for C20H21O5N: 355.1420;
found: 355.1419 [M]+. Byproduct 22 (32.4 mg, 0. 038 mmol, 21%) was
isolated from the fluorous wash. 1H NMR (400 MHz, CDCl3): d=7.19
(2H, d, J=8.8 Hz; ArH), 6.80 (2H, d, J=8.4 Hz; ArH), 6.78 (1H, s;
ArH), 6.56 (1H, s; ArH), 5.11 (1H, d, J=14.4 Hz; 1H of NCH2), 4.79
(1H, s; CHS), 4.75 (1H, d, J=15.6Hz; 1H of ring C H2N), 4.65 (1H, m;
ring CHCH2N), 4.12 (1H, d, J=14.4; 1H of NCH2), 3.81 (3H, s; CH3O),
3.81 (3H, s; CH3O), 3.72 (3H, s; CH3O), 3.52 (1H, dd, J=15.6, 4.8 Hz;
1H of ring CH2N), 2.97–2.78 (2H, m; CH2CH2RF), 2.51–2.33 (2H, m;
CH2RF), 2.00 ppm (1H, brd, J=8.8 Hz; OH); 13C NMR (100 MHz,
CDCl3): d=169.6 (C=O), 159.3 (ArCOMe), 149.5 (ArCOMe), 149.2
(ArCOMe), 131.4 (ArC), 129.6(2”Ar CH), 129.2 (ArC), 123.1 (ArC),
114.2 (2”ArCH), 114.1 (ArCH), 113.9 (ArCH), 70.0 (ring CHCH2N),
56.0 (CH3O), 56.0 (CH3O), 55.5 (CHS), 55.2 (CH3O), 52.8 (NCH2), 49.7
(ring CH2N), 31.2 (t, J=21.9 Hz; CH2RF), 24.1 ppm (CH2CH2RF); IR
5-Chloro-1-methyl-1H-indole-2,3-dione:[37] General procedure D was fol-
lowed. Thus, treatment of 5-chloro-3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
heptadecafluorodecylsulfanyl)-1-methyl-1,3-dihydro-indol-2-one
(6)
(0.15 g, 0.24 mmol, 1 equiv) with CAN (0.40 g, 0.72 mmol, 3 equiv) and
purification by using fluorous silica (eluting with 80% MeCN/H2O then
MeCN) gave the title compound (33 mg, 0.17 mmol, 70%) as an orange
solid. 1H NMR (400 MHz, CDCl3): d=7.52–7.48 (2H, m; ArH), 6.81
(1H, d, J=8.4 Hz; ArH), 3.19 ppm (3H, s; NCH3); 13C NMR (100 MHz,
CDCl3): d=182.4 (C=O), 157.7 (C=O), 149.7 (ArC), 137.8 (ArCH), 129.7
(ArC), 125.2 (ArCH), 118.2 (ArC), 111.3 (ArCH), 26.4 ppm (NCH3); IR
(KBr): n˜ =2359, 1749 (C=O), 1734 (C=O), 1608, 1456, 1354, 1327, 1263,
1175, 1109 cmÀ1; MS (CI mode, isobutane): m/z (%): 196(99) [ M+H]+,
71 (18), 79 (10), 81 (17), 83 (11), 85 (11), 197 (14), 198 (64); HRMS: m/z:
calcd for C9H7O2NCl: 196.0165; found: 196.0164 [M+H]+.
5-Bromo-1-propyl-1H-indole-2,3-dione (20): General procedure D was
followed. Thus, treatment of 7 (0.123 g, 0.168 mmol, 1 equiv) in MeCN
(9 mL) and water (1 mL) with CAN (0.276g, 0.504 mmol, 3 equiv) and
purification by fluorous chromatography gave 20 (0.045 g, 0.168 mmol,
100%) as a red solid. Data given earlier.
À
(thin film): n˜ =3384 (OH), 3004, 2934 (C H), 2842, 1643 (C=O), 1516,
1467, 1442 cmÀ1; MS (FAB mode, NOBA, NaI): m/z (%): 858 (57)
[M+Na]+, 122 (100), 218 (16), 328 (32); HRMS: m/z: calcd for
C30H26O5NF17SNa: 858.1158; found: 858.1161 [M+Na]+.
9-Bromo-6-propyl-6H-indoloCAHTRE[UGN 2,3-b]quinoxaline (54): 1,2-Phenylenedia-
5-Fluoro-1-methyl-1H-indole-2,3-dione:[38] General procedure D was fol-
lowed. Thus, treatment of 8 (0.15 g, 0.23 mmol, 1 equiv) with CAN
(0.38 g, 0.70 mmol, 3 equiv) and purification by using fluorous silica (elut-
ing with 80% MeCN/H2O then MeCN) gave the title compound (42 mg,
0.23 mmol, 100%) as an orange solid. 1H NMR (400 MHz, CDCl3): d=
7.29–7.20 (2H, m; ArH), 6.82–6.79 (1H, m; ArH), 3.19 ppm (3H, s;
NCH3); 13C NMR (100 MHz, CDCl3): d=182.8 (C=O), 159.4 (d, J=
244.3 Hz; ArCF), 158.0 (C=O), 147.5 (ArC), 124.7 (d, J=24.2 Hz;
ArCH), 118.0 (d, J=6.7; ArC), 112.5 (d, J=24.1 Hz; ArCH), 111.1 (d,
J=7.4 Hz; ArCH), 26.4 (NCH3); IR (KBr): n˜ =2359, 1748 (C=O), 1731
(C=O), 1683, 1652, 1622, 1557, 1540, 1488, 1359 cmÀ1; MS (EI mode):
m/z (%): 179 (20) [M]+, 47 (23), 48 (11), 83 (100), 85 (65), 87 (11), 96
(12), 122 (26), 123 (16), 151 (10); HRMS: m/z: calcd for C9H6O2NF:
179.0383; found: 179.0384 [M]+.
mine (0.029 g, 0.269 mmol, 1.4 equiv) was added to a solution of 20
(0.052 g, 0.192 mmol, 1 equiv) in acetic acid (2 mL) and the mixture was
heated under reflux for 1 h. The reaction mixture was then allowed to
cool to room temperature before being placed in an ice bath. The result-
ing solid was concentrated in vacuo to give the crude product as a brown
solid which was purified by flash chromatography using 60% ethyl ace-
tate in petroleum ether to give 54 (0.058 g, 0.17 mmol, 89%) as a yellow
solid. 1H NMR (500 MHz, CDCl3): d=8.55 (1H, s; ArH), 8.23 (1H, d,
J=8.6Hz; Ar H), 8.07 (1H, d, J=8.6Hz; Ar H), 7.73–7.63 (3H, m; 3”
ArH), 7.32 (1H, d, J=8.6Hz; Ar H), 4.39 (2H, t, J=7.4 Hz; CH2), 1.92
(2H, app. q, J=7.4 Hz; CH2), 0.95 ppm (3H, t, J=7.4 Hz; CH3);
13C NMR (75 MHz, CDCl3): d=139.7 (ArC), 133.6(2”Ar CH), 129.7 (2”
ArC), 129.4 (ArCH), 128.2 (2”ArC), 126.5 (2”ArC), 125.7 (2”ArCH),
111.3 (2”ArCH), 43.4 (CH2), 22.1 (CH2), 11.8 ppm (CH3); MS (EI+
Chem. Eur. J. 2007, 13, 1032 – 1046ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1043

D. J. Procter et al.
mode): m/z (%): 341 (5) [M]+, 310 (9), 297 (20), 231 (41), 218 (25), 204
(11), 177 (13), 164 (12), 129 (24), 102 (35), 90 (67), 75 (27), 63 (32), 50
(15); HRMS: m/z: calcd for C17H15N3Br: 340.0442; found: 340.0444 [M]+.
with 50% EtOAc/petroleum ether (40–608C)) to give 58 (63 mg,
0.09 mmol, 74% by conversion) as an off-white solid. 1H NMR
(400 MHz, CDCl3): d=7.36–7.35 (1H, m; ArH), 7.32–7.29 (1H, m;
ArH), 7.13–7.08 (1H, m; ArH), 7.01–6.96 (2H, m; ArH), 6.86–6.83 (1H,
m; ArH), 3.91 (1H, brs; OH), 3.24 ppm (3H, s; NCH3); 13C NMR
(100 MHz, CDCl3): d=176.0 (C=O), 159.6(d, J=240.9 Hz; ArCF), 142.8
(ArC), 139.0 (d, J 1.8, ArC), 132.0 (d, J=7.7 Hz; ArC), 126.9 (d, J=
6.6 Hz; 2”thiophene ArCH), 126.0 (thiophene ArCH), 116.5 (d, J=
23.4 Hz; ArCH), 113.2 (d, J=25.1; ArCH), 109.5 (d, J=7.9 Hz; ArCH),
9-Fluoro-6-methyl-6,11-dihydro-5H-indoloACHTREU[NG 2,3-b]quinoxaline (55): A so-
lution of 5-fluoro-1-methyl-1H-indole-2,3-dione (50 mg, 0.28 mmol,
1 equiv) and 1,2-phenylenediamine (42 mg, 0.39 mmol, 1.4 equiv) in
AcOH (2 mL) was heated under reflux. After 18 h, the reaction mixture
was cooled to room temperature then placed in an ice bath. The resulting
solid was then concentrated in vacuo. The crude product was purified by
flash chromatography on silica (eluting with 30% EtOAc/petroleum
ether (40–608C)) to give 55 (63 mg, 0.25 mmol, 90%) as a bright-yellow
solid. 1H NMR (400 MHz, CDCl3): d=8.33–8.31 (1H, m; ArH), 8.19–
8.15 (2H, m; ArH), 7.83–7.79 (1H, m; ArH), 7.74–7.70 (1H, m; ArH),
7.50–7.40 (2H, m; ArH), 4.00 ppm (3H, s; NCH3); 13C NMR (100 MHz,
CDCl3): d=158.1 (d, J = 237.7 Hz, ArCF), 146.3 (ArC), 141.2 (ArC),
140.8 (ArC), 139.5 (d, J = 3.8 Hz, ArC), 139.2 (ArCH), 129.5 (ArCH),
129.3 (ArCH), 127.7 (ArCH), 126.2 (ArCH), 120.0 (d, J=8.8 Hz; ArC),
118.5 (d, J=25.1 Hz; ArCH), 110.0 (d, J=8.0 Hz; ArCH), 108.8 (d, J=
24.3 Hz; ArCH), 27.7 ppm (NCH3); IR (KBr): n˜ =2926, 1615, 1585, 1482,
1482, 1391, 1350 cmÀ1; MS (EI mode): m/z (%): 250 (35) [M]+, 47 (20),
83 (100), 85 (65), 251 (53), 252 (10); HRMS: m/z: calcd for C15H10N3F:
251.0859; found: 251.0860 [M]+.
À
75.6(d, J=1.5 Hz; C), 26.8 ppm (N CH3); IR (KBr): n˜ =3287 (OH),
3113, 3078, 2968, 2939, 1857, 1701 (C=O), 1619, 1496, 1470 cmÀ1; MS (EI
mode): m/z (%): 263 (99) [M]+, 84 (24), 111 (75), 122 (20), 202 (88), 218
(49), 230 (66), 234 (72), 235 (39); HRMS: m/z: calcd for C13H10O2NFS:
263.0416; found: 263.0415 [M]+.
5-Fluoro-1-methyl-3,3-di-thiophen-2-yl-1,3-dihydroindol-2-one (59): 2-
Thienyllithium (0.8 mL, 1.0m in THF, 0.84 mmol, 3 equiv) was added to a
solution of crude 5-fluoro-1-methyl-1H-indole-2,3-dione (50 mg,
0.28 mmol, 1 equiv) in THF (2 mL) at 08C and the reaction was warmed
to room temperature. After 18 h, the reaction mixture was quenched
with aqueous saturated NH4Cl (5 mL). The layers were then separated
and the aqueous layer was extracted with EtOAc (2”10 mL). The com-
bined organic layers were dried (MgSO4) and concentrated in vacuo. The
crude product was purified by flash chromatography on silica (eluting
with 10% EtOAc/petroleum ether (40–608C)) to give 59 (63 mg,
0.19 mmol, 69%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d=
7.24–7.22 (1H, m; ArH), 7.18–7.16(2H, m; Ar H), 7.03–6.98 (3H, m;
ArH), 6.87–6.85 (2H, m; ArH), 6.79–6.76 (1H, m; ArH), 3.19 ppm (3H,
s; NCH3); 13C NMR (100 MHz, CDCl3): d=175.1 (C=O), 159.2 (d, J=
240.5 Hz; ArCF), 143.4 (2”ArC), 138.8 (d, J=1.8 Hz; ArC), 134.0 (d,
J=7.8 Hz; ArC), 126.7 (d, J=7.8 Hz; 4”thiophene ArCH), 126.0 (2”
thiophene ArCH), 115.6(d, J=23.3 Hz; ArCH), 113.9 (d, J=25.1;
5-Bromo-3,3-difluoro-1-propyl-1,3-dihydroindol-2-one
(56):
DAST
(0.07 mL) was added to a solution of 5-bromo-1-propyl-1H-indol-2,3-
dione (0.055 g, 0.204 mmol, 1 equiv) in CH2Cl2 (1.8 mL) at room temper-
ature and the reaction was stirred for 4 d. The reaction mixture was then
quenched with MeOH (3 mL) and washed with water (2”5 mL). The
aqueous layer was extracted with CH2Cl2 (2”5 mL) and the organic layer
dried (MgSO4), filtered and concentrated in vacuo to give the crude
product as a brown solid. Purification by flash chromatography using
10% ethyl acetate in petroleum ether gave 56 (0.052 g, 0.167 mmol,
82%) as a yellow oil. 1H NMR (500 MHz, CDCl3): d=7.59 (1H, s;
ArH), 7.54 (1H, d, J=8.4 Hz; ArH), 6.73 (1H, d, J=8.4 Hz; ArH), 3.58
(2H, t, J=7.4 Hz; CH2), 1.64 (2H, app. q, J=7.4 Hz; CH2), 0.90 ppm
(3H, t, J=7.4 Hz; CH3); 13C NMR (75 MHz, CDCl3): d=142.6( C=O),
136.4 (ArCH), 128.3 (ArCH), 122.1 (ArC), 116.4 (ArC), 113.6(Ar C),
111.5 (ArCH), 42.1 (CH2), 20.5 (CH2), 11.3 (CH3); 19F NMR (282 MHz,
CDCl3): d=À113 (s; 2”F); IR (neat): n=2929, 1743, 1614, 1476, 1271,
1074, 715 cmÀ1; MS (CI+ mode): m/z (%): 289 (18) [M]+, 229 (67), 135
(18), 58 (22); HRMS: m/z: calcd for C11H11ONBrF2: 289.9987; found:
289.9990 [M]+.
À
ArCH), 109.3 (d, J=7.9 Hz; ArCH), 56.1 (C), 27.1 ppm (N CH3); IR
(KBr): n˜ =1719 (C=O), 1608, 1496, 1466, 1348, 1263 cmÀ1
;
MS (EI
mode): m/z (%): 329 (100) [M]+, 83 (73), 85 (48), 284 (95), 285 (23), 296
(27), 300 (47), 330 (22); HRMS: m/z: calcd for C17H12ONFS2: 329.0344;
found: 329.0342 [M]+.
6’-Fluoro-1’-methyl-1’H-spiro[imidazolidine-4,3’-indole]-2,5,2’-trione (60):
KCN (36mg, 0.56mmol, 2 equiv) was added to a solution of 5-fluoro-1-
methyl-1H-indole-2,3-dione (50 mg, 0.28 mmol, 1 equiv) in MeOH
(3 mL) at room temperature. After 15 min, (NH4)2CO3 (0.27 g,
2.79 mmol, 10 equiv) and H2O (5 mL) were added. The reaction mixture
was then heated to 708C. After 18 h, the reaction mixture was cooled,
MeOH removed in vacuo and H2O (10 mL) was added. The reaction
mixture was acidified with 6m HCl (10 mL) and extracted with Et2O (2”
10 mL). The organic layers were combined and washed with aqueous sa-
turated NaCl (15 mL). The organic layer was then dried (MgSO4) and
concentrated in vacuo. The crude product was purified by flash chroma-
tography on silica (eluting with 80% EtOAc/petroleum ether (40–608C)
then EtOAc) to give 60 (39 mg, 0.16mmol, 56%) as a cream solid.
1H NMR (400 MHz, [D6]DMSO): d=11.42 (1H, brs; NH), 8.60 (1H,
brs; NH), 7.52–7.49 (1H, m; ArH), 7.34–7.29 (1H, m; ArH), 7.18–7.15
(1H, m; ArH), 3.18 ppm (3H, s; NCH3); 13C NMR (100 MHz,
[D6]DMSO): d=170.8 (C=O), 170.1 (C=O), 158.8 (d, J=237.9 Hz;
ArCF), 157.5 (C=O), 140.5 (ArC), 126.3 (ArC), 116.9 (d, J=23.2 Hz;
ArCH), 112.4 (d, J=25.8 Hz; ArCH), 110.5 (d, J=8.0 Hz; ArCH), 69.1
(C), 26.9 ppm (NCH3); IR (KBr): n˜ =3433, 3194, 1747 (C=O), 1705 (C=
O), 1620 (C=O), 1489, 1362, 1265, 1219 cmÀ1; MS (EI mode): m/z (%):
249 [M]+, 28 (20), 44 (21), 95 (12), 108 (15), 122 (24), 149 (60), 150 (78),
3,3,5-Trifluoro-1-methyl-1,3-dihydroindol-2-one (57): DAST (46 mL,
0.35 mmol, 2.5 equiv) was added to a solution of 5-fluoro-1-methyl-1H-
indole-2,3-dione (25 mg, 0.14 mmol, 1 equiv) in CH2Cl2 (1 mL) at room
temperature. After 72 h, the reaction mixture was carefully quenched
with MeOH and then washed with H2O. The organic layer was dried
(MgSO4) and concentrated in vacuo. The crude product was purified by
flash chromatography on silica (eluting with 40% EtOAc/petroleum
ether (40–608C)) to give 57 (22 mg, 0.11 mmol, 77%) as a pale-yellow
solid. 1H NMR (400 MHz, CDCl3): d=7.25–7.12 (2H, m; ArH), 6.80–
6.77 (1H, m; ArH), 3.15 ppm (3H, s; NCH3); 19F NMR (367 MHz,
CDCl3): d=À112.4 (2F, s), À117.5 ppm (1F, s); 13C NMR (100 MHz,
CDCl3): d=165.0 (t, J=29.8 Hz; C=O), 159.5 (d, J=243.5 Hz; ArCF),
139.9 (ArCF), 121.3 (m; CF2), 120.0 (d, J=23.3 Hz; ArCH), 112.9 (d, J=
25.7 Hz; ArCH), 110.5 (d, J=7.7 Hz; ArCH), 107.9 (ArC), 26.4 ppm
(NCH3); IR (KBr): n˜ =3075, 2927, 1747 (C=O), 1651, 1626, 1503, 1425,
1370 cmÀ1; MS (EI mode): m/z (%): 201 (100) [M]+, 47 (21), 63 (30), 78
(23), 83 (89), 85 (57), 145 (26), 153 (38), 154 (22), 172 (51), 173 (36);
HRMS: m/z: calcd for C9H6NF3: 201.0401; found: 201.0403 [M]+.
178 (50), 179 (17), 206(06), 250 (13); HRMS:
m/z: calcd for
C11H8O3N3F: 249.0550; found: 249.0551 [M]+.
5-Fluoro-3-hydroxy-1-methyl-3-thiophen-2-yl-1,3-dihydroindol-2-one
(58): 2-Thienyllithium (0.14 mL, 1.0m in THF, 0.14 mmol, 1 equiv) was
added to a solution of 5-fluoro-1-methyl-1H-indole-2,3-dione (25 mg,
0.14 mmol, 1 equiv) in THF (1 mL) at 08C and the reaction was warmed
to room temperature. After 18 h, the reaction mixture was quenched
with aqueous saturated NH4Cl (5 mL). The layers were then separated
and the aqueous layer was extracted with EtOAc (2”10 mL). The com-
bined organic layers were dried (MgSO4) and concentrated in vacuo. The
crude product was purified by flash chromatography on silica (eluting
5-Bromo-3-(2-bromomethylbenzyl)-3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
heptadecafluorodecane-1-sulfonyl)-1-propyl-1,3-dihydroindol-2-one (61):
K2CO3 (0.099 g, 0.713 mmol, 5 equiv) and a,a’-dibromo-o-xylene (0.188 g,
0.713 mmol, 5 equiv) were added to
a
solution of 5-bromo-3-
(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecane-1-sulfonyl)-1-
propyl-1,3-dihydroindol-2-one (0.109 g, 0.143 mmol, 1 equiv) in DMF
(12 mL) and the reaction mixture was heated to 408C. The reaction was
left to stir for 1.5 h. After this time, ethyl acetate (10 mL) was added to
1044
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1032 – 1046

Synthesis of N-Heterocycles
FULL PAPER
the reaction mixture and the organic layer washed with water (5”
10 mL), dried (MgSO4), filtered and concentrated in vacuo to give a
crude brown oil. The crude product was purified by fluorous chromatog-
raphy to give 61 (0.112 g, 0.118 mmol, 83%) as a yellow oil. 1H NMR
(300 MHz, CDCl3): d=7.85 (1H, d, J=3.0 Hz; ArH), 7.48 (1H, dd, J=
3.0, 9.0 Hz; ArH), 7.20 (1H, dd, J=3.0, 9.0 Hz; ArH), 7.07 (1H, dt, J=
3.0, 9.0 Hz; ArH), 6.93 (1H, dt, J=3.0, 9.0 Hz; ArH), 6.60 (2H, d, J=
9.0 Hz; 2”ArH), 4.82 (1H, d, J=9.0 Hz; 1H of CH2), 4.38 (1H, d, J=
9.0 Hz; 1H of CH2), 4.01 (1H, d, J=15.0 Hz; 1H of CH2), 3.92–3.82 (1H,
m; 1H of CH2), 3.67 (1H, d, J=15.0 Hz; 1H of CH2), 3.60–3.49 (2H, m;
CH2), 3.38–3.29 (1H, m; 1H of CH2), 2.78–2.62 (2H, m; CH2), 1.32–1.25
(2H, m; CH2), 0.57 ppm (3H, t, J=9.0 Hz; CH3); 13C NMR (75 MHz,
CDCl3): d=169.8 (C=O), 143.6(Ar C), 137.2 (ArCH), 134.4 (ArC), 131.3
(ArC), 131.2 (ArCH), 130.7 (ArCH), 129.9 (ArCH), 128.8 (ArCH), 128.6
(ArCH), 122.8 (ArC), 116.2 (ArC), 110.8 (ArCH), 74.9 (CSO2), 42.4
(CH2), 40.9 (CH2), 32.8 (CH2), 31.8 (CH2), 23.4 (t, J=33.8 Hz; CH2), 20.3
(CH2), 11.0 ppm (CH3); IR (ATR): n˜ =1706(C =O), 1601, 1477, 1313,
1201, 1133, 953 cmÀ1; MS (ES+ mode): m/z (%): 970 (100), 968 (32)
[M+Na]+, 934 (20), 927 (12), 892 (30); HRMS: m/z: calcd for
C29H22O3NBr2F17NaS: 967.9308; found: 967.9320 [M+Na]+.
Product 64: 1H NMR (300 MHz, CDCl3): d=7.37 (1H, dd, J=3.0,
9.0 Hz; ArH), 7.24–7.13 (4H, m; 4”ArH), 6.72 (2H, d, J=9.0 Hz; 2”
ArH), 3.77–3.62 (3H, m; CH2N, CH), 3.52 (1H, dd, J=3.0, 15.0 Hz; 1H
of CH2Ar), 2.79 (1H, dd, J=9.0, 15.0 Hz; 1H of CH2), 2.33 (3H, s; CH3),
1.69 (2H, app. q, J=9.0 Hz; CH2), 0.96ppm (3H, t, J=9.0 Hz; CH3);
13C NMR (75 MHz, CDCl3): d=176.8 (C=O), 143.0 (ArC), 136.9 (ArC),
136.3 (ArC), 131.0 (ArCH), 130.9 (ArCH), 130.8 (ArCH), 130.3 (ArCH),
128.3 (ArC), 127.4 (ArCH), 126.2 (ArCH), 114.7 (ArC), 109.8 (ArCH),
45.9 (CH), 41.9 (CH2), 34.6( CH2), 20.9 (CH2), 19.8 (CH3),11.6ppm
(CH3); IR (ATR): n=2924, 2852, 1705 (C=O), 1597, 1474, 1349, 1202,
1110 cmÀ1; MS (CI+ mode): m/z (%): 358 (85) [M]+, 297 (19), 280 (100),
207 (9), 122 (11); HRMS: m/z: calcd for C19H21ONBr: 358.0801; found:
358.0801 [M]+.
Acknowledgements
We thank the Carnegie Trust for the Universities of Scotland (Scholar-
ship to L.A.M.), Celltech R&D (CASE award, L.A.M.), The University
of Glasgow (University Scholarship to R.A.M), The University of Man-
chester (K.M.J.), and Syngenta (CASE award K.M.J.). Additional, unre-
stricted support was provided by AstraZeneca and Pfizer.
Spirocycle 62 and 2-bromo-5-propyl-5H-benzo[b]carbazole (63): SmI2
(2.4 mL, 0.1m solution in THF, 0.24 mmol, 2.2 equiv) was added to a solu-
tion of 61 (0.102 g, 0.12 mmol, 1 equiv) in THF (5 mL) by using a syringe
pump over 0.5 h. The reaction was then stirred at room temperature for
1.5 h. Aqueous saturated NaHCO3 (5 mL) was added to the reaction mix-
ture and the aqueous layer was extracted with EtOAc (3”5 mL). The or-
ganic layer was dried (MgSO4), filtered and concentrated in vacuo. The
crude product mixture was purified by flash chromatography using 10%
ethyl acetate in petroleum ether to give 62 (0.026g, 0.073 mmol, 68%) as
a yellow solid and 63 (0.007 g, 0.021 mmol, 20%) as a yellow solid.
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A. R. Katritzky, C. W. Rees), Pergamon, New York, 1984; b) P. J.
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[4] For recent reviews see: a) D. P. Curran in The Handbook of Fluo-
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4475.
Product 62: 1H NMR (400 MHz, CDCl3): d=7.36(1H, dd, J=2.0,
8.4 Hz; ArH), 7.27 (4H, brs; 4”ArH), 6.93 (1H, d, J=2.0 Hz; ArH),
6.75 (1H, d, J=8.4 Hz; ArH), 3.72 (2H, t, J=7.2 Hz; CH2), 3.63 (2H, d,
J=15.4 Hz; 2”1H from two CH2), 3.06(2H, d, J=15.4 Hz; 2”1H from
two CH2), 1.79–1.70 (2H, m; CH2), 0.98 ppm (3H, t, J=7.2 Hz; CH3);
13C NMR (100 MHz, CDCl3): d=179.3 (C=O), 141.1 (ArC), 140.8 (ArC),
140.7 (ArC), 138.5 (ArC), 130.7 (ArCH), 127.3 (ArCH), 127.2 (ArCH),
124.8 (ArCH), 124.7 (ArCH), 124.6(Ar CH), 115.0 (ArC), 109.7 (ArCH),
54.1 (C), 44.1 (CH2), 44.0 (CH2), 41.7 (CH2), 20.7 (CH2), 11.3 ppm (CH3);
[5] For a preliminary account of this work see: L.A. McAllister, R. A.
McCormick, S. Brand, D. J. Procter, Angew. Chem. 2005, 117, 456;
Angew. Chem. Int. Ed. 2005, 44, 452.
IR (ATR): n˜ =2925, 2854, 1695 (C=O), 1597, 1474, 1349, 1204, 1102 cmÀ1
;
MS (CI+ mode): m/z (%): 356(100) [ M]+, 295 (20), 278 (50), 120 (19),
58 (21); HRMS: m/z: calcd for C19H19ONBr: 356.0648; found: 356.0645
[M]+. Product 63: 1H NMR (400 MHz, CDCl3): d=8.53 (1H, s; ArH),
8.32 (1H, d, J=2.0 Hz; ArH), 8.05 (1H, dd, J=8.4, 0.4 Hz; ArH), 7.97
(1H, dd, J=8.4, 0.4 Hz; ArH), 7.69 (1H, s; ArH), 7.61 (1H, dd, J=8.4,
2.0 Hz; ArH), 7.51 (1H, td, J=8.4, 1.6Hz; Ar H), 7.42 (1H, td, J=8.4,
1.6Hz; Ar H), 7.27 (1H, d, J=8.4 Hz; ArH), 4.30 (2H, t, J=7.3 Hz;
CH2), 1.97 (2H, app. q, J=7.3 Hz; CH2), 1.02 ppm (3H, t, J=7.3 Hz;
CH3); 13C NMR (100 MHz, CDCl3): d=171.9 (C=O), 141.8 (ArC), 140.6
(ArC), 132.8 (ArC), 129.7 (ArCH), 128.5 (ArC), 128.0 (ArCH), 127.0
(ArCH), 125.5 (ArCH), 124.5 (ArCH), 124.0 (ArC), 123.8 (ArC), 122.8
(ArCH), 119.1 (ArCH), 111.3 (ArC), 109.6(Ar CH), 103.6(Ar CH), 44.9
(CH2), 21.8 (CH2), 11.8 ppm (CH3); IR (ATR): n˜ =2929, 1461, 1137,
848 cmÀ1; MS (CI+ mode): m/z (%): 338 (100) [M]+, 260 (17), 74 (25), 63
(18); HRMS: m/z: calcd for C19H17NBr: 338.054; found: 338.0539 [M]+.
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2-Bromo-5-propyl-5H-benzo[b]carbazole (63) and 5-bromo-3-(2-methyl-
benzyl)-1-propyl-1,3-dihydroindol-2-one (64): A solution of 61 (0.091 g,
0.096mmol, 1 equiv) in THF (4.5 mL) was added to a flask containing
SmI2 (4 mL, 0.1m solution in THF, 0.40 mmol, 4.2 equiv) by using a sy-
ringe pump over 0.5 h. The reaction was stirred at room temperature for
2 h. Aqueous saturated NaHCO3 (5 mL) was added to the reaction mix-
ture and the aqueous layer was extracted with EtOAc (3”8 mL). The or-
ganic layer was dried (MgSO4), filtered and concentrated in vacuo. The
crude product was purified by flash chromatography using 10% ethyl
acetate in petroleum ether to give 63 (0.024 g, 0.072 mmol, 75%) as a
yellow solid and 64 (0.007 g, 0.020 mmol, 20%) as a yellow oil. Data for
63 given earlier.
Chem. Eur. J. 2007, 13, 1032 – 1046ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Published online: January 3, 2007
1046
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 1032 – 1046