A fluorous-phase Pummerer cyclative-capture strategy for the synthesis of nitrogen heterocycles

Article abstract of DOI:10.1002/anie.200461930

Catching on: Fluorous-tagged heterocyclic frameworks accessed rapidly through a Pummerer cyclative-capture approach can then be modified conveniently, for example, by Pd-catalyzed cross-coupling. Traceless, reductive cleavage of the fluorous phase tag com

Full text of DOI:10.1002/anie.200461930

Communications
Fluorous-Phase Synthesis
A Fluorous-Phase Pummerer Cyclative-Capture
Strategy for the Synthesis of Nitrogen
Heterocycles**
Laura A. McAllister, Rosemary A. McCormick,
Stephen Brand, and David J. Procter*
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 collections
of heterocyclic compounds in a rapid and efficient high-
throughput manner is therefore a key activity in synthetic
chemistry.[2]
The Pummerer reaction[3] provides a useful tool for the
synthesis of heterocyclic compounds.[4] We recently reported a
solid-phase approach to oxindoles that utilizes the Pummerer
cyclization of substrates attached to a resin by an “enabling”
sulfur atom.[5] The approach is limited by the synthetic
sequence required to access the immobilized heterocyclic
framework (immobilization–oxidation–cyclization). A more
general limitation, common to many solid-phase processes,
arises from the considerable investment required to optimize
solid-phase sequences because of difficulties in monitoring
transformations.[6] Herein, we report our success in addressing
these issues and describe a fluorous-phase[7,2b] Pummerer
cyclative-capture strategy for the synthesis of a range of
N heterocycles.
Our approach is based on the addition of thiols to
glyoxamides 1 to form hemithioacetals at the correct oxida-
tion level for activation and Pummerer cyclization. This
constitutes a new, general strategy for triggering Pummerer
cyclizations.[8] The use of a thiol-containing phase tag[9,10]
leads to cyclative capture of the substrate. The choice of a
fluorous phase tag both allows reactions to be monitored
conveniently and allows phase-tag-assisted purification at
each stage of the process. Our approach constitutes the first
[*] L. A. McAllister, R. A. McCormick, Dr. D. J. Procter[+]
Department of Chemistry
The Joseph Black Building, University of Glasgow
Glasgow G12 8QQ (Scotland)
E-mail: david.j.procter@manchester.ac.uk
Dr. S. Brand
Celltech R&D Ltd
216 Bath Road, Slough, Berkshire SL1 4EN (UK)
[+] Current address:
School of Chemistry, University of Manchester
Oxford Road, Manchester M13 9PL (UK)
Fax: (+44)161-275-4939
[**] We thank The Carnegie Trust for the Universities of Scotland
(scholarship to L.A.M.), Celltech R&D (CASE award to L.A.M.), and
the University of Glasgow (University Scholarship to R.A.M).
Additional, unrestricted support was provided by AstraZeneca and
Pfizer.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200461930
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Table 1: Fluorous-phase Pummerer cyclative capture of glyoxamides.[a]
example of fluorous-phase cyclative capture and utilizes a
fluorous-phase scavenging reagent in a novel manner. Upon
completion of the sequence, the fluorous phase tag can be
removed under mild electron-transfer conditions[11]
(Scheme 1). The treatment of readily accessible glyoxa-
Entry
Glyoxamide
Tagged heterocycle[b] Yield [%][c]
1
65
2
75[d]
3
4
5
X=Cl
R=Me
X=Br
R=nPr
X=F
79
85
80
R=Me
6
7
X,Y,Z=H
R=Me
X=OMe
Y,Z =H
45
51[e]
Scheme 1. Fluorous-phase Pummerer cyclative-capture strategy
(RF =fluorous alkyl).
R=nPr
8
X,Y,Z=OMe
R=n-pentyl
60
mide[12] starting materials with C8F17CH2CH2SH results in
rapid capture of the substrate and hemithioacetal formation.
In the same reaction pot, activation with trifluoroacetic
anhydride and treatment with BF3·OEt2 then gave the
product heterocycle in good yield after rapid purification by
fluorous solid-phase extraction (FSPE).[7] The fluorous-phase
Pummerer cyclative capture of a range of glyoxamides is
summarized in Table 1.
9
X=H
Y=OMe
R=nPr
X=Y=OMe
R=n-pentyl
76[f]
98
10
11
82
Oxindoles (Table 1, entries 1–5), tetrahydroisoquinoli-
nones (Table 1, entries 6–8), and tetrahydrobenzazepinones
(Table 1, entries 9–11) can be prepared by straightforward
variation of the glyoxamide substrate. For the formation of
six- and seven-membered heterocycles (Table 1, entries 6–
11), electronic activation of the aromatic ring leads to higher
yields of the product. In contrast, the formation of oxindoles
(Table 1, entries 1–5) proceeds efficiently with neutral, elec-
tron-deficient, and electron-rich substrates.
The Pummerer cyclative-capture process allows conven-
ient access to fluorous-tagged heterocyclic frameworks. These
tagged heterocycles can be modified in a variety of ways. The
sulfur-atom linkage to the fluorous phase tag can be used to
facilitate elaboration by alkylation and acylation reactions
(Scheme 2). For example, adducts 3 and 5 were prepared by
Michael addition and alkylation, respectively, whereas the
fluorous tetrahydrobenzazepinone and tetrahydroisoquinoli-
none derivatives 7 and 9 were alkylated in an analogous
fashion. Ester 6 was prepared by O acylation followed by
DMAP-catalyzed rearrangement.[13] Crucially, excess
reagents can be used to drive reactions to completion, as
purification after each modification step can be carried out
conveniently by FSPE.
[a] Conditions: C8F17CH2CH2SH, CH2Cl2, 18 h, then trifluoroacetic anhydride, 1 h,
then BF3·OEt2, 1 h; see Supporting Information for details. [b] RF =C8F17CH2CH2.
[c] Yield of isolated product. [d] Isomer ratio: 5:1. [e] Isomer ratio: ~1:1. [f] Isomer
ratio: ~2:1. Major isomers shown.
coupling technologies. Oxidation of the linking sulfur atom to
the corresponding sulfone further facilitates elaboration of
the tagged heterocyclic scaffolds. For example, sequences to
prepare alkynes 11a and 11b include sulfone-assisted alky-
lation and Sonogashira cross-coupling. Tagged 5-bromoox-
indoles 12 and 15 readily undergo Suzuki cross-coupling with
aryl and heteroaryl boronic acids to give 13, 14, and 16. Again,
purification after each modification step can be conveniently
carried out by FSPE.
Traceless cleavage of the fluorous tag is possible with a
range of electron-transfer reagents;[14] however, we have
found that reduction with SmI2[5,11a] results in the clean release
of the heterocyclic product from the fluorous phase. No
additives are required to activate SmI2,[15] regardless of the
oxidation state of the sulfur atom, because of the activated
nature of the carbon–sulfur linkage to the phase tag. For the
cleavage of fluorous sulfides, FSPE can again be used to assist
The transformations illustrated in Scheme 3 show the
compatibility of the linker system with Pd-catalyzed cross-
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Communications
Scheme 2. Manipulation of fluorous-tagged heterocycles—modifica-
Scheme 3. Manipulation of fluorous-tagged heterocycles—Pd-catalyzed
modifications (RF =C8F17CH2CH2). Reagents and conditions:
a) mCPBA, CH2Cl2, room temperature, 2 h; b) K2CO3, MeI, DMF, 408C,
2 h; c) [Pd(PPh3)4], NEt3, 808C, 18 h, propargyl alcohol or trimethyl-
silylacetylene and CuI (20 mol%); d) [Pd(PPh3)3], Na2CO3, H2O,
dioxane, 808C, 3.5 h, ArB(OH)2. mCPBA=m-chloroperbenzoic acid,
TMS=trimethylsilyl.
tions a to sulfur (RF =C8F17CH2CH2). Reagents and conditions:
a) NaOMe, MeOH, methyl acrylate, 18 h; b) LDA, THF, À788C, 2.5 h,
ethyl bromoacetate; c) methyl chloroformate, NEt3, room temperature,
3 h; d) DMAP (30 mol%), toluene, 708C, 3 h; e) NaH, THF/DMF,
808C, 18 h, allyl bromide; f) LHMDS, THF, À788C, 7 h, BnBr.
Bn=benzyl, DMAP=4-dimethylaminopyridine, DMF=N,N-dimethyl-
formamide, HMDS=hexamethyldisilazide, LDA=lithium diisopropyl-
amide.
purification, the desired product now
eluting in the non-fluorous fraction. For
the cleavage of fluorous sulfones, the
fluorous component is lost to the aque-
ous layer during work up, and no puri-
fication is required (Scheme 4).
In conclusion, we have developed a
new strategy for the high-throughput,
fluorous-phase synthesis of N-heterocy-
cle libraries. The sequence involves sev-
eral key features: a fluorous-phase Pum-
merer cyclative-capture strategy for
rapid access to tagged, heterocyclic
frameworks; modification of the fluo-
rous heterocyclic scaffolds by a variety of
approaches, including Pd-catalyzed
cross-coupling
reactions;
traceless,
reductive removal of the fluorous phase
tag. Studies on the application of this
Scheme 4. Products of reductive, traceless cleavage of the fluorous phase tag. (Compound 20
was obtained as a 1:1 mixture of tautomers according to NMR spectroscopic analysis).
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strategy in solution-phase parallel and combinatorial library
synthesis are currently underway.
Received: September 9, 2004
Keywords: fluorous phase · heterocycles · Pummerer reaction ·
.
samarium · synthetic methods
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