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Ketenes in Polymer-Assisted Synthesis.

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A. Rafai Far
Ketene Synthesis and Reactions
Ketenes in Polymer-Assisted Synthesis
Adel Rafai Far*
combinatorial chemistry · heterocycles · reactive
intermediates · solid-phase chemistry · synthesis
Since its inception, ketene chemistry has developed into a unique and
well-established source of useful transformations for conventional
synthetic organic chemistry. It is, therefore, not surprising that soon
after their movement from the realm of peptide and peptoid libraries to
that of small molecules, combinatorial chemists have sought the benefits of ketene chemistry to satisfy their own synthetic needs. The ability
of these versatile molecules to undergo reactions with nucleophiles,
and to participate in cycloadditions and cyclocondensations, has been
utilized for the preparation of diverse heterocyclic compounds, and
has added to the advantages of polymer-assisted synthesis for rapid
purification. Different types of ketenes and different methods for their
generation have been involved, which illustrates the potential diversity
of the chemistry. There is now a better grasp of the effect of the fragility
of these sometimes transient molecules on the reactions involving solid
supports, and this augurs well for the application of some of the more
recent developments in ketene chemistry to the generation of smallmolecule libraries.
1. Introduction
Since the report of the preparation of diphenylketene by
Staudinger in 1905, ketene chemistry has consistently mirrored the progress in organic chemistry.[1] In fact, the unique
ability of these sensitive and generally transient molecules to
undergo [2þ2] cycloadditions often gives ketenes a place of
their own in organic synthesis.[2]
With the mainstreaming of combinatorial chemistry,
matrix-assisted synthetic protocols have become precious
commodities.[3] The necessity to deliver efficient methods in
the preparation of structurally diverse molecules on supports
has shed new light on the particularities of ketene chemistry,
especially as the interests of combinatorial chemists has
grown to include libraries of small molecules.
[*] Dr. A. Rafai Far
GlycoDesign Inc.
480 University Avenue
Toronto, ON M5G 1V2 (Canada)
Fax: (+ 1) 416-593-8988
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1.1. On the Application of Ketene
Chemistry to Supported
Ketenes possess a typically transient nature: They react with electrophiles, nucleophiles, and free radicals
and hence are sensitive to water and
oxygen. In the absence of other possibilities, simple ketenes can dimerize
and/or oligomerize. The consequence is that for any reagent
to react with ketenes, the rate of the reaction must be faster
than, or at least competitive with, the rates of ketene
decomposition pathways.
In principle, the use of supports would permit any of these
reactions to be driven to completion with a large excess of the
desired ketene. In practice, however, what is often seen,
especially with the insoluble supports, is a slowdown in the
rates of the desired reactions, which results from the need for
the reactions to occur across two phases.[4] This slowdown can
drastically impede product formation, which consequently
becomes negligible.
In this respect, reactive supported reagents are generally
the best choice in polymer-assisted syntheses involving
ketenes. Less reactive reagents might be compensated for
by the use of soluble supports and/or more stable dialkyl or
silyl ketenes. Fortunately, these limitations to the transposition of ketene chemistry from solution to solid supports have
not prevented the use of these highly versatile molecules in
polymer-assisted synthesis.
DOI: 10.1002/anie.200201594
Angew. Chem. Int. Ed. 2003, 42, 2340 – 2348
Ketenes in Polymer-Assisted Synthesis
2. Reactions of Ketenes with Polymer-Bound
The addition of ketenes to the support is, in practice, the
ideal case scenario, as a large excess of these sensitive
reagents can be used to drive the reaction to completion.
There are numerous examples of the involvement of ketenes
in polymer-assisted synthesis, and these can be classified
according to the method of generation of these transient
2.1. Dehydrohalogenation of Acid Halides
2.1.1. Esterification
The generation of ketenes from an acid halide by the basemediated elimination of a hydrogen halide is perhaps the
most simple and common approach. In fact, the sequence of
the conversion of an acid to a ketene from the acid chloride
and the subsequent reaction with a chiral alcohol is one of the
oldest stereoselective reactions, and permits the origin of the
stereochemistry to occur at the a position of the acid
This approach was transposed to a solid-supported chiral
alcohol 1 (Scheme 1).[6] This alcohol was treated with a aryl
methyl ketene to generate an ester 2, which can in turn be
saponified to generate the chiral acid 3 in very high yield
(> 99 %) and decent enantiomeric purity (ee > 80 %). The
saponification also releases the polymer-bound chiral alcohol,
which can be recycled without loss of efficacy.
Given the importance of b-lactams to medicinal chemistry, it is not surprising that the Staudinger reaction has found a
variety of uses in polymer-assisted synthesis. Perhaps one of
the cornerstones of ketene chemistry, this reaction is the
[2þ2] cycloaddition of a ketene, generated in situ from an
acid chloride and an amine base, with an imine to afford a blactam.[7]
In a seminal paper, Gallop and co-workers used sasrin,
preloaded with an Fmoc-protected (Fmoc = 9-fluorenylmethoxycarbonyl) amino acid, as the starting material 4
(Scheme 2).[8] After deprotection, the resin yields a free
Scheme 2. a) 30 % Piperidine in NMP; b) R2CHO, HC(OMe)3, CH2Cl2 ;
c) R3CH2COCl, Et3N, CH2Cl2 ; d) 3 % CF3COOH in CH2Cl2. NMP =
N-methylpyrollidone. R1 = alkyl, R2 = alkyl, aryl, R3 = alkyl, O-alkyl,
O-aryl, N-phthalimidoyl.
primary amine, which can be reacted with aldehydes, in the
presence of trimethyl orthoformate as a desiccant, to afford
the desired polymer-bound imines 5. These, in turn, were
treated with an acid chloride in the presence of triethylamine
to produce the polymer-supported b-lactams 6, which were
liberated from the resin in good yields (58–97 %) by treatment with CF3COOH. The polymer-bound lactams can be
further derivatized by Suzuki and Heck coupling reactions,
upon selection of properly functionalized aldehydes, to form
the imines.[9] The lesser substituted parent b-lactams 11 can be
produced similarly through the use of the photolabile
TentaGel B resin (8, Scheme 3).
Scheme 1. a) Et3N, THF; b) LiOH, H2O, THF. Ar = aryl.
Adel Rafai Far, born in Iran in 1972, received a B.Sc. in biochemistry from
McGill University. After gaining an
M.Sc. with Prof. T. H. Chan at the
same institution, he joined Prof. T. T.
Tidwell (Univ. of Toronto) to prepare
and study polymer-bound ketenes and
allenes, receiving his Ph.D. in 2000.
Postdoctoral research with Prof. J. Rebek, Jr. (Scripps, La Jolla) focussed on
immobilization of large host molecules
on polymer supports. In 2002, he joined
GlycoDesign Inc., who develop proprietary drugs for cancer treatment and prevention of cardiovascular and
chronic inflammatory diseases.
Angew. Chem. Int. Ed. 2003, 42, 2340 – 2348
2.1.2. The Staudinger Reaction
Scheme 3. a) 30 % Piperidine in NMP; b) R1CHO, HC(OMe)3, CH2Cl2 ;
c) R2CH2COCl, Et3N, CH2Cl2 ; d) hn (365 nm), DMSO. R1 = alkyl, alkenyl, R2 = N-phthalimidoyl.
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
A. Rafai Far
The stereochemical selectivity of this procedure, through
the effect of chiral ketenes and chiral imines was also
investigated.[10] In both cases only cis diasteromers were
observed. The diastereoselectivities of the b-lactams produced were in a range of 8:1 to greater than 25:1 when using a
ketene bearing a chiral oxazolidinone moiety, and a range of
2:1 to greater than 25:1 when using chiral aldehydes to form
the imines. This method for preparing b-lactams has been
extended to the use of poly(ethylene glycol) monomethyl
ether (MPEGOH, MW = 5000 g mol1) as a soluble support
(Scheme 4).[11]
Scheme 6. a) Substituted o-nitrobenzaldehyde, Na2SO4, CH2Cl2 ;
b) R3OCH2COCl, Et3N, CH2Cl2 ; c) SnCl2, DMF; d) HF/anisole (95:5).
R1 = arylene, alkanediyl, R2 = O-alkyl, halogen, R3 = aryl, acetyl.
Scheme 4. a) 4-CbzNH(C6H4)OH, DCC, DMAP; b) H2, Pd/C;
c) R1CHO, 90 8C; d) R2OCH2COCl, R3N, CH2Cl2 ; e) H2SO4, MeOH,
60 8C. Cbz = carbobenzoxy, DCC = dicyclohexyl carbodiimide,
DMAP = 4-dimethylaminopyridine. R1 = alkyl, aryl, R2 = benzyl, phenyl.
In all of the previous examples, the imine intermediate
was generated from a polymer-bound amine, but it may also
be generated from a polymer-bound aldehyde 16
(Scheme 5).[12] In this case acetoxyketene was used, and this
allowed further modifications to give the carbamate products
20. This approach also exclusively produces the cis-diastereomers of the lactams. This chemistry was extrapolated to the
synthesis of enantiomerically enriched b-lactams starting
from a polymer-bound version of Garner's aldehyde.[13]
b-Lactams are not only interesting as final targets but can
also be used as interesting intermediates towards the prep-
aration of other products. This was demonstrated by using
substituted o-nitrobenzaldehydes in the preparation of imines
22 (Scheme 6), bound to a 4-methylbenzhydrylamine hydrochloride (MBHA) resin.[14] After formation of the b-lactams
23, the nitro groups are reduced by tin(ii) chloride and the
resulting anilines open the four-membered ring to give, after
cleavage from the resin, dihydroquinolinones 25 in excellent
yields (68–100 %) and greater than 85 % purity.
2.1.3. Reaction with Wittig Reagents
The reaction of ketenes with stabilized Wittig reagents is a
well-known and efficient method for the generation of
allenes. The lack of reactivity of stabilized Wittig reagents
on insoluble polymeric supports is, unfortunately, extremely
detrimental to this reaction. However when MPEGOH is
used as a soluble support, this becomes a very efficient way of
(Scheme 7).[15] These can, in turn, be used to generate
polymer-bound enamines 28, a class of reagents that are
central to the preparation of heterocyclic compounds.
Scheme 7. a) R1CH2COCl, Et3N, CH2Cl2 ; b) R2NH2, CH2Cl2. R1 = aryl,
acetyl, R2 = alkyl.
2.2. Thermal Decomposition of Ketene Precursors
2.2.1. 4H-1,3-Dioxin-4-ones
The retro-Diels–Alder-like thermal decomposition of
2,2,6-trimethyl-4H-1,3-dioxin-4-one (diketene acetone adduct 29) efficiently generates acetyl ketene (30) [Eq. (1)].[16]
Scheme 5. a) R1NH2, 4 A molecular sieves or CH(OCH3)3 ; b) AcOCH2COCl, Et3N, CH2Cl2 ; c) K2CO3, MeOH, CH2Cl2 ; d) p-nitrophenylchloroformate, DIPEA, CH2Cl2 ; e) R22NH, CH2Cl2 ; f) 3 % CF3COOH, CH2Cl2.
DIPEA = N,N-diisopropylethylamine; PNB = p-nitrophenyl. R1 = aryl,
alkyl, R2 = alkyl.
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2003, 42, 2340 – 2348
Ketenes in Polymer-Assisted Synthesis
Scheme 8. a) 29, PhMe, 130 8C (bath temperature); b) R2NH2,
HC(OCH3)3, CH2Cl2 ; c) PhMe, 130 8C (bath temperature), repeat;
d) KCN, MeOH, DMF, 60 8C. R1 = alkyl, aryl, R2 = alkyl.
Acetyl ketene (30) can then be trapped by MPEGOH to
yield the parent acetoacetate 31, which can, in turn, yield
enamines 32 by treatment with primary amines in the
presence of a dessicant (Scheme 8).[17] Acetyl ketene can also
undergo cyclocondensation with enamines 28 or 32 to give 4pyridones 33.[15, 17]
2.2.2. Acylated Meldrum's Acid
Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) reacts with aliphatic acyl chlorides in the presence of pyridine to
give acyl derivative 34,[18] in high yield, without the use of
chromatography. These reagents are excellent sources of acyl
ketenes through their thermal decomposition and have
gained in popularity as a result of their facile preparation,
as opposed to the time-consuming functionalization of 4H1,3-dioxin-4-ones [Eq. (2)]. The ability of these ketenes to
react with nucleophiles to give 1,3-dicarbonyl compounds,
which are of interest in heterocyclic chemistry, has been
widely exploited.
Acyl Meldrum's acid derivatives have been used in the
esterification of hydroxy-functionalized resins.[19, 20] The resulting b-ketoesters 35 can then be alkylated and condensed
with phenyl hydrazine to give 1-phenylpyrazolones 38 in 52–
95 % yield and 85–95 % purity (Scheme 9).[19] Such b-ketoes-
Scheme 10. a) Acyl Meldrum's acid derivative 34, PhMe, 70 8C;
b) R2CHO, piperidine, HC(OCH3)3, DMF, 65 8C; c) 40, HC(OCH3)3,
DMF, 80 8C; d) CAN, DMA; e) 3 % CF3COOH in CH2Cl2. CAN =
cerium(iv) ammonium nitrate, DMA = dimethylamine. R1 = aryl, R2,
R3 = alkyl, R4 = alkyl, O-alkyl, halogen.
ters 35 can also undergo Knoevenagel reactions with aldehydes, followed by Hantzsch condensations with enamines to
give dihydropyridines that can be aromatized prior to
cleavage from the resin (Scheme 10).[20] In this particular
case, the method was used to generate 2,2’-bipyridines 42 in
47–79 % yield and 70–85 % purity.
Polymer-bound amines 45 generated from polymer-bound
amino acids 43 by reductive amination were also treated with
acyl Meldrum's acid derivatives 34, to give b-ketoamides 46
(Scheme 11)[21, 22] that undergo an intramolecular cyclization,
accompanied by cleavage from the resin, to give 3-acyltetramic acids 47 (tetramic acid = 2,4-pyrrolidinedione) in mediocre yields (11–61 %), but with excellent purity (80–100 %).
Scheme 11. a) R2CHO, HC(OCH3)3, repeat; b) NaCNBH3, DMF, AcOH,
repeat; c) acyl Meldrum's acid derivative 34, PhMe, 120 8C; d) 30 % DIPEA, dioxane, 80 8C. R1, R3 = alkyl, R2 = aryl.
2.3. Wolff Rearrangements
Thermal or photochemical Wolff rearrangements are
well-known methods for the generation of ketenes. These
reactions stem from the decomposition of diazoketones 48
[Eq. (3)].[23]
This approach has been used in the Arndt–Eistert
homologation, in which the carbon chain of a carboxylic acid
Scheme 9. a) Acyl Meldrum's acid derivative 34, PhH (at reflux);
b) R2X, TBAF, THF; c) PhNHNH2, THF, HC(OCH3)3 ; d) CF3COOH,
MeCN. TBAF = tetrabutylammonium fluoride. R1, R2 = alkyl.
Angew. Chem. Int. Ed. 2003, 42, 2340 – 2348
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
A. Rafai Far
is extended by one methylene unit with respect to its parent
diazoketone.[24] This method has been applied to the preparation of enantiopure b-amino acid derivatives by extending
the skeleton of the parent a-amino acids. Once incorporated
into peptides (so-called b-peptides), these amino acids give
rise to unusual properties, in particular, a number of very
stable secondary structures.[25]
b-Peptides can be generated through conventional peptide coupling methods from the b-amino acids. Alternatively,
the preparation can be made directly onto a solid support by
the reaction of ketenes, generated through the Wolff rearrangement, and the amino terminal group of the peptide
being synthesized using either the Wang resin or the
2-chlorotrityl resin, in the presence of silver benzoate as a
mediator (Scheme 12).[26, 27] More than one b-amino acid can
be incorporated into the peptide by this method, which, in
fact, can be made entirely of such amino acids.
Scheme 13. a) hn, CO (350 KPa), THF; b) 1 n HCl, MeOH or dioxane;
c) H2 (50 psi), Pd(OH)2/C; d) Pb(OAc)4, CH2Cl2, MeOH, then 1 n HCl.
PEG = poly(ethylene glycol). R = alkyl.
3. Polymer-Bound Ketenes
As mentioned previously, the inherent instability of most
ketenes makes them very sensitive substances. This has not
prevented investigations on the use of polymer-bound ketenes in the synthesis of small-molecule libraries. Such
ketenes belong to two broad categories: reactive ketenes
used in intramolecular reactions and stable ketenes used in
intermolecular reactions.
3.1. Intramolecular Reactions
Scheme 12. a) iBuOCOCl, NMM, THF; b) CH2N2, Et2O; c) AgOBz,
NMM, THF, 0 8C. NMM = N-methylmorpholine. Rx, Ry = amino acid
side chain.
2.4. Photolysis of Chromium Carbene Complexes
The irradiation of chromium carbene complexes 54 is
thought to give rise to short-lived chromium–ketene complexes 55.[28] This complex reverts back to the carbene
complex, if it is not otherwise trapped [Eq. (4)].
(Scheme 13) posessing a chiral auxiliary were photolyzed in
the presence of an amino acid ester, dipeptides were formed
in good yields (60–88 %), and with good diastereoselectivity
(80–96 %).[29] This methodology allows the introduction of
nonproteinogenic (nonnatural) a-amino acids into peptides
(Scheme 13). It has been applied to both solid-phase peptide
synthesis[30] and to the synthesis of peptides bound to a soluble
poly(ethylene glycol) support.[31] Although the moderate
yields obtained may be prohibitive in the synthesis of large
peptides, it is certainly of interest in drug design, where small
peptides are generally the standard.
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
The Smith–Hoehn electrocyclization is a reaction sequence yielding phenols through the formation of a transient
dienyl ketene from an appropriately derivatized cyclobutenone. This reaction has been widely exploited in recent
years.[32] One such example is the polymer-bound cyclobutenedione 60, prepared from squaric acid and the 4-iodophenyl
ether of the Wang resin (Scheme 14).[33] Upon sequential
treatment with an amine and an alkenyl lithium species,
compound 60 is converted to the cyclobutenones 61, which
when heated in refluxing toluene undergo an electrocyclic
ring-opening to give the polymer-bound ketenes 62, which
concomitantly cyclize to the hydroquinones 63. Oxidation in
air and treatment with CF3COOH lead to the quinones 64 in
rather low yields (0–53 %) after chromatography.
Acylamino ketenes cyclize to form interesting zwitterionic
heterocyclic compounds known as mBnchnones, which possess a typically transient nature as a result of self-condensation. Bilodeau and Cunningham employed the cyclocondensation of mBnchnones with tosylimines to generate libraries of
imidazoles (Scheme 15).[34] The polymer-bound mBnchnones
68 were generated from the acylated amino acids 66, through
dehydration to ketenes 67. After the condensation reactions,
the polymer-bound imidazoles 69 are freed from the resin in
greater than 95 % purity after washing with CF3COOH (90 %
in H2O) had removed most of the polymer-bound impurities.
3.2. Stable Polymer-Bound Ketenes
As a result of the reactivity of ketenes, it would not be
generally anticipated that polymer-bound ketenes would be
Angew. Chem. Int. Ed. 2003, 42, 2340 – 2348
Ketenes in Polymer-Assisted Synthesis
applications, particularly when involved in reactions
with nucleophiles.
In this respect, the particularly stable silylated
ketenes were used. Reactions involving a ketenyl
moiety of bisketene 71 proceed in a facile fashion; the
reactivity of the remaining ketenyl moiety, however, is
lower by orders of magnitude.[35] Therefore, the basemediated reaction of 71 with either MPEGOH or the
Wang resin cleanly gives the polymer-bound ketenes
72 a and b (Scheme 16).[17, 36] These polymer-bound
ketenes were used to immobilize amines as their
succinamic esters 73. Following desilylation the
amines can be released as their succinamic acids 74,
succinamides 75, or succinimides 76. However, their
reaction with alcohols is limited by competition with
H2O which, after cleavage, results in the increasing
Scheme 14. a) Isopropyl tributyltin squarate, [PdCl2(PPh3)2], CuI, DMF or nBuLi,
of the alcohol being matched with increasing
then diisopropyl squarate, and then HCl in CH2Cl2 ; b) RNH2, THF, 30 min;
amounts of succinic anhydride.[36]
c) vinyllithium, 78 8C (XCH¼CHY = heterocycle); d) PhMe, reflux; e) air
This set of experiments proves the viability of
oxidation; f) 20 % CF3COOH in CH2Cl2. R = alkyl.
polymer-bound silylated ketenes. Such ketenes can
also be generated on the polymer directly. For
instance, the photochemical ring-opening of methylenecyclobutenones is an efficient method for the generation
of allenyl ketenes.[37] Using MPEGOH as a support, the
Wittig reagent 77 was treated with 3,4-bis(trimethylsilyl)cyclobut-3-ene-1,2-dione (78) to give the polymer-bound methylenecyclobutenone 79 (Scheme 17).[15, 36] Photolytic ringopening gave the stable polymer-bound silylated allenylketene 80. Treatment of this ketene with an amine gave
enamines 81, which can be used to produce d-lactams 82 by
Scheme 15. a) R2COCl, DIPEA, CH2Cl2, then KOH, dioxane/H2O;
b) EDC, CH2Cl2, 24–48 h, then R3CHNTs; c) 90 % CF3COOH, H2O, 1 h,
then AcOH, 100 8C. EDC = 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide. R1 = , R2 = aryl, R3 = 3-, 4-pyridyl.
Scheme 17. a) CH2Cl2 ; b) hn (350 nm), CH2Cl2 ; c) RCH2NH2, CH2Cl2 ;
d) acryloyl chloride, imidazole, THF, reflux; e) KCN, MeOH, DMF.
R = alkyl.
4. Ketenes in Polymer-Assisted Synthesis
Scheme 16. a) Et3N, CH2Cl2 ; b) RR’NH2, CH2Cl2 ; c) TBAF, THF, AcOH;
d) for 73 b: CF3COOH, CH2Cl2, H2O; e) for 73 a: nBuNH2, PhMe; f) for
73 a: KCN, MeOH, DMF. R = , R’ = aryl, alkyl.
particularly useful, as side reactions are detrimental to the
preparation of products of high purity. However, just as for
the other less reactive cumulenes, stabilized ketenes may find
Angew. Chem. Int. Ed. 2003, 42, 2340 – 2348
Although solid-phase organic synthesis is an unmatched
method for the generation of huge libraries of compounds, it
is rather time-consuming to develop. A viable alternative has
been the adaptation of soluble substrates using polymerbound reagents and scavengers.[38] This technique allows all of
the conventional analytical tools, such as NMR spectroscopy
and TLC, to be used for optimization of the synthetic
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
A. Rafai Far
protocol, and therefore reduces the time required for its
In an earlier case, the use of stable ketenes for the
polymer-assisted preparation of the corresponding enantiomerically enriched acids through the asymmetric esterification of an immobilized chiral alcohol was examined
(Scheme 1). A similar approach has been employed, which
involved different chiral poly(tertiary amines) derived from
cinchona alkaloids, prolinol, ephedrine, and (5S)-1-azabicyclo[3.1.0]hexane as catalysts in the esterification of methanol
with methyl phenyl ketene to generate methyl 2-phenylpropionate in modest yields.[39]
However, the ketene is generated ideally from polymerbound reagents and, as we have seen previously, the
dehydrohalogenation of acyl halides is probably the most
common method of generating reactive ketenes. Lectka and
co-workers have devised a method in which a polymer-bound
base, used as a packing material for a jacketed column cooled
to 78 8C, effects the dehydrohalogenation.[40–43] When a
solution of the acid chloride is added to the top of the column,
a solution of the ketene percolates at the bottom and can be
either trapped by another reagent or eluted through another
column packed with a different polymer-bound reagent/
scavenger for further transformations (Figure 1).
Figure 1. A) Setup for the polymer-mediated generation of ketenes;
B) setup for the generation of b-lactams.
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ure 1 B).[41, 42] The resulting crude b-lactam solution is passed
through a final column packed with aminomethylated polystyrene, which serves to scavenge the final impurities. The
imine solution can be preformed or can also be generated by
passing a solution of the a-chlorosulfonamide 91 through
another column packed with a mixture of celite and sodium
hydride at 43 8C (Scheme 19).[42] In both cases, yields and
stereoselectivities were similar.
Scheme 19. a) 83, THF, 78 8C; b) 84 a or b, perhalocyclohexadienone,
THF, 78 8C; c) NaH, celite, THF, 43 8C; d) 89, 85, THF, 43 8C;
e) aminomethylated polystyrene, THF; f) 85, 89, K2CO3 or NaH, THF,
43 8C. R = aryl, alkyl, alkenyl, O-phenyl, O-acetyl, halogen.
The polymer-bound form 83 of the phosphazene base
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3diaza-2-phosphorine (BEMP, Scheme 18) is used to affect the
dehydrohalogenation, and allows the generation of the ketene
solution at 78 8C. This solution can be percolated onto a
solution of a perhalocyclohexadienone in the presence of the
cinchona alkaloids 84 a or b to generate the a-halo ester 88 of
the corresponding perhalophenols (Scheme 19) in a stereoselective fashion (ee 90 %).[40] In order to further extend the
methodology to the Staudinger reaction, such ketene solutions can also be passed immediately through a second
jacketed column packed with the polymer-bound cinchona
alkaloid 85 (with an optimized linker to the resin) while a
solution of an imine 89 is concomitantly introduced (Fig-
Scheme 18. Reagents involved in polymer-assisted synthesis using acyl
chlorides to generate ketenes.
Finally, the use of the polymer-bound Cinchona alkaloid
85 as both the nucleophilic catalyst and the base effecting the
dehydrohalogenation was investigated.[42, 43] This rather precious polymeric reagent was regenerated in situ with K2CO3
or sodium hydride in a rather unusual solid-gel shuttle
deprotonation between a solid and a gel. Although this blactam formation involves a single step, the presence of a
regenerating base seems to induce some scrambling in its
stereoselectivity. All of the polymers can be recycled by
simply eluting washing solutions through the columns,
which seems to have only a marginal effect on the reaction
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Ketenes in Polymer-Assisted Synthesis
5. Reactions of Ketenimines with Solid Supports
6. Summary and Outlook
Ketenimines are formally the imines of ketenes, and are
generally generated by the dehydration of amides.[44] Ketenimines can be used as alternatives to ketenes in solid-phase
synthesis, if the latter are not effective. Hence, whereas
ketene–alkene [2þ2] cycloadditions have not been reported
using solid-phase supports, the corresponding reaction of
ketenimines has been investigated (Scheme 20).[45] The reaction of keteniminium salts 95 with polymer-bound alkenes 93
As we have seen here, polymer-assisted synthesis has
greatly benefited from the unique character of ketene
chemistry. These versatile reagents have been applied to the
preparation of a variety of heterocyclic compounds, and the
advantages and limitations of the use of ketenes in the
preparation of various small molecules have been fully
assessed. The current work augurs well for the use of ketenes
to generate diverse libraries. Until now, most attention has
been focused on the Staudinger reaction, but the recent
developments in ketene chemistry would certainly warrant
further extrapolations of these reactions to polymeric supports. This is particularly true of intramolecular ketene
reactions,[32] and especially of silylated ketenes, for which
the scope and the set of possible reactions has been extended
during the last decade.[46, 47]
The author expresses his deepest gratitude to Professor
Thomas T. Tidwell of the Department of Chemistry at the
University of Toronto for useful comments and suggestions, as
well as his thorough review of the manuscript.
Received: August 28, 2002
Revised: October 11, 2002 [M1594]
Scheme 20. a) Unsaturated alcohol, DIC, DMAP, CH2Cl2 ; b) triflic acid,
CH2Cl2, 2,6-di-tert-butylpyridine, 10 8C; c) resin 93, CH2Cl2, reflux;
d) Me4NHB(OAc)3, CH2Cl2 ; e) MeMgCl, THF, 78 8C to 10 8C;
f) KOTMS, MeOH, CH2Cl2 ; g) NaHCO3(aq), THF; h) LiBH4, MeOH,
THF; i) o-mesitylenesulfonylhydroxylamine, CH2Cl2 ; j) mCPBA, CH2Cl2.
DIC = N,N’-diisopropylcarbodiimide, KOTMS = potassium trimethysilanolate, mCPBA = m-chloroperbenzoic acid. X = arylene, alkanediyl, R1,
R3 = H, Me, R2 = H, Me, Ph, R4 = Me.
gives the desired cyclobutanone iminium salts 96. Their
reduction or treatment with methylmagnesium chloride leads,
after release from the resin, to the corresponding cyclobutylamines 97. On the other hand, hydrolysis leads to the
cyclobutanones 98, which are used as an intermediate in the
generation of several scaffolds in a multiple-core combinatorial fashion. These reactions yielded cyclobutanones 99
(two examples), cyclobutanols 100 (six examples), g-lactams
101 (two examples), and g-lactones 102 (two examples).
In this case, the production of a cyclobutanone, which would
be the expected product of a [2þ2] cycloaddition of
ketenes and alkenes, and which derives from the keteniminium salt, is a demonstration of the correlation between the
two species.
Angew. Chem. Int. Ed. 2003, 42, 2340 – 2348
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