Chameleon catches in combinatorial chemistry: Tebbe olefination of polymer supported esters and the synthesis of amines, cyclohexanones, enones, methyl ketones and thiazoles

Article abstract of DOI:10.1039/a805874a

Tebbe olefination of supported esters R¹CO₂CH₂-polymer gave the corresponding vinyl ethers R¹C(=CH₂)OCH₂-polymer which were released, under acidic conditions, to produce methyl ketones R¹COMe; by reductive amination, to produce amines R¹CH(Me)NHR²; by bromination and reaction of R¹CBr(CH₂Br)OCH₂-polymer with thioureas to produce thiazoles; or, for supported dienyl ethers derived from α,β-unsaturated esters, by Diels-Alder reaction and acid mediated cleavage to produce cyclohexanone derivatives.

Full text of DOI:10.1039/a805874a

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Chameleon catches in combinatorial chemistry: Tebbe olefination of polymer
supported esters and the synthesis of amines, cyclohexanones, enones, methyl
ketones and thiazoles
a
a
b
a
a
Christopher P. Ball, Anthony G. M. Barrett,* † Alain Commerçon,* Delphine Compère, Cyrille Kuhn,
a
a
a
Richard S. Roberts, Marie L. Smith* and Olivier Venier
a
Department of Chemistry, Imperial College of Science, Technology and Medicine, London, UK SW7 2AY
New Lead Generation, Rhône-Poulenc Rorer, Vitry, France
b
1
Tebbe olefination of supported esters R CO
2
CH
2
–polymer
)OCH
evaporation gave thiazole 6 (R = Bn) contaminated with excess
thiourea. This impurity was removed by reverse phase HPLC
or, more simply, using the polymer supported a-bromo ketone
1
gave the corresponding vinyl ethers R C(§CH
2
2
–
polymer which were released, under acidic conditions, to
1
9
21
produce methyl ketones R COMe; by reductive amination,
scavenger 14 (200–400 mesh, 0.96 mequiv.g , 2 equiv.).
Using either of these purification methods, thiazole 6 (R = Bn)
was obtained in 40% yield based on the loading of the
1
2
to produce amines R CH(Me)NHR ; by bromination and
1
2 2
reaction of R CBr(CH Br)OCH -polymer with thioureas to
2
1
produce thiazoles; or, for supported dienyl ethers derived
from a,b-unsaturated esters, by Diels–Alder reaction and
acid mediated cleavage to produce cyclohexanone deriva-
tives.
Merrifield resin (1.0 mmol g ) to which the phenylacetic acid
had been attached. This methodology, which has been extended
to a range of thiazoles 6,∑ has the major advantage of starting
from readily available carboxylic acids rather than less diverse
commercial a-bromo ketones.
Solid phase synthesis is invaluable for the construction of
libraries of small organic compounds for biological evaluation.
Tebbe methylenation of the resin bound a,b-unsaturated
1
10
21
esters 7 ‡ (nmax/cm 1720–1740) gave the corresponding
2
1
Such bioassay is frequently carried out in solution using an
appropriate enzyme or receptor. The method of attachment and
detachment of the requisite substrates to the resin is critical. In
many solid phase syntheses, the substrates are conveniently
attached to the polymer support through a carboxylic acid
function. This is readily achieved using supports including
supported dienyl ethers 8 (1635–1650 cm ) which could be
either hydrolysed (1% TFA in CDCl ) to provide the enones
3
9** or converted into the Diels–Alder adducts 10. The diene
Br
O
CH2
Br
i
iv
2
R1
R1
R1
Merrifield, Wang and Tentagel resins etc. Following substrate
O
O
O
modification, cleavage affords a carboxylic acid, ester, amide
or, via reductive cleavage, a primary alcohol. Methods that
allow for the cleavage of resin bound carboxylate derivatives
yet which access alternative and variable functionality would be
extremely desirable. Herein we report the conversion of
supported esters into enol ethers, with subsequent on-resin
functionalisation and detachment with amplification of di-
versity.
1
2
5
ii
iii
v
S
N
1
1
2
R3
3
R COMe
R CH(Me)NHR
R1
3
4
6
Methylenation of the resin bound esters 1‡ with the Tebbe
reagent 12 (PhMe–THF 25 °C, 12 h) gave the corresponding
4
O
CH2
vinyl ethers 2 (Scheme 1). The reaction mixtures were quenched
with 15% aq. NaOH and the resin washed consecutively with
i
O
R5
O
R5
R4
R4
THF, H
2
O, EtOAc, EtOAc–MeOH (1:1) and MeOH followed
7
8
by removal of solvent in vacuo. In this reaction, commercial
Tebbe reagent (Aldrich) proved to be superior to either 12
ii
vi
4
5
(
E)-MeCOC(R )=CHR
5
generated in situ, where premature cleavage from the support
9
6
was a problem, or the Petasis reagent (Cp
SO in DMF or 1% TFA in CH Cl
2
TiMe
2
2
). Hydrolysis
R9 R8
(1
M
H
2
4
2
) of ethers 2 brought
R9
R8
R7
R6
R5
R7
about cleavage from the resin and gave the corresponding
ketones 3§ (41–92%). Alternatively, acid mediated hydrolysis
R6
ii
7
and reductive amination using amine 13 and NaBH(OAc)
gave the corresponding amines 4¶ (13–89%).
3
O
R5
O
R4
R4
The ethers 2 were found to be useful intermediates for further
transformations prior to detachment from the resin. Thiazoles,
important pharmacophores with diverse biological activities,8
are available from a-bromo ketones via the Hantzsch thiazole
10
11
R6
R7
R8
R9
Cp
Cp
Me
2
synthesis. Thus reaction of the vinyl ether 2 (R = Bn) with Br
2
Ti
Al
R NH
2
COCH Br
2
Cl Me
(1
M
2 2 2 2
in CH Cl , 2 equiv., 1 h) and washing (CH Cl ) gave the
corresponding supported dibromide 5 as indicated by the
12
13
14
15
disappearance of the enol ether (IR), gel phase magic angle
Scheme 1 Reagents and conditions: i, 12, PhMe, THF, 25 °C; ii, 1% TFA,
1
spinning H NMR [400 MHz; CDCl
elemental analysis (loading 0.65 mmol g ). Reaction of the
3
: d 4.25(CH
2
Br)] and
CH
CH
2
Cl
Cl
2
, 25 °C; iii, 1
M
H
2
SO
4
, DMF, then 13, NaBH(OAc)
3
, 25 °C; iv, Br
2
,
2
1
3
2
2
(1 , 2 equiv.), 25 °C; v, R CSNH
M
2
(4 equiv.), MeOH, reflux, then
dibromide 5 (R = Bn) with thiourea (4 equiv., MeOH at reflux,
14 (2 equiv.), MeOH, reflux; vi, 15, PhMe, 25 °C (maleimide) or 80–100 °C
(other dienophiles)
12 h), neutralisation (K
2 3
CO ), filtration with MeOH and
Chem. Commun., 1998
2019

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resins 8 may be stored for up to six months without loss of
activity but were generally used directly. Diels–Alder reaction
with N-methylmaleimide (PhMe, 25 °C) or 2-chloroacrylo-
nitrile, methyl vinyl ketone, dimethyl fumarate or 2-ethylacro-
lein (PhMe, 80–100 °C) gave the immobilised cyclohexene
derivatives 10. Subsequent cleavage from the resin (1% TFA in
3-MeOC
6
H
4
, NHBn (13%); Me(CH
2 6 2 2 6
) , NH (15%); Me(CH ) , NHMe
(10%); Me(CH , NHBn (12%).
2 6
)
4
5
*
* The enones 9 [R , R (%)] were quantified by cleavage (1% TFA in
) and 1H NMR with a (Me
Si) O reference: H, Ph (50%); H, Me
28%); H, Et (31%); H, Pr (33%); H, Me(CH (48%); (CH (53%).
† The cyclohexanones 11 [R , R , dienophile, (%, diastereoselectivity)]
) and 1H NMR with a
O reference: H, Ph, N-methylmaleimide (30%, 97:3); H, Me,
N-methylmaleimide (30%, 97:3); H, Et, N-methylmaleimide (18%, 97:3);
H, Pr, N-methylmaleimide (27%, 97:3); H, Me(CH , N-methylmaleimide
CDCl
3
3
2
(
†
2
)
6
2 4
)
4
5
were quantified by cleavage (1% TFA in CDCl
Me Si)
3
CH
2
Cl
2
) gave the corresponding cyclohexanone derivatives
We observed high endo-selectivity with
(
3
2
11.††
N-methylmaleimide consistent with the solution phase reactions
2 6
)
of 2-silyloxy dienes with maleimides11 and in contrast with
(35%,
E)-MeO
H, Ph, H
2 4
7:3); (CH ) , N-methylmaleimide (51%, 97:3); H, Ph,
(
2
CCH§CHCO
2
Me (17%, 1:1); H, Ph, H
C§CHAc (44%, 7:3); H, Me,
C§CEtCHO (19%, 3:1); H,
C§CEtAc (22%, 4:1); (CH C§CEtCHO (20%,
, H C§CHAc (43%, 3:2).
‡ For other chameleons see refs. 13 and 14. Petasis has mentioned the
TiMe
2
2
C§CClCN (23%, 7:3);
Diels–Alder reactions of resin bound 4-substituted 2-amino-
butadienes.12
2
C§CEtCHO (21%, 5:3); H, Ph, H
2
H
2
C§CHAc (11%, 5:3); H, Me(CH
2 6 2
) , H
In summary, we have developed a novel detachment method
for the removal of substrates from a solid support which allows
for the concomitant introduction of further diversity. This
strategy using chameleon‡‡ catches should be applicable to the
generation of diverse libraries from polymer supported car-
boxylic esters. Further reactions of the supported enol ethers
will be reported in due course.
Me(CH
2
)
6
,
H
2
2 4 2
) , H
2
:2:1:1); (CH
)
2 4
2
‡
possibility of the olefination of polymer supported peptides using Cp
2
but has yet to report any details: Fifth Chemical Congress of North America,
Cancun, Mexico, November 13, 1997.
We thank Rhône-Poulenc Rorer for the most generous
support of our programmes on parallel and combinatorial
syntheses under the auspices of the TeknoMed project. In
addition we thank GlaxoWellcome Research Ltd. for their
endowment (to A. G. M. B.), the Royal Society for a Dorothy
Hodgkin fellowship (to M. L. S) and the Wolfson Foundation
for establishing the Wolfson Centre for Organic Chemistry in
Medical Science at Imperial College.
1
For examples see: P. H. H. Hermkens, H. C. J. Ottenheijm and D. C.
Rees, Tetrahedron, 1997, 53, 5643; S. H. D. J. Gravert and K. D. Janda,
Chem. Rev., 1997, 97, 489; L. A. Thompson and J. A. Ellman, Chem.
Rev., 1996, 96, 555.
2 J.-P. Montheard, M. Chatzopoulos and M. Camps, J. Macromol. Sci.,
Rev. Macromol. Chem. Phys., 1988, C28, 503; V. Krchnak, D. Cabel, A.
Weichsel and Z. Flegelova, Lett. Pept. Sci., 1995, 1, 27; M. Bodanszky
and D. T. Fagan, Int. J. Pept. Protein Res., 1977, 10, 375.
3
4
F. Effenberger, Angew. Chem., Int. Ed. Engl., 1969, 8, 295.
S. H. Pine, R. Zahler, D. A. Evans and R. H. Grubbs, J. Am. Chem. Soc.,
Notes and References
1
980, 102, 3270.
5
6
L. F. Cannizzo and R. H. Grubbs, J. Org. Chem., 1985, 50, 2386.
N. Petasis and E. I. Bzowej, J. Am. Chem. Soc., 1990, 112, 6392.
†
‡
(
E-mail: m.stow@ic.ac.uk
The supported esters 1 and 7 were prepared from Merrifield resin
200–400 mesh, 1.0–1.7 mequiv. g2 ) (Cs
1
7 A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff and
R. D. Shah, J. Org. Chem., 1996, 61, 3849; C. G. Boojamra, K. M.
Burow and J. A. Ellman, J. Org. Chem., 1995, 60, 5742.
2
CO
3
, KI, DMF, 80 °C) [the
Tebbe olefination chemistry in this paper has also been carried out on Wang
resin (200–400 mesh, 0.7–1.13 mequiv. g21)]. For an alternative synthesis
of supported a,b-unsaturated esters see ref. 12. All syntheses in this paper
were carried out both manually, using single bead FT-IR spectroscopy to
follow reactions (1 1720–1740, 2 1635–1645, 7 1720–1740, 8 1635–1650
8
P. C. Kearney, M. Fernandez and J. A. Flygare, J. Org. Chem., 1998, 63,
96 and references cited therein.
S. Kobayashi and M. Moriwaki, Tetrahedron Lett., 1997, 38, 4251.
1
9
2
1
TM
10 C. R. Johnson and B. Zhang, Tetrahedron Lett., 1995, 36, 9253; P. Wipf
and T. C. Henninger, J. Org. Chem., 1997, 62, 1586.
cm ) and in a parallel fashion on a Nautilus 2400 Organic Synthesizer
(
(
Argonaut Technologies, Inc.). All the products were at least 90% pure
HPLC, GC–MS). All yields were determined with respect to the original
1
1 M. Adeva, E. Caballero, F. Garcia, M. Medarde, H. Sahagun and F.
Tome, Tetrahedron Lett., 1997, 38, 6893.
loading of chloride for Merrifield resin.
§
Me(CH
1
12 M. Crawshaw, N. W. Hird, K. Irie and K. Nagai, Tetrahedron Lett.,
997, 38, 7115.
The ketones 3 [R (%)] were isolated by filtration and evaporation:
1
2
)
6
(87%); Ph (62%); 4-BrC
(92%); 3-MeOC (56%); 2,4,6-(MeO)
2 2
CH (74%); 4-PhC (65%) and 3-indolyl–CH CH
6
H
4
(41%); 4-IC
6
H
C H
3 6 2
4
(71%);
(47%);
(74%).
1
3 G. H. Posner, T. D. Nelson, C. M. Kinter and K. Afarinkia, Tetrahedron
Lett., 1991, 32, 5295; B. M. Trost and G. K. Mikhail, J. Am. Chem. Soc.,
1987, 109, 4124; E. Schaumann, and A. Kirschning, Tetrahedron Lett.,
4
4
¶
Et
(
-MeOC
6
H
H
4
6
H
4
-MeOC
6
4
2
6
H
4
1
2
The amines 4 [R , R (%)] were isolated by filtration, partition between
O and 1 NaOH, drying (MgSO ) and evaporation: Me(CH , Pr
13%); Me(CH cyclopropyl (19%); Me(CH allyl (27%);
1
988, 29, 4281; D. H. R. Barton, L. Bohe and X. Lusinchi, Tetrahedron
2
M
4
2 6
)
Lett., 1987, 28, 6609; A. Padwa, W. Dent and P. E. Yeske, J. Org.
Chem., 1987, 52, 3944; A. G. M. Barrett, Chimica, 1982, 36, 248.
4 M. R. Gowravaram and M. A. Gallop, Tetrahedron Lett., 1997, 38,
2
)
6
,
2 6
) ,
4
4
CH
-MeOC
-MeOC
6
H
H
4
CH
CH
2
,
Pr (89%); 4-MeOC
6
4
H CH
2
,
cyclopropyl (85%);
1
6
4
2
, allyl (89%); 3-indolyl–CH
2
CH
2
, Pr (65%); 3-indolyl–
6
973.
2
CH
2
, cyclopropyl (61%); 3-indolyl–CH
2
2
CH , allyl (79%).
1
3
∑
The thiazoles 6 [R , R (%)] were isolated following purification using
scavenger 14: Ph, NH (40%); Ph, NHMe (15%); Ph, NHBn (10%); Ph, Me
NH (23%); 3-MeOC NHMe (15%);
2
Received in Liverpool, UK, 26th March 1998; revised manuscript received,
27th July 1998; 8/05874A
(14%); 3-MeOC
6
H ,
4
2
6 4
H ,
2020
Chem. Commun., 1998