Traceless linkers for solid-phase synthesis. Homo- and hetero-Diels-Alder reactions of o-quinodimethanes

Article abstract of DOI:10.1055/s-1998-1968

The synthesis and Diels-Alder reactions of a polymer-supported o-quinodimethane are described. Reaction with dimethyl acetylenedicarboxylate, benzoquinone and trichloroacetonitrile as dienophiles gives respectively substituted naphthalenes or an isoquinoline off-resin, whilst reaction with aldehydes and imines gives polymer-supported benzodihydropyrans and tetrahydroisoquinolines. The latter heterocyclic products undergo Lewis or Br?nsted acid-mediated cleavage reactions which allow incorporation of further functionality at the point of cleavage whilst leaving no trace of attachment to the polymer support.

Full text of DOI:10.1055/s-1998-1968

December 1998
SYNLETT
1381
Traceless Linkers for Solid-phase Synthesis. Homo- and Hetero-Diels–Alder Reactions of
o-Quinodimethanes
Donald Craig, * Michael J. Robson and Simon. J. Shaw
a
b
a
a
Centre for Chemical Synthesis, Department of Chemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY, U.K.
b
ZENECA Agrochemicals, Jealott’s Hill Research Station, Bracknell, Berkshire RG42 6ET, U.K.
fax: +44 171-594 5804; e-mail: dcraig@ic.ac.uk
Received 8 October 1998
Abstract: The synthesis and Diels–Alder reactions of a polymer-
supported o-quinodimethane are described. Reaction with dimethyl
acetylenedicarboxylate, benzoquinone and trichloroacetonitrile as
dienophiles gives respectively substituted naphthalenes or an
isoquinoline off-resin, whilst reaction with aldehydes and imines gives
polymer-supported benzodihydropyrans and tetrahydroisoquinolines.
The latter heterocyclic products undergo Lewis or Brønsted acid-
mediated cleavage reactions which allow incorporation of further
functionality at the point of cleavage whilst leaving no trace of
attachment to the polymer support.
One of the central thrusts of modern solid-phase synthesis involves the
design of reaction sequences which allow the 'traceless' cleavage of the
product from the polymeric material on which it was elaborated.
dicarboxylate in moderate overall yield from benzocyclobutenol.
Interestingly, 4 was inert towards the mono-activated dienophile methyl
propiolate. Reaction with benzoquinone gave directly 2,3-
naphthoquinone, presumably by a process involving sequential [4+2]
1
Amongst established reactions which have been adapted to serve this
2
purpose are inter- and intramolecular addition–elimination sequences,
3
4
Wittig reactions,
fluoride-mediated desilylation,
reductive
cycloaddition, elimination and oxidation. Reaction of
4 with
5
6
desulfurisation and ring-closing olefin metathesis. We have begun a
programme for the development of [4+2] cycloaddition reactions which
are amenable to deployment on solid supports. In this context, we are
trichloroacetonitrile gave 3-(trichloromethyl)-isoquinoline in low yield
(Scheme 2).
7
seeking to identify sequences which allow both elaboration of the
cycloadducts prior to cleavage, and the incorporation of further
structural diversity at the moment of release into solution. This letter
presents our initial findings.
We elected at the outset to study Diels–Alder reactions of a highly
reactive diene system which could be generated from a stable precursor.
o-Quinodimethanes seemed an attractive choice on account of their
availability from readily accessible precursors, and the driving-force for
8
cycloaddition provided by aromatisation. Benzocyclobutenol 1 was
synthesised from 1,1-dichloroethene and anthranilic acid according to a
9
literature procedure. In a model reaction, attempted etherification of
the sodium salt of 1 with benzyl chloride gave the lactol 2 rather than
the required benzyl ether. Presumably the alkoxide of 1 underwent ring-
opening to give the conjugate base of o-tolualdehyde, which then
dimerised. This prompted a search for a non-basic method of
Attempts to enhance the yields of the reactions depicted in Scheme 2 by
increasing the quantity of dienophile used clearly were compromised by
the direct release of product into solution, where separation from the
unconsumed excess of solution-phase starting material would be
necessary. Therefore, attention was turned to reactions of 4 which would
give products still attached to the solid support, allowing the facile
removal of excess dienophile. Such materials could in principle be
elaborated further by functional group manipulation prior to cleavage
from the support, providing the potential for structural diversification in
the products.
attachment, and we chose to adapt the benzyl trichloroacetimidate
10
method
for
use
on
11
solid
support.
Reaction
of
hydroxymethylpolystyrene with NaHMDS and trichloroacetonitrile in
THF gave the functionalised resin 3, which underwent reaction with 1
12
in the presence of triflic acid to give the polymer-supported
13
o-quinodimethane precursor 4 (Scheme 1) in excellent yield. During
the course of our study a closely similar procedure for attachment of
alcohols to solid supports under acidic conditions was independently
14
reported by Hanessian.
Diels–Alder reactions were typically carried out by adding ca. 1M
solutions of dienophile to resin 4 which had been pre-swollen with an
approximately equivalent volume of the same solvent. The solvent/resin
We took this opportunity to look at hetero-Diels–Alder reactions of resin
4. Although 4 was found to be inert towards heptanal, it combined with
two-fold excesses of 4-nitrobenzaldehyde, 4-bromobenzaldehyde and
mixtures were degassed by N purging/ultrasonication and the mixtures
2
15
methyl glyoxalate to give Diels–Alder cycloadducts. Furthermore,
then heated at ca. 110°C for the times indicated. For reactions giving
directly solution-phase products the reaction mixtures could be analysed
after filtration and rinsing of the resin. Thus, reaction of 4 with dimethyl
acetylenedicarboxylate (DMAD) gave dimethyl naphthalene-2,3-
after removal of the excess dienophile by simple washing of the resin,
the polymer-supported products 5 could be subjected to reaction with
Brønsted or Lewis acid–nucleophile combinations to give

1382
LETTERS
SYNLETT
dihydrobenzopyrans in moderate to good yield, and with excellent
stereoselectivity for the anti isomers. Similar sequences were realised
3.
4.
Johnson, C. R.; Zhang, B. Tetrahedron Lett. 1995, 36, 9253;
Hughes, I. Tetrahedron Lett. 1996, 37, 7595; Nicolaou, K. C.;
Pastor, J.; Winssinger, N.; Murphy, F. J. Am. Chem. Soc. 1998,
120, 5132.
16
for N-tosylbenzaldimine and its 4-nitro analogue, providing substituted
tetrahydroisoquinolines. The key observed difference with the oxygen
cases was that the cleavage/substitution products had predominantly or
Woolard, F. X.; Paetsch, J.; Ellman, J. A. J. Org. Chem 1997; 62,
6102. Newlander, K. A.; Chenera, B.; Veber, D. F.; Yim, N. C. F.;
Moore, M. L. J. Org. Chem. 1997, 62, 6726; Hone, N. D.; Davies
S. G.; Devereux, N. J.; Taylor, S. L.; Baxter, A. D. Tetrahedron
Lett. 1998, 39, 897.
17
exclusively syn stereochemistry. Propionitrile was used as solvent for
the cycloaddition step because of the limited solubility of the
benzaldimines in toluene. The reactions are summarised in Scheme 3
18
and in the Table.
5.
6.
7.
Jung, K. W.; Zhao, X.; Janda, K. D. Tetrahedron Lett. 1996, 37,
6491. Zhao, X.; Jung, K. W.; Janda, K. D. Tetrahedron Lett. 1997,
38, 977; Zhao, X.; Janda, K. D. Tetrahedron Lett. 1997, 38, 5437.
Van Marseveen, J. H.; den Hartog, J. A. J.; Engelen, V.; Visser, G.;
Kruse, C. G. Tetrahedron Lett. 1996, 37, 8249; Piscopio, A. D.;
Miller, J. F.; Koch, K. Tetrahedron Lett. 1997, 38, 7143.
For an early example, see: Yedidia, V.; Leznoff, C. C.; Can. J.
Chem. 1980, 58, 1144.
8.
9.
Charlton, J. L.; Alauddin, M. M. Tetrahedron 1987, 43, 2873.
Benzocyclobutenol was prepared by NaBH reduction of
4
benzocyclobutenone, prepared according to a literature procedure:
South, M. S.; Liebeskind, L. S.; J. Org. Chem. 1982, 47, 3815.
10. Wessel, H.-P.; Iversen, T.; Bundle, D. R. J. Chem. Soc., Perkin
Trans 1 1985, 2247.
11. Burdick, D. J.; Struble, M. E.; Burnier, J. P. Tetrahedron Lett.
1993, 34, 2589.
12. Triflic acid was added as a solution in hexane (see below). The use
of neat TfOH led to darkening of the polystyrene beads and
decomposition.
13. Yields throughout are calculated from the amount of recovered 1
in the first step.
14. Hanessian, S.; Xie, F. Tetrahedron Lett. 1998, 39, 733.
15. Prior to the solid-phase studies, solution-phase model reactions
were carried out using the benzyl ether of 1. Cycloadducts were
obtained in good yields in all cases.
16. Compound 6b exhibited a 7% n.O.e.between the methyl group
and the nitrophenyl benzylic methine proton; we thank Mr Dick
Sheppard and Mr Paul Hammerton of this department for this
determination. The structure of compound 6c was confirmed by
X-ray crystallography; we thank Professor David Williams and Dr
Andrew White of this department for this determination.
In summary, we have demonstrated that resin 4 is a viable precursor for
a reactive, solid-supported diene which enters into Diels–Alder
reactions with homo- and heterodienophiles. The products of the latter
reactions may be cleaved from the solid support in both reductive and
C–C bond-forming modes.
17. Compound 6h exhibited no n.O.e.between the methyl group and
the nitrophenyl benzylic methine proton; we thank Mr Dick
Sheppard and Mr Paul Hammerton of this department for this
determination.
18. Preparation of 2,2,2-trichloroacetimidate resin 3.
Acknowledgements
Into a dry flask under nitrogen was placed hydroxymethyl resin
-1
We thank the EPSRC and ZENECA Agrochemicals (CASE Studentship
to S. J. S.) for financial support of this research.
(3.67 mmol g , 0.200 g, 0.734 mmol, 1.0 equiv) and THF (8.0
ml) added to swell the beads. The excess THF was removed and
fresh THF (7.5 ml) added. To the suspension was added NaHMDS
(0.70 ml of a 1M solution in THF, 0.70 mmol, 0.9 equiv) before
shaking at room temperature for 1 h. The suspension was cooled
to 0°C and trichloroacetonitrile (0.146 ml, 1.468 mmol, 2.0 equiv)
added dropwise, forming a yellow solution. The suspension was
shaken at room temperature for 14 h before filtering the resin. The
References and Notes
1.
Cleavage from the resin of products from solid-phase synthesis
usually leaves a polar residue, most often hydroxyl or -NH, on the
cleaved molecule. ‘Traceless’ cleavage avoids the generation of
such polar functionalities.
resin was washed with CH Cl (4 x 15 ml) and MeOH (2 x 15
2
2
2.
Gowravaram, M. R.; Gallop, M. A. Tetrahedron Lett. 1997, 38,
6973; Whitehouse, D. L.; Nelson K. H.; Savinov, S. N.; Austin, D.
J. Tetrahedron Lett. 1997, 38, 7139; Tietze, L. F.; Steinmetz, A.
Synlett 1996, 667; Gordon, D. W.; Steele, J. BioMed. Chem. Lett.
1995, 5, 47.
ml), and dried under vacuum to give 0.298 g material;
ν
(diffuse reflectance) 1632, 1602, 1494, 1453, 1249, 1028,
max
-1
769 cm ; δ (68 MHz, gel-phase) 162.6, 91.4, 70.7 (Found: C,
C

December 1998
SYNLETT
1383
-1
59.80; H, 4.76; N, 3.63; Cl, 26.65. Resin with 3.67 mmol g
filtered and the beads washed with CH Cl (4 x 7 ml), and MeOH
2 2
loading requires N, 3.36; Cl, 25.56%).
Preparation of benzocyclobutene ether resin 4.
(3 x 7 ml). The beads were dried under vacuum to give 0.229 g
material. To a sample of the resin so formed (1.69 mmol g based
-1
Into a dry flask under nitrogen was placed trichloroacetimidate
resin 3 (2.40 mmol g , 0.136 g, 0.326 mmol, 1.0 equiv) and
on recovered 4-nitrobenzaldehyde, 0.042 g, 0.071 mmol, 1.0
equiv) was added CH Cl (1.0 ml) to swell the beads. The excess
2 2
-1
CH Cl (0.8 ml) added to swell the beads. The excess solvent was
solvent was removed, and fresh CH Cl (1.0 ml) added.
2 2
2
2
removed and fresh CH Cl (0.4 ml) added. Benzocyclobutenol
Trimethylaluminium (0.048 ml of a 2.0M solution in hexane,
0.096 mmol, 1.3 equiv) was added, forming an orange solution.
The suspension was shaken at room temperature for 18 h before
2
2
(0.059 g, 0.489 mmol, 1.5 equiv) was added before adding a
solution of triflic acid (0.006 ml, 0.065 mmol, 0.2 equiv) in
hexane (0.6 ml). The suspension was shaken at room temperature
for 14 h before removing the resin by filtration. The beads were
filtering the mixture and washing the resin with CH Cl (2 x 5
2
2
ml), aq. HCl (2M, 2 x 5 ml), CH Cl (2 x 5 ml) and MeOH (2 x 5
2
2
washed with CH Cl (4 x 10 ml) and MeOH (2 x 7 ml) before
ml). The combined filtrate and washings was concentrated under
reduced pressure before partitioning between CH Cl (15 ml) and
2
2
drying under vacuum to give 0.129 g resin 4; ν
(diffuse
max.
2
2
-1
reflectance) 1504, 1121, 815, 747 cm ; δ (125 MHz, nanoprobe)
aq. HCl (0.5M, 15 ml). The aqueous phase was extracted with
CH Cl (3 x 10 ml), and the combined organics dried (MgSO ).
C
146.1, 142.4, 129.2, 126.9, 123.3, 122.7, 76.2, 70.9, 38.6 (Found:
C, 77.12; H, 6.27; N, 0.92). The filtrate was concentrated under
2
2
4
Concentration under reduced pressure yielded 6b (0.005 g, 26%
from 1) without further purification; R 0.42 (30% Et O–petrol);
reduced pressure. Column chromatography (SiO 20% hexane–
2
f
2
petrol) yielded unreacted benzocyclobutenol (0.022 g, 37%).
ν
(film) 2959, 2921, 2852, 1602, 1518, 1450, 1345, 1102,
max
-1
Hetero-Diels–Alder reaction of 4 and reaction with Me Al.
1035, 849, 757 cm ; δ (270 MHz) 8.29 (2H, d, J 8.5 Hz, m-
3
H
Into a dry pressure tube under nitrogen was placed resin 4 (2.28
mmol g , 0.226 g, 0.514 mmol, 1.0 equiv), and toluene (0.7 ml)
ArNO ), 7.62 (2H, d, J 9.0 Hz, o-ArNO ), 7.26-7.08 (4H, m,
2 2
ArH), 5.21 (1H, q, J 6.5 Hz, OCHCH ), 5.05 (1H, dd, J 10.0, 4.0
3
-1
added to swell the resin beads. The excess solvent was removed
and the tube charged with toluene (0.51 ml) before adding
4-nitrobenzaldehyde (0.156 g, 1.023 mmol, 2.0 equiv). The
suspension was ultrasonicated and degassed four times before
sealing the tube and heating to 108°C for 14 h. The mixture was
Hz, OCHCH ), 3.02-2.96 (2H, m, CH CH), 1.62 (3H, d, J 6.5 Hz,
2 2
CHCH ); δ (125 MHz) 149.8, 147.3, 138.7, 132.3, 128.6, 126.8,
3
C
126.5, 125.3, 123.7, 71.7, 69.1, 36.1, 22.0; m/z (CI) 287
+
+
[M+NH ] , 118 (Found: [M+NH ] , 287.1393. C
H NO
16 15 3
4
4
+
requires [M+NH ] , 287.1396).
4