Radical and palladium-mediated cyclizations of ortho-iodo benzyl enamines: Application to solid phase synthesis

Article abstract of DOI:10.1055/s-1998-1901

Ortho-iodo benzyl enamines bound to polystyrene were efficiently cyclized under radical and Pd-mediated reaction conditions.

Full text of DOI:10.1055/s-1998-1901

November 1998
SYNLETT
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Radical and Palladium-Mediated Cyclizations of Ortho-Iodo Benzyl Enamines:
Application to Solid Phase Synthesis.
Sabine Berteina, Sebastian Wendeborn, Alain De Mesmaeker*
Novartis Crop Protection AG, R-1060, CH-4002 Basel, Switzerland
Email: alain.de_mesmaeker@cp.novartis.com; Fax: +41-61-697-8529
Received 4 June 1998
Abstract: Ortho-iodo benzyl enamines bound to polystyrene were
efficiently cyclized under radical and Pd-mediated reaction conditions.
nBuNH2, RT, 42h; vi) 3 eq. Me2C=C(NMe2)Cl, CH2Cl2, RT, 5h; vii) 10
eq. nBuNH2, 2 eq. nBu4NBr, 3 eq. NEt3, RT, 96h; viii) 6 eq. MeONa,
MeOH/dioxane (1/4), RT, 24h.
In the preceding paper,1 we reported a scope and limitation study of
radical and palladium-mediated cyclizations of ortho-iodo benzyl
enamines and enol ethers performed in solution. Standard reaction
conditions were identified, which could be translated to solid support
synthesis. Palladium-mediated and radical cyclizations are
complementary processes and would be very useful in combinatorial
chemistry.2,3 We describe here the successful application of these
methods to aryl iodides bound to polystyrene.4
The silyl protecting group was easily removed by use of tetrabutyl
ammonium fluoride in the presence of acetic acid. The conversion of the
benzylic alcohol 7 into the corresponding bromide using carbon
tetrabromide and triphenyl phosphine was not efficient on solid support
(V, Scheme 1), probably due to the insolubility of the phosphonium
intermediate. On the contrary, the use of chlorenamine5 followed by
substitution with nBuNH2 in the presence of nBu4NBr, led to the
desired core structure 9 in high yield.
For the attachment of the aryliodide moiety to polystyrene we have used
a base-labile linker 21,3c which was coupled with 1 (Scheme 1). After
removal of the tert-butyl ester group, the carboxylic acid 4 was
Different enamines or allyl amines were synthesized by reaction of the
solid phase-bound amine
9 with Michael acceptors (C≡C) or
allylbromide derivatives in good yields (Scheme 2). The intermediates
before cyclization were cleaved from the resin by treatment with
MeONa and isolated in very high overall yield (Table 1).
connected to the resin
5
using the corresponding N-
hydroxybenzotriazole activated ester. For each chemical transformation,
we investigated different reaction conditions on solid support. A
cleavage by basic transesterification using MeONa in a mixture of
MeOH/dioxane was realized after each step. The isolated yield of
products cleaved from the resin were, in all cases, superior to 80%.
Scheme 2 i) 4 eq. R1-≡-H, CH2Cl2, RT, 24h. ii) 4 eq. Br-CH2-CH=CH-
R2, 2 eq. Schwesinger base6, dioxane, RT, 70 h. iii) 0.2 eq. Pd(OAc)2,
0.4 eq. Ph3P, 2 eq. nBu4NCl, 4 eq. K2CO3, DMA(0.05M), 100°C, 24h.
iv) 6 eq. MeONa, MeOH/dioxane (1/4), RT, 24h. v) O2, dichloroethane,
RT, 24h.
Our optimized conditions1 for palladium-mediated reactions7 were
successfully applied to resins 15a,b (Scheme 2) to give the 6-exo
cyclized products 17a,b, and to substrates 11a-c leading to the 6-endo
cyclized products 13a-c. The latter underwent slow air oxidation to
isoquinolones 14a-c (Scheme 2). The transformation of 13a-c into 14a-c
was followed by 1H NMR spectroscopy. Practically, a stream of oxygen
was bubbled into a dichloroethane solution of the cyclized products
13a-c for 24h at room temperature to perform a complete conversion
into the corresponding isoquinolones. Almost pure samples of 13a-c
Scheme 1 i) 1 eq. 2, 1.1 eq. Me2C=C(NMe2)Cl (chlorenamine),
CH2Cl2, RT, 3h; then 1 eq. 1, 1.5 eq. NEt3, 10 eq. pyridine, 0.2 eq.
DMAP, CH2Cl2, RT, 21h, 89%; ii) CF3CO2H / CH2Cl2 (5/95), RT, 15h,
99%; iii) 4 eq. 4, 4.4 eq. NEt3, 4.4 eq. O-(1H-benzotriazol-1-yl)-
N,N,N’,N’-tetramethyl uronium tetrafluoroborate,
2
eq. N-
hydroxybenzotriazole, dioxane, RT, 5h; then 1 eq. resin 5, 10 eq. NEt3, 1
eq. DMAP, dioxane, RT, 60h; iv) 8 eq. nBu4NF, 8 eq. AcOH, dioxane,
RT, 18h; v) 5 eq. CBr4, 4.8 eq. Ph3P, dioxane, RT, 3.5h; then 10 eq.

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SYNLETT
Radical9 and Pd-mediated7 cyclization reaction conditions were
successfully applied to Rink resin 22a,b. After acid cleavage with
CF3COOH, the desired products 24a,b and 25a,b were obtained in
almost quantitative yield (Scheme 4).
could be isolated and characterized by 1H NMR immediately after
cleavage from the resin.
These conditions were applied to the corresponding vinyl ether 18
(Scheme 3). The cyclization precursor was synthesized on solid support
from resin 7 by reaction with methyl propiolate activated by N-
methylmorpholine8 (Scheme 3). The conversion was complete for both
processes, as demonstrated by cleavage from the resin. Nevertheless, the
cyclized compounds 19 and 20 could not be isolated in satisfactory yield
(30-40%). This resulted partially from a decomposition of the final
product during the treatment of the resin with sodium methylate. This
was confirmed by submitting purified 19 and 20 to standard cleavage
conditions. Only 30-50% of 19 and 20 were recovered. Therefore, the
cyclization of enol ethers was investigated with the acid labile Rink
linker (Scheme 4).
Scheme 4 i) 4 eq. 4, 4.4 eq. NEt3, 4.4 eq. O-(1H-benzotriazol-1-yl)-
N,N,N',N'-tetramethyl-uroniumtetrafluoroborate,
2
eq. N-hydroxy
benzotriazole, dioxane, RT, 5h; then 1 eq. Rink resin, 10 eq. NEt3, 1 eq.
DMAP, dioxane, RT, 60h. ii) 8 eq. nBu4NF, 8 eq. AcOH, dioxane, RT,
18h. iii) 6 eq. R1CO-≡-H, 6 eq. N-methylmorpholine, dioxane (0.05M),
RT 24h. iv) TFA/CH2Cl2 (1/4), RT. v) 3 eq. nBu3SnH, 0.6 eq. AIBN,
benzene (0.05M), reflux, 48h. vi) 0.3 eq. Pd(OAc)2, 0.6 eq. PPh3, 2 eq.
nBu4NCl, 4 eq. K2CO3, DMA (0.05M), 100°C, 27h.
Radical cyclizations can be extended to ortho-iodo benzyl anilides
(Scheme 5). The substrate for cyclization was obtained in very high
yield by substitution of the solid phase-bound benzyl chloride 8 with an
excess of aniline in the presence of nBu4NI and diisopropylethylamine.
Complete conversion of the iodide into the cyclized product 28 was
reached by sequential treatment with nBu3SnH and a large excess of
AIBN (Table 2). Isobutyronitrile radicals were required for the
rearomatization of the cyclized radical intermediate by abstraction of
the β hydrogen atom.10
Scheme 3 i) 6 eq. methyl propiolate, 6 eq. N-methylmorpholine,
dioxane (0.1M), RT 48h. ii) 0.3 eq. Pd(OAc) 2, 0.6 eq. Ph3P, 2 eq.
nBu4NCl, 4 eq. K2CO3, DMA (0.05M), 100°C, 27h, 30-40%. iii) 3 eq.
nBu3SnH, 0.6 eq. AIBN, benzene (0.05M), reflux, 48h, 30-40%. iv) 6
eq. MeONa, MeOH/dioxane (1/4) (0.25M), RT, 24h.
It is noteworthy that efficient radical cyclization could be obtained, even
on an aromatic ring, without interference of the polystyrene skeleton.
Benzylic hydrogen atoms of polystyrene could have reduced the
incipient phenyl radical prior to its cyclization on the N-phenyl ring
which involves the disruption of aromaticity in the transition state.10
The iodide 4 was connected to the commercially available Rink resin,
followed by cleavage of the tBuPh2Si group with nBu4NF in the
presence of AcOH. The reaction with electron-poor acetylenes and N-
methylmorpholine led to the corresponding enol ethers 22 in high
overall yield.
In conclusion, we have demonstrated that ortho-iodo benzyl alcohols
bound to polystyrene can be converted in very high overall yield into the
corresponding enol ethers and enamines. These intermediates can be
efficiently cyclized by radical initiation and by palladium catalysis.

November 1998
SYNLETT
1233
3.
4.
For radical cyclizations on solid support, see: a) Routledge, A.;
Abell, C.; Balasubramanian, S. Synlett, 1997, 61. b) Du, X.;
Armstrong, R.W. J. Org. Chem., 1997, 62, 5678. c) Berteina, S.;
De Mesmaeker, A. Tetrahedron Lett., 1998, 39, 5759.
All reactions have been performed on scale 150-200 mg
polystyrene beads (cross-linked with 1% divinyl benzene), (0.6
mmol/g), allowing the isolation of at least 20 mg crude product.
The structure were determined by 1H NMR and mass
spectrometry and the yields refer to the weight of the crude
product corrected by the purity evaluated by 1H NMR (400MHz).
The yields reported in parentheses are obtained after purification
by flash chromatography or preparative t.l.c.
Scheme 5 i) 10 eq. aniline, 3 eq. diisopropylethylamine, 2 eq. nBu4NI,
dioxane (0.05M), 100°C, 36h; ii) nBu3SnH, AIBN, benzene (0.05M),
reflux; iii) 6 eq. MeONa, MeOH/dioxane (1/4) (0.25M), RT, 24h.
5.
6.
7.
Devos, A.; Remion, J.; Frisque-Hesbain, A.; Colens, A.; Ghosez,
L.; J. Chem. Soc., Chem. Commun. 1979, 1180.
2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-
diazaphosphorine.
Experimental procedure: 150-200 mg of resin (0.1mmol of
loading substrate) were suspended in DMA (2 ml); then Ph3P,
nBu4NCl and K2CO3 were added. The mixture was degassed for
20 min then Pd(OAc)2 was added. After 24h at 100°C, the resin
was washed with DMA (6×3ml), CH2Cl2 (6×3ml), dioxane
(6×3ml), H2O (6×3ml), EtOH/H2O (1/1) (3×3ml), EtOH (3×3ml),
CH2Cl2 (6×3ml), MeOH (6×3ml), dioxane (6×3ml), CH2Cl2
(6×3ml), diethyl ether (3×3ml), and dried under vacuum.
8.
9.
Winterfeldt, E.; Preuss, H. Chem. Ber. 1966, 99, 450.
Experimental procedure: 150-200 mg of resin (0.1mmol of
loading substrate) was suspended in degassed benzene; then 0.5
eq. nBu3SnH and 0.1 eq. AIBN were added. The mixture was
heated to reflux under an argon atmosphere. Every 5-8 h, 5
additional amounts of nBu3SnH (0.5 eq.) and AIBN (0.1 eq.) were
added. The resin was washed with benzene (6×4ml), toluene
(6×4ml), hexane (6×4ml), CH2Cl2 (6×4ml), EtOH (6×4ml),
EtOH/H2O (1/1) (6×4ml), H2O (6×4ml), dioxane (6×4ml),
CH2Cl2 (6×4ml), MeOH (6×4ml), CH2Cl2 (6×4ml), diethyl ether
(3×4ml) in order to eliminate the organotin compounds, and dried
under vacuum.
Using this methodology, highly diverse bicyclic and tricyclic structures
could be produced on solid support.
References and Notes
1.
2.
Berteina, S.; De Mesmaeker, A. Synlett 1998, 1227.
For intramolecular Heck reactions on solid phase, see: a) Goff,
D.A.; Zuckermann, R.N. J. Org. Chem. 1995, 60, 5748. b) Yun,
W.; Mohan, R. Tetrahedron Lett. 1996, 37, 7189.
10. Bachi, M.D.; Denenmark, D. J. Am. Chem. Soc. 1989, 111, 1886.