Solid-phase synthesis of β-Amino ketones and six-ring carbamates via immobilized α-alkoxycarbonylamino sulfones

Article abstract of DOI:10.1021/ol016487d

(figure presented) β-Amino ketones and substituted 1,3-oxazinan-2-ones have been synthesized utilizing polymer-bound and carbamate-linked α-alkoxycarbonylamino sulfones. Key steps in the synthesis are the immobilization of the N-acylimine precursor, the Mannich-type addition of various nucleophiles, and the diastereoselective reduction of the resin-bound ketone.

Full text of DOI:10.1021/ol016487d

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3177-3180
Solid-Phase Synthesis of â-Amino
Ketones and Six-Ring Carbamates via
Immobilized r-Alkoxycarbonylamino
Sulfones
Stefan Schunk and Dieter Enders*
Institut fu¨r Organische Chemie, Rheinisch-Westfa¨lische Technische Hochschule,
Professor-Pirlet-Strasse 1, 52074 Aachen, Germany
enders@rwth-aachen.de
Received July 24, 2001
ABSTRACT
â-Amino ketones and substituted 1,3-oxazinan-2-ones have been synthesized utilizing polymer-bound and carbamate-linked r-alkoxycarbo-
nylamino sulfones. Key steps in the synthesis are the immobilization of the N-acylimine precursor, the Mannich-type addition of various
nucleophiles, and the diastereoselective reduction of the resin-bound ketone.
The Mannich reaction is an effective carbon-carbon bond-
forming reaction that has been applied to solid-phase organic
synthesis (SPOS) by immobilizing a variety of amines,1
imines,2 and iminium species,3 yielding piperazine derivates,1
amino esters,2a pyrazolone derivates,2b R-amino acids,2c
pyrrolidines,3c and homoallylic amines.3d Handling and
preparation of resin-bound N-acyliminium ions is difficult
due to their high reactivity and instability.3a,b The use of also
very reactive but uncharged N-acylimines, which can easily
be prepared from stable precursors, provides an attractive
alternative. These acylimines, generated in situ from R-amino
sulfones, are known to react with a wide variety of nucleo-
philes4 (e.g., ketone enolates,4a Reformatsky reagents,4b
nitromethane anion,4c vinylmagnesium bromide,4d and
1-alkynyllithiums4d). This versatility is of great importance
for SPOS as it provides access to diverse compounds from
a common intermediate.
We herein report the immobilization of N-acylimines by
utilizing an R-amino sulfone precursor5 and its application
in a Mannich-type reaction for the solid-phase synthesis of
â-amino ketones and six-ring carbamates. The reaction of
this precursor with an ester enolate, an aryl Grignard reagent,
and allylzinc bromide is also demonstrated.
Scheme 1 illustrates the preparation of the N-acylimine
precursor. The carbamate resin 13d was synthesized from
commercially available benzyl alcohol resin. We decided to
use this resin instead of Wang resin in order to avoid
(1) Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000, 56,
10023-10030.
(2) For imines: (a) Kobayashi, S.; Aoki, Y. Tetrahedron Lett. 1998, 39,
7345-7348. For acylhydrazones: (b) Kobayashi, S.; Furuta, T.; Sugita,
K.; Okitsu, O.; Oyamada, H. Tetrahedron Lett. 1999, 40, 1341-1344. For
R-imino acetates: (c) Kobayashi, S.; Akiyama, R.; Kitagawa, H. J. Comb.
Chem. 2000, 2, 438-440.
Scheme 1a
(3) For acyliminium ions: (a) Vanier, C.; Wagner, A.; Mioskowski, C.
Chem. Eur. J. 2001, 7, 2318-2323. (b) van Maarseveen, J. H.; Meester,
W. J. N.; Veerman, J. J. N.; Kruse, C. G.; Hermkens, P. H. H.; Rutjes, F.
P. J. T.; Hiemstra, H. J. Chem. Soc., Perkin Trans. 1 2001, 994-1001. (c)
Veerman, J. J. N.; Rutjes, F. P. J. T.; van Maarseveen, J. H.; Hiemstra, H.
Tetrahedron Lett. 1999, 40, 6079-6082. (d) Meester, W. J. N.; Rutjes, F.
P. J. T.; Hermkens, P. H. H.; Hiemstra, H. Tetrahedron Lett. 1999, 40,
1601-1604.
a (a) 6 equiv of R1CHO, 3 equiv of p-toluene-sodiumsulfinate,
6 equiv of TFA, CH2Cl2, 60 °C, 1 h.
10.1021/ol016487d CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/12/2001

premature cleavage of the linking system during the TFA-
promoted synthesis of the R-N-carbamato-sulfone resin 2.6
p-Nitrobenzaldehyde was chosen as the aldehyde compo-
nent to optimize the reaction conditions, since it provides a
basis for CHN combustion analysis. The loading of resin 2
for R1 ) p-NO2Ph was determined to be 81% (based on the
loading of resin 1). Evidence for a successful synthesis of
resins 2 are the C-H out of plane vibrations of the para-
substituted aromatic ring in the IR spectrum at ν˜ ≈ 850 cm-1.
To study the suitability of different resins 2 for the prepara-
tion of â-amino ketones, we had to investigate their reaction
with ketone enolates (Scheme 2). An excess of basic
Table 1. Yields of Bz-Protected â-Amino Ketones 5
Scheme 2a
a Compounds 5 were characterized by 1H/13C NMR spectroscopy and
MS experiments after chromatography (SiO2; Et2O/pentane 1:1). b Yields
of amino ketones 5 after four steps based on loading of resin 1.
a (a) 4 equiv of R2CHdC(OLi)R3, THF, -78 °C, 2 h then rt, 30
min; (b) Cleavage A: (i) BF3‚Et2O, Me2S, CH2Cl2, rt, 14 h. (ii)
benzoyl chloride, NEt3, 30 min. Cleavage B: (i) ZnBr2, benzoyl
chloride, CH2Cl2, rt, 14 h. (ii) NEt3, 30 min.
A brief investigation of further nucleophiles in the reported
addition-cleavage procedure showed that we could success-
fully add allylzinc bromide, an ester enolate, and an aryl
Gringard reagent to yield the expected homoallylic amine
6, secondary amine 7, and â-amino acid ester 8, respectively
(Scheme 3).
nucleophile leads, after carbamate deprotonation and elimi-
nation of lithium p-toluolsulfinate, to the desired, im-
mobilized N-acylimines 3. These react with the remaining
ketone enolate to yield the resin-bound amino ketones 4.
Several cleavage protocols for carbamate linkers are
known which usually require strongly acidic conditions.7 We
first applied a dimethyl sulfide promoted BF3‚Et2O cleavage8
(cleavage A, Table 1), which only allowed for the cleavage
of aromatic amino ketone resins 4 (R3 ) Ph), yielding
benzoyl (Bz) protected â-amino ketones 5a-d.
Scheme 3a
Failure of this procedure in the case of aliphatic ketone
components (R3 ) alkyl) is probably due to a Lewis acid
catalyzed dimerization of amino ketones, yielding imines.
Therefore, milder cleavage conditions should give the desired
amino ketones 5e-h, which were isolated after ZnBr2/
benzoyl chloride cleavage9 (cleavage B) and chromatography
in lower yields.
(4) (a) Palomo, C.; Oiarbide, M.; Gonza´lez-Rego, C.; Sharma, A. K.;
Garc´ıa, J. M.; Gonza´lez, A.; Landa, C.; Linden, A. Angew. Chem. 2000,
112, 1105-1107; Angew. Chem., Int. Ed. 2000, 39, 1063-1065. (b)
Mecozzi, T.; Petrini, M. Tetrahedron Lett. 2000, 41, 2709-2712. (c) Ballini,
R.; Petrini, M. Tetrahedron Lett. 1999, 40, 4449-4452. (d) Mecozzi, T.;
Petrini, M. J. Org. Chem. 1999, 64, 8970-8972. (e) Kanazawa, A. M.;
Denis, J.-N.; Greene, A. E. J. Org. Chem. 1994, 59, 1238-1240. (f) Pearson,
W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am. Chem. Soc. 1993, 115, 2622-
2636. (g) Kinoshita, H.; Hayashi, Y.; Murata, Y.; Inomata, K. Chem. Lett.
1993, 8, 1437-1440. (h) Morton, J.; Rahim, A.; Walker, E. R. H.
Tetrahedron Lett. 1982, 23, 4123-4126.
a (a) (i) 4 equiv of allylzinc bromide, (ii) BF3‚Et2O, Me2S,
CH2Cl2, rt, 14 h; aqueous acid/base workup; (b) (i) 4 equiv of
PhMgCl, (ii) Cleavage A; (c) (i) 4 equiv of ethyl acetate enolate,
(ii) BF3‚Et2O, Me2S, CH2Cl2, rt, 14 h; aqueous acid/base workup.
3178
Org. Lett., Vol. 3, No. 20, 2001

Scheme 4a
Table 2. Purities, de/dr Values and Yields of Six-Ring
Carbamates 14
a (a) 4 equiv of H2CdC(OLi)CH2(CH3)2, THF, -78 °C, 15 min;
(b) 3 equiv of LiAl[OC(CH3)3]3H, THF, -78 °C, 1 h then 0 °C to
rt, 14 h; (c) 1 equiv of LiHMDS, THF, rt, 30 min.
Because of the continuously high interest in solid-
supported heterocycle synthesis,10 we decided to utilize the
immobilized amino ketones for the synthesis of 1,3-oxazinan-
2-ones via a cyclization-cleavage strategy.
Preliminary investigations concerning the optimization of
the reduction and cyclization procedures were conducted on
a solution-phase model compound (Scheme 4). Lithium tri-
tert-butoxyaluminohydride gave the best results in the
reduction of the amino ketone 10 (de ) 71% of syn-
diastereomer) obtained via a Mannich-type reaction with
excess ketone enolate (R2 ) H, R3 ) i-Bu) from 9. NMR
experiments showed that both diastereomers of 11 cyclized
upon treatment with LiHMDS within 30 min at room
temperature to give 4-ethyl-6-isobutyl-1,3-oxazinan-2-one
12.11 A diastereoselective cyclization-cleavage of resin-
bound amino alcohols 13 can therefore be ruled out.
The reaction conditions used in liquid phase could easily
be transferred to solid phase (Scheme 5).
The addition of 4-methylpentane-2-one enolate to different
resins 2 gave after reduction and cyclization of 13 excellent
results concerning the purity and diastereomeric excess of
the final products 14a-d. Addition of different ketones to
immobilized propanalaldehyde acylimine equivalents (14e,
14f) gave also good results. Diethyl ketone, cyclopentanone,
and cyclohexanone as ketone components in this synthesis
yielded diastereomeric mixtures of 4,5,6-substituted 1,3-
oxazinan-2-ones (14g) or bicyclic 1,3-oxazinan-2-ones (14h,
a Compounds were characterized by 1H/13C NMR spectroscopy and GC-
MS measurements. b Purities determined after filtration by GC. c de and dr
determined by 13C NMR spectroscopy. d Yields of carbamates 14 after four
steps based on loading of resin 1.
14i). The relative configuration of the carbamates was
established as cis via NMR analysis. The two major
diastereomers of trisubstituted carbamates 14g-i are as
expected cis concerning positions 4 and 6, with no preference
at position 5 (Table 2).
Scheme 5a
(5) (a) Engberts, J. B. F. N.; Olijnsma, T.; Strating, J. Recl. TraV. Chim.
Pays-Bas 1966, 85, 1211-1222. (b) Engberts, J. B. F. N.; Strating, J. Recl.
TraV. Chim. Pays-Bas 1965, 84, 942-950.
(6) For premature cleavage problems of Wang carbamates caused by
BF3‚Et2O, see ref 3c.
(7) Do¨rwald, F. Z. Organic Synthesis on Solid Phase; Wiley-VCH:
Weinheim, 2000; Chapter 3.
(8) Sa´nchez, I. H.; Lo´pez, F. J.; Soria, J. J.; Larraza, M. I.; Flores, H. J.
J. Am. Chem. Soc. 1983, 105, 7460-7643.
(9) Li, W.; Lin, Y.; Yo, Y. Tetrahedron Lett. 2000, 41, 6619-6622.
(10) Recent Review: Franzen, R. G. J. Comb. Chem. 2000, 2, 195-
214.
a (a) (i) 4 equiv of R2CHdC(OLi)R3, THF, -78 °C, 2 h then rt,
30 min, (ii) 3 equiv of LiAl[OC(CH3)3]3H, THF, -78 °C, 1 h then
0 °C to rt, 14 h; (b) 1 equiv of LiHMDS, THF, -78 °C, 15 min
then rt, 2 h.
(11) Compund 12 was not isolated from byproducts.
Org. Lett., Vol. 3, No. 20, 2001
3179

In conclusion, we have demonstrated the use of im-
mobilized N-acylimines, which were generated from stable
R-amino sulfone precursors, for the synthesis of benzoyl-
protected â-amino ketones and the synthesis of mono- and
bicyclic 1,3-oxazinan-2-ones. Furthermore, the preparation
of homoallylic amines, secondary arylamines, and â-amino
acid esters has also been exemplified.
work was supported by the Fonds der Chemischen Industrie
and by the Deutsche Forschungsgemeinschaft (SFB 380,
Graduiertenkolleg 440, Stipend to S.S.). We thank Degussa
AG, BASF AG, and Bayer AG for the donation of chemicals.
Supporting Information Available: Experimental pro-
cedures and characterizations for compounds 5a, 5e, 14b,
and 14c. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We especially thank N. Fricke for
excellent experimental support and Dr. J. Runsink for NMR
measurements and carrying out NOE investigations. This
OL016487D
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