α-methylene-β-amino ketone derivatives from β- ketoallylsilanes

Article abstract of DOI:10.1021/jo052330d

β-Ketoallylsilanes are synthesized by the Horner-Emmons reaction starting from novel silylated ketophosphonates and various aldehydes. The reactions of β-ketoallylsilanes with NsONHCO₂Et and CaO produce α-methylene-N-(ethoxycarbonyl)-β-amino ke

Full text of DOI:10.1021/jo052330d

SCHEME 1. Amination Reaction of 2
r-Methylene-â-amino Ketone Derivatives from
â-Ketoallylsilanes
M. Antonietta Loreto,*,†,‡ Antonella Migliorini,†,‡ and
P. Antonio Tardella†
Dipartimento di Chimica, UniVersita` “La Sapienza”, Piazzale
Aldo Moro 5, 00185 Rome, Italy, and Istituto C.N.R. di Chimica
Biomolecolare, Sezione Roma, Dipartimento di Chimica,
UniVersita` “La Sapienza”, Rome, Italy
these compounds is an attractive objective in chemical synthesis.
In the recent literature, some R,â-unsaturated â-amino ketones
were synthesized by the aza Baylis-Hillman reaction of
N-sulfonated imines with methyl vinyl ketone in the presence
of catalytic amounts of Lewis bases such as triphenylphosphine
or DABCO.5
mariaantonietta.loreto@uniroma1.it
ReceiVed NoVember 10, 2005
We propose here a new approach to R,â-unsaturated â-amino
ketone derivatives, based on our previous results, obtained in
the amination reaction of electron-poor olefins, using ethyl
N-{[(4-nitrobenzene)sulfonyl]oxy}carbamate (NsONHCO2Et) 1.
In recent years, we have reported that the reaction of either
â-silylated R,â-unsaturated carboxylates6a or phosponates6b with
1 and solid CaO gives rise to N-(ethoxycarbonyl)-â-amino-R-
methylene esters, through the formation of an intermediate
aziridine and its subsequent ring opening. On these bases, we
felt that the extension of the above amination procedure to other
functionalized allylsilanes, as compounds 2, could result in a
new approach to N-(ethoxycarbonyl)-â-amino-R-methylene
ketones such as 3 (Scheme 1).
Allylsilanes have emerged as useful intermediates in organic
synthesis. They are extensively used in carbonyl addition
reactions7 and coupling reactions8 and have been recently
employed as key intermediates for the total synthesis of natural
products.9 In particular, allylsilanes bearing a carbonyl group
at the â-position, as in 2, are interesting because they can react
either with nucleophiles10 or with electrophiles.11 Known
literature procedures for their synthesis, catalyzed by transition-
metal complexes, are those reported by Kang and co-workers,
who proposed a methodology based on the palladium-catalyzed
cross-coupling of 2-trimethylstannyl-3-trimethylsilylpropene
with organic halides12 or the new phosphine-free palladium-
catalyzed three-component assembly of allenes, acyl chlorides,
and hexamethyldisilane, recently developed by Cheng’s group.
This procedure led to the synthesis of some new â-ketoallyl-
silanes in good yields.13 Another efficient palladium-catalyzed
â-Ketoallylsilanes are synthesized by the Horner-Emmons
reaction starting from novel silylated ketophosphonates and
various aldehydes. The reactions of â-ketoallylsilanes with
NsONHCO2Et and CaO produce R-methylene-N-(ethoxy-
carbonyl)-â-amino ketones through the ring opening of the
intermediate aziridine, which is favored by the presence of
the trimethylsilyl group. With chiral â-ketoallylsilanes we
obtained a stereoselective amination reaction with a 90%
diastereomeric excess. R-Methylene-N-(ethoxycarbonyl)-â-
amino ketones are isolated in 39-60% yields and character-
ized.
â-Amino carbonyl moieties are found as structural subunits
of natural and synthetic products such as alkaloids and po-
liketides1 and can be used in the synthesis of 1,3-amino alcohols
and â-amino acids.2 Some â-amino ketone derivatives such as
R-alkyl-â-dimethylaminopropiophenones are reported to have
analgesic and bacteriostatic properties.3 In addition, unsaturated
â-amino ketones are interesting products, i.e., N-substituted
R-(aminomethyl)acrylophenones are reported to be weak inhibi-
tors of colchicine binding and markedly decrease the serum
cholesterol, triglyceride, and phospholipid levels of rats.4
Therefore, the development of methods for the preparation of
(5) Shi, M.; Xu, Y. M. J. Org. Chem. 2003, 68, 4784-4790.
(6) (a) Gasperi, T.; Loreto, M. A.; Tardella, P. A. Tetrahedron Lett. 2003,
44, 8467-8470. (b) Loreto, M. A.; Pompili, C.; Tardella, P. A. Tetrahedron
2001, 57, 4423-4427.
(7) (a) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763-2794. (b)
Kennedy, J. W. J.; Hall, D. G. Angew. Chem., Int. Ed. 2003, 42, 4732-
4739.
(8) Hiyama, T. In Metal-Catalyzed-Cross-Coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VHC: Weinheim, 1998; Chapter 10.
(9) (a) Peng, Z. H.; Woerpel, K. A. Org. Lett. 2002, 4, 2945-2948. (b)
Angle, S. R.; El-Said, N. A. J. Am. Chem. Soc. 2002, 124, 3608-3613. (c)
Denmark, S. E.; Fu, J. Org. Lett. 2002, 4, 1951-1953.
(10) Fleming, I.; Maiti, P.; Ramarao, C. Org. Biomol. Chem., 2003, 1,
3989-4004.
(11) (a) Kuroda, C.; Honda, S.; Nagura, Y.; Koshio, H.; Shibue, T.;
Takeshita, T. Tetrahedron 2004, 60, 319-331. (b) Kuroda, C.; Kasahara,
T.; Akiyama, K.; Amemiya, T.; Kunishima, T.; Rimura, Y. Tetrahedron
2002, 58, 4493-4504.
(12) Kang, K.; Kim, S. S.; Lee, J. C. Tetrahedron Lett. 1991, 32, 4341-
4344.
* To whom correspondence should be addressed. Tel: +39 0649913668.
Fax: +39 06490631.
† Dipartimento di Chimica, Universita` “La Sapienza”.
‡ Istituto C.N.R. di Chimica Biomolecolare, Sezione Roma, Dipartimento di
Chimica, Universita` “La Sapienza”.
(1) (a) Xu, L.; Xia, C.; Li, J.; Zhou, S. Synlett 2003, 2246-2248. (b)
Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000, 6, 1-15.
(2) Davis, F. A.; Yang, B. Org. Lett. 2003, 5011-5014.
(3) Daruwala, A. B. et al. J. Med. Chem. 1974, 17, 819-824.
(4) Lesieur, I. et al. Arzneimittel-Forschung 1986, 36, 20-24.
(13) Cheng, C. H. et al. J. Am. Chem. Soc. 2003, 125, 12576-12583.
10.1021/jo052330d CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/03/2006
J. Org. Chem. 2006, 71, 2163-2166
2163

TABLE 1. Synthesis of Substrates 2: Conditions and Yields
a Method A: 50% NaOH/CH2Cl2/37% H2CO. Method B: NaH/DME/aldehyde/anhydrous conditions.
SCHEME 2. Synthesis of Novel Silylated
â-Ketophosphonates 4
Emmons reaction (Table 1). For substrates 2a-c, the Horner-
Emmons reaction was carried out in a two-phase system using
50% aqueous NaOH as base in CH2Cl2 and a 37% formaldehyde
aqueous solution (method A). For the substrates 2d-g, we
needed NaH in dry DME at room temperature (method B) to
obtain the desired allylsilanes (Scheme 3). In these last cases,
we obtained the Z isomer as the main product and only a very
small amount of the E isomer. The Z isomers were separated
and purified by chromatography on silica gel. Spectroscopic
data confirm their structure.
Starting from the good results obtained in the synthesis of
â-ketoallylsilanes 2a-g, we focused our interest on chiral
substrates. In particular, using the D-glyceraldehyde acetonide,
we prepared the (S)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-tri-
methylsilanylmethyl-3-alken-2-ones 2h and 2i (Table 1) using
the hypothesis that the presence of a resident chiral γ-carbon
in the acetonide structure should allow the stereoselective
introduction of the aziridine ring in the reaction with NsONHCO2-
Et, providing a new route to optically active â-amino ketone
derivatives after ring opening and removal of the trimethylsilyl
group.
synthesis has recently been reported by Kabalka and consists
of the reaction of the Baylis-Hillman acetate adduct with
hexamethyldisilane.14
In our case, â-ketoallylsilanes 2 were prepared by the
Horner-Emmons reaction between aldehydes and novel sily-
lated â-ketophosphonates 4. These last compounds were syn-
thesized in turn by alkylation of commercially available
â-ketophosphonates 5 with iodomethyltrimethylsilane in the
presence of NaH, according to the procedure reported for the
alkylation of the triethylphosphonoacetate (see Scheme 2).15
After chromatography on silica gel, products 4a-c were
isolated in a yields ranging from 40 to 45% (see the Experi-
mental Section for full spectroscopic characterization). Byprod-
ucts 6 and 7 were also found (Figure 1).
The amination reactions on substrates 2 (Z isomers) were
carried out in CH2Cl2 by adding NsONHCO2Et and CaO
portionwise, according to the reported procedure,6 reaching the
molar ratio shown in Table 2. After addition of 3-6 equiv of
reagents and short reaction times, we observed the complete
disappearance of the starting material and the formation of the
intermediate N-(ethoxycarbonyl)aziridine, detected in the crude
1
reaction mixture by H NMR.
FIGURE 1. Byproducts of the synthesis of 4
In the presence of traces of acid, removal of the trimethylsilyl
group occurred and the corresponding unsaturated â-amino
ketone derivatives 3 were isolated. In all cases, the trimethylsilyl
group plays a key role in driving and facilitating the aziridine
ring opening (Scheme 4).
The best reaction conditions were found using DME as
solvent and 7-8 h of heating. All attempts to improve the yields
of alkylation reaction, e.g., by using THF or toluene as solvent,
failed; in the first case, the reflux temperature was too low to
promote the reaction, and in the second one, higher temperature
and long reaction times led to extensive decomposition.
With the novel silylated ketophosphonates 4 in hand, we
proceeded to prepare the allylsilanes 2 through the Horner-
All compounds 3a-i were purified by chromatography on
1
silica gel, and their structure was confirmed by H NMR and
13C NMR analysis.
The amination reaction performed on the chiral substrates
2h and 2i (mixture of Z/E isomers ) 10/1) was highly
diastereoselective; in fact, we obtained one diastereomer with
a 90% of diastereomeric excess in both reactions. The main
diastereomer was easily isolated by chromatography on silica
(14) Kabalka, G. W.; Venkataiah, B.; Dong, G. Organometallics 2005,
24, 762-764.
(15) Henning, R.; Hoffmann, H. M. R. Tetrahedron Lett. 1982, 23, 2305-
2308.
2164 J. Org. Chem., Vol. 71, No. 5, 2006

SCHEME 3. Synthesis of Allylsilanes 2
TABLE 2. Synthesis of â-Amino Ketone Derivatives 3: Conditions and Yields
SCHEME 4. Synthesis of â-Amino Ketone Derivatives 3
gel with high purity, 3h, [R]20D ) +10.7 (c 3,CHCl3); 3i, [R]20
In conclusion, in this work we propose a new simple synthetic
D
) +7.1 (c 3.6,CHCl3). As far as the stereoselectivity of the
reaction is concerned, in the hypothesis that the amination
reaction occurs by an aza Michael mechanism,16 we believe that
products are formed preferentially through a â-re attack on
compounds 2h-i according to that reported by other authors
for similar chiral γ,δ-dialkoxy unsaturated ketones.17
Removal of the isopropylidene protecting group in 3h and
3i could allow us to get precursors of unsaturated optically active
amino derivatives as amino alcohols or 3-branched-amino
sugars.17 Thus, we are encouraged to continue our investigation
in this field.
route for the preparation of R-methylene-â-amino ketone
derivatives by the amination reaction of â-ketoallylsilanes
obtained in turn from readily available â-ketophosphonates and
aldehydes. Using an optically active aldehyde such as D-
glyceraldehyde acetonide, this route allowed us to obtain new
chiral â-ketoallylsilanes and, after amination reaction, optically
active â-amino ketone derivatives with a very good diastereo-
meric excess.
Experimental Section
General Procedure for the Synthesis of Silylated Ketophos-
phonates 4a-c. (2-Oxo-1-trimethylsilanylmethylpropyl)phos-
phonic Acid Diethyl Ester (4b). To 60% NaH (495 mg, 11.34
mmol; suspension in mineral oil) in anhydrous DME (12 mL) was
added ketophosphonate 5b (2 g, 10.30 mmol) in anhydrous DME
(6 mL) dropwise, under argon at 0 °C. After 1 h at 0 °C and 1 h
at room temperature, a solution of iodomethyltrimethylsilane (8.8
(16) Colantoni, D.; Fioravanti, S.; Pellacani, L.; Tardella, P. A. Org.
Lett. 2004, 6, 197-200.
(17) (a) Dondoni, A.; Marra, A.; Boscarato, A. Chem. Eur. J. 1999, 5,
3562-3572. (b) Lima, P. G.; Caruso, R. R. B.; Alves, S. O.; Pesso, R. F.;
Mendonca-Silva, D. L.; Nunes, R. J.; Noe F.; Castroc, N. G.; Costaa, P. R.
R. Bioorg. Med. Chem. Lett. 2004, 1, 4399-4403.
J. Org. Chem, Vol. 71, No. 5, 2006 2165

g, 41.20 mmol) in anhydrous DME (21 mL) was added, and the
resulting mixture was heated to 70 °C. After being stirred for 7-8
h, the mixture was poured into saturated ammonium chloride
solution, and the aqueous phase was extracted with Et2O. The
combined organic phases were washed with brine and dried over
Na2SO4. After solvent evaporation, the crude was purified by
chromatography on silica gel (hexane/acetone ) 7/3) to obtain the
product 4b as a yellowish oil (1 g, 4 mmol, 40% yield): IR (CHCl3)
the pure Z isomer (98 mg, 0.40 mmol) as a yellow oil, and a mixture
of E/Z isomers (16 mg, 0.06 mmol) in a ratio of 4/1 (35% total
1
yield). Spectral data of 2e (Z): IR (CHCl3) 1672, 1660 cm-1; H
NMR (CDCl3, 200 MHz) δ -0.02 (s, 9H), 1.19 (t, J ) 7.3 Hz,
3H), 2.18 (s, 2H), 2.86 (q, J ) 7.3 Hz, 2H), 7.28-7.42 (m, 6H);
13C NMR (CDCl3, 50 MHz) δ -1.9, 8.4, 15.7, 29.3, 126.6, 127.3,
127.9, 133.4, 135.5, 140.0, 201.9; GC-MS m/z 246 [M+] (18.8),
73 (100); HRMS calcd for C15H22NaOSi m/z 269.1338, found m/z
269.1333.
1
1719, 1252 cm-1; H NMR (CDCl3, 200 MHz) δ -0.07 (s, 9H),
0.83-0.99 (m, 1H), 1.20-1.38 (m, 7H), 2.29 (s, 3H), 3.14 (ddd, J
General Procedure for the Synthesis of R-Methylene-â-amino
Ketone Derivatives 3a-i. (2-Benzoylallyl)carbamic Acid Ethyl
Ester (3a). To a stirred solution of the substrate 2a (151 mg, 0.69
mmol) in CH2Cl2 (0.2 mL) were added NsONHCO2Et (201 mg,
0.69 mmol) and CaO (39 mg, 0.69 mmol) every hour, reaching
the molar ratio substrate/NsONHCO2Et/CaO up to 1:3.5:3.5.
Because the reaction was exothermic, during the addition the flask
was cooled in a water bath to avoid overheating. After 4 h, pentane
was added. The organic phase was filtered, concentrated under
vacuum and dissolved in CHCl3. After 24 h, the solvent was
evaporated, and the mixture was chromatographed on silica gel
(hexane/ethyl acetate 6:4) to obtain the product 3a as a yellow oil
(63 mg, 0.27 mmol, 39% yield): IR (CHCl3) 3500, 1715 cm-1; 1H
NMR (CDCl3, 200 MHz) δ 1.23 (t, J ) 7.3 Hz, 3H), 4.07-4.17
(m, 4H), 5.33 (br, 1H), 5.79 (s, 1H), 6.11 (s, 1H), 7.40-7.75 (m,
5H); 13C NMR (CDCl3, 50 MHz) δ 13.4, 41.3, 59.7, 126.4, 127.1,
128.2, 131.2, 136.3, 143.1, 155.5, 196.2; GC-MS m/z 233 [M+]
(3.7), 105 (100); HRMS calcd for C13H15NNaO3 m/z 256.0950,
found m/z 256.0958.
) 24.9 Hz, J ) 11.7 Hz, J ) 2.2 Hz, 1H), 3.98-4.15 (m, 4H); 13
C
NMR (CDCl3, 50 MHz) δ -1.6, 12.3 (d, JCCP ) 6.1 Hz), 16.2 (d,
JCCOP ) 7.6 Hz), 30.7, 49.0 (d, JCP ) 122.1 Hz), 62.5 (d, JCOP
)
3.0 Hz), 62.7 (d, JCOP ) 3.0 Hz), 203.7; GC-MS m/z 280 [M+]
(5.7%), 165 (100); HRMS calcd for C11H25NaO4PSi m/z 303.1157,
found m/z 303.1150.
General Procedure for the Synthesis of â-Ketoallylsilanes
2a-c (Method A). 1-Phenyl-2-trimethylsilanylmethylpropenone
(2a).12 To a stirred solution of the substrate 4a (300 mg, 0.88 mmol)
in dichloromethane (1 mL) was added dropwise a 50% (w/w)
sodium hydroxide aqueous solution (1.05 mL). After 1 h at room
temperature, a 37% (w/w) formaldehyde aqueous solution (73 mg,
0.90 mmol) was added dropwise, and the resulting heterogeneous
mixture was stirred for 6 h. Then the mixture was extracted with
dichloromethane, and the organic phase was dried over Na2SO4
and evaporated under vacuum. The product 2a was obtained pure
as a yellow oil (163 mg, 0.75 mmol, 85% yield): IR (CHCl3) 1680
1
cm-1; H NMR (CDCl3, 200 MHz) δ 0.06 (s, 9H), 2.03 (s, 2H),
5.50 (s, 1H), 5.72 (s, 1H), 7.39-7.75 (m, 5H); GC-MS m/z 218
[M+] (14.2), 73 (100).
Acknowledgment. We thank the Italian Ministero dell’Istru-
zione dell’Universita` e della Ricerca (MIUR) and the University
“La Sapienza” of Rome (National Project “Stereoselezione in
Sintesi Organica, Metodologie ed Applicazioni”) for financial
support.
General Procedure for the Synthesis of â-Ketoallylsilanes
2d-i (Method B). 4-Phenyl-3-trimethylsilanylmethylbut-3-en-
2-one (2e). To 60% NaH (81 mg, 1.86 mmol; suspension in mineral
oil) in anhydrous DME (1.5 mL) was added the substrate 4c (390
mg, 1.33 mmol) in anhydrous DME (0.3 mL) dropwise, under argon
at 0 °C. After 1 h at 0 °C and 1 h at room temperature, a solution
of benzaldehyde (310 mg, 2.93 mmol) in anhydrous DME (0.8 mL)
was added at 0 °C, and the resulting mixture was stirred at room
temperature. After being stirred for 10 h, the mixture was poured
into saturated ammonium chloride solution, and the aqueous phase
was extracted with Et2O. The combined organic phases were dried
over Na2SO4. After solvent evaporation, the crude was purified by
chromatography on silica gel (hexane/diethyl ether ) 98/2) to obtain
Supporting Information Available: General experimental
methods, procedures for the synthesis of â-ketophosphonates 4a-
c, â-ketoallylsilanes 2a-i, and â-amino ketone derivatives 3a-i,
1
their characterization data, and copies of H NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO052330D
2166 J. Org. Chem., Vol. 71, No. 5, 2006