Preparation of β-amido ketones and aldehydes via amidoalkylation of enamines, enol silyl ethers, and vinyl ethers

Article abstract of DOI:10.1021/jo990608u

Novel syntheses of β-amidoalkyl ketones and aldehydes via amidoalkylations of enamines, silyl enol ethers, and vinyl ethers with N-(1- benzotriazol-1-ylalkyl)amides are described.

Full text of DOI:10.1021/jo990608u

7622
J . Org. Chem. 1999, 64, 7622-7624
P r ep a r a tion of â-Am id o Keton es a n d Ald eh yd es via
Am id oa lk yla tion of En a m in es, En ol Silyl Eth er s, a n d Vin yl Eth er s
Alan R. Katritzky,* Yunfeng Fang, and Alina Silina
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received April 9, 1999
Novel syntheses of â-amidoalkyl ketones and aldehydes via amidoalkylations of enamines, silyl
enol ethers, and vinyl ethers with N-(1-benzotriazol-1-ylalkyl)amides are described.
In tr od u ction
â-Amido ketones and â-amido aldehydes are important
as building blocks and intermediates in synthesis: for
example, they are important precursors of 3-amino
alcohols, which are common units in both natural and
synthetic biologically active compounds.1 â-Amido alde-
hydes are a protected form of â-amino aldehydes, key
intermediates in the synthesis, e.g., of aminocyclitols.2
â-Amido aldehydes of type RCH2CH(NHCOR′)CHRCHO
can be prepared by condensation of primary amides with
aliphatic aldehydes (2 equiv) in the presence of trifluo-
romethanesulfonic acid.3 A diastereoselective synthesis
of â-amido aldehydes has been achieved by rearrange-
ment of O-vinyl-N,O-acetals.4
Many approaches to â-amido ketones have been re-
ported. These can be classified according to the bond
formed (Figure 1), and include preparations by formation
of the A bond by acylation of â-amino ketones,5 of the B
bond by Michael addition to an R,â-unsaturated ketone,6a-c
or of the D bond by photolysis of phthalimides.7 However,
most â-amido ketones are prepared by forming the C
bond: (i) Iqbal et al. report a cobalt-catalyzed synthesis
of â-amido ketones from enolates and R-acetoxyamides;8a,b
(ii) under Lewis acid catalysis, 4-acetoxyazetidin-2-one
reacts with various silyl enol ethers to give â-amido
ketones in good to excellent yields;9 (iii) in the presence
of 2.1 equiv of various metallic oxidants, 2-pivaloyl-1-
tributylstannyl-1,2,3,4-tetrahydroisoquinoline converts
diverse silyl enol ethers into â-amido ketones.10
F igu r e 1.
strated N-(1-benzotriazol-1-ylalkyl)amides to be versatile
reagents for the amidoalkylation13 of malonates and
acetoacetates,14 reactive aromatics,15 cyanide anion,16
mercaptans,17 alcohols,18 ammonia,19 ethyl diphenylphos-
phinite anion,20 primary and secondary amines,21 and
triallylstannanes22a,b giving in each case the expected
products. We have previously reported one example that
used an N-(benzotriazol-1-ylmethyl)benzamide to react
with isopropenyl acetate to afford a â-amido ketone in
relatively poor yield.23 We now report applications of
N-(benzotriazol-1-ylalkyl)amides for the synthesis of
â-amido ketones and aldehydes via the amidoalkylation
of enamines, enol silyl ethers, and vinyl ethers.
Resu lts a n d Discu ssion
The amidoalkylation reagents N-(1-benzotriazol-1-yl-
alkyl)amides 1a -j and 2-5, derived from primary or
(11) (a) Zaugg, H. E. Synthesis 1984, 85. (b) Zaugg, H. E. Synthesis
1984, 181.
(12) (a) Bott, K. Angew. Chem., Int. Ed. Engl. 1980, 19, 171. (b)
Danishefsky, S.; Guingant, A.; Prisbylla, M. Tetrahedron Lett. 1980,
21, 2033. (c) Shono, T.; Matsumura, Y.; Tsubata, K. J . Am. Chem. Soc.
1981, 103, 1172. (d) Wanner, K. Th.; Praschak, I. Heterocycles 1989,
29, 29. (e) Kraus, G. A.; Neuenschwander, K. Tetrahedron Lett. 1980,
21, 3841.
Amidoalkylations, which have been used widely in
organic synthesis,11a,b have provided many â-amidocar-
bonyl compounds.12a-e Our previous work has demon-
(1) Barluenga, J .; Viado, A. L.; Aguilar, E.; Fustero, S.; Olano, B. J .
Org. Chem. 1993, 58, 5972.
(2) Suami, T.; Tadano, K.; Horiuchi, S. Bull. Chem. Soc. J pn. 1975,
48, 2895.
(13) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O. V. Chem.
Rev. 1998, 98, 409.
(14) Katritzky, A. R.; Pernak, J .; Fan, W. Q.; Saczewski, F. J . Org.
Chem. 1991, 56, 4439.
(3) Marson, C. M.; Fallah, A. Chem. Commun. 1998, 83.
(4) Frauenrath, H.; Arenz, T.; Raabe, G.; Zorn, M. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 83.
(5) Dallemagne, P.; Rault, S.; Se´vricourt, M.; Hassan, Kh. M.; Robba,
M. Tetrahedron Lett. 1986, 27, 2607.
(15) Katritzky, A. R.; Pernak, J .; Fan, W. Q. Synthesis 1991, 868.
(16) Katritzky, A. R.; Shobana, N.; Harris, P. A. Org. Prep. Proced.
Int. 1992, 121.
(17) Katritzky, A. R.; Takahashi, I.; Fan, W. Q.; Pernak, J . Synthesis
1991, 1147.
(6) (a) Inubushi, Y.; Kikuchi, T.; Ibuka, T.; Tanaka, K.; Saji, I.;
Tokane, K. Chem. Comm. 1972, 1252. (b) J effs, P. W.; Redfearn, R.;
Wolfram, J . J . Org. Chem. 1983, 48, 3861. (c) Bal, M. S.; Deep, K.;
Singh, H. Ind. J . Chem., Sect. B 1982, 21, 805.
(7) Paleo, M. R.; Dominguez, D.; Castedo, L. Tetrahedron Lett. 1993,
34, 2369.
(8) (a) Bhatia, B.; Reddy, M. M.; Iqbal, J . Chem. Commun. 1994,
713. (b) Reddy, M. M.; Bhatia, B.; Iqbal, J . Tetrahedron Lett. 1995,
36, 4877.
(18) Katritzky, A. R.; Fan, W. Q.; Black, M.; Pernak, J . J . Org. Chem.
1992, 57, 547.
(19) Katritzky, A. R.; Urogdi, L.; Mayence, A. Chem. Commun. 1989,
337.
(20) Katritzky, A. R.; Wu, H.; Xie, L. Synth. Commun. 1995, 25,
1187.
(21) Katritzky, A. R.; Fali, C. N.; Bao, W.; Qi, M. Synthesis 1998,
1421.
(22) (a) Katritzky, A. R.; Chang, H. X.; Wu, J . Synthesis 1994, 907.
(b) Pearson, W. H.; Stevens, E. P. Synthesis 1994, 904.
(23) Katritzky, A. R.; Ignatchenko, A. V.; Lang, H. J . Org. Chem.
1995, 60, 4002.
(9) Reider, P. J .; Rayford, R.; Grabowski, E. J . J . Tetrahedron Lett.
1982, 23, 379.
(10) Narasaka, K.; Kohno, Y.; Shimada, S. Chem. Lett. 1993, 125.
10.1021/jo990608u CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/11/1999

Preparation of â-Amido Ketones and Aldehydes
J . Org. Chem., Vol. 64, No. 20, 1999 7623
Ta ble 1. Th e P r ep a r a tion of â-Am id o Keton es 7a -s a n d
Sch em e 1
Ald eh yd es 10a ,b
nucleo-
yield
(%)
sma phile product
R1
R2 R3
R4
R5
1a 6a
1b 6a
1c 6a
1d 6a
1e 6a (8b)
1f 6a
1g 6a
1h 6a
1i 6a
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
Ph
Ph
Ph
H
Me
Me
p-MeOPh
3-pyridyl
2-furyl
-PhCH2-
Ph
Ph
Ph
p-MeOPh
Ph
Me
Me
H
Me
Ph
Me
H
H
H
H
H
n-Pr -(CH2)4- 50
Ph
H
-(CH2)4- 62
-(CH2)4- 90
-(CH2)4- 70
-(CH2)4- 75 (52)
-(CH2)4- 70
-(CH2)4- 61
-(CH2)4- 55
-(CH2)4- 30
-(CH2)4- 60
Ph
Ph
Me Ph
H
H
H
H
H
H
H
2
6a
1a 6b
1b 6b
1c 6b
1g 6b
1c 6c
1e 6c
1f 8a
1d 8c
1e 8c
H
H
H
H
H
H
n-Pr Et
Ph
H
H
H
Me 50
Me 72
Me 85
Me 60
Me 66
Me 34
Et
Et
Et
Ph
Ph
Ph
Me Ph
-(CH2)3- 50
H
H
H
H
Ph
Ph
n-Pr
Ph
Me
Me
H
H
H
H
H
65
40
40
40
7s
10a
10b
1a
1e
9
9
H
a
sm ) starting material.
Sch em e 3
Sch em e 2
Sch em e 4
secondary amides and aliphatic or aromatic aldehydes,
were prepared following literature procedures (Scheme
1).23,24a,b Among them, 1g,i are new compounds. Their
1
structures were confirmed by H and 13C NMR spectra
and by elemental analyses.
50% yield. Compound 1e also was used as starting
material to react with 1-(trimethylsiloxy)cyclohex-1-ene
(8b) to give product 7e, but the yield was slightly lower
compared with the yield using enamine 6a as nucleophile
(see Table 1) (Scheme 3).
Ethyl vinyl ether (9) reacted as a nucleophile with
compounds 1a or 1e in this reaction sequence to afford
â-amido aldehydes 10a and 10b, respectively, in reason-
able yields. (Scheme 4).
As expected, two diastereoisomers were found for
product 7 when R3 * H: their GC/MS spectra clearly
showed two peaks possessing the same molecular weight.
Only one peak was found for 7f in the GC/MS spectrum,
which could indicate only one isomer was formed or that
the two diastereoisomers overlapped in the GC/MS
spectrum. Although the reaction appears to proceed
smoothly with a variety of starting materials, derived
both from primary and from secondary amides, some
failures were noted. Thus, when compounds 1j or 3-5
were treated with enamines 6 in the presence of zinc
bromide, complex mixtures and no desired products were
obtained.
It was previously reported that benzotriazole adducts
are readily assisted by Lewis acids to form the benzo-
triazole anion and the corresponding carbocations which
then react with nucleophiles.15 Accordingly, compounds
1a -i or 2 reacted smoothly with enamines 6 on refluxing
in CH2Cl2 in the presence of zinc bromide (Scheme 2).
Enamines 6 from cyclic 6a , acyclic 6b and aryl ketone
6c could all be used as nucleophiles. The desired products
7a -p were obtained in 50-90% yields (Table 1). Struc-
tures 7a -p were confirmed by their 1H and 13C NMR
spectra and by elemental analyses or high-resolution MS
data. The amide and ketonic carbonyl groups showed the
expected chemical shifts in the 13C NMR spectra.
Following these successful results, we extended our
nucleophiles to enol silyl ethers under similar reaction
conditions. Using compound 1f as starting material to
react with 1-(trimethylsiloxy)cyclopent-1-ene (8a ) under
the same reaction conditions, we obtained product 7q in
(24) (a) Katritzky, A. R.; Drewniak, M. J . Chem. Soc., Perkin Trans.
1 1988, 2339. (b) Katritzky, A. R.; Yao, G.; Lan, X.; Zhao, X. J . Org.
Chem. 1993, 58, 2086.

7624 J . Org. Chem., Vol. 64, No. 20, 1999
Katritzky et al.
Column chromatography was carried out on MCB silica gel
(230-400 mesh). Methylene chloride (CH2Cl2) was distilled
from phosphorus pentoxide. Compounds 1a -j and 2-5 were
prepared by literature methods.23,24a,b
Con clu sion s
In conclusion, the versatile amidoalkylation reagents
N-(1-benzotriazol-1-ylalkyl)amides react with enamines,
enol silyl ethers, and vinyl ethers to afford â-amido
ketones and aldehydes in good yields. Unlike many
amidoalkylation reagents, which are difficult to prepare,
unstable, and/or need severe reaction conditions, our
stable and easily prepared starting materials are avail-
able from a wide range of aldehydes and amides and react
in relatively mild conditions with good yields. The
byproduct benzotriazole formed during the reaction was
easily removed by washing the reaction mixture with
dilute alkali, making the whole procedure very simple.
Gen er a l P r oced u r e for th e Syn th esis of â-Am id o
Keton es a n d Ald eh yd es 7a -s a n d 10a ,b. Zinc bromide (1.1
g, 5 mmol) was added to a solution of 1a -i or 2 (5 mmol) in
methylene chloride (15 mL), and the mixture was refluxed with
stirring under argon during 2 h. Enamine 6a -c, enol silyl
ether 8a -c, or ethyl vinyl ether (9) (10 mmol) was added in
one portion, and the mixture was refluxed during 20 h. The
reaction mixture was cooled and subsequently washed with
saturated aqueous solutions of ammonium chloride (15 mL),
sodium carbonate (15 mL), and sodium chloride. The organic
phase was dried over anhydrous sodium sulfate. After removal
of solvent, the residue was subjected to column chromatogra-
phy to produce 7a -s and 10a ,b.
Exp er im en ta l Section
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 1g,i, 7a -s, and 10a ,b. This material is
available free of charge via the Internet at http://pubs.acs.org.
Gen er a l Com m en ts. Melting points were determined on
a hot stage apparatus and are uncorrected. 1H NMR (300 MHz)
and 13C NMR (75 MHz) spectra were recorded in CDCl3 with
TMS and CDCl3, respectively, as the internal reference.
J O990608U