Asymmetric synthesis of nitrogen heterocycles by reaction of chiral β-enaminocarbonyl substrates with acrylate derivatives

Article abstract of DOI:10.1016/S0040-4039(02)00336-2

We have studied the reactivity of β-enaminoesters 1 (R²=OMe) or β-enaminoketone 1 (R²=Me), derived from (S)-phenylglycinol, with activated acrylate derivatives. Substrates 1 (R¹=Me) afforded by aza-annulation oxazololactam

Full text of DOI:10.1016/S0040-4039(02)00336-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2521–2523
Asymmetric synthesis of nitrogen heterocycles by reaction of
chiral b-enaminocarbonyl substrates with acrylate derivatives
Claude Agami, Luc Dechoux* and S e´ verine Hebbe
Laboratoire de Synth e` se Asym e´ trique (UMR 7611), Universit e´ P. et M. Curie, 4 place Jussieu, 75005 Paris, France
Received 3 January 2002; revised 14 February 2002; accepted 16 February 2002
2
2
Abstract—We have studied the reactivity of b-enaminoesters 1 (R =OMe) or b-enaminoketone 1 (R =Me), derived from
1
(
S)-phenylglycinol, with activated acrylate derivatives. Substrates 1 (R =Me) afforded by aza-annulation oxazololactams 2 and
1
3
,4-dihydro-2-pyridones 3. In the same conditions b-enaminoesters 1 (R =H) furnish N-acylated oxazolidines 4. © 2002
Published by Elsevier Science Ltd.
1
The aza-annulation of enamines or b-enaminocarbonyl
The formation of the oxazolidine ring might arise from
internal nucleophilic trapping of an iminium intermedi-
ate formed during the aza-annulation process.
compounds with acrylate derivatives, originally studied
by Hickmott, is a convenient, efficient and now well-
2
known route for the synthesis of d-lactams. The aza-
annulation is believed to proceed via an initial
Condensation of (S)-phenylglycinol with methyl propi-
1
,4-addition of the b-enaminoester to an a,b-unsatu-
olate or methyl acetoacetate and 2,4-pentanedione
1
2
afforded b-enaminoesters 1 (R =H or Me, R =OMe)
rated acid derivative followed by an intramolecular
N-acylation. Several research groups have used success-
fully this aza-annulation procedure in the synthesis of
various nitrogen heterocycles. Recently the aza-annu-
lation was applied to solid-phase synthesis.
1
2
and b-enaminoketone 1 (R =Me, R =Me) respec-
tively, which were used in the next step without purifi-
cation. The aza-annulation reactions were performed
by adding 1 equiv. of acryloyl chloride derivatives to
b-enaminocarbonyl compounds 1 in THF at 0°C. The
reaction mixtures were then treated with an aqueous
saturated sodium bicarbonate solution and extracted
twice with dichloromethane. The results are presented
in Table 1.
3
4
To our knowledge, the aza-annulation of b-enam-
inocarbonyl compounds bearing an internal nucleophile
as an hydroxyl function has not been yet described.
Here we wish to present our first results concerning this
topic. Our initial objective was the preparation of oxa-
zololactams 2. Meyers reported that similar chiral non-
racemic bicyclic lactams derived from homochiral
b-amino alcohols are versatile building blocks for the
enantioselective synthesis of pyrrolidines and piperidi-
Three types of heterocycles (2–4) were formed and were
1
fully characterized. The R group in compounds 1 has
a dramatic effect on the selectivity of the reaction.
Products 2 and 3 arise from an aza-annulation process
1
when R =Me (entries 1–5); whereas oxazolidines 4
5
nes derivatives. In these syntheses, the bicyclic ring
stem from competitive N-acylation when the b-position
system is usually generated by cyclocondensation of
d-oxoacid derivatives with b-amino alcohols. Formally
bicyclolactams such as compound 2, which contain an
electron-withdrawing group on the C5 position of the
lactam ring, could be obtained by treatment of b-enam-
6
was not substituted (entries 6, 7). In these experiments
no product resulting from aza-annulation could be
detected. The cis-N-acyloxazolidines 4 resulting were
7
obtained with d.e. >90%.
inocarbonyl compounds
Scheme 1).
1
with acryloyl chloride
COR2
R1
2
R OC
O
(
+
O
N
HN
Ph
R1
Cl
O
OH
Ph
2
1
Keywords: b-enaminoesters; oxazolactams; 3,4-dihydro-2-pyridones;
oxazolidines; aza-annulation.
*
Corresponding author. E-mail: dechoux@ccr.jussieu.fr
Scheme 1.
0
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00336-2

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522
C. Agami et al. / Tetrahedron Letters 43 (2002) 2521–2523
Table 1. Aza-annulation of b-enaminocarbonyl compounds 1
R3
N
R3
N
R3
2
R OC
COR2
R1
COR2
COR2
R1
THF, conditions
Cl
HN
Ph
R1
R1
+
O
O
O
N
O
O
R3
O
OH
OH
Ph
Ph
Ph
1
2
3
4
R1
R2
R3
Conditions
Ratio 2+3/4
c
Ratio 2/3
c
Yield (%)
Entry
a
1
2
3
4
5
6
7
Me
Me
Me
Me
Me
H
OMe
OMe
OMe
OMe
Me
H
H
H
Me
H
0°C/3 h
\95/5
\95/5
\95/5
50/50
\95/5
B5/95
B5/95
83/17
\95/5
52/48
\95/5
\95/5
–
70
a
0°C/3 h–rt/72 h
0°C/1 min
0°C/3 h–rt/72 h
0°C/3 h
0°C/3 h
0°C/3 h
85
ND
ND
a
91
b
OMe
OMe
H
Me
38
21
b
H
–
a
Combined yields of the two oxazolactam diastereomers 2.
Yield of isolated oxazolidines 4.
b
c
Ratios determined by 1H NMR analysis of the crude mixture. ND: not determined.
Generally, the reaction of enamines, which exist in an
equilibrium mixture with imine tautomers, with a,b-
unsaturated acid chlorides, provides the annulation in
low yield due to the formation of the uncyclized enam-
ide derived from the competitive N-acylation. In con-
trast, with b-enaminocarbonyl compounds in which the
amine function exists only as the enamine tautomer
such as in substrates 1, the annulation process is more
The ratios 2/3 (entries 1–3) suggest that the mechanism
of formation of oxazololactams 2 involves the forma-
tion of an intermediate 3,4-dihydro-2-pyridone 3.
Nevertheless, a relatively high proportion of oxazolac-
tams 2 was detected when the reaction was quenched
just after addition of acryloyl chloride (entry 3). This
result suggests that a second mechanistic pathway is
involved in the formation of oxazolactams 2. This
might be a fast internal trapping of an iminium inter-
mediate formed after the 1,4-addition of enaminoester 1
to acryloyl derivatives. Noteworthy, b-enaminoketone 1
8
easy. Stille et al. have investigated the selectivity of this
reaction in the presence of various acidic reagents to
9
increase the yield of the annulated product. Thus,
compounds 1 bearing a hydrogen on the b-position
1
(
R =H) react exclusively like imines by N-acylation.
1
2
(
R =Me, R =Me) is transformed after 3 h nearly
The methyl group enhances the electron density on the
a-carbon and hence favors the annulation process.
When the Michael acceptor is b-substituted (entry 4)
the ratio 2+3/4 falls down and N-acyloxazolidine 4 was
also formed. The low yield in oxazolidine 4 (entries 6,
quantitatively into two bicyclolactam diastereomers 2
11
(
entry 5).
7
) is due to competitive formation of dihydropyridine 5
(
yields=30 and 38%, respectively) resulting from the
trimerization of the starting b-enaminoester (Scheme 2).
Oxazololactams 2 were in all cases (entries 1–5) formed
as a mixture of two diastereomers with a low
diastereomeric excess (0–10%) and separated by chro-
matography on silica gel. The stereochemical assign-
ment of the two oxazololactams 2a, 2b and oxazolidines
4
(entries 6, 7) was inferred by NMR spectroscopy
NOE experiments, Fig. 1).
10
(
Figure 1.
Cl
O
R3
N
CO2Me
CO2Me
CO2Me
MeO2C
HN
MeO2C
+
R3
THF
H
O
O
N
OH
Ph
OH
Ph
Ph
1
4
5
Scheme 2.

C. Agami et al. / Tetrahedron Letters 43 (2002) 2521–2523
2523
In summary, we have found an easy and efficient route
to oxazolactams 2 in two steps from (S)-phenylglycinol.
We are currently investigating the stereochemical aspect
of this bis-cyclization in order to enhance the stereose-
lectivity of the process. Moreover, we have shown that
the regioselectivity of the reaction (i.e. aza-annulation
versus N-acylation) is strongly dependent on the substi-
tution of the b-carbonyl position.
Sun, L. Q.; Wang, S.; Saxena, A.; Doctor, B. P. J. Am.
Chem. Soc. 1996, 118, 11357; (m) Benovsky, P.; Stille, J.
R. Tetrahedron Lett. 1997, 38, 8475; (n) Beholz, L. G.;
Benovsky, P.; Ward, D. L.; Barta, N. S.; Stille, J. R. J.
Org. Chem. 1997, 62, 1033; (o) Danieli, B.; Martinelli, L.
M.; Passarella, D.; Silvani, A. J. Org. Chem. 1997, 62,
6519; (p) Benovsky, P.; Stephenson, G. A.; Stille, J. R. J.
Am. Chem. Soc. 1998, 120, 2493; (q) Hadden, M.;
Nieuwenhuyzen, M.; Potts, D.; Stevenson, P. J. J. Chem.
Soc., Perkin Trans. 1 1998, 3437; (r) Cimarelli, C.;
Palmieri, G. Tetrahedron 1998, 54, 915.
The use of oxazolactams 2 as chiral templates in asym-
metric synthesis should allow a rapid access to polysub-
stituted chiral non racemic piperidines. In this context,
our first objective is the preparation of enantiopure
4
. (a) Wagman, A. S.; Wang, L.; Nuss, J. M. J. Org. Chem.
2000, 65, 9103; (b) Paulvannan, K.; Chen, T. J. Org.
12
derivatives of nipecotinic acid.
Chem. 1994, 65, 6160.
5
6
. For a review see: Graning, M. D.; Meyers, A. I. Tetra-
hedron 2000, 56, 9843.
. A similar N-acyloxazolidine was obtained by treatment
of ethoxycarbonyl norephedrine with 3,3-diethoxy propi-
onate under acidic conditions: Garcia-Valverde, M.;
Nieto, J.; Pedrosa, R.; Vicente, M. Tetrahedron 1999, 55,
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7
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1
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(
(
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3
3
1
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13
C NMR (63 MHz, CDCl ): 20.3, 20.5, 29.8, 50.1, 52.4,
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5
8.7, 70.2, 93.9, 125.5, 127.4, 128.7, 139.2, 168.4, 171.4.
20
Mp: 115°C. [h] : +137 (c 0.68, CHCl ). Anal. calcd for
3
1
D
3
C H NO ; C, 66.42; H, 6.62; N, 4.84. Found: C, 66.37;
15 19
4
H, 6.78; N, 4.77%. IR (CHCl ) 1734, 1655, 1395, 1218,
3
−
1
1
165 cm .
2
1
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