Stereoselective synthesis of new chiral N-tertiary tetrasubstituted β-enamino ester piperidines through an ammonia-catalyzed process

Article abstract of DOI:10.1021/jo052490p

We report here two approaches for the preparation of new N-substituted β-enamino ester piperidines featuring an exocyclic tetrasubstituted double bond, based either on the direct alkylation of piperidine β-enamino esters bearing an exocyclic trisubstitute

Full text of DOI:10.1021/jo052490p

Stereoselective Synthesis of New Chiral N-Tertiary Tetrasubstituted
â-Enamino Ester Piperidines through an Ammonia-Catalyzed
Process
Sandrine Calvet-Vitale, Corinne Vanucci-Bacque´,* Marie-Claude Fargeau-Bellassoued, and
Ge´rard Lhommet*
UniVersite´ Pierre et Marie Curie, Institut de Chimie Mole´culaire FR 2769, Laboratoire de Chimie
Organique, UMR 7611, Equipe de Chimie des He´te´rocycles, 4 Place Jussieu,
75252 Paris Cedex 05, France
Vanucci@ccr.jussieu.fr; lhommet@ccr.jussieu.fr
ReceiVed December 2, 2005
We report here two approaches for the preparation of new N-substituted â-enamino ester piperidines
featuring an exocyclic tetrasubstituted double bond, based either on the direct alkylation of piperidine
â-enamino esters bearing an exocyclic trisubstituted double bond or on the intramolecular cyclization of
linear amino â-keto esters. The target compounds were obtained as unusual (Z)-stereoisomers in high
yields. The key role of ammonia as reagent, acting both as a nucleophile and a base, was underlined. The
diastereoselective formation of the products was rationalized on the basis of an ammonia addition-syn
elimination catalytic process.
Introduction
Considering the outstanding interest of heterocyclic â-en-
amino esters as intermediates in the total syntheses of alkaloids,1
we have developed a program aimed at preparing various chiral
pyrrolidine and piperidine â-enamino esters.2 In particular,
â-enamino esters 1 and 2 featuring both an exocyclic tetrasub-
stituted double bond (R2 * H) and a chiral auxiliary on the
nitrogen atom (R1 * H) have attracted our attention (Figure 1)
as a way to access chiral pyrrolidines and piperidines following
the stereocontrolled reduction of the double bond, which would
simultaneously create two stereogenic centers. A general method
for the preparation of pyrrolidines 12a relied upon Eschenmoser
FIGURE 1.
reaction between the corresponding thiolactam and secondary
R-bromo esters to lead to a mixture of (E)- and (Z)-isomers,
the latter being always minor (Scheme 1). In contrast, when
applied to piperidine-2-thiones,3 the same procedure was
reported to lead either to tetrahydrothieno[2,3-b]pyridin-3-ones
3a or to thiazolidinones 3b (depending on the nature of R1),
instead of the expected piperidine enamino esters 2 (Scheme
1). The only known preparation of a compound of type 2 (R1
and R2 * H) by Eschenmoser condensation involves the reaction
of R-bromobutyrolactone with chiral piperidine thiolactam 44
(1) See, for example: (a) Fujimoto, R.; Kishi, Y. Tetrahedron Lett. 1981,
22, 4197-4198. (b) Hart, D. J.; Kanai, K. J. Am. Chem. Soc. 1983, 105,
1255-1263. (c) Cook, G. R.; Beholz, L. G.; Stille, J. R. Tetrahedron Lett.
1994, 35, 1669-1672. (d) Herna´ndez, A.; Marcos, M.; Rapoport, H. J. Org.
Chem. 1995, 60, 2683-2691. (e) Michael, J. P.; Gravestock, D. Synlett
1996, 981-982. (f) Michael, J. P.; Gravestock, D. Eur. J. Org. Chem. 1998,
865-870.
(2) (a) David, O.; Blot, J.; Bellec, C.; Fargeau-Bellassoued, M.-C.;
Haviari, G.; Ce´le´rier, J.-P.; Lhommet, G.; Gramain, J.-C.; Gardette, D. J.
Org. Chem. 1999, 64, 3122-3131. (b) David, O.; Fargeau-Bellassoued,
M.-C.; Lhommet, G. Tetrahedron Lett. 2002, 43, 3471-3474. (c) Calvet
S.; David, O.; Vanucci-Bacque´, C.; Fargeau-Bellassoued M.-C.; Lhommet,
G. Tetrahedron 2003, 59, 6333-6339. (d) David, O.; Calvet, S., Chau, F.;
Vanucci-Bacque´, C.; Fargeau-Bellassoued, M.-C.; Lhommet, G. J. Org.
Chem. 2004, 69, 2888-2891.
(3) (a) Marchand, P.; Bellec, C.; Fargeau-Bellassoued, M.-C.; Nezry,
C.; Lhommet, G. Heterocycles 1996, 43, 63-70. (b) Michael, J. P.; de
Koning, C. B.; van der Westhuyzen, C. W.; Fernandes, M. A. J. Chem.
Soc., Perkin Trans. 1 2001, 2055-2062. (c) Russowsky, D.; da Silveira
Neto, B. A. Tetrahedron Lett. 2003, 44, 2923-2926. (d) Russowsky, D.;
da Silveira Neto, B. A. Tetrahedron Lett. 2004, 45, 1437-1440.
(4) David, O.; Bellec, C.; Fargeau-Bellassoued M.-C.; Lhommet, G.
Heterocycles 2001, 55, 1689-1701.
10.1021/jo052490p CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/01/2006
J. Org. Chem. 2006, 71, 2071-2077
2071

Calvet-Vitale et al.
SCHEME 1
SCHEME 4
isomers, was first deprotonated by treatment with excess aqueous
saturated potassium carbonate. Surprisingly, the NMR spectrum
of the resulting reaction mixture showed that this two-step
procedure had not generated the expected enamino ester, but a
mixture consisting mainly of the endocyclic enamine 7a as a
70:30 mixture of diastereoisomers (as determined by 1H NMR),
along with various amounts (10-30%) of the linear amino
â-keto ester 6a7 (Scheme 5). Isolation of 7a turned out to be
particularly troublesome, since aqueous workup as well as
chromatography on silica gel8 quantitatively transformed 7a into
â-keto ester 6a. Alternative treatment of iminium Ia with sodium
hydride in THF (1.5 equiv) or triethylamine in MeOH (1.5
equiv) as the base resulted in the same outcome (Scheme 5).
We finally thought to deprotonate crude iminium Ia with an
anhydrous 7 N methanolic ammonia solution. After 48 h, the
expected â-enamino ester 2a was obtained along with keto ester
SCHEME 2
SCHEME 3
1
6a in a 80:20 ratio as determined by H NMR in CDCl3.9
Subsequently, we found that successive treatment of the crude
iminium Ia with the ammonia solution (15 min) and then with
sodium hydride allowed to reduce the reaction time and to
generate compound 2a as the sole product according to the 1H
NMR spectrum of the reaction mixture. This compound was
relatively unstable and moisture sensitive, which prevented any
aqueous workup. Moreover, attempted silica gel column chro-
matography delivered compound 6a as the major compound.
Finally, bulb-to-bulb distillation afforded 2a in 89% yield as a
single isomer. The stereochemistry of the double bond was
assigned as (Z) on the basis of NOE experiments that showed
interactions between the methyl group on the double bond (δ
1.74) and the C-3′ (δ 2.19) hydrogens. This result was
unexpected since N-substituted pyrrolidine and piperidine
â-enamino esters bearing an exocyclic double bond had been
previously obtained generally as the (E)-isomer, with at worst
the (Z)-isomer as a minor product.2a,4,10
Attempted extension of this procedure to various R2 groups
(ethyl, allyl, benzyl) invariably failed, the formation of iminium
ions Ib-d being not even observed. Therefore, we moved to
the second strategy based on the intramolecular cyclization of
R-substituted ω-amino â-keto esters 6 (Scheme 3, route b).
Preparation of compound 6a (R2 ) Me) was carried out starting
from methyl 7-chloro-3-oxoheptanoate.2c The latter was treated
with methyl iodide in the presence of potassium carbonate11 to
cleanly afford compound 9a in 96% yield (Scheme 6). Direct
condensation of (S)-1-phenylethylamine on keto ester 9a, under
different reaction conditions,12 gave rise to the expected product
6a as the minor component, along with the starting material
and side products resulting from the reaction of the amine on
the ketone.13 At this point, we reasoned that initial protection
of the keto function of 9a would prevent these concurrent
(Scheme 2). An access to piperidine 2 (R1 ) R2 ) Me; R3 )
Et) by condensation of ethyl bromoacetate with lactim ether
under Reformatsky conditions has moreover been described.5
However, to our knowledge, a general method to access
piperidines 2 (R1 and R2 * H) has never been reported. We
wish now to report the first general synthesis of compounds 2
displaying various alkyl substituents R2 on the double bond and
the (S)-phenylethyl moiety as the chiral auxiliary attached to
the nitrogen atom.
Results and Discussion
Access to the target compounds 2 was envisioned according
to two strategies, relying either on the direct alkylation of chiral
â-enamino ester 5 (Scheme 3, route a) or on the intramolecular
cyclization of R-substituted ω-amino â-keto ester 6 (Scheme
3, route b).
We initially focused our attention on route a. We previously
reported the synthesis of pyrrolidine 1a (R1 ) R2 ) R3 ) Me)
by reacting methyl (1-methylpyrrolidin-2-ylidene)acetate in
refluxing methyl iodide followed by the addition of potassium
carbonate (Scheme 4).6
(7) It is noteworthy that NMR spectra of enamine 7a in CDCl3 always
show the presence of amino keto ester 6a. Thus, 7a can never be observed
in pure form. Moreover, we have observed that NMR sample of 7a in CDCl3
was totally converted into 6a over 6 h.
(8) The obtention of 6a was also observed using deactivated silica gel
which prevented any further purification.
As an extension of this procedure, compound 52c was refluxed
in methyl iodide to afford an iminium intermediate Ia (Scheme
5). The latter, shown by NMR to consist of a 70:30 mixture of
(9) It is of note that enamino ester 2a was not converted into 6a in CDCl3.
(10) Shiosaki, K. In ComprehensiVe Organic Chemistry; Trost B. M.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 2, pp 865-892.
(11) Lambert, P. H.; Vaultier, M.; Carrie´, R. J. Org. Chem. 1985, 50,
5352-5356.
(5) Jain, S.; Jain, R.; Singh, J.; Anand, N. Tetrahedron Lett. 1994, 35,
2951-2954.
(6) Ce´le´rier, J.-P.; Deloisy-Marchalant, E.; Lhommet, G. J. Heterocycl.
Chem. 1984, 21, 1633-1635.
2072 J. Org. Chem., Vol. 71, No. 5, 2006

Synthesis of N-Tertiary Tetrasubstituted â-Enamino Ester Piperidines
SCHEME 5
determined by 1H NMR. On the other hand, in refluxing
methylene chloride and in the presence of sodium sulfate, 6a
led to enamine 7a as a 1:1 mixture of isomers. Based on our
SCHEME 6
previous study on the direct alkylation of enamino ester 5
-
(Scheme 3, route a), we treated in parallel iminium Ia, ClO4
,
and compound 7a with ammonia in methanol and then with
sodium hydride (Scheme 7). Under these conditions, â-enamino
ester 2a was obtained in, respectively, 55% and 72% crude yield
from 6a. Finally, cyclization conditions were improved by
reacting 6a directly in the presence of sodium sulfate and
ammonia in refluxing methanol followed by treatment with
sodium hydride. This one-pot procedure afforded 2a in 71%
isolated yield, once again as the only (Z)-isomer.
To explore the scope of this methodology, we prepared
various substituted ω-amino â-keto esters 6b (R2 ) ethyl), 6c
(R2 ) allyl), and 6d (R2 ) benzyl) according to the procedure
developed for 6a (Scheme 6). The alkylation step leading to
compounds 9b-d, using less reactive alkyl halide than methyl
iodide, proceeded with lower yields compared to 9a, due to the
competitive formation of dialkylated derivatives. The subsequent
protection-substitution-deprotection sequence efficiently led
to amino keto esters 6b-d in good yields. Compounds 6b-d
were then reacted under the optimized conditions previously
developed for the preparation of 2a to afford the expected
corresponding piperidines 2b, 2c, and 2d in, respectively, 75%,
77%, and 79% isolated yields16 as the only (Z)-isomers (Scheme
8). The stereochemistry of the double bonds was assigned on
the basis of 1H NMR data. The chemical shifts of the hydrogen
atoms at C-3′ of 2a-d appeared in the range 2.10-2.15
ppm,17,3c shielded compared to the corresponding one observed
in compounds with the (E)-stereochemistry (δ above 3 ppm2b,4).
These results confirmed that our strategy based on the cycliza-
tion of compounds 6 efficiently and stereoselectively afforded
variously substituted compounds 2.
reactions. Compound 9a was therefore readily converted into
the corresponding dioxolane 10a in 85% yield. Subsequent
substitution of the halogen atom by (S)-1-phenylethylamine was
achieved in refluxing acetonitrile to give amino ester 11a, which
was deprotected upon treatment with boron trifluoride etherate2c
to lead to the expected amino â-keto ester 6a in 70% isolated
yield.14
We next turned our attention toward the cyclization of
compound 6a (Scheme 7), considering only dehydrating reaction
conditions that would require no aqueous workup. Compound
6a was first reacted with zinc perchlorate and magnesium
sulfate15 to afford iminium Ia as a 1:1 mixture of isomers, as
To rationalize our results, we will now discuss the mechanistic
and stereochemical outcome of the involved reactions. We will
mainly base our analysis on the methyl-substituted compounds.
Iminium ion Ia (R2 ) CH3) is the key intermediate to explain
the formation of the different products we isolated. According
(12) Among the different reaction conditions screened: (a) condensation
without solvent at 110 °C; (b) Na2CO3, NaI, cat. TBAI in refluxing CH3-
CN; (c) Na2SO4, NaH2PO4, cat. I2 at 65 °C; (d) Zn(ClO4)2‚6H2O, MgSO4
in refluxing CH2Cl2.
(13) ω-Chloro and/or ω-amino enamino esters were obtained as side
products depending on the reaction conditions.
(14) One notes that contrary to what was observed for the unsubstituted
compound 11 (R2 ) H),2c no in situ cyclisation of intermediate 6a into
compound 2a occurred during the deprotection step.
(15) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.; Melchiorre,
P.; Sambri, L. Synlett 2004, 2, 239-242.
(16) Contrary to 2a, silica gel column chromatography of compounds
2b-d generates only a small amount of linear amines 6b-d.
(17) Ce´le´rier, J.-P.; Deloisy, E.; Lhommet, G.; Maitte, P. J. Org. Chem.
1979, 44, 3089.
J. Org. Chem, Vol. 71, No. 5, 2006 2073

Calvet-Vitale et al.
SCHEME 7a
a Key: (a) crude yields from 6a; (b) isolated yield.
SCHEME 8
SCHEME 10. Proposed Mechanism for the Formation of 7a
from Iminium Ion Ia
SCHEME 9
to the base used to deprotonate Ia, two different compounds
7a or 2a were obtained. The surprising formation of enamine
7a in the presence of potassium carbonate, sodium hydride, or
triethylamine sharply contrasts with what was observed with
the N-substituted pyrrolidine analogue. In the latter case,
deprotonation of the intermediate iminium exclusively occurred
as expected at the more acidic site, R to the ester moiety, to
generate an exocyclic double bond (Scheme 4).6 This result
demonstrates the influence of the ring size on the outcome of
the reaction. Also noteworthy is the observation that reaction
with sodium hydride of iminium ion Io (R2 ) H, formation
confirmed by NMR) stemming from 5 returned compound 5 as
the only (E)-isomer (Scheme 9), suggesting that deprotonation
had taken place with the same regioselectivity R to the ester
group. This observation underlines the key role of the R2
substituent in the deprotonation process in the case of the
piperidine compounds.
In the case of iminium ion Ia (R2 ) CH3), based on simple
pKa considerations, one could suppose that deprotonation would
occur at the more acidic carbon R to the ester group to give
compound 2a, which in turn could isomerize under basic
conditions to yield enamine 7a. However, we showed that
enamino ester 2a when reacted with sodium hydride did not
give rise to 7a, but remained unchanged. The formation of
enamine 7a may be rationalized on the basis of orbital and
conformational factors (Scheme 10). We have drawn in Scheme
10 the reactive conformations of iminium ions (2R)-Ia and (2S)-
Ia that allow hydrogen abstraction (C-H bond nearly parallel
to the π-orbital of the iminium double bond).18 For conforma-
tions (2R)-Ia2 and (2S)-Ia2 in which the allylic 1,3-strains are
both minimized, only the axial hydrogen atom at C-3′ is in an
adequate position to be abstracted. This leads to the isolated
enamines 7a as a mixture of isomers in the same ratio as
iminium ion Ia. Conversely, conformations Ia1 and Ia3 that
would lead to the expected â-enamino ester 2a by abstraction
of the hydrogen R to the ester group appear strongly disfavored
due to developing allylic 1,3-strains. Because of the absence of
these allylic 1,3-strains in the case of iminium ion Io (R2 )
H), conformation Io1 is no longer disfavored compared to Io2.
Therefore, deprotonation in the presence of NaH occurs as
expected at the most acidic carbon to generate 5 as the (E)-
isomer. In the case of the pyrrolidine iminium analogue to I,
hydrogen abstraction at C-3′ is not stereoelectronically favored
compared to piperidine iminium Ia, due to the pseudoaxial
orientation of the C3′-H bond, while allylic 1,3-strains would
not be as important as in the six-membered ring case. Combined
with the reluctance of a five-membered ring to accommodate
an endocyclic double bond, these reasons would explain
formation of 1a via deprotonation R to the ester function
(Scheme 4).
(18) Deslongchamps, P. In Stereoelectronic Effects in Organic Chemistry;
Pergamon Press: New York, 1983; Vol. 1, pp 209-290.
2074 J. Org. Chem., Vol. 71, No. 5, 2006

Synthesis of N-Tertiary Tetrasubstituted â-Enamino Ester Piperidines
SCHEME 11. Proposed Mechanism for the Formation of 2a via Iminium Ia in NH3/MeOH
SCHEME 12. Proposed Mechanism for the
Stereoconvergent Formation of (Z)-2a from Iminium Ions Ia
Striking is the different behavior of iminium ion Ia in the
presence of methanolic ammonia (with or without the subse-
quent treatment with sodium hydride), that afforded selectively
the expected compound 2a as a single isomer. To show the key
role of ammonia, iminium ion Ia was successively treated with
pure methanol and then with NaH in THF: this sequence
delivered enamine 7a. Moreover, reaction of iminium ion Io
(R2 ) H) with NH3/MeOH and then NaH led to 5 as a 1:1
mixture of the (E)-isomer and of the unprecedented (Z)-isomer
(Scheme 9),19 which again stresses the key role of ammonia.
We suppose that ammonia would react first as a base to give
enamine 7a as previously observed. To account for the obtention
of 2a, we reasoned that ammonia would react also as a
nucleophile, adding on the double bond of iminium ion Ia,20
which is believed to result from an underlying enamine-iminium
equilibrium under the protic conditions of the reaction21 (Scheme
11) The existence of such an equilibrium is supported by the
transformation of enamine 7a into enamino ester 2a following
successive treatment with ammonia in methanol and then with
sodium hydride (Scheme 7). The resulting intermediate am-
monium IIa would deprotonate under the basic reaction
conditions to generate amine IIIa. The latter would undergo
ammonia elimination involving a formal hydrogen abstraction
at the more acidic carbon R to the ester group, through a
diasteroconvergent mechanism, to afford exocyclic â-enamino
ester 2a (Scheme 11). The formation of compound 6a along
with 2a (as shown by NMR) following treatment of iminium
ion Ia with ammonia in methanol for 48h, might be due to the
opening of instable intermediate species IIa and/or IIIa during
workup. The role of sodium hydride, added at the end of the
process, would be to complete the reaction by quenching the
acid species and hence to displace the equilibrium toward
formation of the amine IIIa and ultimately that of compound
2a.
as that observed for iminium Ia. Since this result is not observed,
we have to suppose that the stereogenic center R to the ester
group control the facial selectivity of the addition of ammonia.
To account for the formation of 2a, we ruled out an E2
mechanism because elimination of the amide ion appears
unlikely. We rather propose a syn elimination mechanism. To
rationalize the isolation of the sole isomer (Z)-2a, we postulate
addition of ammonia anti to the carbomethoxy group of the most
stable conformation Ia2 of each isomer (Scheme 12). The
resulting amines (2R, 2′S)-IIIa and (2S, 2′R)-IIIa would undergo
elimination of ammonia through the same concerted bimolecular
process catalyzed by ammonia. We suggest that hydrogen
bonding between intermediates IIIa and a second molecule of
ammonia would allow a syn elimination process via a possible
six-membered ring transition state22 to give rise to (Z)-2a
(Scheme 12). Although we could not isolate any intermediate
in this reaction, the above original mechanism accounts for both
the stereoconvergence of the reaction and the unusual (Z)
stereochemistry of the double bond of 2a. Furthermore, the
mechanistic analysis developed for the formation of (Z)-2a can
be extended to account for the formation of the variously
substituted â-enamino esters 2b-d.
Concerning the stereochemical outcome of this reaction that
afforded 2a as a single (Z)-isomer from an isomeric mixture of
iminium Ia, we postulate a diastereocontrolled addition of
ammonia on iminium Ia. If selectivity were induced by the (S)-
1-phenylethyl auxiliary, ammonia would add anti to the bulky
phenyl group of both isomers of iminium Ia2 to afford, following
ammonia elimination via aminals (2R, 2′R)-IIIa and (2S, 2′R)-
IIIa, a mixture of (Z)-2a and (E)-2a isomers in the same ratio
(19) The 1:1 mixture of (E) and (Z) isomers of 5 slowly isomerized (3
days) into the (E)-isomer in CDCl3.
(20) (a) Hauser, C. R.; Lednicer, D. J. Org. Chem. 1959, 24, 46-49.
(b) Parenty, A. D. C.; Smith, L. V.; Pickering, A. L.; Long, D.-L.; Cronin,
L. J. Org. Chem. 2004, 69, 5934-5946.
(21) Hart, D. J.; Hong, W.-P.; Hsu, L.-Y. J. Org. Chem. 1987, 52, 4665-
4673.
(22) (a) Ilieva, S.; Galabov B.; Musaev, D. G.. Morokuma, K.; Schaefer,
H. F., III. J. Org. Chem. 2003, 68, 1496-1502. (b) Jencks, W. P.; Carriuolo,
J. J. Am. Chem. Soc. 1960, 82, 675-681.
J. Org. Chem, Vol. 71, No. 5, 2006 2075

Calvet-Vitale et al.
h. A 5% aqueous solution of NaH2PO4 (3 mL) was added. The
reaction mixture was stirred for 15 min, and Et2O (40 mL) was
added. The organic layer was successively washed with 5% NaH2-
PO4 solution (3 × 10 mL), water (15 mL), and brine (15 mL),
dried over Na2SO4, and concentrated in vacuo. Column chroma-
tography on silica gel gave pure compounds 10.
Conclusions
In this paper, we have disclosed two related methods for the
diastereoselective synthesis of the unprecedented chiral N-
substituted â-enamino ester piperidines with a tetrasubstituted
double bond. Direct alkylation of piperidine â-enamino ester 5
was efficient only in the case of the methyl substituent. On the
other hand, intramolecular cyclization of ω-amino â-keto esters
allowed the preparation of variously substituted compounds 2
in good yields. Our study showed that the common intermediate
iminium I for these two approaches displayed different behavior
depending on the nature of the base. Obtention of compounds
2 as a single unexpected (Z)-isomer was only possible using
ammonia as the reagent. A stereoconvergent ammonia-assisted
syn elimination was proposed to account for the observed high
diastereoselectivity. Further work to develop the synthetic
applications of these polyfunctional heterocycles is underway
in our laboratory.
2-[2-(4-Chlorobutyl)[1,3]dioxolan-2-yl]propionic Acid Methyl
Ester (10a). Compound 10a was obtained as colorless oil in 85%
yield following the general procedure: Rf (cyclohexane/AcOEt 8/2)
1
0.3; IR (neat) 1740 cm-1; H NMR (CDCl3) δ 1.20 (d, J ) 7 Hz,
3H), 1.40-1.62 (m, 2H), 1.65-1.87 (m, 4H), 2.84 (q, J ) 7 Hz,
1H), 3.53 (t, J ) 6.5 Hz, 2H), 3.69 (s, 3H), 3.95-4.10 (m, 4H);
13C NMR (CDCl3) δ 12.5, 20.2, 32.5, 33.7, 44.8, 46.6, 51.6, 65.4,
110.9, 173.7. Anal. Calcd for C11H19ClO4: C, 52.70; H, 7.64.
Found: C, 52.61; H, 7.38.
2-[2-(4-Chlorobutyl)[1,3]dioxolan-2-yl]butyric Acid Methyl
Ester (10b). Compound 10b was obtained as colorless oil following
the general procedure in 86% yield: Rf (cyclohexane/AcOEt 9/1)
0.25; IR (neat) 1730 cm-1; 1H NMR (CDCl3) δ 0.88 (t, J ) 7 Hz,
3H), 1.50-1.82 (m, 8H), 2.63 (dd, J ) 3.75 and 11.5 Hz, 1H),
3.53 (t, J ) 7 Hz, 2H), 3.70 (s, 3H), 3.94-4.03 (m, 4H); 13C NMR
(CDCl3) δ 12.5, 20.2, 21.1, 32.7, 33.9, 45.0, 51.7, 55.4, 65.5, 110.9,
173.3. Anal. Calcd for C12H21ClO4: C, 54.44; H, 8.00. Found: C,
54.21; H, 8.16.
Experimental Section
General Procedure for the Preparation of Compounds 9. To
a suspension of K2CO3 (14 mmol, 2 equiv) in dry acetone (25 mL)
was added dropwise methyl 7-chloro-3-oxo-heptanoate (7 mmol,
1 equiv). The reaction mixture was stirred at room temperature for
30 min, and the alkyl halide (7.7 mmol, 1.1 equiv) was added
dropwise. After being stirred for 12 h, the reaction mixture was
concentrated in vacuo and the residue dissolved in CH2Cl2 (20 mL).
The organic layer was washed with water, dried over Na2SO4, and
concentrated in vacuo to afford after column chromatography on
silica gel the expected compounds 9.
7-Chloro-2-methyl-3-oxoheptanoic Acid Methyl Ester (9a).
Compound 9a was obtained as a colorless oil following the general
procedure using methyl iodide as alkylating agent in 96% yield: Rf
(cyclohexane/AcOEt 8/2) 0.3; IR (neat) 1745, 1720 cm-1; 1H NMR
(CDCl3) δ 1.32 (d, J ) 7 Hz, 3H), 1.71-1.90 (m, 4H), 2.57-2.64
(m, 2H), 3.52-3.62 (m, 3H), 3.73 (s, 3H); 13C NMR (CDCl3) δ
12.4, 20.5, 31.4, 40.1, 44.3, 52.0, 52.2, 170.6, 204.9. Anal. Calcd
for C9H15ClO3: C, 52.30; H, 7.32. Found: C, 52.29; H, 7.21.
7-Chloro-2-ethyl-3-oxoheptanoic Acid Methyl Ester (9b).
Compound 9b was obtained as a colorless oil following the general
procedure using ethyl iodide as alkylating agent in 60% yield: Rf
(cyclohexane/AcOEt 8/2) 0.3; IR (neat) 1740, 1710 cm-1; 1H NMR
(CDCl3) δ 0.92 (t, J ) 7.5 Hz, 3H), 1.69-1.81 (m, 4H), 1.82-
1.91 (m, 2H), 2.51-2.72 (m, 2H), 3.39 (t, J ) 7.5 Hz, 1H), 3.51-
3.56 (m, 2H), 3.73 (s, 3H); 13C NMR (CDCl3) δ 11.8, 20.5, 21.5,
31.6, 40.8, 44.5, 52.1, 60.2, 170.1, 204.6. Anal. Calcd for C10H17-
ClO3: C, 54.42; H, 7.76. Found: C, 54.47; H, 7.93.
2-[2-(4-Chlorobutyl)[1,3]dioxolan-2-yl]pent-4-enoic Acid Meth-
yl Ester (10c). Compound 10c was obtained as colorless oil in
80% yield following the general procedure: Rf (cyclohexane/AcOEt
1
9/1) 0.3; IR (neat) 1740, 1640 cm-1; H NMR (CDCl3) δ 1.41-
1.60 (m, 2H), 1.62-1.94 (m, 4H), 2.33-2.53 (m, 2H), 2.80 (dd, J
) 3.75 and 11.5 Hz, 1H), 3.53 (t, J ) 6.5 Hz, 2H), 3.67 (s, 3H),
3.95-4.05 (m, 4H), 4.94-5.09 (m, 2H), 6.42-6.81 (m, 1H); 13C
NMR (CDCl3) δ 20.0, 31.9, 32.4, 33.8, 44.7, 51.4, 52.8, 65.3, 110.4,
116.4, 135.2, 172.3. Anal. Calcd for C13H21ClO4: C, 56.42; H, 7.65.
Found: C, 56.69; H, 7.66.
2-[2-(4-Chlorobutyl)[1,3]dioxolan-2-yl]-3-phenylpropionic Acid
Methyl Ester (10d). Compound 10d was obtained as colorless oil
in 80% yield following the general procedure: Rf (cyclohexane/
1
AcOEt 9/1) 0.3; IR (neat) 1730, 1600 cm-1; H NMR (CDCl3) δ
1.43-1.61 (m, 2H), 1.73-1.97 (m, 4H), 2.88-3.04 (m, 3H), 3.52
(t, J ) 6.5 Hz, 2H), 3.53 (s, 3H), 3.96-4.05 (m, 4H), 7.10-7.29
(m, 5H); 13C NMR (CDCl3) δ 20.1, 32.5, 33.8, 34.0, 44.9, 51.5,
55.5, 65.4, 110.6, 126.2, 128.3, 128.5, 139.2, 172.4. Anal. Calcd
for C17H23ClO4: C, 62.48; H, 7.09. Found: C, 62.47; H, 7.26.
General Procedure for the Preparation of Compounds 11.
To a solution of compound 10 (6 mmol, 1 equiv) in acetonitrile
(50 mL) were added NaI (6 mmol, 1 equiv), Na2CO3 (30 mmol, 3
equiv), tetrabutylammonium iodide (0.6 mmol, 0.1 equiv), and (S)-
1-phenylethylamine (6 mmol, 1 equiv). The reaction mixture was
refluxed for 48 h. The solvent was evaporated, and water (30 mL)
was added. The aqueous layer was extracted with Et2O (3 × 30
mL). The combined organic layer was washed with brine (20 mL),
dried over Na2SO4, and concentrated in vacuo. Column chroma-
tography on silica gel gave pure compounds 11.
7-Chloro-2-allyl-3-oxoheptanoic Acid Methyl Ester (9c).
Compound 9c was obtained as a colorless oil following the general
procedure using allyl bromide as alkylating agent in 54% yield:
Rf (cyclohexane/AcOEt 8/2) 0.3; IR (neat) 1750, 1720, 1640 cm-1
;
1H NMR (CDCl3) δ 1.69-1.90 (m, 4H), 2.43-2.64 (m, 4H), 3.48-
3.67 (m, 3H), 3.71 (s, 3H), 4.95-5.12 (m, 2H), 5.51-5.85 (m,
1H); 13C NMR (CDCl3) δ 20.2, 31.2, 31.8, 41.4, 44.2, 51.8, 57.6,
116.9, 133.9, 169.1, 203.4. Anal. Calcd for C11H17ClO3: C, 56.78;
H, 7.36. Found: C, 56.80; H, 7.58.
2-{2-[4-(1(S)-Phenylethylamino)butyl][1,3]dioxolan-2-yl)pro-
pionic Acid Methyl Ester (11a). Compound 11a was obtained as
pale yellow oil in 72% yield following the general procedure: Rf
1
(AcOEt) 0.25; IR (neat) 1740 cm-1; H NMR (CDCl3) δ 1.18 (d,
7-Chloro-2-benzyl-3-oxoheptanoic Acid Methyl Ester (9d).
Compound 9d was obtained as a colorless oil following the general
procedure using benzyl bromide as alkylating agent in 43% yield:
J ) 7 Hz, 3H), 1.34 (d, J ) 6.5 Hz, 3H), 1.35-1.50 (m, 5H),
1.60-1.80 (m, 2H), 2.33-2.55 (m, 2H), 2.82 (q, J ) 7 Hz, 1H),
3.67 (s, 3H), 3.72 (q, J ) 6.5 Hz, 1H), 3.90-4.00 (m, 4H), 7.20-
7.32 (m, 5H); 13C NMR (CDCl3) δ 12.4, 20.5, 24.3, 30.2, 34.6,
46.6, 47.5, 51.6, 58.2, 65.4, 111.0, 126.4, 126.6, 128.2, 145.7, 173.6;
HMRS (CI) m/z calcd for C19H30NO4 (MH+) 336.2175, found,
336.2164.
Rf (cyclohexane/AcOEt 8/2) 0.35; IR (neat) 1750, 1720, 1600 cm-1
;
1H NMR (CDCl3) δ 1.51-1.66 (m, 4H), 2.21-2.40 (m, 1H), 2.65-
2.77 (m, 1H), 3.11-3.17 (m, 2H), 3.42-3.51 (m, 2H), 3.67 (s,
3H), 3.80 (t, J ) 7.5 Hz, 1H), 7.10-7.29 (m, 5H); 13C NMR
(CDCl3) δ 20.4, 31.4, 34.1, 41.9, 44.2, 52.4, 60.1, 126.6, 128.3,
128.7, 138.0, 169.3, 204.0. Anal. Calcd for C15H19ClO3: C, 63.71;
H, 6.77. Found: C, 64.14; H, 7.16.
2-{2-[4-(1(S)-Phenylethylamino)butyl][1,3]dioxolan-2-yl)bu-
tyric Acid Methyl Ester (11b). Compound 11b was obtained as
pale yellow oil in 77% yield following the general procedure: Rf
General Procedure for the Preparation of Compounds 10.
A mixture of â-keto ester 8 (10 mmol, 1 equiv), methyl orthofor-
mate (20 mmol, 2 equiv), ethylene glycol (50 mmol, 5 equiv), and
p-TSA (1 mmol, 0.1 equiv) was stirred at room temperature for 48
1
(AcOEt) 0.2; IR (neat) 1730 cm-1; H NMR (CDCl3) δ 0.86 (t, J
) 7 Hz, 3H), 1.33 (d, J ) 6.5 Hz, 3H), 1.29-1.80 (m, 9H), 2.27-
2.52 (m, 2H), 2.61 (dd, J ) 3.75 and 11.5 Hz, 1H), 3.67 (s, 3H),
2076 J. Org. Chem., Vol. 71, No. 5, 2006

Synthesis of N-Tertiary Tetrasubstituted â-Enamino Ester Piperidines
3.74 (q, J ) 6.5 Hz, 1H), 3.88-4.01 (m, 4H), 7.20-7.33 (m, 5H);
13C NMR (CDCl3) δ 12.4, 20.4, 20.9, 24.3, 30.1, 34.7, 47.6, 51.5,
55.3, 58.2, 65.3, 111.1, 126.5, 126.7, 128.3, 145.6, 173.2; HMRS
(CI) m/z calcd for C20H32NO4 (MH+) 350.2331, found 350.2336.
2-{2-[4-(1(S)-Phenylethylamino)butyl][1,3]dioxolan-2-yl)pent-
4-enoic Acid Methyl Ester (11c). Compound 11c was obtained
as pale yellow oil in 76% yield following the general procedure:
4H), 3.13 (d, J ) 7.75 Hz, 2H), 3.66 (s, 3H), 3.64-3.80 (m, 2H),
7.12-7.35 (m, 10H); 13C NMR (CDCl3) δ 20.9, 24.3, 29.3, 34.1,
42.7, 47.2, 52.4, 58.3, 60.2, 126.5, 126.7, 126.9, 128.4, 128.6, 128.8,
138.1, 145.6, 169.5, 204.5; HRMS (CI) m/z calcd for C23H30NO3
(MH+) 368.2226, found 368.2233.
General Procedure for the Preparation of Compounds 2 from
Compounds 6. To a solution of compound 6 (1 mmol, 1 equiv) in
7 N methanolic solution of ammonia (15 mL) was added Na2SO4
(1 g). The reaction mixture was stirred at reflux temperature for 3
h and concentrated in vacuo. The residue was dissolved in dry THF
(10 mL) and dropwise cannulated under argon atmosphere over a
suspension of NaH (1.5 mmol, 1.5 equiv) in dry THF (8 mL). After
15 min of stirring, the reaction mixture was filtered, the solid residue
was thoroughly washed with THF, and the organic layer was
concentrated in vacuo to give crude compound 2. Bulb-to-bulb
distillation (180 °C, 0.1 mmHg) or column chromatography yielded
pure compounds 2 as colorless oils.
1
Rf (AcOEt) 0.2; IR (neat) 1735, 1640 cm-1; H NMR (CDCl3) δ
1.26 (d, J ) 6.5 Hz, 3H), 1.19-1.52 (m, 5H), 1.56-1.89 (m, 2H),
2.26-2.54 (m, 4H), 2.79 (dd, J ) 3.5 and 12 Hz, 1H), 3.62 (s,
3H), 3.71 (q, J ) 6.5 Hz, 1H), 3.85-4.02 (m, 4H), 4.93-5.07 (m,
2H), 5.61-5.82 (m, 1H), 7.15-7.32 (m, 5H); 13C NMR (CDCl3)
δ 20.4, 24.3, 30.1, 31.9, 34.9, 47.6, 51.5, 52.9, 58.3, 65.4, 110.7,
116.5, 126.4, 126.7, 128.3, 135.4, 145.7, 172.5; HMRS (CI) m/z
calcd for C21H32NO4 (MH+), 362.2331, found 362.2337.
3-Phenyl-2-{2-[4-(1(S)-phenylethylamino)butyl][1,3]dioxolan-
2-yl)propionic Acid Methyl Ester (11d). Compound 11d was
obtained as pale yellow oil in 70% yield following the general
2-[1-(1(S)-Phenylethyl)piperidin-2-ylidene]propionic Acid Meth-
yl Ester (2a). Compound 2a was obtained as colorless oil in 89%
from 5 and in 71% yield from 6a following the general procedure
after purification by bulb-to-bulb distillation: [R]25D - 33.5 (c 1.03,
1
procedure: Rf (AcOEt) 0.2; IR (neat) 1730, 1600 cm-1; H NMR
(CDCl3) δ 1.35 (d, J ) 6.75 Hz, 3H), 1.22-1.57 (m, 5H), 1.62-
1.91 (m, 2H), 2.37-2.58 (m, 2H), 2.85-3.07 (m, 3H), 3.52 (s,
3H), 3.75 (q, J ) 6.75 Hz, 1H), 3.90-4.06 (m, 4H), 7.32-7.11
(m, 10H); 13C NMR (CDCl3) δ 20.5, 24.2, 30.1, 33.8, 34.9, 47.5,
51.5, 55.5, 58.3, 65.5, 110.8, 126.3, 126.5, 126.9, 128.4, 128.6,
139.4, 145.5, 172.5; HMRS (CI) m/z calcd for C25H34NO4 (MH+)
412.2488, found 412.2480.
General Procedure for the Preparation of Compounds 6. To
a solution of compound 11 (2 mmol, 1 equiv) in CH2Cl2 (20 mL)
was added dropwise BF3‚Et2O (20 mmol, 10 equiv). The reaction
mixture was stirred at rt for 12 h. An aqueous saturated solution of
NaHCO3 (15 mL) was slowly added, and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4 and concentrated in vacuo. Column chromatography
on silica gel gave pure compounds 6.
1
CHCl3); IR (neat) 1660, 1610 cm-1; H NMR (CDCl3) δ 1.35 (d,
J ) 6. 5 Hz, 3H), 1.42-1.57 (m, 4H), 1.72 (s, 3H), 2.17 (t, J )
7.25 Hz, 2H), 2.35-2.57 (m, 2H), 3.66 (s, 3H), 3.73 (q, J ) 6.5
Hz, 1H), 7.23-7.33 (m, 5H); 13C NMR (CDCl3) δ 11.9, 24.1, 25.3,
29.7, 33.9, 47.1, 50.2, 58.2, 87.7, 126.4, 126.7, 128.2, 145.4, 160.3,
171.1; HRMS (CI) calcd for C17H24NO2 (MH+) 274.1807, found
274.1808.
2-[1-(1(S)-Phenylethyl)piperidin-2-ylidene]butyric Acid Meth-
yl Ester (2b). Compound 2b was obtained from 6b as colorless
oil in 75% yield following the general procedure after purification
by bulb-to-bulb distillation: [R]25D -31.8 (c 1.19, CHCl3); IR (neat)
1
1600, 1655 cm-1; H NMR (CDCl3) δ 0.93 (t, J ) 7.25 Hz, 3H),
1.34 (d, J ) 6.5 Hz, 3H), 1.19-1.56 (m, 4H), 2.08-2.22 (m, 4H),
2.29-2.60 (m, 2H), 3.66 (s, 3H), 3.62-3.78 (m, 1H), 7.20-7.34
(m, 5H); 13C NMR (CDCl3) δ 15.5, 19.8, 24.2, 26.1, 29.9, 33.1,
47.2, 50.2, 58.3, 95.2, 126.4, 126.7, 128.3, 145.6, 160.2, 171.2;
HRMS (CI) calcd for C18H26NO2 (MH+) 288.1964, found 288.1951.
2-Methyl-3-oxo-7-(1(S)-phenylethylamino)heptanoic Acid Meth-
yl Ester (6a). Compound 6a was obtained from 11a as pale yellow
oil in 70% yield following the general procedure: Rf (AcOEt) 0.1;
1
IR (neat) 3320, 1740, 1710 cm-1; H NMR (CDCl3) δ 1.30 (d, J
) 7.25 Hz, 3H), 1.36 (d, J ) 6.5 Hz, 3H), 1.23-1.60 (m, 4H),
2.36-2.63 (m, 4H), 2.80 (br s, 1H), 3.51 (q, J ) 7 Hz, 1H), 3.69
(s, 3H), 3.81 (q, J ) 6.5 Hz, 1H), 7.21-7.34 (m, 5H); 13C NMR
(CDCl3) δ 12.8, 20.9, 23.7, 28.9, 41.0, 47.1, 52.3, 52.5, 58.5, 126.6,
127.2, 128.5, 144.3, 170.9, 205.7; HRMS (CI) calcd for C17H26-
NO3 (MH+), 292.1913, found 292.1907.
2-[1-(1(S)-Phenylethyl)piperidin-2-ylidene]pent-4-enoic Acid
Methyl Ester (2c). Compound 2c was obtained from 6c as colorless
oil in 77% yield following the general procedure after purification
by bulb-to-bulb distillation: [R]23D -34.6 (c 1.16, CHCl3); IR (neat)
1605, 1635, 1655 cm-1; 1H NMR (CDCl3) δ 1.33 (d, J ) 6.5 Hz,
3H), 1.43-1.56 (m, 4H), 2.16 (t, J ) 7.5 Hz, 2H), 2.30-2.61 (m,
2H), 2.92 (dt, J ) 1.7 and 5.7 Hz, 2H), 3.64 (s, 3H), 3.65-3.77
(m, 1H), 4.83-5.14 (m, 2H), 5.72-5.90 (m, 1H), 7.19-7.37 (m,
5H); 13C NMR (CDCl3) δ 24.3, 25.9, 29.9, 30.7, 33.3, 47.3, 50.5,
58.4, 90.7, 113.1, 126.5, 126.9, 128.4, 138.6, 145.7, 161.5, 171.1;
HRMS (CI) calcd for C19H29N2O2 (MNH4+) 317.2229, found
317.2237.
2-Ethyl-3-oxo-7-(1(S)-phenylethylamino)heptanoic Acid Meth-
yl Ester (6b). Compound 6b was obtained from 11b as pale yellow
oil in 77% yield following the general procedure: Rf (AcOEt) 0.1;
IR (neat) 1710, 1740, 3325 cm-1; 1H NMR (CDCl3) δ 0.90 (t, J )
7.5 Hz, 3H), 1.35 (d, J ) 6.75 Hz, 3H), 1.43-1.69 (m, 5H), 1.82
(q, J ) 7.5 Hz, 2H), 2.23-2.67 (m, 4H), 3.34 (t, J ) 7.5 Hz, 1H),
3.70 (s, 3H), 3.74 (q, J ) 6.75 Hz, 1H), 7.23-7.32 (m, 5H); 13C
NMR (CDCl3) δ 11.9, 21.0, 21.6, 24.0, 29.2, 41.6, 47.1, 52.1, 58.3,
60.4, 126.6, 127.0, 128.4, 145.0, 170.2, 205.1; HRMS (CI) m/z calcd
for C18H28NO3 (MH+) 306.2069, found 306.2075.
3-Phenyl-2-[1-(1(S)-phenylethyl)piperidin-2-ylidene]propano-
ic Acid Methyl Ester (2d). Compound 2d was obtained from 6d
as colorless oil in 79% yield following the general procedure after
silica gel column chromatography: Rf (AcOEt) 0.2; [R]20D - 25.1
2-Allyl-3-oxo-7-(1(S)-phenylethylamino)heptanoic Acid Meth-
yl Ester (6c). Compound 6c was obtained from 11c as pale yellow
oil in 73% yield following the general procedure: Rf (AcOEt) 0.1;
1
(c 1.05, CHCl3); IR (neat) 1600, 1650 cm-1; H NMR (CDCl3) δ
1.32 (d, J ) 6.5 Hz, 3H), 1.40-1.55 (m, 4H), 2.15 (t, J ) 7.5 Hz,
2H), 2.30-2.45 (m, 2H), 3.595 (s, 2H), 3.61 (s, 3H), 3.68 (q, J )
6.5 Hz, 1H), 7.10-7.32 (m, 10H); 13C NMR (CDCl3) δ 24.2, 25.5,
29.7, 31.9, 33.4, 47.0, 50.4, 58.2, 91.3, 125.3, 126.4, 126.8, 127.5,
128.0, 128.3, 142.7, 145.6, 162.0, 171.2; HRMS (CI) calcd for
C23H31N2O2 (MNH4+) 367.2386, found 367.2382.
1
IR (neat) 1620, 1695, 1725 cm-1; H NMR (CDCl3) δ 1.33 (d, J
) 6.5 Hz, 3H), 1.41-1.76 (m, 5H), 2.31-2.62 (m, 6H), 3.52 (t, J
) 7.5 Hz, 1H), 3.68 (s, 3H), 3.70 (q, J ) 6.5 Hz, 1H), 4.97-5.14
(m, 2H), 5.61-5.79 (m, 1H), 7.21-7.34 (m, 5H); 13C NMR
(CDCl3) δ 21.0, 24.3, 29.5, 32.2, 42.0, 47.3, 52.3, 58.2, 58.3, 117.5,
126.5, 126.8, 128.4, 134.2, 145.6, 169.6, 204.3; HRMS (CI) m/z
calcd for C19H28NO3 (MH+) 318.2069, found 318.2066.
Supporting Information Available: Experimental procedures
for the isomerization of (E)-5 and the preparations of 7a and 2a
2-Benzyl-3-oxo-7-(1(S)-phenylethylamino)heptanoic Acid Meth-
yl Ester (6d). The general procedure was followed but the reaction
was conducted using 30 equiv of boron trifluoride etherate to give
compound 6d from 11d as pale yellow oil in 74% yield: Rf (AcOEt)
1
from 5. H and 13C NMR spectra of compounds 7a, 11a-d, 6a-
d, and 2a-d. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
0.1; IR (neat) 1710, 1735 cm-1; H NMR (CDCl3) δ 1.32 (d, J )
7 Hz, 3H), 1.35-1.55 (m, 4H), 1.85 (br s, 1H), 2.20-2.54 (m,
JO052490P
J. Org. Chem, Vol. 71, No. 5, 2006 2077