A direct entry to substituted piperidinones from α, β-unsaturated amides by means of aza double Michael reaction

Article abstract of DOI:10.1016/j.tetlet.2003.08.025

An intermolecular aza-double Michael reaction has been developed leading to functionalized piperidin-2-ones from simple starting materials. The method allows to utilize α,β-unsaturated amides as a synthon of piperidine nucleus. The short synthesis of anti

Full text of DOI:10.1016/j.tetlet.2003.08.025

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7429–7432
A direct entry to substituted piperidinones from a,b-unsaturated
amides by means of aza double Michael reaction
Kiyosei Takasu,* Naoko Nishida and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama,
Sendai 980-8578, Japan
Received 26 July 2003; revised 7 August 2003; accepted 8 August 2003
Abstract—An intermolecular aza-double Michael reaction has been developed leading to functionalized piperidin-2-ones from
simple starting materials. The method allows to utilize a,b-unsaturated amides as a synthon of piperidine nucleus. The short
synthesis of anti-depressant paroxetine was demonstrated by using the new methodology.
© 2003 Elsevier Ltd. All rights reserved.
The piperidine ring system is a ubiquitous structural
component of naturally occurring alkaloids, biologi-
cally active synthetic molecules, and organic fine chem-
icals.1 Generally, the biological properties of piperidines
are highly dependent on the type and location of sub-
stituents on the heterocyclic ring. Consequently, numer-
ous strategies have been developed for construction of
functionalized piperidines.2 Despite this, new method-
ologies which rely on the use of readily available start-
ing materials are still required for high throughput
syntheses of substances in this family.
would add unsaturated amides to the family of versatile
building blocks in synthetic organic chemistry.
Previously, we have developed a method to prepare
piperidinones by intramolecular reactions of a,b-unsat-
urated amides possessing enoate moieties.5 Below, we
present the results of our recent studies which have
uncovered an intermolecular aza-annulation process
that constructs 4-, 5- and/or 6-substituted piperidin-2-
ones starting with simple precursors.
Initial investigations concentrated on the reaction of
N-benzyl-trans-cinnamamide (1a) and methyl acrylate
(2a) (Scheme 1). When an equimolar mixture of 1a and
2a in 1,2-dichloroethane (DCE; 0.2 M solution of 1a) is
We envisioned that substituted piperidin-2-ones could
be generated by coupling reactions between a,b-unsatu-
rated amides and a,b-unsaturated esters or ketones
(Fig. 1). Although a,b-unsaturated amides are com-
monly employed as monomers in the preparation of
polymers, they have been used less often as building
blocks in the synthesis of heterocyclic compounds.3 In
this regard, only a few reports exist describing how
a,b-unsaturated amides serve as NꢀC(ꢁO)ꢀCꢀC syn-
thons of piperidinones.4 The potential difficulty using
a,b-unsaturated amides in this manner results from its
diverse reactivity. Specifically, unsaturated amides have
several reactive sites, including electrophilic carbonyls
and b-carbons and nucleophilic nitrogen, oxygen and
a-carbon atoms. Thus, the advent of methods to con-
trol chemoselective reactions at each of these centers
Figure 1. Our strategy for the formation of piperidin-2-ones
from unsaturated amides.
Keywords: heterocycles; piperidines; 1,4-additions; domino reactions;
unsaturated amides; anti-depressant.
* Corresponding authors. Tel.: +81-22-217-6887; fax: +81-22-217-
6877; e-mail: mihara@mail.pharm.tohoku.ac.jp
Scheme 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.025

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K. Takasu et al. / Tetrahedron Letters 44 (2003) 7429–7432
Table 1. Aza double Michael reaction of 1a with 2aa
Run
Solventb
Conc. (M)
Et3N (equiv.)
% Yield of 3ac
Ratio of trans/cisd
1
2
3
4
5
6
7
8
DCE
DCE
DCE
DCE
DCM
MeCN
Toluene
Neat
0.2
0.2
0.2
1.0
1.0
1.0
1.0
—
1.5
0.7
0.2
0.7
0.7
0.7
0.7
0.7
0
–
37 (74)
0
41:59
–
80 (93)
53 (76)
49 (65)
29 (57)
60 (75)
53:47
49:51
49:51
41:59
40:60
a Reactions were performed using 1.2 equiv. TBSOTf (unpurified), 1.0 equiv. 1a, and 1.0 equiv. 2a at ambient temperature for 24 h.
b Abbreviations; DCE=1,2-dichloroethane, DCM=dichloromethane.
c Conversion yields are shown in parentheses.
d trans/cis Ratios were determined based on isolated yields.
treated at room temperature with 1.2 equiv. of TBSOTf
in the presence of 1.5 equiv. of Et3N,5a the formation of
piperidinone 3a is, unfortunately, not observed.
Acylate-oligomers and recovered 1a are the only sub-
stance as observed in the crude reaction mixture (Table
1, run 1). In contrast, when 0.7 equiv. of Et3N are used,
reaction of 1a and 2a (under otherwise identical condi-
tions) occurs to produce 3a in 37% yield along with
50% of recovered 1a (run 2). However, reaction does
not take place when 0.2 equiv. of Et3N are employed
(run 3). Although we yet do not have detailed insight
into the source of the phenomenon, it appears that the
aza-annulation reaction is promoted by using 1.2 equiv.
of TBSOTf in the presence of Et3N within the 0.5–1.0
equiv. range.6
Table 2. Formation of triple Michael adduct and effect of
tBuOHa
Run
tBuOH
% Yieldb
3a (trans/cis)c
4
1ad
1e
2
0
0
0
0.25
1.0
80 (53: 47)
68 (53: 47)
38 (nd)
74 (49: 51)
35 (51: 49)
Trace
14
17
0
25
56
5
48
0
3f
4
5
0
a Reactions were performed using 1.2 equiv. TBSOTf (freshly dis-
tilled), 0.7 equiv. Et3N, 1.0 equiv. 1a, and 1.0 equiv. 2a at ambient
temperature in DCE for 24 h.
b Isolated yields.
c trans/cis Ratios were determined based on isolated yields.
d Recovered yields.
Additional studies showed that 0.7 equiv. of TMSI can
be used as an alternative to TBSOTf, but the yield for
production of 3a is lower. Furthermore, we have found
that substrate concentration has a significant effect
upon the efficiency of this process. For example, reac-
tion of a 1.0 M solution of 1a and 2a in DCE affords
3a in 80% yield (93% conversion yield) as a ca. 1:1
mixture of diastereomers (run 4). The reaction occurs in
several other solvents, such as dichloromethane and
acetonitrile, but the yields are not satisfactory (runs
5–7). It is noteworthy that the annulation reaction also
occurs under neat conditions to give 3a in 60% yield
(run 8). As can be seen by viewing the data in Table 1,
the diastereoselectivities of all reactions are low. How-
ever, we have found that cis-3a can be smoothly con-
verted into trans-3a by reaction with NaOMe in
refluxing MeOH–toluene.7
e Unpurified TBSOTf was used.
f 5 equiv. of 2a was used.
undergo rapid protodesilylation rather than secondary
reaction with the acrylate ester. Actually, the addition
of tBuOH as a proton source suppresses production of
the triple Michael-adduct 4 even in reactions promoted
by pure TBSOTf. However, when large amounts of
tBuOH are employed, formation of 3a is also inhibited
(run 5). Finally, 0.25 equiv. of tBuOH was found to be
optimal, affording only 3a in 74% yield (99% conver-
sion yield) (run 4).
These investigations led to the unexpected observation
that the yield for production of piperidinone 3a is
lowered when freshly distilled TBSOTf is employed
(Table 2, run 2 versus run 1).8 In this case, 3,4,5-trisub-
stituted piperidin-2-one 4 is obtained in 5% yield as a
mixture of diastereomers. Use of excess 2a in the reac-
tion promoted by the purified Lewis acid results in 48%
yielding formation of 4 (run 3). We presume that 4 is
generated by additional Michael reaction of double
Michael intermediate 5. In contrast, when triflic acid
(the most likely impurity in non-purified TBSOTf) is
present, the silyl-enolate intermediate 5 would likely
The scope of the aza double Michael reaction was
probed by using various combinations of substrates.
The results of this effort, summarized in Table 3, show
that a,b-unsaturated amides possessing aromatic or
aliphatic substituent in the b-position participate in
efficient annulations reactions with methyl acrylate (2a)
(runs 1, 2, and 4–7). On the other hand, acrylamide (1d)
does not undergo the desired reaction. Rather, the
homo-dimeric piperidin-2-one 6 is generated in quanti-

K. Takasu et al. / Tetrahedron Letters 44 (2003) 7429–7432
Table 3. Formation of substituted piperidin-2-onesa
7431
Run
1 (R1, R2)
2 (X)
Product
% yieldc
Ratio of trans/cisd
1a
2a
3b
4b
5b
6b
7b
8a
9a
10a
1b (4-MeOPh, H)
1c (4-FPh, H)
1d (H, H)
1e (Me, H)
1f (iPr, H)
1g ((CH2)2OTBS, H)
1h (Me, Me)
1a (Ph, H)
1a
2a (CO2Me)
2a
2a
2a
2a
2a
2a
2b (CO2cHex)
2c (COMe)
2d
3b
3c
3d
3e
3f
3g
3h
3i
52 (61)
59 (92)
0
66 (86)
76 (84)
72 (93)
88 (nd)
80 (88)
32 (63)
51 (nd)
46:54
51:49
–
50:50
49:51
71:29
–
48:52
>99:<1
>99:<1
3j
3k
1a
a Reactions were performed using 1.2 equiv. TBSOTf (freshly distilled), 0.7 equiv. Et3N, 0.25 equiv. tBuOH, 1.0 equiv. 1, and 1.0 equiv. 2 in DCE
at ambient temperature for 24 h.
b Reactions were performed using 1.2 equiv. TBSOTf (unpurified), 0.7 equiv. Et3N, 1.0 equiv. 1, and 1.0 equiv. 2 in DCE at ambient temperature
for 24 h.
c Conversion yields are shown in parentheses.
d trans/cis Ratios were determined based on isolated yields.
tative yield (run 3). The mono-Michael adduct 7 is
formed, albeit in low yield, by reaction of b-disubsti-
tuted acrylamide 1h. This observation suggests that the
aza-annulation reaction takes place through a stepwise
double Michael pathway.
The cyclohexyl acrylate (2b) reacts with 1a to afford the
corresponding piperidinone 3i in good yield (run 8).
Conjugated enones, such as 2c and 2d, also participate
in the aza double Michael reaction to diastereoselec-
tively generate the corresponding piperidies in low
yields (runs 9 and 10). Interestingly, reaction of 1a with
cyclohexenone (2d) produces 2-quinolone 3k as a single
diastereomer in modest yield (run 10). The relative
stereochemistry of 3k was assigned by using 1D and 2D
NMR methods.
To demonstrate its synthetic potential, the aza double
Michael reaction was applied to the formal synthesis of
Scheme 2. Reagents and conditions: (i) 2a (1.0 equiv.),
paroxetine (8).7,9,10 Enantiomerically pure (−)-parox-
TBSOTf (1.2 equiv.), Et3N (0.7 equiv.), tBuOH (0.25 equiv.),
etine hydrochloride [Paxil®, Seroxat®] is a selective
DCE, rt; (ii) NaOMe, MeOH–toluene, reflux (58% for two
serotonin reuptake inhibitor (SSRI) used clinically for
steps); (iii) LiAlH4 (2 equiv.), THF, reflux (quant.).
the treatment of depression, panic disorder, and post-
traumatic stress disorder (PTSD). The sequence
employed to prepare 8, outlined in Scheme 2, begins
demonstrate that the intermolecular aza double
Michael reaction can be used effectively to develop new
with reaction of the unsaturated amide 1c with acrylate
concise routes for the synthesis of functionally complex
2a in the presence of TBSOTf, Et3N (0.7 equiv.) and
piperidines like paroxetine.
tBuOH (0.25 equiv.) in DCE. This provides a mixture
of trans- and cis-3,4-disubstituted piperidinones 3c
In conclusion, the studies reported above have led to
the development of a novel method for facile formation
of substituted piperidinones which is based on the
intermolecular aza double Michael reaction. The
method serves as the first general example in which
a,b-unsaturated amides are used as a new class of
piperidine ring synthons. In addition, we have applied
the new process to a short synthesis of anti-depressant
which without purification is treated with NaOMe to
afford trans-3c in 58% overall yield (for two steps). The
first annulation step can be performed under solvent-
free conditions, in which case a 47% yield of trans-3c is
obtained after subsequent epimerization.11 Reduction
of trans-3c with LiAlH4 quantitatively furnishes the
known pipereidinol 9, whose transformation into
paroxetine (8) has been reported by Yu.10d The results

7432
K. Takasu et al. / Tetrahedron Letters 44 (2003) 7429–7432
paroxetine. Further studies are underway aimed at
uncovering strategies to control the stereochemistry of
the process and at determining the detailed mechanism
of the reaction.
ture, and then, if necessary, was added tBuOH (0.25
equiv.). After being stirred for 12–24 h at the same
temperature, the resulting mixture was quenched by addi-
tion of satd NaHCO3 and extracted with AcOEt. The
organic layer was dried over MgSO4 and evaporated. The
residue was purified by flash column chromatography on
silica gel to afford piperidinone 3. trans-3a; Colorless
needles, mp 117–119°C; IR (KBr): w 1734, 1645, 1497,
Acknowledgements
1
1439, 1257 cm−1; H NMR (400 MHz, CDCl3): l 7.34–
7.16 (m, 10H), 4.74 (d, 1H, J=14.6 Hz), 4.55 (d, 1H,
J=14.6 Hz), 3.52 (dd, 1H, J=12.3, 9.1 Hz), 3.43 (s, 3H),
3.45–3.34 (m, 2H), 3.02–2.96 (m, 1H), 2.85 (dd, 1H,
J=5.6, 17.8 Hz), 2.68 (dd, 1H, J=10.2, 17.8 Hz); 13C
NMR (100 MHz, CDCl3): l 168.4, 140.9, 136.5, 128.7,
128.6, 128.2, 127.5, 127.2, 126.9, 52.0, 50.0, 47.7, 46.7,
41.5, 38.0; LRMS (m/z); 323(M+). Anal. calcd for
C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 74.25;
H, 6.52; N, 4.34. cis-3a; colorless oil; IR (neat): w 2932,
This work was financially supported by the Fujisawa
Foundation, a Grant-in-Aid for Encouragement of
Young Scientists (No. 14771239) and a Grant-in-Aid
for Scientific Research on Priority Areas (A) ‘Exploita-
tion of Multi Element Cyclic Molecules’ from the Min-
istry of Education, Culture, Sports, Science and
Technology, Japan.
1730, 1641, 1493, 1450, 1252, 1198, 1169, 702 cm−1 1H
;
References
NMR (400 MHz, CDCl3): l 7.35–7.22 (m, 8H), 7.03–7.00
(m, 2H), 4.67 (s, 2H), 3.71 (dd, 1H, J=12.5, 5.1 Hz), 3.58
(s, 3H), 3.36–3.27 (m, 2H), 3.16–3.11 (m, 1H) 2.93 (d, 2H,
J=5.4 Hz); 13C NMR (100 MHz, CDCl3): l 170.2, 168.6,
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reproducible results. We have reported purity of TMSI
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11. In this sequence, cis-3c was obtained in 14% yield along
with trans-3c. cis-3c can be converted into trans-3c by
treatment with NaOMe.
6. General procedures for aza-double Michael reactions. To a
mixture of 1 (1.0 equiv.), 2 (1.0 equiv.), and NEt3 (0.7
equiv.) in 1,2-dichloroethane (1 M solution for 1) was
slowly added TBSOTf (1.2 equiv.) at ambient tempera-