Convenient synthesis of substituted piperidinones from α,β- unsaturated amides: Formal synthesis of deplancheine, tacamonine, and paroxetine

Article abstract of DOI:10.1021/jo050261x

An intermolecular aza-double Michael reaction leading to functionalized piperidin-2-ones from simple starting materials has been developed. The method allows α,β-unsaturated amides to be used as a synthon of the piperidine nucleus. In addition, the utilit

Full text of DOI:10.1021/jo050261x

Convenient Synthesis of Substituted Piperidinones from
r,â-Unsaturated Amides: Formal Synthesis of Deplancheine,
Tacamonine, and Paroxetine
Kiyosei Takasu,* Naoko Nishida, Akiko Tomimura, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University,
Aobayama, Sendai 980-8578, Japan
mihara@mail.pharm.tohoku.ac.jp
Received February 9, 2005
An intermolecular aza-double Michael reaction leading to functionalized piperidin-2-ones from
simple starting materials has been developed. The method allows R,â-unsaturated amides to be
used as a synthon of the piperidine nucleus. In addition, the utility of this methodology is
demonstrated by its application to a formal synthesis of the indolo[2,3-a]quinolizidine alkaloids,
(()-deplancheine, (()-tacamonine, and the antidepressant paroxetine.
SCHEME 1
Introduction
A piperidine ring is a ubiquitous molecular skeleton,
which appears in naturally occurring substances as well
as synthetic biologically active molecules.1 It is widely
accepted that the biological properties of piperidines are
highly dependent on the type and location of substituents
on the heterocyclic ring. Accordingly, great attention has
been paid to the construction of functionalized piperidine
compounds.2 It is well-documented that piperidin-2-ones
are common synthetic precursors for biologically impor-
tant polycyclic alkaloids, such as indolo[2,3-a]quinoliz-
idines and benzo[a]quinolizidines.
We envisioned that substituted piperidin-2-ones could
be generated by coupling reactions between R,â-unsatur-
ated amides and R,â-unsaturated esters or ketones
(Scheme 1). R,â-Unsaturated carbonyl compounds com-
prise one of the most important families of organic
substances. Conjugate addition and Diels-Alder reac-
tions of members of this family, including enones, enals,
and enoates, have been utilized often in the total syn-
thesis of naturally occurring substances.3 In addition,
much attention has been given to these substances in the
context of formation of fundamentally important materi-
als in polymer chemistry. Although R,â-unsaturated
amides are commonly employed as monomers in the
preparation of polymers, less attention has been given
to their use as building blocks in the synthesis of
heterocyclic compounds.4 In this regard, only a few
reports exist describing how R,â-unsaturated amides
serve as N-C(dO)-C-C synthons of piperidinones.5,6
(1) (a) Elbein, D. A.; Molyneux, R. In Alkaloids; Chemical and
Biological Perspectives; Palletier, S. W., Ed.; John Wiley & Son: New
York, 1987; Vol. 57. (b) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435-
446.
(2) (a) Laschat, S.; Dickner, T. Synthesis 2000, 1781-1813. (b)
Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R.
Tetrahedron 2003, 59, 2953-2989 (c) Buffat, M. G. P. Tetrahedron
2004, 69, 1701-1729 and references therein.
(3) (a) Carruthers, W. In Cycloaddition Reactions in Organic
Synthesis; Pergamon Press: Oxford, UK, 1990. (b) Kobayashi, S.;
Jørgensen, K. A., Eds. Cycloaddition Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, Germany, 2002. (c) Boger, D. L.; Weinreb, S.
M. Hetero Diels-Alder Methodology in Organic Synthesis; Academic
Press: San Diego, CA, 1987. (d) Jayakumar, S.; Ishar, M. P. S.;
Mahajan, M. P. Tetrahedron 2002, 58, 379-471.
10.1021/jo050261x CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/12/2005
J. Org. Chem. 2005, 70, 3957-3962
3957

Takasu et al.
CHART 1
SCHEME 2
The potential difficulty of using R,â-unsaturated amides
in this manner results from their diverse reactivity.
Specifically, unsaturated amides have several reactive
sites, including electrophilic carbonyls and â-carbons and
nucleophilc nitrogen, oxygen, and R-carbon atoms. Thus,
the advent of methods to control chemoselective reactions
at each of these centers would add unsaturated amides
to the family of versatile building blocks in synthetic
organic chemistry. In this paper, we describe a new and
facile strategy to form multi-substituted piperidin-2-ones
from R,â-unsaturated amides by means of the inter-
molecular aza-double Michael reaction, and its synthetic
application toward (()-deplancheine (1), (()-tacamonine
(2), and paroxetine (3).7
SCHEME 3
TABLE 1. Homocycloaddition of 7 by Means of
Intermolecular Aza-Double Michael Reaction
yield (%)
entry
7 (R1)
conditionsa solvent
8
9
1
2
3
4
5
6
7
8
7a (Bn)
A
B
B
B
B
B
B
A
DCM
DCM
DCM
DCM
DCE
DCE
DCE
DCE
86
80
78
56
90
94
0
0
7a
0
0
Results and Discussion
7b (cyclohexyl)
7c (2-indolylethyl)
7c
7d (2-phenylethyl)
7e (Ph)
7e
0
Intermolecular Aza-Double Michael Reaction (Ho-
mocycloaddition Reaction). Previously, we have de-
scribed a new process, termed the intramolecular aza-
double Michael reaction, that transforms R,â-unsaturated
amide tethered R,â-unsaturated esters to 5-alkoxycarbo-
nylpiperidin-2-ones.8 In the course of our investigation,
we observed that reaction of the substituted acrylamide
4 with trimethylsilyl iodide (TMSI) in the presence of
hexamethyldisilazane (HMDS) in 1,2-dichloroethane
(DCE) did not yield the intramolecular adduct 5. Rather,
the intermolecular dimeric adduct 6 was produced in high
yield under these conditions (Scheme 2). When other
Lewis acids and/or amine bases were used, only compli-
0
0
0
10
18
a Conditions A: Reactions were carried out with 1.2 equiv of
TMSI and 1.5 equiv of HMDS in 0.2 M solution at ambient
temperature for 2 h. Conditions B: Reactions were carried out
with 1.2 equiv of TBSOTf and 1.5 equiv of NEt3 in 0.2 M solution
at ambient temperature for 2 h.
cated mixtures of products including acrylamide oligo-
mers were generated.
First, we considered that the acrylamide cyclodimer-
ization reaction would serve as a new method for the
formation of 5-carbamoylpiperidin-2-ones (Scheme 3).
Studies with several N-monosubstituted acrylamides
7a-e have demonstrated the validity of this proposal
(Table 1). The procedure used for these reactions is
exemplified by reaction of N-benzylacrylamide 7a. To a
0.2 M solution of 7a and HMDS (1.5 equiv) in dichlo-
romethane (DCM) is added TMSI (1.2 equiv) and the
resulting mixture was stirred at ambient temperature
for 2 h. Workup followed by chromatography on silica gel
furnished the piperidinone 8a in 86% yield (entry 1). The
reaction of 7a promoted by using tert-butyldimethylsilyl
triflate (TBSOTf) and triethylamine also afforded 8a in
a high yield (entry 2). Because of its better stability and
ease of handling, TBSOTf-NEt3, rather than TMSI-
HMDS, was used for the reactions of acrylamides 7b-d
to give 5-substituted piperidinones 8b-d in high yields
(entries 3-6). When DCE was used as a solvent, the
reaction yield was significantly enhanced (entry 4 versus
5). On the contrary, reaction of N-phenylacrylamide (7e)
afforded no desired piperidinone 8e under the TBSOTf-
(4) Cycloaddition reactions of R,â-unsaturated imines, which are
monoreduced derivertives of R,â-unsaturated amides, are well inves-
tigated: (a) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodol-
ogy in Organic Synthesis; Academic Press: San Diego, CA, 1987; pp
240-255. (b) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetra-
hedron 2002, 58, 379-471. (c) Wei, L.-L.; Hsung, R. P.; Sklenicka, H.
M.; Gerasyuto, A. I. Angew. Chem., Int. Ed. 2001, 40, 1516-1518.
(5) To our best knowledge, only limited examples were reported for
the synthesis of piperidines by means of cyclodimerization of acryla-
mide equivalents: (a) Lorente, A.; Navio, J. L. G.; Perez, J. C. L.; Soto,
J. L. Synthesis 1985, 89-92. (b) Elliott, M. C.; Galea, N. M.; Long, M.
S.; Willock, D. J. Tetrahedron Lett. 2001, 42, 4937-4939. (c) Dietz,
G.; Fielder, W.; Faust, G. Chem. Ber. 1967, 100, 3127-3134. (d)
O’Callagham, C. N.; McMurry, T. B. H.; Cardin, C. J.; Wilcock, D. J.
J. Chem. Res. (S) 1994, 401-427.
(6) Our recent examples for the use of R,â-unsaturated amides as a
piperidine synthon: (a) Takasu, K.; Nishida, N.; Ihara, M. Synlett 2004,
1844-1846. (b) Takasu, K.; Nishida, N.; Ihara, M. Synthesis 2004,
2222-2225.
(7) A part of this work was published as a preliminary communica-
tion: Takasu, K.; Nishida, N.; Ihara, M. Tetrahedron Lett. 2003, 44,
7429-7432.
(8) (a) Ihara, M.; Ishida, Y.; Tokunaga, Y.; Kabuto, C.; Fukumoto,
K. J. Chem. Soc., Chem. Commun. 1995, 2085-2086. (b) Suzuki, M.;
Ihara, M. Heterocycles 2000, 52, 1083-1084. (c) Mekouar, K.; Genisson,
Y.; Leue, S.; Greene, A. E. J. Org. Chem. 2000, 65, 5212-5215.
3958 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Substituted Piperidinones from Amides
SCHEME 4
SCHEME 5. Formal Synthesis of
(()-Deplancheinea
NEt3 conditions (entry 7). It is noteworthy that the
reaction of 7e with TMSI-HMDS gave the mono-Michael
adduct 9e along with cycloadduct 8e (entry 8). This
observation suggests that the piperidinone 8e is formed
through a stepwise double Michael pathway via the
intermediacy of 9e.
The homocycloaddition is applicable to both R- or
â-substituted R,â-unsaturated amides (Scheme 4). Al-
though the processes require further optimization, reac-
tions of methacrylamide 7f and crotonamide 7g proceeded
to furnish multi-substituted piperidinones 8f and 8g in
26% and 51% yields, respectively. Interestingly, both
adducts were obtained as single diastereomers. The
structures and stereochemistries of 8f and 8g were firmly
established by using 1D and 2D NMR as well as NOE
methods.
Formal Synthesis of (()-Deplancheine and (()-
Tacamonine. The products of these reactions, e.g., 8c
and 8d, are expected to be potentially useful intermedi-
ates in the synthesis of piperidine alkaloids. Owing to
this, our attention was next directed at the formal
synthesis of indole alkaloids (()-deplancheine (1)9,10 and
(()-tacamonine (2)11,12 starting with 8c. (+)-Deplanchei-
ne, having an unusual Corynantheine-type structure, was
isolated from the New Caledonian plant Alstonia de-
planchei.9 Tacamonine, one of the takamane-type alka-
loids, was isolated from Tabersonaemontana eglandu-
losa.11 Natural tacamonine displays vasodilator and
hypertensive activity. Recently, it has been found by us
that the synthetic (()-tacamonine shows a selective
inhibitory effect against muscarine M2 receptor.12d Sev-
eral groups have reported racemic and asymmetric total
syntheses of the targets.10,12
a Reagents and conditions: (a) Boc2O, DMAP, NEt3 (96%); (b)
NaOMe (86%); (c) (i) POCl3, (ii) NaBH4 (12a; 55%, 12b; 26%); (d)
TFA, reflux (43%); (e) for 12a, MeONHMe‚HCl, AlMe3 (92%); (f)
MeMgBr (50%); (g) see ref 10d.
The route used for the formal synthesis of deplancheine
(1) is shown in Scheme 5. The tri-Boc derivative 10 was
formed from 8c in 96% yield and then treated with
sodium methoxide to give methyl ester 11 in 86% yield
along with Boc-tryptamine.13 Bischler-Napieralski reac-
tion of 11 with POCl3 in acetonitrile, followed by NaBH4
reduction, afforded a diastereomeric mixture of 12a and
12b in respective yields of 55% and 26%. The stereo-
chemistries of 12a and 12b were assigned by comparison
of their spectral data with those reported previously.14
In addition, 12b could be converted to the desired
diastereomer 12a by stirring at reflux in TFA.15 The Boc
group at the nitrogen atom of indole in 11 was lost under
the conditions used for Bischler-Napieralski cyclization.
Treatment of 12a with methoxymethylamine hydrochlo-
ride in the presence of AlMe3 furnished the Weinreb
amide 13 in 92% yield. Then, 13 was subjected to
Grignard addition to give the known ketone 14 in 50%
yield, which had been converted into (()-deplancheine
(1) by Pakrashi and co-workers.10d Spectral data for the
synthetic compound 14 were identical with those reported
in the literature.10d
Formal synthesis of tacamonine (2) was achieved from
11 as shown in Scheme 6. Selective reduction of ester 11
by treatment with LiBH4, followed by acidic treatment,
afforded the known alcohol 15 in good yield. Conversion
of alcohol 15 into 2 has been previously reported.12c
Intermolecular Aza-Double Michael Reaction
(Heterocycloaddition Reaction). We have demon-
strated the direct entry to a functionalized piperidinone
by way of the aza-double Michael reaction between the
same two R,â-unsaturated amides (homocoupling reac-
tion) as above. However, the reaction is still less atom-
(9) Besselie´vre, R.; Cosson, J.-P.; Das, B. C.; Husson, H.-P. Tetra-
hedron Lett. 1980, 21, 63-66.
(10) (a) Ashcroft, W. R.; Joule, J. A. Tetrahedron Lett. 1980, 21,
2341-2344. (b) Calabi, L.; Danieli, B.; Lesma, G.; Palmisano, G.
Tetrahedron Lett. 1982, 23, 2139-2142. (c) Rosenmund, P.; Casutt,
M. Tetrahedron Lett. 1983, 24, 1771-1774. (d) Mandal, S. B.; Pakrashi,
S. C. Heterocycles 1987, 26, 1557-1562. (e) Itoh, T.; Matsuya, Y.;
Enomoto, Y.; Ohsawa, A. Heterocycles 2001, 55, 1165-1171. (f) Meyers,
A. I.; Sohda, T.; Loewe, M. F. J. Org. Chem. 1986, 51, 3108-3112.
(11) Van Beek, T. A.; Verpoorte, R.; Lankhorst, P. P.; Svendsen, A.
B. Tetrahedron 1984, 40, 737-748.
(12) (a) Ihara, M.; Setsu, F.; Shohda, M.; Taniguchi, N.; Fukumoto,
K. J. Org. Chem. 1994, 59, 5317-5323. (b) Lounasmaa, M.; Karinen,
K.; Din Belle, D.; Tolvanen, A. Tetrahedron 1998, 54, 157-164. (c)
Danieli, B.; Lesma, G.; Macecchini, S.; Passarella, D.; Silvani, A.
Tetrahedron: Asymmetry 1999, 10, 4057-4064. (d) Suziki, M.; Ihara,
M. Heterocycles 2000, 52, 1083-1085. (e) Ho, T.-L.; Gorbets, E.
Tetrahedron 2002, 58, 4969-4973. (f) Chen, C.-Y.; Chang, M.-Y.; Hsu,
R.-T.; Chen, S.-T.; Chang, N.-C. Tetrahedron Lett. 2003, 44, 8627-
8630.
(13) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48,
2424-2426.
(14) Lounasmaa, M.; Ha¨meila¨, M. Tetrahedron 1978, 34, 437-442.
(15) Lounasmaa, M.; Berner, M.; Brunner, M.; Suomalainen, H.;
Tolvanen, A. Tetrahedron 1998, 54, 10205-10216.
J. Org. Chem, Vol. 70, No. 10, 2005 3959

Takasu et al.
TABLE 2. Aza-Double Michael Reaction of 7h (R1 ) Bn,
R2 ) Ph, R3 ) H) with Methyl Acrylatea
SCHEME 6. Formal Synthesis of (()-Tacamoninea
concn
(M)
NEt3
(equiv)
% yield
ratio of
entry
solvent
of 17hb
trans/cisc
1
2
3
4
5
6
7
8
DCE
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
DCE
37 (74)
0
41:59
DCE
DCE
DCM
MeCN
toluene
neat
80 (93)
53 (76)
49 (65)
29 (57)
60 (75)
53:47
49:51
49:51
41:59
40:60
a Reagents and conditions: (a) LiBH4; H+; (b) see ref 12c.
SCHEME 7
a Reactions were performed with 1.2 equiv of TBSOTf (unpu-
rified), 1.0 equiv of 7h, and 1.0 equiv of acrylate at ambient
temperature for 24 h. b Conversion yields are shown in parenthe-
ses. c Trans/cis ratios were determined based on isolated yields.
TABLE 3. Formation of Triple Michael Adduct and
Effect of tBuOHa
SCHEME 8
% yieldb
entry
tBuOH
17h (trans/cis)c
18
7hd
1e
2
0
80 (53:47)
68 (53:47)
38 (nd)
74 (49:51)
35 (51:49)
trace
14
17
0
25
56
0
5
3f
4
0
0.25
1.0
48
0
0
5
a Reactions were performed with 1.2 equiv of TBSOTf (freshly
distilled), 0.7 equiv of NEt3, 1.0 equiv of 7h, and 1.0 equiv of
acrylate at ambient temperature in DCE for 24 h. b Isolated yields.
c Trans/cis ratios were determined based on isolated yields.
d Recovered yields. e Unpurified TBSOTf was used f 5 equiv of
acrylate was used.
economic because the product has the same substituents
on the nitrogen atom of both amide functions. Next, we
examined the heterocycloaddition reaction between an
R,â-unsaturated amide and another R,â-unsaturated
carbonyl compound as the coupling partner. Despite our
considerable efforts using acrylamide 7a as a substrate,
no heterocoupling adduct but the formation of homodimer
8a was observed with use of a variety of activated olefins,
such as R,â-unsaturated ketones, aldehydes, and esters,
under the above conditions. When 7a was treated with
N,N-dimethylacrylamide, a small amount of heterodimer
16 (∼30% yield) was produced along with homodimer 8a
(Scheme 7). The observation indicates that the acryl-
amide itself is more reactive as a Michael acceptor rather
than the other activated olefins in our reaction system.
Consequently, control of the reactivity at the â-position
of unsaturated amide should be crucial for the hetero-
cycloaddition reaction. Thus, we considered that instal-
lation of a bulky â-subsitutent would suppress the
undesired homocycloaddition reaction.
When an equimolar mixture of N-benzyl-trans-cin-
namamide (7h) and methyl acrylate in DCE (0.2 M
solution of 7h) was treated at ambient temperature with
1.2 equiv of TBSOTf in the presence of 1.5 equiv of NEt3
(the same conditions as the above homocycloaddition
reaction), neither homo- nor heterocoupling adducts were
obtained (Scheme 8 and Table 2, entry 1). Acrylate-
oligomers and recovered 7h were the only substances
observed in the crude reaction mixture. In contrast, when
0.7 equiv of NEt3 was used, reaction of 7h and methyl
acrylate produced 17h in 37% yield along with 50% of
recovered 7h (entry 2). However, no reaction took place
when 0.2 equiv of NEt3 was employed (entry 3). Although
we do not have detailed insight into the source of the
phenomenon, it appears that the heterocycloaddition is
promoted by using 1.2 equiv of TBSOTf in the presence
of NEt3 within the 0.5-1.0 equiv range.
Additional studies showed that 0.7 equiv of TMSI could
be used as an alternative to TBSOTf, but the yield for
production of 17h was lower. Furthermore, we have
found that substrate concentration has a significant effect
upon the efficiency of this process. For example, reaction
of a 1.0 M solution of 7h in DCE afforded 17h in 80%
yield (93% conversion yield) as a ca. 1:1 mixture of
diastereomers (entry 4). The reaction occurred in several
other solvents, such as DCM and acetonitrile, but the
yields were not satisfactory (entries 5-7). It is notewor-
thy that the cycloaddition reaction also occurred under
neat conditions to give 17h in 60% yield (entry 8). As
can be seen by viewing the data in Table 2, the diaste-
reoselectivities of all reactions were low. However, we
have found that cis-17h could be smoothly converted into
trans-17h by reaction with NaOMe in refluxing MeOH-
toluene.16
These investigations led to the unexpected observation
that the yield for production of piperidinone 17h was
lowered when freshly distilled TBSOTf was employed
(Table 3, entry 2 versus 1).17 In this case, 3,4,5-trisub-
stituted piperidin-2-one 18 was obtained in 5% yield as
a mixture of diastereomers. Use of excess acrylate in the
reaction promoted by the purified Lewis acid resulted in
48% yield of 18 (entry 3). We presume that compound
(16) Sugi, K.; Itaya, N.; Katsura, T.; Igi, M.; Yamazaki, S.; Ishibashi,
T.; Yamaoka, T.; Kawada, Y.; Tagami, Y.; Otsuki, M.; Ohshima, T.
Chem. Pharm. Bull. 2000, 48, 529-536.
(17) Reactions with unpurified R3SiX sometimes gave different
results (for 17a; 60-80% yield), whereas use of freshly distilled
TBSOTf with tBuOH (0.25 equiv) afforded highly reproducible results.
We have reported that the purity of TMSI affects the chemical yield
of intramolecular Michael-aldol reactions. Takasu, K.; Ueno, M.; Ihara,
M. J. Org. Chem. 2001, 66, 4667-4672.
3960 J. Org. Chem., Vol. 70, No. 10, 2005

Synthesis of Substituted Piperidinones from Amides
TABLE 4. Formation of Substituted Piperidin-2-onesa
entry
amide (R1, R2, R3)
activated olefin
product
% yieldc
trans/cisd
1a
7i (Bn, 4-MeOPh, H)
7j (Bn, 4-FPh, H)
7a (Bn, H, H)
7g (Bn, Me, H)
7k (iPr, H, Bn)
7l (Bn, (CH2)2OTBS, H)
7m (Bn, Me, Me)
7n (Bn, -(CH2)5-)
7o (see Chart 2)
7p (see Chart 2)
7h (Bn, Ph, H)
7h
methyl acrylate
methyl acrylate
methyl acrylate
methyl acrylate
methyl acrylate
methyl acrylate
methyl acrylate
methyl acrylate
methyl acrylate
methyl acrylate
cyclohexyl acrylate
methyl vinyl ketone
2-cyclohexenone
17i
52 (61)
59 (92)
0
46:54
51:49
2a
17j
3b
17a
17g
17k
17l
17m
17n
17o
17p
17q
17r
17s
4b
66 (86)
76 (84)
72 (93)
88
50:50
49:51
71:29
5b
6b
7b
8b
85
9a
48 (87)
52 (79)
80 (88)
32 (63)
51
48:52
52:48
10
11a
12a
13a
48:52
>99:<1
>99:<1
7h
a Reactions were performed with 1.2 equiv of TBSOTf (freshly distilled), 0.7 equiv of NEt3, 0.25 equiv of tBuOH, 1.0 equiv of 7, and 1.0
equiv of acrylate (or enone) in DCE at ambient temperature for 24 h. b Reactions were performed with 1.2 equiv of TBSOTf (unpurified),
0.7 equiv of NEt3, 1.0 equiv of 7, and 1.0 equiv of acrylate (or enone) 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.
CHART 2
FIGURE 1. Formation of triple Michael adduct
18 is generated by additional Michael reaction of double
Michael intermediate 19 (Figure 1). In contrast, when
triflic acid (the most likely impurity in nonpurified
TBSOTf) was present, the silyl enol ether intermediate
19 would likely undergo rapid protodesilylation rather
than secondary reaction with the acrylic ester. Actually,
the addition of tBuOH as a proton source suppressed
production of the triple Michael-adduct 18 even in
reactions promoted by pure TBSOTf. However, when
large amounts of tBuOH were employed, formation of
17h was also inhibited (entry 5). Finally, 0.25 equiv of
tBuOH was found to be optimal, affording only 17h in
74% yield (99% conversion yield) (entry 4).
The scope of the aza-double Michael reaction was
probed by using various combinations of substrates
(Table 4). The results of this effort show that R,â-
unsaturated amides possessing aromatic or aliphatic
substituents at the â-position participate in efficient
cycloaddition reactions with methyl acrylate (entries 1,
2, and 4-10). The heterocycloaddition reaction of acryl-
amide 7a did not undergo the desired reaction under even
the newly optimized conditions and gave homodimer 8a
(entries 3). In the reaction of crotonamide 7g with methyl
acrylate, homodimer 8g was produced in ∼10% yield
along with heterodimer 17g (66% yield, entry 4). In
contrast, â-disubstituted acryl amides, such as 7m and
7n, afforded the desired heterodimers in a higher yield
(entries 7 and 8).Mono-Michael adduct 20 was formed,
albeit in low yield, by reaction of â-disubstituted acryl-
amide 7m. This observation suggests that the heterocy-
cloaddition reaction takes place through a stepwise
double Michael pathway.
corresponding piperidinones (entries 12 and 13). Inter-
estingly, reaction of 7h with cyclohexenone produced
2-quinolone 17s as a single diastereomer in modest yield
(entry 13). The relative stereochemistry of 17s was
assigned by using 1D and 2D NMR methods.
Formal Synthesis of Paroxetine. To demonstrate
its synthetic potential, the aza-double Michael reaction
was applied to the formal synthesis of paroxetine (3).16,18,19
Enantiomerically pure (-)-paroxetine hydrochloride [Pax-
il, Seroxat] is a selective serotonin reuptake inhibitor
(SSRI) used clinically for the treatment of depression,
panic disorder, and post-traumatic stress disorder (PTSD).
The sequence employed to prepare 3, outlined in Scheme
9, started with reaction of the unsaturated amide 7j with
methyl acrylate in the presence of TBSOTf (1.2 equiv),
NEt3 (0.7 equiv), and tBuOH (0.25 equiv) in DCE. This
provided a mixture of trans- and cis-3,4-disubstituted
piperidinones 17j, which without purification was treated
with NaOMe to afford trans-17j in 58% overall yield (for
2 steps). The first cycloaddition step could be performed
under solvent-free conditions, in which case a 47% yield
of trans-17j was obtained after subsequent epimeriza-
(18) Dechant, K. L.; Clissold, S. P. Drugs 1991, 41, 225-253.
(19) Recent examples for the synthesis of paroxetine, see: (a)
Greenhalgh, D. A.; Simpkins, N. S. Synlett 2002, 2074-2076. (b) Senda,
T.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66, 6852-6856.
(c) Cossy, J.; Mirguet, O.; Pardo, D. G.; Desmurs, J.-R. Eur. J. Org.
Chem. 2002, 3543-3551. (d) Yu, M. S.; Lantos, I.; Peng, Z.-Q.; Yu, J.;
Cacchio, T. Tetrahedron Lett. 2000, 41, 5647-5651. (e) Murthy, K. S.
K.; Rey, A. W.; Tjepkema, M. Tetrahedron Lett. 2003, 44, 5355-5358.
(f) Chen, C.-Y.; Chang, B.-R.; Tsai, M.-R.; Chang, M.-Y.; Chang, N.-C.
Tetrahedron 2003, 59, 9383-9387. (g) Igarashi, J.; Ishikawa, H.;
Kobayashi, Y. Tetrahedron Lett. 2004, 45, 8065-8068. (h) Laszlo, C.;
Nemes, A.; Seboek, F.; Szantay, C., Jr.; Mak, M. Eur. J. Org. Chem.
2004, 3336-3339.
Cyclohexyl acrylate reacted with 7h to afford the
corresponding piperidinone 17q in good yield (entry 11).
Conjugated enones, such as methyl vinyl ketone (MVK)
and 2-cyclohexenone, also participated in the aza-double
Michael reaction to diastereoselectively generate the
J. Org. Chem, Vol. 70, No. 10, 2005 3961

Takasu et al.
SCHEME 9. Formal Synthesis of Paroxetinea
) 12.2, 5.2 Hz), 2.62-2.48 (m, 2H), 2.41-2.30 (m, 1H), 2.03-
1.96 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 171.8, 169.0, 138.0,
136.7, 128.7, 128.1, 127.7, 127.6, 50.1, 48.6, 43.4, 40.8, 30.9,
24.9; LRMS m/z 322 (M+); HRMS calcd for C20H22N2O2
322.1681, found 322.1676.
(3S*,5S*)-1-Benzyl-5-(N-benzylcarbamoyl)-3,5-dimeth-
ylpiperidin-2-one (8f): colorless oil; IR (neat) ν 3330, 2931,
1
1627 cm-1; H NMR (500 MHz, CDCl3) δ 7.30-7.20 (m, 8H),
7.06 (d, 2H, J ) 8.0 Hz), 5.54 (br s, 1H), 5.04 (d, 1H, J ) 14.2
Hz), 4.27 (dd, 1H, J ) 14.8, 5.8 Hz), 4.12 (dd, 1H, J ) 14.8,
5.8 Hz), 4.05 (d, 1H, J ) 14.2 Hz), 3.47 (dd, 1H, J ) 13.2, 2.6
Hz), 3.13 (d, 1H, J ) 13.2 Hz), 2.45-2.40 (m, 1H), 2.32 (ddd,
1H, J ) 13.2, 6.2, 2.6 Hz), 1.47 (t, 1H, J ) 13.2 Hz), 1.24 (d,
3H, J ) 7.0 Hz), 1.12 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
174.0, 172.5, 138.0, 136.8, 128.8, 128.7, 127.9, 127.55, 127.49,
54.1, 50.2, 43.6, 42.0, 40.8, 34.2, 25.2, 17.4; LRMS m/z 350
(M+); HRMS calcd for C22H26N2O2 350.1994, found 350.1989.
(3R*,4R*,5S*)-1-Benzyl-5-(N-benzylcarbamoyl)-4,6-dim-
ethylpiperidin-2-one (8g): colorless oil; IR (neat) ν 3280,
3067, 2931, 1648, 1540 cm-1 1H NMR (500 MHz, CDCl3) δ
;
a Reagents and conditions: (a) TBSOTf (1.2 equiv), NEt3 (0.7
equiv), tBuOH (0.25 equiv), DCE, rt; (b) NaOMe, MeOH-toluene,
reflux (58% for 2 steps); (c) LiAlH4 (2 equiv), THF, reflux (quant);
(d) see ref 19d.
7.30-7.21 (m, 8H), 7.16 (d, 2H, J ) 6.0 Hz), 5.72 (s, 1H), 5.34
(d, 1H, J ) 15.2 Hz), 4.30 (dd, 1H, J ) 14.8, 6.0 Hz), 4.20 (dd,
1H, J ) 14.8, 6.0 Hz), 3.99 (d, 1H, J ) 15.2 Hz), 3.73-3.69
(m, 1H), 2.54-2.42 (m, 2H), 2.34-2.31 (m, 2H), 1.23 (d, 3H, J
) 6.4 Hz), 1.01 (d, 3H, J ) 6.4 Hz); 13C NMR (125 MHz, CDCl3)
δ 170.9, 169.3, 138.1, 137.2, 128.7, 128.6, 128.2, 127.7, 127.5,
127.4, 51.7, 51.3, 46.9, 43.4, 38.3, 27.3, 20.3, 16.9; LRMS m/z
350 (M+); HRMS calcd for C22H26N2O2 350.1994, found 350.2002.
General Procedures for the Heterocycloaddition Re-
action (Scheme 8). To a mixture of 7 (1.0 equiv), acrylate
(1.0 equiv), and NEt3 (0.7 equiv) in 1,2-dichloroethane (1 M
solution for 7) was slowly added TBSOTf (1.2 equiv) at ambient
temperature, and then tBuOH (0.25 equiv) was added. After
being stirred for 12-24 h at the same temperature, the
resulting mixture was quenched by addition of saturated
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 pip-
eridinone 17.
tion.20 Reduction of trans-17j with LiAlH4 quantitatively
furnished the known pipereidinol 21, whose transforma-
tion into paroxetine (3) has been reported.19d The results
demonstrate that the intermolecular aza-double Michael
reaction can be used effectively to develop new concise
routes for the synthesis of functionally complex pip-
eridines such as paroxetine.
Conclusions
In conclusion, the studies reported above have led to
the development of a novel method for facile formation
of substituted piperidinones from simple R,â-unsaturated
amides by means of the intermolecular aza-double Michael
reaction. The new strategy should have broad applica-
tions to the synthesis of alkaloids as well as medicinally
important heterocyclic compounds. A demonstration of
the potential of homocycloaddition reaction is found in
the formal racemic synthesis of two natural indole
alkaloids, deplancheine and tacamonine. In addition, we
have applied the heterocycloaddition reaction to a short
synthesis of the antidepressant paroxetine. Further
studies are underway aimed at uncovering strategies to
control the stereochemistry of the process and at deter-
mining the detailed mechanism of the reaction.
(4S*,5R*)-1-Benzyl-5-(methoxycarbonyl)-4-phenylpip-
eridin-2-one (trans-17h): colorless needles, mp 117-119 °C
(from AcOEt-hexane); IR (KBr) ν 1734, 1645, 1497, 1439, 1257
1
cm-1; H NMR (400 MHz, CDCl3) δ 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) δ 171.9, 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.
(4S*,5S*)-1-Benzyl-5-(methoxycarbonyl)-4-phenylpip-
eridin-2-one (cis-17h): colorless oil; IR (neat) ν 2932, 1730,
1
1641, 1493, 1450, 1252, 1198, 1169, 702 cm-1; H NMR (400
Experimental Section
MHz, CDCl3) δ 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) δ 170.2, 168.6, 139.1, 136.5, 128.5, 128.5,
128.4, 127.5, 127.3, 51.8, 50.3, 44.7, 43.8, 39.6, 36.5; LRMS
m/z 323 (M+). Anal. Calcd for C20H21NO3‚0.25H2O: C, 73.26;
H, 6.61; N, 4.27. Found: C, 73.12; H, 6.48; N, 4.21.
General Procedure for the Homocycloaddition Reac-
tion (Schemes 2-4). To a solution of acrylamide 7 (1.0 equiv)
and triethylamine (1.5 equiv) in 1,2-dichloroethane (0.2 M
solution) was added TBSOTf (1.2 equiv) at ambient temper-
ature. After being stirred for 2 h and quenched with aqueous
NaHCO3, the mixture was extracted with AcOEt. The organic
layer was washed with brine, dried, and concentrated. The
resulting residue was chromatographed on silica gel (AcOEt)
to afford piperidinone 8.
Acknowledgment. This work was financially sup-
ported by a Grant-in-Aid from the Fujisawa Foundation
and a Grant-in-Aid from the MEXT, Japan.
1-Benzyl-5-(N-benzylcarbamoyl)piperidin-2-one (8a):
colorless oil; IR (neat) ν 3288, 3068, 2932, 1633, 1555 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.34-7.18 (m, 10H), 6.25 (br s,
1H), 4.64 (d, 1H, J ) 14.7 Hz), 4.44 (d, 1H, J ) 14.7 Hz), 4.42-
4.27 (m, 2H), 3.48 (dd, 1H, J ) 12.2, 10.2 Hz), 3.31 (dd, 1H, J
Supporting Information Available: General experimen-
tal procedures, full spectral data for all new compounds, and
copies of NMR spectra for all new compounds without elemen-
tal analysis. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) In this sequence, cis-17c was obtained in 14% yield along with
trans-17c. cis-17c could be converted into trans-17c by the treatment
with NaOMe.
JO050261X
3962 J. Org. Chem., Vol. 70, No. 10, 2005