(l)-Proline-catalysed novel tandem reactions of 1-substituted piperidin-4-ones with (E)-4-arylbut-3-en-2-ones: N-substituent mediated product selectivity and synthesis of novel nitrogen heterocycles

Article abstract of DOI:10.1016/j.tet.2007.01.038

(l)-Proline-catalysed reaction of 1-alkyl/aralkylpiperidin-4-ones with (E)-4-arylbut-3-en-2-ones furnishes novel isoquinoline derivatives, with two or three rings, in good yields via tandem Robinson annulation-Michael addition(s) sequences, while the reaction of 1-arylpiperidin-4-ones with (E)-4-arylbut-3-en-2-ones affords 3-azabicyclo[3.3.1]nonan-9-ones via a tandem Michael addition-aldol reaction sequence.

Full text of DOI:10.1016/j.tet.2007.01.038

Tetrahedron 63 (2007) 2865–2874
(L)-Proline-catalysed novel tandem reactions of 1-substituted
piperidin-4-ones with (E)-4-arylbut-3-en-2-ones:
N-substituent mediated product selectivity and
synthesis of novel nitrogen heterocycles
*
Murugesan Srinivasan and Subbu Perumal
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India
Received 30 October 2006; revised 5 January 2007; accepted 18 January 2007
Available online 21 January 2007
Abstract—(L)-Proline-catalysed reaction of 1-alkyl/aralkylpiperidin-4-ones with (E)-4-arylbut-3-en-2-ones furnishes novel isoquinoline
derivatives, with two or three rings, in good yields via tandem Robinson annulation–Michael addition(s) sequences, while the reaction of
1-arylpiperidin-4-ones with (E)-4-arylbut-3-en-2-ones affords 3-azabicyclo[3.3.1]nonan-9-ones via a tandem Michael addition–aldol
reaction sequence.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
as it is known to be efficient in several reactions, such as
Michael addition,19 Robinson annulation,20 Mannich reac-
tion, 21 aldol reaction,22 etc.
Nitrogen heterocycles like isoquinolines and azabicyclo-
[3.3.1]nonanes assume great importance, as several sub-
stituted isoquinolines display important biological activities
like cytotoxic,1 antimalarial,2 antileishmanial,3 trypano-
somal,4 antiestrogenic,5 antiproliferative5 and antitumour.6
Azabicyclo[3.3.1]nonanes are found to possess useful
biological activities such as antiarrhythmic,7 analgesic,8
antitussive,9 anti-inflammatory,10 local anaesthetic11 and
neuroleptic.12 Several 3-azabicyclo[3.3.1]nonanes are found
to be useful as sedative,13 analgesic,13 antipyretic,14 psycho-
laleptic14 and hypoglycemic15 agents.
2. Results and discussion
2.1. Tandem reactions of 1-alkyl- and 1-aralkyl-
piperidin-4-ones with (E)-4-arylbut-3-en-2-ones
The 1-substituted piperidin-4-ones 1a–i were prepared
following a literature method23 from the reaction of the ap-
propriate amine with N,N-dimethyl-4-oxopiperidinium sul-
fate. The reaction of 1-R-piperidin-4-ones 1a–d [R¼CH3,
CH2C6H5, (CH2)3CH3 or C(CH3)3] with (E)-4-arylbut-
3-en-2-ones 2 in a 1:2 molar ratio in presence of 25 mol %
of (L)-proline at ambient temperature affords novel bicyclic
compounds, 2-alkyl-4-(3-oxo-1-arylbutyl)-8-aryl-1,3,4,7,8,8a-
hexahydro-6(2H)-isoquinolinones 3a–f, while the reaction
of (R)-1-phenylethylpiperidin-4-one 1e with 2 affords novel
tricyclic compounds, 4,8-diaryl-6-[(R)-1-phenylethyl]octa-
hydro-1H-benzo[d]isoquinoline-2,10(3H,11H)-diones 4a–c
(Scheme 1). The products, 3 and 4 were isolated in a pure
form by flash chromatography in 58–76% yield.
Tandem reactions are one-pot multi-step processes and
hence very powerful for the rapid construction of complex
organic molecules efficiently and elegantly in a convergent
and eco-friendly manner with minimum waste generation.16
The biological importance of the above nitrogen hetero-
cycles and our continued interest in the synthesis of novel
organic molecules employing tandem sequences17 prompted
us to investigate the reactions of several 1-substituted
piperidin-4-ones with (E)-4-arylbut-3-en-2-ones furnishing
hitherto unreported complex nitrogen heterocycles, impor-
tant from a synthetic perspective. (L)-Proline, known as the
smallest enzyme18 was chosen for catalysing these reactions,
The products, 3a–f were found to exist as a single diastereo-
mer in each case, as evident from one set of signals found in
the NMR spectra. They show no optical rotation and are also
resolved into two peaks of equal intensity in chiral HPLC
and hence are racemic. The structure of 3a–f was determined
from one- and two-dimensional NMR spectroscopic studies.
The H,H-COSYand HMBC correlations (Fig. 1) and the 1H
Keywords: (L)-Proline; 1-Substituted piperidin-4-ones; (E)-4-Arylbut-3-en-
2-ones; Isoquinolines; Azabicyclo[3.3.1]nonan-9-ones; Tandem Robinson
annulation; Michael addition; Aldol reaction.
* Corresponding author. Tel./fax: +91 0452 2459845; e-mail: subbu.
perum@gmail.com
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.038

2866
M. Srinivasan, S. Perumal / Tetrahedron 63 (2007) 2865–2874
O
O
O
O
O
Ar
O
H
Ar
Ar
Ar
(Ar = aryl)
2
R
OH
CH3
N
N
R
N
R
1
H
Ar
Ar
O
N
(L)-Proline
R
EtOH, rt
3a-f
4a-c
5a-f
1 and 3-5
1a
R
Ar
3a
3b
3c
3d
3e
3f
CH3
CH3
CH3
C6H5
4-ClC6H4
4-CH3C6H4
C6H5
1a
1a
1b
1c
1d
1e
1e
1e
1f
C6H5CH2
(CH3)3C
C6H5
CH3(CH2)3
C6H5(CH3)CH
C6H5(CH3)CH
C6H5(CH3)CH
C6H5
C6H5
4a
4b
4c
5a
5b
5c
5d
5e
5f
C6H5
4-ClC6H4
4-CH3C6H4
C6H5
1f
C6H5
4-ClC6H4
4-CH3C6H4
C6H5
1f
C6H5
1g
1h
1i
4-ClC6H4
3-ClC6H4
3-O2NC6H4
C6H5
C6H5
Scheme 1.
and 13C chemical shifts of 3a assigned from one- and two-
dimensional NMR spectroscopic data (Fig. 2) are given as
an example. As it proved difficult to obtain crystals of 3 suit-
able for single crystal X-ray study, the stereochemistry of 3
was deduced from NMR spectroscopic data and mechanistic
considerations as described below.
(Fig. 3). From the above, it follows that C-8a–H-8a and
C-8a–C-8 bonds are oriented, respectively, pseudoaxially
and equatorially from the piperidine ring.
(ii) The J values of the triplet of doublets of doublets at
3.27 ppm due to H-4 (10.6, 5.7 and 1.8 Hz) are in accord
with the predominance of the rotamer, 3a0 (Fig. 4). The pro-
ton H-4 has a diaxial coupling with H-3ax (10.6 Hz) and an
equal coupling (10.6 Hz) with the side chain proton, H-10, an
axial–equatorial coupling with H-3eq (5.7 Hz), and a long
range coupling with H-5 (1.8 Hz). This discloses an axial
orientation for H-4 and an equatorial orientation for the
side chain at C-4. This conclusion is also supported by the
existence of a NOESY correlation of H-4 with H-3eq, but
not with H-3ax. Presumably, the rotamer 3a0 is more stable
than 3a (Fig. 3), as evident from the large J value
(i) The J values of the doublet of doublets of doublets at
3.95 ppm due to H-8 (11.1, 7.8 and 4.5 Hz) show that this
proton, oriented axially, is having diaxial coupling with
both H-8a (11.1 Hz) and H-7ax (7.8 Hz) and an axial–equa-
torial coupling with H-7eq (4.5 Hz). This, in turn, shows that
the phenyl at C-8 is oriented equatorially. The axial orienta-
tion of H-8 is also supported by the fact that H-8 and H-7eq
have a NOESY correlation, while H-8 and H-7ax do not
O
O
2.48 (dd,
6.03 (d,
H
H
5
6
J = 16.2, 4.5 Hz)
J = 1.8 Hz)
O
Ph
199.1
7
8
H
H
127.2
6
5
H
44.8
O
7
Ph
2.56 (m)
H
H
2.87 (m)
H
8a
1
4a
41.4
8
45.4
165.7
H3C
Ph
206.7
H3C
3.95 (ddd, J =
4
3
49.8
46.4
4a
8a
Ph 11.1, 7.8, 4.5 Hz)
2.00 (s)
30.8
4
H
52.2
H
H
2.33 (m)
H
H
H
H
2.85 (m)
2.65 (m)
2
N
1
3 61.5
H 2.33 (m)
H
H
57.8
1.62 (t,
N
H 1.82 (dd, J = 11.7, 3.3 Hz)
3.27 (tdd, J =
10.6, 5.7, 1.8 Hz)
H
J = 10.6 Hz)
CH3
CH31.98 (s)
46.1
H,H-COSY
HMBC
2.77 (ddd, J =
10.6, 5.7, 1.5 Hz)
Figure 2. 1H and 13C chemical shifts of 3a.
Figure 1. Selected two-dimensional NMR correlations for 3a.

M. Srinivasan, S. Perumal / Tetrahedron 63 (2007) 2865–2874
2867
configuration of C-10 for 3 as depicted in Figures 3 and 4.
It is pertinent to note that stereoselectivity of (L)-proline-
catalysed Michael additions has been ascribed to the hydro-
gen bonding between the carboxyl group of proline in the
enamines and the Michael acceptors.19a,b,24
O
3'
3.27, tdd,
J = 10.6, 5.7, 1.8 Hz
4'
2'
2.00,s
Me
2.87,
1'
6.03, d, J = 1.8 Hz
2.56, m
H
5
m
H
Ph
H
4
H
3
4a
2.77, ddd,
J = 10.6, 5.7, 1.5 Hz
Me
H
7
6
H
The heterocycle, 4 was obtained as a 1:1 mixture of diaste-
reomers, as evident from: (i) the equal intensities of the 1H
NMR signals (doublets) of the methyl of the phenylethyl
group of the diastereomers, and (ii) GC–MS analysis, which
gives two peaks of equal intensity in the gas chromatogram,
while both the diastereomers underwent decomposition in
the mass spectrometer of the GC–MS instrument. The
heterocycle 4, comprising of a 1:1 mixture of two diastereo-
mers: (i) shows optical activity implying that the dia-
stereomers have an unequal optical rotation, and (ii) are
characterised by sharp melting points like any pure single
compound. The diastereomers of 4 could not be separated
as they differ little in their Rf values. Hence, 4 affords a large
number of proton and carbon signals with close chemical
shift values for the diastereomers, whose individual assign-
ments and structure extraction from NMR spectroscopic
data proved difficult. Hence, the structure of 4 was eluci-
dated completely by an X-ray crystallographic study of a
single crystal of 4a (Fig. 6), which also shows that the diaste-
reomers are in a 1:1 ratio, four molecules each, in the unit
cell. The absolute configuration of the stereocentres of the
diastereomers, viz. (4S,4aR,7aR,8R) and (4S,4aS,7aS,8R)
available from an X-ray study, is shown in the structures in
Figure 6.
H
H
H
O
8a
Ph
8
N
2
2.48, dd,
J = 16.2, 4.5 Hz
1
H
H
2.33, m
3.95, ddd,
J = 11.1, 7.8, 4.5 Hz
Figure 3. NOESY correlations of 3a.
4'
Me
O
H
3'
H
1'
2'
4
H
5
Ph
4a
3
H
H
6
H
7
Me
O
8a
Ph
8
N
2
1
H
3a'
Figure 4. Predominant rotamer, 3a0.
(10.6 Hz) for the coupling of H-10 and H-4, as in the latter,
the CH2–CO–CH3 could interact sterically with H-3ax.
(iii) The relative arrangements of the enone and enamine in
the Michael addition step (Fig. 5) is likely to be favoured by
the hydrogen bonding between the carboxyl group of the
proline of the enamine and the enone, which could facilitate
the Michael addition. This would result in the relative
The 1:1 ratio of mixture of diastereomers of 4 shows that the
(R)-1-phenylethyl group in 1e fails to favour the formation
of any one diastereomer of 4. As the configuration of the
a-phenylethyl group in 4 is fixed as (R), as only (R)-1e is
subjected to the reaction, formation of a pair of enantiomers
for each diastereomer (and enantioselectivity) of 4 does not
arise for this reaction.
hydrogen
H
Me
Ph
bond
O
2
H
O
The reaction of 1-alkyl/aralkylpiperidin-4-ones 1a–e with 2
was investigated in the presence of pyrrolidine and DBU
also with a view to (i) unearthing the role of the catalyst
and (ii) optimising the yield of 3. The data furnished in Table
1 reveal that the yield of 3a remains almost constant, when
(L)-proline employed in this reaction is varied from 15–
100 mol % (entries 1–4). The reaction of 1-methylpiperi-
din-4-one with (E)-4-phenylbut-3-en-2-one in a 1:2 molar
H
H
O
C
N
..
H
3a
3a'
H
Ph
H
H
Me
N
H
H
10
H
H
Figure 5. Stereochemistry of Michael addition of 10 to 2.
Figure 6. X-ray structure of 4,8-diphenyl-6-(1-phenylethyl)octahydro-1H-benzo[d]isoquinoline-2,10(3H,11H)-dione 4a [two diastereomeric molecules,
(4S,4aR,7aR,8R) and (4S,4aS,7aS,8R), picked out from the lattice reoriented appropriately and shown].

2868
M. Srinivasan, S. Perumal / Tetrahedron 63 (2007) 2865–2874
Table 1. Tandem reactions of 1-substituted piperidin-4-ones with (E)-4-arylbut-3-en-2-ones affording 3–5
Entry
R
Ar
Reagent (mol %)
Product
Yield
Reaction time (days)
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
CH3
CH3
CH3
PhCH2
(CH3)3C
CH3(CH2)3
Ph(CH3)CH
Ph(CH3)CH
Ph(CH3)CH
Ph(CH3)CH
C6H5
C6H5
C6H5
C6H5
4-ClC6H4
3-ClC6H4
3-O2NC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
4-ClC6H4
4-CH3C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
4-ClC6H4
4-CH3C6H4
C6H5
(L)-Proline (15)
(L)-Proline (25)
(L)-Proline (50)
(L)-Proline (100)
Pyrrolidine (25)
(L)-Proline (25)
(L)-Proline (25)
(L)-Proline (25)
(L)-Proline (25)
(L)-Proline (25)
(L)-Proline (25)
Pyrrolidine (25)
(L)-Proline (25)
(L)-Proline (25)
(L)-Proline (25)
Pyrrolidine (25)
(L)-Proline (25)
(L)-Proline (25)
(L)-Proline (25)
(L)-Proline (25)
(L)-Proline (25)
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
4a
4a
4b
4c
5a
5a
5b
5c
5d
5e
5f
71
73
73
73
36
68
64
72
62
58
76
42
71
66
81
58
77
73
76
79
71
2
2
2
2
4
2
2
3
1
2
2
4
2
2
2
3
2
2
2
2
2
9
10
11
12
13
14
15
16
17
18
19
20
21
C6H5
4-ClC6H4
4-CH3C6H4
C6H5
C6H5
C6H5
ratio using 25 mol % of pyrrolidine in ethanol took 4 days
for completion affording 3a in 36% yield (entry 5). In pres-
ence of (L)-proline, this reaction is completed within 2 days
furnishing an enhanced yield of 3a (71%; entry 1). This re-
action in the presence of DBU failed to afford 3–5, which
suggests that catalyses by (L)-proline and pyrrolidine pro-
bably involve the intermediacy of enamines. The greater
efficacy of (L)-proline than pyrrolidine may probably be
ascribed to the concerted nucleophilic and acidic catalyses
by (L)-proline, wherein the secondary amino functionality
presumably forms enamine and enhances the nucleophilicity
of the carbon a- to the carbonyl towards Michael addition,
while the carboxyl group increases the electrophilicity of
the carbonyl of the Michael acceptor towards aldol forma-
tion by hydrogen bonding.
The influence of solvent on the reaction of 1 with 2 was stud-
ied with a view to examine whether enantioselectivity can be
achieved in some solvents. In the present study, the reaction
between 1 and 2 does not occur in chloroform, while in DMF
this reaction proceeds very slowly and in poor yield. The re-
action in DMSO affords a lower yield (35%) of 3a along with
other products, which could not be characterised. Analysis of
the product 3a obtained from the reaction in DMSO using
chiral HPLC shows that it is racemic and hence the reaction
occurs non-enantioselectively. Hence all the reactions of the
present investigation were investigated in detail in ethanol.
The reaction sequence leading to either 3 or 4 is envisaged
to occur via an initial Michael addition of the enamine
6 with (E)-4-arylbut-3-en-2-ones affording 7 (Scheme 2).
O
O
COOH
COOH
Ar
O
O
O
Ar
N
N
Michael
(L)-Proline
(L)-Proline
Addition
+
N
R
1
N
R
2
N
R
Ar
N
R
8
7
6
condensation
O
O
COOH
Ar
N
O
Ar
vinylogous
Michael
Addition
O
Ar
Ar
(L)-Proline
2
Ar
N
R
N
N
R
R
3a-f
9
10
R = CH3, C6H5CH2, (Me)3C, Me(CH2)3;
Ar = Ph, 4-ClC6H4, 4-MeC6H4
(L)-Proline
O
O
COOH
Ar
Ar
N
Michael
Addition
R
N
Ar
H
Ar
O
N
R
11
4a-4c
11 and 4 : R = CH(CH3)C6H5; Ar = Ph, 4-ClC6H4, 4-MeC6H4
Scheme 2. Mechanism for the proline-catalysed formation of 3a–f and 4a–c.

M. Srinivasan, S. Perumal / Tetrahedron 63 (2007) 2865–2874
2869
O
COOH
Ar
O
Ar
O
O
N
COOH
N
N
Ar
Michael
addition
(L)-Proline
(L)-Proline
N
R
N
R
N
R
O
R
6
12
7
1f-i
Aldol
reaction
O
R = C6H5, 4-ClC6H4, 3-ClC6H4, 3-O2NC6H4
Ar = Ph, 4-ClC6H4, 4-CH3C6H4
OH
CH3
Ar
N
R
H
H
5a-f
Scheme 3. Mechanism for the proline-catalysed formation of 5a–f.
Condensation of 7 via enamine 8 furnishes a,b-unsaturated
ketone 9. Presumably, 9 reacts with (L)-proline forming
enamine 10, which subsequently undergoes Michael addition
over 2 giving 3a–f. In the case of (R)-1-phenylethylpip-
eridin-4-one, the tricyclic compound 4 is formed from an
intramolecular Michael addition of the enamine 11, formed
from the reaction of the side chain carbonyl of 3a–f with
(L)-proline, over the b-carbon of the a,b-unsaturated carbon-
yl functionality as shown in Scheme 2. Probably, the steric
interactions arising from the N-a-phenylethyl group cause
some flattening of the piperidin-4-one ring in 1e, which could
facilitate the approach of the side chain enamine functional-
ity towards intramolecular Michael addition over the b-car-
bon of the a,b-unsaturated carbonyl of 11 resulting in 4a–c.
the two or three Michael additions observed in the case of
1-alkylpiperidin-4-ones. This is ascribable to the fact that
the carbons a to the carbonyl of 5a–f are at bridgehead
positions, which is likely to preclude the formation of
enamines.
The structure of azabicyclo[3.3.1]nonanones 5a–f has also
been deduced from NMR spectroscopic data. The HMBC
1
correlations (Fig. 7) and complete assignment of the H
and 13C chemical shifts of 5a (Fig. 8) made from one- and
two-dimensional NMR spectroscopic data are given as an
example. That the nonanones 5 adopt a twin-chair confor-
mation is evident from the fact that H-7ax of 5a occurs far
downfield at 3.19 ppm than H-7eq at 1.88 ppm due van
It was found that even when 1-methylpiperidin-4-one 1a and
2 are taken in a 1:1 molar ratio in presence of (L)-proline with
a view to statistically direct the reaction to afford 9, only 3a
is obtained as the major product. This suggests that the sec-
ond Michael addition occurs more rapidly than the Robinson
annulation so that as soon as 9 is formed, it is converted into
10 and subsequently to 3. This may arise from the greater
stability of the enamine, with extended conjugation 9 requir-
ing less free energy of activation for its formation, as well 6
that leads to the Michael addition.
O
H
H
1
5
H
H
H
OH
8
2
6
4
H
CH3
H
H
N
7
3
Ph
H
H,H-COSY
HMBC
2.2. Tandem reactions of 1-arylpiperidin-4-ones
with (E)-4-arylbut-3-en-2-ones
Figure 7. Selected two-dimensional NMR correlations for 5a.
The reaction of 1-arylpiperidin-4-ones 1f–i with 2 in a 1:1
molar ratio in the presence of (L)-proline at ambient tem-
perature affords 6-hydroxy-6-methyl-3,8-diaryl-3-azabi-
cyclo[3.3.1]nonan-9-ones, 5 (Scheme 3) stereoselectively.
The products, 5a–f, isolated in a pure state by flash chroma-
tography in 71–81% yields were found to be racemic by chi-
ral HPLC analysis and they also show no optical rotation.
This shows that (L)-proline functions as a non-enantioselec-
tive catalyst in reactions leading to 3 and 5. It is found that
the reaction of 1-arylpiperidin-4-ones 1f–i and 2 in a 1:2
molar ratio in the presence of (L)-proline also affords 5a–f
only. Under these conditions, the isoquinolinones 3a–f and
4a–c could not be detected even in traces. Further Michael
addition of 5a–f with 2 is also not observed, in contrast to
O
2.52 (m)
H
215.1
H
2.52 (bs)
3.23 (m)
9
58.8
52.7
1
4
3.74 (m)
H
6
5
2.92 (dd, J =
12.3, 2.4 Hz)
H
OH
H
51.7
2.35 (bs)
43.4
8
77.0
2
53.0
Ph
1.57 (s)
7
H
CH
H
H
328.6
3.71 (m)
N
1.88 (dd, J =
38.6
3
Ph
:
H
13.5, 5.1 Hz)
4.01 (dt,
J = 12.6, 3.0 Hz)
3.19 (dd,
J = 13.5, 9.6 Hz)
Figure 8. 1H and 13C chemical shifts of 5a.

2870
M. Srinivasan, S. Perumal / Tetrahedron 63 (2007) 2865–2874
substituents, viz., aryl instead of methyl at C-6, two more
methyl groups in the piperidone ring and N–Me instead of
N–Ar have been synthesised by Vatsadze et al.25 from the
reaction of 1,2,5-trimethylpiperidin-4-one to chalcones in
presence of potassium hydroxide in low yields.
3. Conclusions
This work describes one-pot tandem sequences providing
a rapid access to novel complex substituted isoquinolinones
and azabicyclo[3.3.1]nonanones from 1-substituted piperi-
din-4-ones and (E)-4-arylbut-3-en-2-ones in presence of
(L)-proline, at ambient temperature. Incidentally, this study
discloses the subtle dependence of the product-selectivity
of these reactions on the N-substituent of the piperidin-
4-ones. These novel heterocycles with two or more function-
alities can be useful building blocks for further synthetic
manipulations. The versatility and the synthetic utility of
these tandem reactions are being currently explored in our
research group employing a host of carbo- and heterocyclic
ketones and other Michael acceptors.
Figure 9. X-ray structure of 6-hydroxy-6-methyl-3,8-diphenyl-3-azabi-
cyclo[3.3.1]nonan-9-one 5a.
der Waals interaction between the nitrogen lone pair and H-
7ax. The structure of 5a determined by a single crystal X-ray
study (Fig. 9) is in good agreement with that deduced from
NMR spectroscopic studies.
This reaction leading to 5 presumably proceeds through
a
4. Experimental section
4.1. General methods
tandem Michael addition–aldol reaction sequence
(Scheme 3). The aryl ring attached to the nitrogen of 1f–j
is likely to flatten the piperidone ring of 2 by N–Ar conjuga-
tion facilitating the formation of enamine 12, which
could add over the side chain carbonyl affording azabi-
cyclo[3.3.1]nonanones, 5. On the other hand, the Michael
adduct 7 with N-alkyl substituent, without much ring flatten-
ing (Scheme 2) might probably find it difficult (i) to form
enamine 13 relative to the enamine 8 and/or (ii) to react
with 2 through the enamine 13 (Fig. 10).
The mp of the isoquinolinones and azabicyclo[3.3.1]nona-
nones are uncorrected. Unless stated otherwise, solvents
and chemicals were obtained from commercial sources
and used without further purification. Flash chromatography
was performed on silica gel (230–400 mesh). The 1H NMR
and 13C NMR spectra were recorded on a 300 MHz Bruker
(Avance) NMR spectrometer operating at 300 and 75 MHz,
respectively and the chemical shifts are reported as d values
(ppm) relative to tetramethylsilane. Two-dimensional NMR
spectra were also measured in the same instrument emp-
loying standard Bruker software throughout. Elemental
analyses of all the hitherto unreported isoquinolinones and
azabicyclo[3.3.1]nonanones were performed on a Perkin
Elmer 2400 Series II Elemental CHNS Analyser. Optical
rotation values were measured using an autopol IVautomatic
polarimeter at sodium D line at 25 ꢀC. HPLC analyses
were carried out on a Shimadzu SPD-10ATvp model with
CHIRALPAK AD-H column using n-hexane/isopropyl
alcohol [90:10 (v/v)] eluent at a flow rate of 1 ml/min. The
GC–MS analysis of 4 was performed on a Thermo-Finnigan
GC–MS instrument.
It is pertinent to note that the heterocycles 3 and 5 are new
and, to the best of the knowledge of the authors, even com-
pounds having structures closely resembling 3 and 5 are not
available in the literature, while two compounds 6 (Fig. 11),
having the same structure as 5, but carrying different
COOH
N
Ar
O
N
R
R = alkyl
(difficult to form or react)
13
4.2. General procedure for the preparation
of tandem products 3 and 4
Figure 10.
To a mixture of (L)-proline (0.086 g, 0.75 mmol, 15 mol %),
1-methylpiperidin-4-one 1a (0.6 mL, 5 mmol) and (E)-4-
phenylbut-3-en-2-one 2 (1.46 g, 10 mmol) was added dry
ethanol (5 mL) at room temperature. The mixture was stirred
at room temperature until TLC analysis indicated comple-
tion of the reaction. The reaction mixture was treated
with saturated aqueous ammonium chloride solution and
extracted with CH2Cl2 (35 mL). The combined organic
extracts were washed successively with water (20 mL), dried
over anhydrous Na2SO4 and concentrated in vacuum. The
O
CH3
OH
H C
N
Ar
Ph
H33C
Ar = 4-ClC6H4, C6H5
6a and 6b
Figure 11.

M. Srinivasan, S. Perumal / Tetrahedron 63 (2007) 2865–2874
2871
product was purified by column chromatography on silica
gel using pet. ether/ethyl acetate [4:1 (v/v)] mixture as an
eluent.
4.2.4. 2-Benzyl-4-(3-oxo-1-phenylbutyl)-8-phenyl-
1,3,4,7,8,8a-hexahydro-6(2H)-isoquinolinone 3d. Isolated
as a white solid (72%), mp 124 ꢀC [Found: C, 82.85; H, 7.21;
N, 3.07. C32H33NO2 requires C, 82.90; H, 7.17; N, 3.02%];
Rf (20% ethyl acetate/pet. ether) 0.27; nmax (KBr) 1718,
1679, 1641 cmꢁ1; dH (300 MHz, CDCl3) 6.88–7.46 (15H,
m, Ph), 5.95 (1H, d, J 1.5 Hz, COCH]C), 3.98 (1H, m,
CH(Ph)CH2), 3.62 (1H, d, J 12.9 Hz, CHaHbPh), 3.36 (1H,
m, CHC]CH), 3.01 (1H, d, J 12.9 Hz, CHaHbPh), 2.91
(1H, m, CH(Ph)CH2), 2.87 (1H, m, CHaHbCO), 2.81 (1H,
m, CHaHbNMe), 2.68 (1H, m, CHaHbCO), 2.58 (1H, m,
CHaHbCO), 2.44 (1H, dd, J 16.2, 4.5 Hz, CHaHbCO), 2.35
(1H, m, CHCH2), 2.35 (1H, m, CHaHbNMe), 1.95 (1H, dd,
J 11.7, 3.3 Hz, CHaHbNMe), 1.89 (1H, t, J 10.8 Hz,
CHaHbNMe), 1.76 (3H, s, COMe); dC (75 MHz, CDCl3)
207.4, 198.6, 163.1, 142.3, 142.2, 138.8, 129.5, 129.3,
128.9, 128.7, 128.3, 127.8, 127.7, 127.4, 127.2, 62.5, 60.9,
53.6, 50.0, 47.6, 45.2, 44.4, 42.6, 41.8, 30.8.
4.2.1. 2-Methyl-4-(3-oxo-1-phenylbutyl)-8-phenyl-
1,3,4,7,8,8a-hexahydro-6(2H)-isoquinolinone 3a. Isolated
as a white solid (71%), mp 137 ꢀC [Found: C, 80.65; H,
7.49; N, 3.64. C26H29NO2 requires C, 80.59; H, 7.54; N,
3.61%]; Rf (20% ethyl acetate/pet. ether) 0.35; nmax (KBr)
1731, 1705, 1647 cmꢁ1; dH (300 MHz, CDCl3) 7.22–7.41
(10H, m, Ph), 6.03 (1H, d, J 1.8 Hz, COCH]C), 3.95
(1H, ddd, J 11.1, 7.8, 4.5 Hz, CH(Ph)CH2), 3.27 (1H, tdd,
J 10.6, 5.7, 1.8 Hz, CHC]CH), 2.87 (1H, m, CH(Ph)CH2),
2.85 (1H, m, CHaHbCO), 2.77 (1H, ddd, J 10.6, 5.7, 1.5 Hz,
CHaHbNMe), 2.65 (1H, m, CHaHbCO), 2.56 (1H, m,
CHaHbCO), 2.48 (1H, dd, J 16.2, 4.5 Hz, CHaHbCO), 2.33
(1H, m, CHCH2), 2.33 (1H, m, CHaHbNMe), 2.00 (3H, s,
COMe), 1.98 (3H, s, NMe), 1.82 (1H, dd, J 11.7, 3.3 Hz,
CHaHbNMe), 1.62 (1H, t, J 10.6 Hz, CHaHbNMe); dC
(75 MHz, CDCl3) 206.7, 199.1, 165.7, 143.7, 142.2, 129.3,
129.1, 128.4, 127.9, 127.6, 127.2, 126.9, 61.5, 57.8, 52.2,
49.8, 46.4, 46.1, 45.4, 44.8, 41.4, 30.8.
4.2.5. 2-(tert-Butyl)-4-(3-oxo-1-phenylbutyl)-8-phenyl-
1,3,4,7,8,8a-hexahydro-6(2H)-isoquinolinone 3e. Isolated
as a yellow solid (62%), mp 117 ꢀC [Found: C, 81.12; H,
8.16; N, 3.30. C29H35NO2 requires C, 81.08; H, 8.21; N,
3.26%]; Rf (20% ethyl acetate/pet. ether) 0.35; nmax (KBr)
1722, 1701, 1642 cmꢁ1; dH (300 MHz, CDCl3) 7.11–7.46
(10H, m, Ph), 5.89 (1H, d, J 1.8 Hz, COCH]C), 3.86 (1H,
m, CH(Ph)CH2), 3.21 (1H, tdd, J 10.6, 5.7, 2.1 Hz, CHC]
CH), 2.89 (1H, m, CH(Ph)CH2), 2.86 (1H, m, CHaHbCO),
2.71 (1H, m, CHaHbNMe), 2.61 (1H, m, CHaHbCO), 2.59
(1H, m, CHaHbCO), 2.51 (1H, m, CHaHbCO), 2.35 (1H, m,
CHCH2), 2.35 (1H, m, CHaHbNMe), 1.95 (3H, s, COMe),
1.88 (1H, dd, J 11.7, 3.3 Hz, CHaHbNMe), 1.78 (1H, t, J
10.6 Hz, CHaHbNMe), 0.99 (3H, s, CMe3), 0.98 (6H, s,
CMe3); dC (75 MHz, CDCl3) 206.6, 198.7, 165.1, 143.5,
142.0, 129.5, 128.9, 128.6, 128.2, 127.8, 127.5, 127.2,
62.3, 61.7, 58.2, 52.6, 49.2, 45.7, 44.3, 41.6, 40.7, 30.6,
18.5, 18.4, 18.3.
4.2.2. 8-(4-Chlorophenyl)-4-[1-(4-chlorophenyl)-3-oxo-
butyl]-2-methyl-1,3,4,7,8,8a-hexahydro-6(2H)-isoquino-
linone 3b. Isolated as a white solid (68%), mp 141 ꢀC
[Found: C, 68.39; H, 5.91; N, 3.11. C26H27Cl2NO2 requires
C, 68.42; H, 5.96; N, 3.07%]; Rf (20% ethyl acetate/pet.
ether) 0.28; nmax (KBr) 1725, 1702, 1653 cmꢁ1; dH
(300 MHz, CDCl3) 7.01–7.48 (8H, m, 4-ClC6H4), 6.06
(1H, d, J 1.8 Hz, COCH]C), 4.03 (1H, ddd, J 11.1, 7.8,
4.5 Hz, CH(Ph)CH2), 3.41 (1H, tdd, J 10.6, 5.7, 2.1 Hz,
CHC]CH), 2.92 (1H, m, CH(Ph)CH2), 2.89 (1H, m,
CHaHbCO), 2.80 (1H, ddd, J 10.6, 5.7, 1.5 Hz, CHaHbNMe),
2.69 (1H, m, CHaHbCO), 2.59 (1H, m, CHaHbCO), 2.51 (1H,
dd, J 16.2, 4.5 Hz, CHaHbCO), 2.41 (1H, m, CHCH2), 2.41
(1H, m, CHaHbNMe), 2.03 (3H, s, COMe), 1.95 (3H, s,
NMe), 1.81 (1H, dd, J 11.7, 3.3 Hz, CHaHbNMe), 1.66
(1H, t, J 10.6 Hz, CHaHbNMe); dC (75 MHz, CDCl3)
207.3, 199.3, 165.4, 143.3, 142.1, 129.4, 129.0, 128.5,
128.0, 127.5, 127.1, 126.4, 61.2, 58.2, 52.5, 50.4, 46.5,
45.7, 44.9, 41.7, 40.7, 30.4.
4.2.6. 2-Butyl-4-(3-oxo-1-phenylbutyl)-8-phenyl-
1,3,4,7,8,8a-hexahydro-6(2H)-isoquinolinone 3f. Isolated
as a yellow solid (58%), mp 132 ꢀC [Found: C, 81.03; H,
8.25; N, 3.21. C29H35NO2 requires C, 81.08; H, 8.21; N,
3.26%]; Rf (20% ethyl acetate/pet. ether) 0.34; nmax (KBr)
1713, 1702, 1640 cmꢁ1; dH (300 MHz, CDCl3) 7.14–7.46
(10H, m, Ph), 6.12 (1H, d, J 1.8 Hz, COCH]C), 3.89
(1H, m, CH(Ph)CH2), 3.21 (1H, tdd, J 10.6, 5.7, 2.1 Hz,
CHC]CH), 2.90 (1H, m, CH(Ph)CH2), 2.87 (1H, m,
CHaHbCO), 2.80 (1H, ddd, J 10.6, 5.7, 1.5 Hz, CHaHbNMe),
2.71 (1H, dd, J 17.4, 4.8 Hz, CHaHbCO), 2.62 (1H, m,
CHaHbCO), 2.52 (1H, dd, J 16.2, 4.5 Hz, CHaHbCO), 2.36
(1H, m, CHCH2), 2.36 (1H, m, CHaHbNMe), 2.12 (2H, m,
NCH2), 1.95 (3H, s, COMe), 1.86 (1H, dd, J 11.7, 3.3 Hz,
CHaHbNMe), 1.67 (1H, t, J 10.6 Hz, CHaHbNMe), 1.41
(4H, m, CH2CH2Me), 0.88 (3H, t, J 6.6 Hz, CH2Me); dC
(75 MHz, CDCl3) 206.9, 198.6, 165.5, 143.5, 141.8, 129.1,
128.7, 128.1, 127.7, 127.5, 126.9, 126.1, 61.8, 57.9, 52.1,
49.4, 46.3, 45.6, 44.9, 41.5, 41.0, 30.7, 30.2, 20.8, 15.6.
4.2.3. 2-Methyl-8-(4-methylphenyl)-4-[1-(4-methyl-
phenyl)-3-oxobutyl]-1,3,4,7,8,8a-hexahydro-6(2H)-iso-
quinolinone 3c. Isolated as a white solid (64%), mp 123 ꢀC
[Found: C, 80.88; H, 7.97; N, 3.41. C28H33NO2 requires C,
80.93; H, 8.00; N, 3.37%]; Rf (20% ethyl acetate/pet. ether)
0.30; nmax (KBr) 1728, 1707, 1652 cmꢁ1; dH (300 MHz,
CDCl3) 7.17–7.45 (8H, m, 4-MeC6H4), 6.12 (1H, d, J
1.8 Hz, COCH]C), 3.97 (1H, ddd, J 11.1, 7.8, 4.5 Hz,
CH(Ph)CH2), 3.21 (1H, tdd, J 10.6, 5.7, 2.1 Hz, CHC]CH),
2.86 (1H, m, CH(Ph)CH2), 2.86 (1H, m, CHaHbCO), 2.79
(1H, ddd, J 10.6, 5.7, 1.5 Hz, CHaHbNMe), 2.69 (1H, m,
CHaHbCO), 2.59 (1H, m, CHaHbCO), 2.45 (1H, dd, J 16.2,
4.5 Hz, CHaHbCO), 2.26 (1H, m, CHCH2), 2.26 (1H, m,
CHaHbNMe), 2.23 (3H, s, 4-MeC6H4), 2.21 (3H, s, 4-
MeC6H4), 1.99 (3H, s, COMe), 1.91 (3H, s, NMe), 1.85
(1H, dd, J 11.7, 3.3 Hz, CHaHbNMe), 1.58 (1H, t, J
10.6 Hz, CHaHbNMe); dC (75 MHz, CDCl3) 206.2, 199.0,
165.1, 143.4, 142.5, 129.5, 129.0, 128.7, 127.6, 127.3,
127.1, 126.5, 61.8, 57.5, 51.7, 49.9, 46.2, 45.5, 45.0, 41.3,
40.5, 31.3, 21.2, 21.1.
4.2.7. (4S,4aR,7aR,8R)- and (4S,4aS,7aS,8R)-4,8-
Diphenyl-6-[(R)-1-phenylethyl]octahydro-1H-benzo[d]-
isoquinoline-2,10(3H,11H)-dione 4a (mixture of diaste-
reoisomers in the ratio of 1:1).26 Isolated as yellow
needles (76%), mp 118 ꢀC [Found: C, 82.93; H, 7.33; N,

2872
M. Srinivasan, S. Perumal / Tetrahedron 63 (2007) 2865–2874
2.97. C66H70N2O4 requires C, 82.98; H, 7.39; N, 2.93%]; Rf
(20% ethyl acetate/pet. ether) 0.33; [a]2D5 ꢁ20.1 (c 0.1,
4.3.1. 6-Hydroxy-6-methyl-3,8-diphenyl-3-azabicyclo-
[3.3.1]nonan-9-one 5a. Isolated as yellow needles (81%),
mp 148 ꢀC [Found: C, 78.52; H, 7.18; N, 4.40. C21H23NO2
requires C, 78.47; H, 7.21; N, 4.36%]; Rf (20% ethyl ace-
tate/pet. ether) 0.39; nmax (KBr) 3470, 1711 cmꢁ1; dH
(300 MHz, CDCl3) 6.83–7.38 (10H, m, Ph), 4.01 (1H, dt, J
12.6, 3.0 Hz, CHaHbNPh), 3.74 (1H, m, CH(Ph)CH2), 3.71
(1H, m, CHaHbNPh), 3.23 (1H, m, CHaHbNPh), 3.19 (1H,
dd, J 13.5, 9.6 Hz, CHaHbCHPh), 2.92 (1H, dd, J 12.3,
2.4 Hz, CHaHbNPh), 2.52 (1H, m, CHCHPh), 2.52 (1H, m,
CHCO), 2.35 (1H, s, OH), 1.88 (1H, dd, J 13.5, 5.1 Hz,
CHaHbCHPh), 1.57 (3H, s, CH3); dC (75 MHz, CDCl3)
215.1, 149.2, 140.9, 129.3, 128.7, 128.1, 127.1, 119.9,
115.8, 77.0, 58.8, 53.0, 52.7, 51.7, 43.4, 38.6, 28.6.
MeOH); nmax (KBr) 1720, 1712, 1704, 1695, 1648 cmꢁ1
;
dH (300 MHz, CDCl3) 6.89–7.34 (30H, m, Ph), 3.84 (2H,
m), 3.53 (3H, m), 3.26 (1H, q, J 7 Hz, CHMe), 3.09 (3H,
m), 2.49 (14H, m), 2.05 (11H, m), 0.99 (3H, d, J 7 Hz,
CHMe), 0.95 (3H, d, J 7 Hz, CHMe); dC (75 MHz, CDCl3)
209.7, 209.6, 208.6, 208.4, 143.2, 140.7, 140.5, 140.2,
129.3, 128.9, 128.8, 128.7, 128.5, 128.3, 128.0, 127.9,
127.8, 127.6, 127.5, 127.4, 127.3, 127.2, 127.0, 126.9,
126.8, 126.6, 64.3, 63.9, 51.3, 50.1, 49.6, 49.1, 48.7, 47.4,
47.1, 46.7, 45.6, 45.9, 44.4, 44.3, 43.8, 43.6, 42.8, 41.2,
39.8, 39.5, 39.4, 18.2, 17.4.
4.2.8. (4S,4aR,7aR,8R)- and (4S,4aS,7aS,8R)-4,8-Bis(4-
chlorophenyl)-6-[(R)-1-phenylethyl]octahydro-1H-benzo-
[d]isoquinoline-2,10(3H,11H)-dione 4b (mixture of dia-
stereoisomers in the ratio of 1:1).26 Isolated as yellow solid
(71%), mp 124 ꢀC [Found: C, 72.48; H, 6.14; N, 2.52.
C66H66 Cl4N2O4 requires C, 72.52; H, 6.09; N, 2.56%]; Rf
(20% ethyl acetate/pet. ether) 0.38; [a]2D5 ꢁ22.6 (c 0.1,
4.3.2. 8-(4-Chlorophenyl)-6-hydroxy-6-methyl-3-phenyl-
3-azabicyclo[3.3.1]nonan-9-one 5b. Isolated as a white solid
(77%), mp 152 ꢀC [Found: C, 70.92; H, 6.20; N, 3.98.
C21H22ClNO2 requires C, 70.88; H, 6.23; N, 3.94%]; Rf (20%
ethyl acetate/pet. ether) 0.40; nmax (KBr) 3476, 1702 cmꢁ1
;
dH (300 MHz, CDCl3) 6.78–7.41 (9H, m, Ph), 4.13 (1H, dt, J
12.6, 3.0 Hz, CHaHbNPh), 3.77 (1H, m, CH(Ph)CH2), 3.75
(1H, m, CHaHbNPh), 3.27 (1H, m, CHaHbNPh), 3.24 (1H,
dd, J 13.5, 9.6 Hz, CHaHbCHPh), 2.98 (1H, dd, J 12.3,
2.4 Hz, CHaHbNPh), 2.64 (1H, m, CHCHPh), 2.64 (1H, m,
CHCO), 2.41 (1H, s, OH), 1.76 (1H, dd, J 13.5, 5.1 Hz,
CHaHbCHPh), 1.48 (3H, s, CH3); dC (75 MHz, CDCl3)
214.2, 149.6, 141.3, 129.3, 128.4, 127.7, 126.5, 120.2, 116.1,
76.6, 59.2, 53.4, 52.9, 52.3, 42.9, 38.2, 28.1.
MeOH); nmax (KBr) 1725, 1711, 1699, 1692, 1650 cmꢁ1
;
dH (300 MHz, CDCl3) 6.80–7.48 (26H, m, Ph), 3.91 (2H,
m), 3.67 (3H, m), 3.34 (1H, q, J 7 Hz, CHMe), 3.17 (3H,
m), 2.42 (14H, m), 2.11 (11H, m), 1.02 (3H, d, J 7 Hz,
CHMe), 0.96 (3H, d, J 7 Hz, CHMe); dC (75 MHz, CDCl3)
209.9, 209.5, 209.2, 208.9, 143.4, 140.6, 140.2, 139.7,
129.6, 129.3, 129.1, 128.9, 128.7, 128.4, 128.3, 128.1,
127.9, 127.7, 127.6, 127.4, 127.3, 127.1, 126.9, 126.8,
126.5, 126.1, 64.5, 63.7, 51.4, 50.2, 49.4, 49.0, 48.5, 47.7,
47.3, 46.4, 45.9, 45.7, 44.5, 44.2, 43.9, 43.2, 42.5, 41.8,
39.9, 39.6, 39.2, 18.6, 17.1.
4.3.3. 6-Hydroxy-6-methyl-8-(4-methylphenyl)-3-phenyl-
3-azabicyclo[3.3.1]nonan-9-one 5c. Isolated as a white
solid (73%), mp 136 ꢀC [Found: C, 78.81; H, 7.48; N,
4.23. C22H25NO2 requires C, 78.77; H, 7.51; N, 4.18%]; Rf
(20% ethyl acetate/pet. ether) 0.44; nmax (KBr) 3464,
1715 cmꢁ1; dH (300 MHz, CDCl3) 6.91–7.42 (9H, m, Ph),
3.99 (1H, dt, J 12.6, 3.0 Hz, CHaHbNPh), 3.75 (1H, m,
CH(Ph)CH2), 3.75 (1H, m, CHaHbNPh), 3.25 (1H, m,
CHaHbNPh), 3.21 (1H, dd, J 13.5, 9.6 Hz, CHaHbCHPh),
2.91 (1H, dd, J 12.3, 2.4 Hz, CHaHbNPh), 2.55 (1H,
m, CHCHPh), 2.55 (1H, m, CHCO), 2.32 (1H, s, OH),
2.21 (3H, s, 4-CH3C6H4), 1.92 (1H, dd, J 13.5, 5.1 Hz,
CHaHbCHPh), 1.61 (3H, s, CH3); dC (75 MHz, CDCl3)
214.2, 148.5, 140.5, 129.2, 128.9, 128.4, 127.5, 119.6,
115.2, 76.7, 59.2, 53.2, 52.5, 51.8, 43.1, 38.4, 28.7, 21.3.
4.2.9. (4S,4aR,7aR,8R)- and (4S,4aS,7aS,8R)-4,8-Bis(4-
methylphenyl)-6-[(R)-1-phenylethyl]octahydro-1H-benzo-
[d]isoquinoline-2,10(3H,11H)-dione 4c (mixture of dia-
stereoisomers in the ratio of 1:1).26 Isolated as yellow solid
(66%), mp 109 ꢀC [Found: C, 83.08; H, 7.80; N, 2.72.
C70H78N2O4 requires C, 83.13; H, 7.77; N, 2.77%]; Rf
(20% ethyl acetate/pet. ether) 0.35; [a]2D5 ꢁ18.8 (c 0.1,
MeOH); nmax (KBr) 1728, 1715, 1701, 1692, 1643 cmꢁ1
;
dH (300 MHz, CDCl3) 6.85–7.54 (26H, m, Ph), 3.85 (2H,
m), 3.59 (3H, m), 3.29 (1H, q, J 7 Hz, CHMe), 3.17 (3H,
m), 2.57 (14H, m), 2.22 (3H, s, 4-MeC6H4), 2.21 (6H, s,
4-MeC6H4), 2.20 (3H, s, 4-MeC6H4), 2.02 (11H, m), 1.08
(3H, d, J 7 Hz, CHMe), 0.98 (3H, d, J 7 Hz, CHMe); dC
(75 MHz, CDCl3) 209.6, 209.4, 208.8, 208.2, 142.7, 140.8,
140.7, 140.4, 129.4, 129.1, 128.9, 128.6, 128.4, 128.2,
128.1, 127.8, 127.7, 127.6, 127.5, 127.4, 127.2, 127.1,
127.0, 126.8, 126.5, 126.2, 64.6, 64.3, 51.7, 50.4, 49.8,
49.2, 48.5, 47.3, 47.0, 46.8, 45.8, 45.7, 44.7, 44.5, 43.9,
43.4, 42.5, 41.3, 40.2, 39.8, 39.6, 21.3, 21.2, 21.1, 21.0,
18.0, 17.6.
4.3.4. 3-(4-Chlorophenyl)-6-hydroxy-6-methyl-8-phenyl-
3-azabicyclo[3.3.1]nonan-9-one 5d. Isolated as a white
solid (76%), mp 142 ꢀC [Found: C, 70.84; H, 6.18; N,
3.98. C21H22ClNO2 requires C, 70.88; H, 6.23; N, 3.94%];
Rf (20% ethyl acetate/pet. ether) 0.41; nmax (KBr) 3513,
1714 cmꢁ1; dH (300 MHz, CDCl3) 6.81–7.40 (9H, m, Ph),
4.12 (1H, dt, J 12.6, 3.0 Hz, CHaHbNPh), 3.68 (1H, m,
CH(Ph)CH2), 3.68 (1H, m, CHaHbNPh), 3.26 (1H, m,
CHaHbNPh), 3.26 (1H, m, CHaHbCHPh), 2.95 (1H, dd, J
12.3, 2.4 Hz, CHaHbNPh), 2.48 (1H, m, CHCHPh), 2.48
(1H, m, CHCO), 2.31 (1H, s, OH), 1.90 (1H, dd, J 13.5,
5.1 Hz, CHaHbCHPh), 1.55 (3H, s, CH3); dC (75 MHz,
CDCl3) 214.7, 149.6, 141.3, 138.4, 129.1, 128.3, 127.4,
119.8, 115.2, 76.7, 59.2, 53.4, 52.6, 51.9, 43.3, 38.7, 28.8.
4.3. General procedure for the preparation of 5
To a mixture of (L)-proline (0.287 g, 2.5 mmol, 25 mol %),
1-phenylpiperidin-4-one 1f (1.75 g, 10 mmol) and (E)-4-
phenylbut-3-en-2-one 2 (1.46 g, 10 mmol) dry ethanol
(5 ml) was added at room temperature and the mixture
stirred until TLC analysis indicated the completion of the re-
action. Work up of the reaction mixture, as done for 3 and 4,
afforded 5.
4.3.5. 3-(3-Chlorophenyl)-6-hydroxy-6-methyl-8-phenyl-
3-azabicyclo[3.3.1]nonan-9-one 5e. Isolated as a white

M. Srinivasan, S. Perumal / Tetrahedron 63 (2007) 2865–2874
2873
solid (79%), mp 136 ꢀC [Found: C, 70.91; H, 6.28; N, 3.90.
C21H22ClNO2 requires C, 70.88; H, 6.23; N, 3.94%]; Rf
(20% ethyl acetate/pet. ether) 0.39; nmax (KBr) 3432,
1724 cmꢁ1; dH (300 MHz, CDCl3) 6.80–7.42 (9H, m, Ph),
4.07 (1H, dt, J 12.6, 3.0 Hz, CHaHbNPh), 3.67 (1H, m,
CH(Ph)CH2), 3.67 (1H, m, CHaHbNPh), 3.22 (1H, m,
CHaHbNPh), 3.22 (1H, m, CHaHbCHPh), 2.91 (1H, dd, J
12.3, 2.4 Hz, CHaHbNPh), 2.47 (1H, m, CHCHPh), 2.47
(1H, m, CHCO), 2.32 (1H, s, OH), 1.85 (1H, dd, J 13.5,
5.1 Hz, CHaHbCHPh), 1.61 (3H, s, CH3); dC (75 MHz,
CDCl3) 215.2, 149.7, 141.0, 139.1, 129.0, 128.5, 128.4,
128.1, 127.0, 119.6, 115.7, 77.1, 59.0, 53.1, 52.7, 51.8,
43.5, 38.5, 28.5.
collected were 3793 of which 3168 unique [R(int)¼0.0894];
2034 reflections I>2s(I), R1¼0.0907 and wR2¼0.2390
for 2034 [I>2s(I)] and R1¼0.1304 and wR2¼0.2740 for
all (3168) intensity data. Goodness of fit¼1.008, residual
electron density in the final Fourier map was 0.516 and
ꢁ0.482 eAꢁ3. CCDC number is 616379.
˚
Acknowledgements
S.P. thanks the Council of Scientific and Industrial Research,
New Delhi for a major research project. S.P. also thanks De-
partment of Science and Technology, New Delhi for funds
under (i) IRHPA programme for the purchase of a high res-
olution NMR spectrometer and (ii) FIST programme and
University Grants Commission, New Delhi for funds under
the DRS and ASIST programmes. M.S. thanks CSIR for
the award of a Senior Research Fellowship.
4.3.6. 3-(3-Nitrophenyl)-6-hydroxy-6-methyl-8-phenyl-3-
azabicyclo[3.3.1]nonan-9-one 5f. Isolated as a white solid
(71%), mp 151 ꢀC [Found: C, 68.89; H, 6.01; N, 7.71.
C21H22N2O4 requires C, 68.84; H, 6.05; N, 7.65%]; Rf
(20% ethyl acetate/pet. ether) 0.40; nmax (KBr) 3466,
1724 cmꢁ1; dH (300 MHz, CDCl3) 6.89–7.88 (9H, m, Ph),
4.11 (1H, dt, J 12.6, 3.0 Hz, CHaHbNPh), 3.69 (1H, m,
CH(Ph)CH2), 3.69 (1H, m, CHaHbNPh), 3.27 (1H, m,
CHaHbNPh), 3.27 (1H, m, CHaHbCHPh), 2.96 (1H, dd, J
12.3, 2.4 Hz, CHaHbNPh), 2.55 (1H, m, CHCHPh), 2.55
(1H, m, CHCO), 2.34 (1H, s, OH), 1.91 (1H, dd, J 13.5,
5.1 Hz, CHaHbCHPh), 1.56 (3H, s, CH3); dC (75 MHz,
CDCl3) 213.4, 149.3, 140.9, 139.4, 138.6, 128.9, 128.6,
128.3, 128.0, 127.5, 119.7, 115.6, 76.9, 58.8, 53.3, 52.4,
51.6, 43.4, 38.8, 28.9.
Supplementary data
Supplementary data (chiral HPLC chromatograms of 3a and
1
5a, and H NMR, 13C NMR, H,H–COSY, C,H–COSY and
HMBC spectra of compounds 3a, 4a and 5a) associated
with this article are available online. Supplementary data as-
sociated with this article can be found in the online version,
at doi:10.1016/j.tet.2007.01.038.
References and notes
4.4. X-ray crystallographic determination of 4a and 5a
Data were collected at room temperature on an Enraf-Nonius
MACH 3 four-circle diffractometer (Mo Ka radiation,
l¼0.71073 A) for compounds 4a and 5a. The data collec-
1. Bermejo, A.; Andreu, I.; Suvire, F.; Leonce, S.; Caignard,
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2. Bringmann, G.; Messer, K.; Brun, R.; Mudogo, V. J. Nat. Prod.
2002, 65, 1096.
˚
tion, integration and data reduction for 4a and 5a were
performed using CAD-4 EXPRESS27 and XCAD428 pro-
grammes and an empirical absorption correction was applied
using c scan method.29 The unit cell parameters were deter-
mined by a least square fitting of 25 randomly selected
strong reflections and an empirical absorption correction
was applied using the azimuthal scan method. The structures
were solved by direct methods (SHELXS 97)30 and sub-
sequent Fourier synthesis, and refined by full matrix least
squares on SHELXL 9731 for all non-hydrogen atoms in
4a and 5a. All hydrogen atoms were placed at calculated
positions.
3. Bringmann, G.; Wohlfarth, M.; Rischer, H.; Schlauer, J.; Brun,
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4.4.1. Compound 4a. C33H35NO2, M¼477.62, monoclinic,
˚
˚
space group C2, a¼30.051(8) A, b¼11.696(7) A, c¼
3
ꢀ
˚
˚
20.899(9) A, b¼133.55 (6), V¼5323.5(8) A, Z¼8, f(000)¼
1620, m¼0.059 mmꢁ1, Dc¼0.946 mg/m3. The reflections
collected were 5356 of which 4924 unique [R(int)¼0.0359];
2115 reflections I>2s(I), R1¼0.0432 and wR2¼0.0727 for
2115 [I>2s(I)] and R1¼0.1730 and wR2¼0.1016 for all
(4924) intensity data. Goodness of fit¼1.003, residual
electron density in the final Fourier map was 0.187 and
ꢁ0.160 eAꢁ3. CCDC number is 616378.
˚
4.4.2. Compound 5a. C21H23NO2, M¼321.40, monoclinic,
˚
˚
space group P21/a, a¼15.311(8) A, b¼8.322(3) A, c¼
3
ꢀ
˚
˚
15.866(6) A, b¼116.91 (5), V¼1802.9(8) A , Z¼4, f(000)¼
688, m¼0.076 mmꢁ1, Dc¼01.184 mg/m3. The reflections
13. Yoshitomi. Fr. Patent 1,557,671, 1969; Chem. Abstr. 1969, 72,
43472.

2874
M. Srinivasan, S. Perumal / Tetrahedron 63 (2007) 2865–2874
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