2-(N-Allylaminomethyl)cinnamaldehydes as substrates for syntheses of aza-polycycles via intramolecular cycloaddition reactions

Article abstract of DOI:10.1016/j.tet.2012.01.016

Syntheses of a variety of aza-polycycles employing 2-(N-allylaminomethyl) cinnamaldehydes derived from Morita-Baylis-Hillman adducts of acrylates via intramolecular 1,3-dipolar cycloaddition, or Aza-Diels-Alder or domino Knoevenagel/hetero Diels-Alder cyc

Full text of DOI:10.1016/j.tet.2012.01.016

Tetrahedron 68 (2012) 2146e2154
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
2-(N-Allylaminomethyl)cinnamaldehydes as substrates for syntheses
of aza-polycycles via intramolecular cycloaddition reactionsq
,
Amita Mishra a, Neeraj Rastogi b, Sanjay Batra a
*
a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute PO Box 173, Lucknow 226001, UP, India
b Centre of Biomedical Magnetic Resonance, Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow 226014 UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Syntheses of a variety of aza-polycycles employing 2-(N-allylaminomethyl)cinnamaldehydes derived
from MoritaeBayliseHillman adducts of acrylates via intramolecular 1,3-dipolar cycloaddition, or Aza-
DielseAlder or domino Knoevenagel/hetero DielseAlder cycloaddition reactions are described. Whereas
the Aza-DielseAlder afforded a mixture of cis- and trans-isomers of substituted 1,2,3,4,4a,5,10,10a-oc-
tahydrobenzo[b][1,6]naphthyridines, the 1,3-dipolar cycloaddition and domino Knoevenagel/hetero
DielseAlder were diastereoselective to produce exclusively cis-derivatives of 1,2,3,4,4a,6,7,8,9,9a-deca-
hydro-1H-pyrido[3,4-b]pyrrolizine-8a-carboxylates and 3,4,4a,5,7,8,9,10b-octahydro-1H-chromeno[3,4-
c]pyridin-10(2H)-ones, respectively.
Received 27 November 2011
Received in revised form 31 December 2011
Accepted 10 January 2012
Available online 17 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
to give sugar-containing aza-polycyclic compounds,4 there is lack of
investigation on reaction of azomethine ylide dipole originating
The intramolecular cycloaddition is considered to be a robust
strategy for accomplishing the synthesis of complex heterocycles.1
In general; the reaction involves formation of at least two chemical
bonds and a new ring system with high regio- and stereo-
selectivity. Amongst a wide spectrum of intramolecular cycload-
dition reactions, the ones performed with the azomethine ylides
are very popular as they result in pyrrolidine core, which is part of
several alkaloid natural products.2 Essentially this reaction is re-
alized from a substrate carrying a dipole and a dipolarophile to-
gether. Remarkable influence of MoritaeBayliseHillman (MBH)
reaction on development of strategies for preparing heterocycles
has motivated several research groups to perform intramolecular
cycloaddition reactions on MBH derivatives for the synthesis of
a number of polycycles.3 A critical analysis of these protocols
however, reveals that the azomethine ylides participating in these
cycloaddition reactions originates from the formyl group present
either in the aromatic system or the heteroaromatic system. Al-
though in a recent report it was demonstrated that a formyl group
in carbohydrate-based substrate can also be employed to prepare
azomethine ylide, which participate in such cycloaddition reaction
from MBH derivative containing an alkenylic formyl group. In
context of our work concerning the exploitation of substituted
allylamines derived from MBH adducts for constructing aza-het-
erocycles,5 it occurred to us that the 2-(N-allylaminomethyl)cin-
namaldehydes produced from the MBH adducts of acrylates can
undergo intramolecular cycloaddition to furnish pyrido[3,4-b]pyr-
rolizine and pyrrolo[3,2-c]pyridine. Such target compounds are
reported to be associated with anti-inflammatory (oxygenase in-
hibitors), anti-tumour (alkylating) agents and CNS activity.6aec
A
retrosynthetic scheme outlining the rational of the envisaged ap-
proach is presented in Scheme 1. Herein we present the results of
q
CDRI Communication No. 8184; In part presented as poster at 15th ISCB
International Conference held between 4th and 7th February, 2011 at Saurashtra
University, Rajkot, Gujarat.
* Corresponding author. Tel.: þ91 522 2612411 18x4234, 4368; fax: þ91 522
2623405, 2623938; e-mail addresses: batra_san@yahoo.co.uk, s_batra@cdri.res.in
(S. Batra).
Scheme 1. Retrosynthetic plan for the synthesis of pyrido[3,4-b]pyrrolizine and pyr-
rolo[3,2-c]pyridine.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.016

A. Mishra et al. / Tetrahedron 68 (2012) 2146e2154
2147
our study towards successful use of 2-(allyl(substituted amino)
methyl)-3-arylacrylaldehyde for the intramolecular cycloaddition
reactions. To extend the scope of the methodology, during the
course of this study we also prepared 2-((substituted(3-methylbut-
2-enyl)amino)methyl)-cinnamaldehyde and examined its applica-
tion towards Aza-DielseAlder (ADA) and Domino Knoevenagel/
hetero DielseAlder reactions.
Fig. 1. Preferred geometry for the formation of 10a.
2. Results and discussion
reaction of 8a with methyl proline ester under MW irradiation. To
our delight the reaction was complete in 30 min to afford 10a,
which was isolated in 68% yields. With the optimized condition in
hand we tested the protocol with other substrates 8bed,9a. It was
satisfying to note that the reaction between 8bed,9a and methyl
proline ester under MW conditions afforded the expected poly-
cycles 10bed,11a in good yields. All reactions were found to be
diastereoselectives to afford the cis-isomers exclusively. Sub-
sequently with the objective to increase the scope of the reactions,
we considered replacing the methyl proline ester with methyl
glycine ester as it would lead to bicyclic products instead of tricyclic
compounds. Therefore reactions of 8a and 9a with methyl glycine
ester under MW were examined. Expectedly here too reactions
were diastereoselectives and afforded the corresponding products
12a and 13a as cis-isomer in good yield.
The success with 1,3-dipolar cycloaddition, provoked us to in-
vestigate the utility of the same substrates for ADA reactions, which
would lead to new tetrahydroquinoline derivatives.10 Therefore the
reaction of aldehyde 9a with aniline was examined in the presence
of several Lewis acids in dry MeCN. Unfortunately all attempt led to
the formation of a mixture of products, which could not be isolated
in pure form. It is widely reported that amines activated with prenyl
group are better substrate for ADA reaction.11 Thus, starting from
3a,b prenyl derivatives 16a,b were prepared as described above and
in Scheme 3. Initially the ADA of 16a with aniline was attempted in
the presence of Yb(OTf)312 but the reaction failed and a mixture of
products was isolated. This led us to examine TFA and different
Lewis acids including InCl3, Sc(OTf)3, BiCl3 for the success of the
reaction. It was interesting to discover that the reaction proceeded
smoothly in the presence of BiCl3 but in the presence of all other
additives the reaction did not go beyond the formation of imine.
Under the influence of BiCl3, the reaction furnished the expected
product 17a as diastereomeric mixture in good yields (Scheme 3).
Pure cis and trans isomers were isolated via silica gel based column
chromatography. Next, to examine the scope of this reaction, only
a limited study was performed. In the first opportunity, in place of
aniline, the reaction of 16a with 4-fluoroaniline was carried out.
Expectedly this reaction too furnished the corresponding product
The work towards the desired objective commenced from the
MBH acetates 1aed, whichwere transformed to allylamines 2aed,3a
via SN20-reaction with benzylamine or tosylamine, respectively,
following the reported procedures.7a,b The stereochemistry of these
amines was assigned to be E exclusively.7a The reaction of substituted
allylamines with allyl bromide in the presence of K2CO3 in DMF at
room temperature afforded (E)-methyl 2-((N-allyl(substituted)
amino)methyl)-cinnamates (4aed,5a). To reduce the ester to formyl
group, 4aed,5a were initially treated with DIBAL-H at room tem-
perature to afford the corresponding alcohols 6aed,7a, which were
then oxidized in the presence of MnO2 to furnish (E)-2-((allyl(benzyl)
amino)methyl)-cinnamaldehyde 8aed,9a (Scheme 2). Next with the
required aldehydes in hand, their intramolecular cycloadditions
through formation of azomethine ylides were investigated. Initially
8a was treated with methyl proline ester in the presence of Et3N in
toluene at reflux. The reaction was completed in 12 h and afforded
a product, which was isolated in 33% yield. Structure elucidation of
the isolated product via spectroscopic analysis led us to establish the
structure of the compound as 10a. Importantly, the reaction was
observed to be diastereoselective to furnish the cis-isomer only. The
assignmentof cis stereochemistry to the protons at the ring junctions
of 10a was initially made by analogy with the stereochemistry ob-
served for conventional azomethine ylide cycloadditions in similar
systems8 and further corroborated by the coupling constant value of
5.1 Hz between them, which is consistent with a cis ring fusion. The
relative stereochemistry of the ester group was assigned to be cis on
the basis of the fact that the intramolecular cycloaddition proceeds
through an ylide with S-shaped geometry (Fig. 1).
It has been reported that such cycloaddition reactions proceed
more efficiently under microwave (MW) irradiation.9 Therefore, in
an attempt to increase the yield of the product we investigated the
Scheme 2. Reagents and conditions: (i) BnNH2, MeOH, rt, 1e2 h or TsNH2, K2CO3, THF,
75 ꢀC, 2 h; (ii) allyl bromide, K2CO3, DMF, rt, 2 h; (iii) DIBAL-H, PhMe, 0 ꢀC-rt, 0.5 h; (iv)
MnO2, CH2Cl2 (dry), rt, 2 h; (v) methyl proline/glycine ester hydrochloride, Et3N, PhMe,
MW, 120 ꢀC, 0.5e1 h.
Scheme 3. Reagents and conditions: (i) prenyl bromide, K2CO3, DMF, rt, 2e2.5 h;
(ii) DIBAL-H, PhMe, 0 ꢀC-rt, 0.5 h; (iii) MnO2, CH2Cl2 (dry), rt, 2 h; (iv) ArNH2, BiCl3,
MeCN, rt, 3e4 h.

2148
A. Mishra et al. / Tetrahedron 68 (2012) 2146e2154
18a as diastereomeric mixture, which was separated via column
chromatography. In the second sequence another aldehyde 16b was
synthesized and subjected to reaction with aniline and 4-
fluoroaniline. Likewise this aldehyde also furnished the respective
adducts 17b and 18b as diastereomeric mixture in good yields. Both
the cis and trans isomers were readily separated. In order to un-
ambiguously assign the structure of the products a single crystal X-
ray analysis of cis-18a was carried and the result is presented in
Fig. 2.13
synthesized. Importantly, the 1,3-dipolar cycloaddition and domino
Knoevenagel/hetero DielseAlder were diastereoselective to pro-
duce exclusively cis-products. Further exploration towards the
synthetic utility of these 2-(N-allylaminomethyl)cinnamaldehydes
is underway in our laboratory.
4. Experimental
4.1. General
Melting points are uncorrected and were determined in capil-
lary tubes on a Precision melting point apparatus containing silicon
oil. IR spectra were recorded using a PerkineElmer’s RX I FTIR
spectrophotometer. 1H NMR and 13C NMR spectra were recorded
either on a Bruker DPX-200 FT or Bruker Avance DRX-300 spec-
trometer, using TMS as an internal standard (chemical shifts in d).
The detailed 2D NMR experiments were conducted on Bruker-
400 MHz spectrometer. The ESMS were recorded on MICROMASS
Quadro-II LCMS system. The HRMS spectra were recorded as EI-
HRMS on a JEOL system or as DART-HRMS (recorded as ESþ) on
a JEOL-AccuTOF JMS-T100LC Mass spectrometer having DART (Di-
rect Analysis in Real Time) source. Elemental analyses were per-
formed on a Carlo Erba’s 108 or an Elementar’s Vario EL III
microanalyzer. The room temperature varied between 20 ꢀC and
35 ꢀC. The stereochemistry displayed in the products is relative and
not absolute.
Fig. 2. Ortep structure of cis-18a at 35% probability level.
4.2. General procedure for the synthesis of 4aed,5a as
exemplified by 4a
Finally, the utility of the aldehyde 16a,b in domino Knoevenagel/
Hetero DielseAlder reactions was investigated. The optimization
study was carried out using 16a and 5,5-dimethyl-1,3-cyclo-
hexanedione. After conducting a series of reactions for optimiza-
tion, it was discovered that 16a reacts with 5,5-dimethyl-1,3-
cyclohexanedione in the presence of piperidine as a catalyst in
toluene under MW condition to afford the product 19a stereo-
selectively as cis-isomer (Scheme 4). The cis stereochemistry of 19a
was confirmed via literature precedence14 and corroborated by
carrying out detailed NMR experiments (see Supplementary data).
To test the scope of the method 16b was reacted with 5,5-dimethyl-
1,3-cyclohexanedione and both 16a and 16b were reacted with 1,3-
cyclohexanedione. It was satisfying to note that all reactions
smoothly afford the respective products 19b and 20a,b as cis-
isomer exclusively.
To a stirred solution of 3a (1.00 g, 3.56 mmol) in anhyd DMF
(8 mL) was added K2CO3 (0.74 g, 5.34 mmol) and the mixture was
stirred for 10 min. Then allyl bromide (0.37 mL, 4.27 mmol) was
added and the mixture was stirred at room temperature for 2 h.
When the reaction was complete, the mixture was diluted with H2O
(30 mL) and extracted with EtOAc (3ꢁ20 mL). The combined or-
ganic layers were dried (anhyd Na2SO4) and concentrated to obtain
the crude product. Purification via column chromatography over
silica gel (100e200 mesh) using EtOAc/hexanes (1:9, v/v) as the
eluent furnished pure 4a (0.91 g, 80%) as colourless oil.
4.2.1. Methyl (E)-2-[(N-allyl-N-benzylamino)methyl]-3-phenylprop-
2-enoate (4a). Rf¼0.45 (EtOAc/hexanes 1:4, v/v). IR (Neat):
nmax¼1710 (CO2Me) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
¼3.04 (d, 2H,
d
J¼6.5 Hz, CH2), 3.53 (d, 4H, J¼1.9 Hz, 2ꢁ CH2), 3.80 (s, 3H, OCH3),
5.06e5.11 (m, 2H, ]CH2), 5.79e5.93 (m, 1H, ]CH), 7.21e7.36 (m,
8H, ArH), 7.59 (dd, 2H, J1¼6.5 Hz, J2¼1.5 Hz, ArH), 7.74 (s, 1H, ]CH)
ppm. 13C NMR (CDCl3, 75 MHz):
128.0, 129.1, 129.9, 130.5, 133.4, 135.7, 139.0, 139.5, 142.4, 169.5 ppm.
MS (ES): m/z¼322.1 [Mþ1]þ. C21H23NO2 (321.1729): calcd C 78.47, H
7.21, N 4.36; found C 78.63, H 7.02, N 4.23.
d
¼51.9, 56.7, 58.0, 62.3, 117.4, 126.8,
4.2.2. Methyl (E)-2-[(N-allyl-N-benzylamino)methyl]-3-(2-
chlorophenyl)prop-2-enoate (4b). This compound was isolated in
75% yield (1.69 g from 2.00 g) as brown oil. Rf¼0.44 (EtOAc/hexanes
1:4, v/v). IR (Neat): nmax¼1723 (CO2Me) cmꢂ1
.
1H NMR (CDCl3,
Scheme 4. (i) Substituted 1,3-cyclohexanedione, piperidine, PhMe, MW, 120 ꢀC,
0.5e2 h.
300 MHz):
d
¼3.27 (d, 4H, J¼1.3 Hz, 2ꢁ CH2), 3.60 (s, 2H, CH2), 3.80
(s, 3H, OCH3), 5.05e5.16 (m, 2H, ]CH2), 5.83e5.97 (m, 1H, ]CH),
7.34e7.49 (m, 9H, ArH), 7.82 (s, 1H, ]CH) ppm. 13C NMR (CDCl3,
3. Conclusions
75 MHz):
d
¼45.4, 52.2, 52.3, 57.9, 116.4, 128.7, 129.0, 129.7, 130.8,
135.2, 136.7, 142.2, 168.7 ppm. MS (ES): m/z¼356.3 [Mþ1]þ.
C21H22ClNO2 (355.1339): calcd C 70.88, H 6.23, N 3.94; found C
70.93, H 6.30, N 3.83.
In summary we have demonstrated for the first time that the b-
allylaminoaldehydes derived from MoritaeBayliseHillman adducts
can be employed as substrates for the synthesis of aza-polycycles
via different classes of cycloaddition reactions. As demonstrated
these 2-(N-allylaminomethyl)cinnamaldehydes can be readily
4.2.3. Methyl (E)-2-[(N-allyl-N-benzylamino)methyl]-3-(4-
fluorophenyl)prop-2-enoate (4c). This compound was isolated in

A. Mishra et al. / Tetrahedron 68 (2012) 2146e2154
2149
83% yield (0.94 g from 1.00 g) as brown oil. Rf¼0.44 (EtOAc/hexanes
CH2), 5.11e5.17 (m, 2H, ]CH2), 5.72e5.89 (m, 1H, ]CH), 6.69 (s, 1H,
]CH), 7.09e7.12 (m, 1H, ArH), 7.22e7.42 (m, 8H, ArH) ppm. 13C
.
1:4, v/v). IR (Neat): nmax¼1715 (CO2Me) cmꢂ1 1H NMR (CDCl3,
300 MHz):
d
¼3.12 (d, 2H, J¼6.3 Hz, CH2), 3.44 (d, 4H, J¼1.0 Hz, 2ꢁ
NMR (CDCl3, 50 MHz):
d
¼53.1, 56.6, 58.4, 69.0, 119.2, 126.5, 127.6,
CH2), 3.67 (s, 3H, OCH3), 5.15e5.24 (m, 2H, ]CH2), 5.76e5.93 (m,
1H, ]CH), 7.00e7.09 (m, 3H, ArH), 7.21e7.31 (m, 7H, ]CH and ArH)
127.8, 128.8, 129.3, 129.6, 131.2, 134.1, 134.6, 135.4, 138.3, 139.3 ppm.
MS (ES): m/z¼328.4 [Mþ1]þ. C20H22ClNO (327.1390): calcd C 73.27,
H 6.76, N 4.27; found C 73.15, H 6.84, N 4.18.
ppm. 13C NMR (CDCl3, 75 MHz):
d
¼51.7, 52.5, 56.3, 57.8, 115.7, 117.8,
123.9, 124.0, 127.1, 128.3, 129.1, 129.8, 129.9, 135.6, 139.3, 169.3 ppm.
MS (ES): m/z¼340.3 [Mþ1]þ. C21H22FNO2 (339.1635): calcd C 74.31,
H 6.53, N 4.13; found C 74.39, H 6.42, N 4.22.
4.3.3. (E)-2-{[N-Allyl-(N-benzyl)amino]methyl}-3-(4-fluorophenyl)
prop-2-en-1-ol (6c). This compound was isolated in 80% yield
(0.59 g from 0.80 g) as red oil. Rf¼0.20 (EtOAc/hexanes 1:4, v/v). IR
4.2.4. Methyl (E)-2-[(N-allyl-N-benzylamino)methyl]-3-(4-
methylphenyl)prop-2-enoate (4d). This compound was isolated in
83% yield (2.36 g from 2.50 g) as brown oil. Rf¼0.42 (EtOAc/hexanes
(Neat): nmax¼3569 (OH) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
¼3.17 (d,
d
2H, J¼6.4 Hz, CH2), 3.37 (s, 2H, CH2), 3.67 (s, 2H, CH2), 4.32 (s, 2H,
CH2), 5.24e5.28 (m, 2H, ]CH2), 5.84e5.99 (m, 1H, ]CH), 6.47 (s,
1H, ]CH), 7.10e7.13 (m, 1H, ArH), 7.23e7.29 (m, 8H, ArH) ppm. 13C
1:4, v/v). IR (Neat): nmax¼1710 (CO2Me) cmꢂ1
.
1H NMR (CDCl3,
¼2.38 (s, 3H, CH3), 3.04 (d, 2H, J¼6.6 Hz, CH2), 3.54 (s,
300 MHz):
d
NMR (CDCl3, 75 MHz):
d
¼56.3, 58.3, 61.5, 63.0, 115.4, 115.7, 119.4,
4H, 2ꢁ CH2), 3.79 (s, 3H, OCH3), 5.07e5.12 (m, 2H, ]CH2),
5.81e5.95 (m, 1H, ]CH), 7.15e7.26 (m, 7H, ArH), 7.53 (d, 2H,
J¼8.0 Hz, ArH), 7.73 (s, 1H, ]CH) ppm. 13C NMR (CDCl3, 75 MHz):
123.5, 124.0, 127.7, 128.8, 129.3, 129.4, 129.5, 131.0, 134.4, 139.4 ppm.
MS (ES): m/z¼312.3 [Mþ1] .C20H22FNO (311.1685): calc C 77.14, H
7.12, N 4.50; found C 77.20, H 7.06, N 4.55.
d
¼21.4, 50.1, 51.9, 56.7, 58.0, 117.5, 126.8, 128.0, 129.1, 129.9, 130.5,
132.5, 133.4, 135.7, 139.0, 139.5, 142.4, 169.5 ppm. MS (ES) m/
z¼336.0 [Mþ1]þ. C22H25NO2 (335.1885): calcd C 78.77, H 7.51, N
4.18; found C 78.85, H 7.43, N 4.33.
4.3.4. (E)-2-{[N-Allyl-(N-benzyl)amino]methyl}-3-(4-methylphenyl)
prop-2-en-1-ol (6d). This compound was isolated in 80% yield
(1.10 g from 1.50 g) as reddish brown oil. Rf¼0.29 (EtOAc/hexanes
1:4, v/v). IR (Neat): nmax¼3402 (OH) cmꢂ1
.
1H NMR (CDCl3,
¼2.36 (s, 3H, CH3), 2.99 (d, 2H, J¼6.4 Hz, CH2), 3.40 (s,
4.2.5. Methyl (E)-2-[(N-allyl-N-4-methylphenylsulfonamido)methyl]-
3-phenylprop-2-enoate (5a). This compound was isolated in 75%
yield (0.84 g from 1.00 g) as a white solid, mp 142e143 ꢀC. Rf¼0.35
300 MHz):
d
2H, CH2), 3.48 (s, 2H, CH2), 4.28 (s, 2H, CH2), 5.10e5.17 (m, 2H, ]
CH2), 5.74e5.87 (m, 1H, ]CH), 6.68 (s, 1H, ]CH), 7.06 (d, 2H,
J¼7.9 Hz, ArH), 7.15 (d, 2H, J¼7.9 Hz, ArH), 7.24e7.32 (m, 5H, ArH)
(EtOAc/hexanes 1:4, v/v). IR (KBr): nmax¼1713 (CO2Me) cmꢂ1
.
1H
NMR (CDCl3, 300 MHz):
d
¼2.44 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 3.75
ppm. 13C NMR (CDCl3, 50 MHz):
127.4, 128.6, 129.0, 129.2, 130.4, 133.9, 134.7, 136.7, 137.2, 138.2 ppm.
MS (ES): m/z¼308.0 [Mþ1]þ. C21H25NO (307.1936): calcd C 82.04, H
8.20, N 4.56; found C 82.23, H 8.05, N 4.63.
d
¼21.3, 52.8, 56.6, 58.3, 69.4, 118.8,
(s, 2H, CH2), 4.24 (s, 2H, CH2), 4.90e4.95 (m, 2H, ]CH2), 5.46e5.59
(m, 1H, ]CH), 7.22e7.26 (m, 2H, ArH), 7.41 (br s, 5H, ArH), 7.55 (d,
2H, J¼8.2 Hz, ArH), 7.80 (s, 1H, ]CH) ppm. 13C NMR (CDCl3,
75 MHz):
d
¼21.7, 43.6, 51.4, 52.3, 118.5, 127.7, 128.3, 128.8, 129.3,
129.7, 130.0, 133.6, 134.7, 136.4, 143.4, 143.7, 168.2 ppm. MS (ES): m/
z¼385.9 [Mþ1]þ. C21H23NO4S (385.1348): calcd C 65.43, H 6.01, N
3.63; found C 65.55, H 6.12, N 3.51.
4.3.5. (E)-2-{[N-Allyl-(N-tosyl)amino]methyl}-3-phenylprop-2-en-ol
(7a). This compound was isolated in 80% yield (0.59 g from 0.80 g)
as colourless oil. Rf¼0.20 (EtOAc/hexanes 1:4, v/v). IR (Neat):
nmax¼3655 (OH) cmꢂ1
.
1H NMR (CDCl3, 200 MHz):
d
¼2.42 (s, 3H,
4.3. General procedure for the synthesis of 6aed,7a, 15a,b as
exemplified by 6a
CH3), 3.63 (d, 2H, J¼6.7 Hz, CH2), 4.01 (s, 2H, CH2), 4.34 (s, 2H, CH2),
4.56 (dd, 1H, J1¼17.0 Hz, J2¼1.3 Hz, CH2), 4.76 (dd, 1H, J1¼10.1 Hz,
J2¼1.2 Hz, ]CH2), 5.19e5.39 (m, 1H, ]CH), 6.78 (s, 1H, ]CH),
7.07e7.11 (m, 2H, ArH), 7.22e7.30 (m, 5H, ArH), 7.65 (dd, 2H,
To a stirred solution of 4a (0.80 g, 2.49 mmol) in toluene (20 mL),
was added 1.0 M DIBAL-H in toluene (6.23 mL, 6.23 mmol) at 0 ꢀC
under N2. The mixture was stirred at room temperature for 30 min.
When the reaction was completed as monitored by TLC, the re-
action mixture was quenched with MeOH (15 mL) and the sepa-
rated precipitate was filtered through Celite. The filtrate was
evaporated under reduced pressure to obtain a residue, which upon
column chromatography over silica gel (100e200 mesh) using
EtOAc/hexanes (1:4, v/v) as the eluent furnished 6a (0.58 g, 80%) as
brown oil.
J1¼6.6 Hz, J2¼1.7 Hz, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
¼21.7,
d
43.8, 50.6, 65.1, 77.5, 119.8, 127.3, 127.4, 128.5, 129.0, 130.0, 131.4,
131.5, 136.3, 136.9, 143.8 ppm. MS (ES): m/z¼357.9 [Mþ1]þ.
C20H23NO3S (357.1399); calcd C 67.20, H 6.49, N 3.92; found C 67.28,
H 6.53, N 3.83.
4.3.6. (E)-2-{[N-3-Methylbut-2-enyl-(N-tosyl)amino]methyl}-3-
phenylprop-2en-ol (15a). This compound was isolated in 88% yield
(1.23 g from 1.50 g) as colourless oil. Rf¼0.25 (EtOAc/hexanes 1:4, v/
v). IR (Neat): nmax¼3454 (OH) cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
¼1.30 (s, 3H, CH3), 1.41 (s, 3H, CH3), 2.42 (s, 3H, CH3), 3.68 (d, 2H,
4.3.1. (E)-2-{[N-Allyl-(N-benzyl)amino]methyl}-3-phenylprop-2-en-
d
1-ol (6a). Rf¼0.31 (EtOAc/hexanes 1:4, v/v). IR (Neat): nmax¼3430
J¼6.7 Hz, CH2), 4.02 (s, 2H, CH2), 4.35 (s, 2H, CH2), 4.63e4.68 (m,1H,
]CH), 6.74 (s, 1H, ]CH), 7.09 (d, 2H, J¼6.8 Hz, ArH), 7.22e7.31 (m,
5H, ArH), 7.63 (d, 2H, J¼8.2 Hz, ArH) ppm. 13C NMR (CDCl3,
(OH) cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
d
¼3.00 (d, 2H, J¼6.4 Hz,
CH2), 3.41 (s, 2H, CH2), 3.50 (s, 2H, CH2), 4.30 (s, 2H, CH2), 5.10e5.18
(m, 2H, ]CH2), 5.72e5.87 (m, 1H, ]CH), 6.73 (s, 1H, ]CH), 7.16 (d,
2H, J¼7.0 Hz, ArH), 7.28e7.37 (m, 8H, ArH) ppm. 13C NMR (CDCl3,
50 MHz):
d
¼17.6, 21.6, 25.6, 44.2, 45.7, 65.1, 118.0,126.6, 127.2, 127.3,
128.2, 129.0, 129.8, 130.5, 136.2, 136.6, 137.28, 137.31, 143.5 ppm. MS
(ES) m/z¼385.6 [Mþ1]þ. C22H27NO3S (385.1712): calcd C 68.54, H
7.06, N 3.63; found C 68.42, H 6.92, N 3.72.
75 MHz):
d
¼52.7, 56.5, 58.3, 69.5, 119.1, 127.0, 127.4, 128.2, 128.5,
129.0, 129.2, 130.6, 136.7, 137.5 ppm. MS (ES): m/z¼294.2 [Mþ1]þ.
C20H23NO (293.1780): calcd C 81.87, H 7.90, N 4.77; found C 81.92, H
8.10, N 4.63.
4.3.7. (E)-2-{[N-3-Methylbut-2-enyl-(N-tosyl)amino]methyl}-3-(2-
chlorophenyl)prop-2-en-ol (15b). This compound was isolated in
80% yield (1.12 g from 1.50 g) as colourless oil. Rf¼0.23 (EtOAc/
hexanes 1:4, v/v). IR (Neat): nmax¼3459 (OH) cmꢂ1. 1H NMR (CDCl3,
4.3.2. (E)-2-{[N-Allyl-(N-benzyl)amino]methyl}-3-(2-chlorophenyl)
prop-2-en-1-ol (6b). This compound was isolated in 85% yield
(1.33 g from 1.70 g) as brown oil. Rf¼0.25 (EtOAc/hexanes 1:4, v/v).
300 MHz):
d
¼1.37 (s, 3H, CH3), 1.41 (s, 3H, CH3), 2.42 (s, 3H, CH3),
IR (Neat): nmax¼3567 (OH) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
d
¼2.99
3.69 (d, 2H, J¼6.7 Hz, CH2), 3.92 (s, 2H, CH2), 4.38 (d, 2H, J¼6.9 Hz,
CH2), 4.56e4.61 (m, 1H, ]CH), 6.75 (s, 1H, ]CH), 7.04e7.07 (m, 1H,
(d, 2H, J¼6.4 Hz, CH2), 3.27 (s, 2H, CH2), 3.47 (s, 2H, CH2), 4.35 (s, 2H,

2150
A. Mishra et al. / Tetrahedron 68 (2012) 2146e2154
ArH), 7.17e7.37 (m, 5H, ArH), 763 (d, 2H, J¼8.2 Hz, ArH) ppm. 13
C
[Mþ1]þ. C21H23NO (305.1780): calcd C 82.58, H 7.59, N 4.59; found
NMR (CDCl3, 50 MHz):
d
¼18.0, 21.7, 25.8, 30.5, 41.2, 67.7,119.1,125.7,
C 82.44, H 7.68, N 4.72.
126.4, 126.8, 127.4, 127.6, 128.5, 129.8, 137.3, 137.8, 143.5 ppm. MS
(ES) m/z¼420.1 [Mþ1]þ. C22H26ClNO3S (419.1322): calcd C 62.92, H
6.24, N 3.34; found C 62.84, H 6.18, N 3.39.
4.4.5. (E)-2-{[N-Allyl-(N-tosyl)amino]methyl}-3-phenylprop-2-enal
(9a). This compound was isolated in 80% yield (0.40 g from 0.50 g)
as a white solid, mp 66e67 ꢀC. Rf¼0.30 (EtOAc/hexanes 1:4, v/v). IR
4.4. General procedure for the formation of 8aed,9a and
16aeb as exemplified by 8a
(KBr): nmax¼1681 (CHO) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
¼2.44
d
(s, 3H, CH3), 3.69 (d, 2H, J¼6.0 Hz, CH2), 4.20 (s, 2H, CH2), 4.91e5.00
(m, 2H, ]CH2), 5.50e5.59 (m, 1H, ]CH), 7.26e7.31 (m, 2H, ArH),
7.47e7.52 (m, 4H, ArH), 7.62 (d, 2H, J¼8.2 Hz, ArH), 7.73e7.76 (m,
2H, ]CH and ArH), 9.49 (s,1H, CHO) ppm. 13C NMR (CDCl3, 50 MHz)
To a stirred solution of 6a (0.40 g, 1.37 mmol) in dry DCM
(10 mL) at room temperature was added activated MnO2 (1.78 g,
20.55 mmol) and the reaction was continued at same temperature
for 1 h. When the reaction was completed as monitored by TLC,
the reaction mixture was diluted with DCM and filtered through
Celite. The filtrate was evaporated to afford the crude product as
oil. Purification by column chromatography over silica gel
(100e200 mesh) using EtOAc/hexanes (1:9, v/v) as the eluent
furnished 8a (0.34 g, 85%) as brown oil.
d
¼21.7, 41.7, 51.4, 118.0, 127.9, 129.1, 129.9, 130.9, 131.0, 133.75,
133.78, 135.3, 135.7, 143.8, 154.6, 194.5 ppm. MS (ES): m/z¼355.9
[Mþ1]þ. C20H21NO3S (355.1242): calcd C 67.58, H 5.95, N 3.94;
found C 67.60, H 6.00, N 3.82.
4.4.6. (E)-2-{[N-3-Methylbut-2-enyl-(N-tosyl)amino]methyl}-3-
phenylprop-2-enal (16a). This compound was isolated in 81% yield
(1.05 g from 1.30 g) as a white solid, mp 90e93 ꢀC. Rf¼0.30 (EtOAc/
hexanes 1:4, v/v). IR (KBr): nmax¼1682 (CHO) cmꢂ1. 1H NMR (CDCl3,
4.4.1. (E)-2-{[N-Allyl-(N-benzyl)amino]methyl}-3-phenylprop-2-enal
(8a). Rf¼0.40 (EtOAc/hexanes 1:4, v/v). IR (Neat): nmax¼1679 (CHO)
300 MHz):
d
¼1.47 (s, 3H, CH3), 1.50 (s, 3H, CH3), 2.43 (s, 3H, CH3),
cmꢂ1. 1H NMR (CDCl3, 300 MHz):
d
¼3.06 (d, 2H, J¼6.6 Hz, CH2), 3.50
3.68 (d, 2H, J¼6.3 Hz, CH2), 4.21 (s, 2H, CH2), 4.81e4.83 (m, 1H, ]
CH), 7.26e7.29 (m, 2H, ArH), 7.46e7.51 (m, 4H, ArH), 7.61 (d, 2H,
J¼8.2 Hz, ArH), 7.71e7.74 (m, 2H, ]CH and ArH), 9.50 (s, 1H, CHO)
(s, 2H, CH2), 3.54 (s, 2H, CH2), 5.11e5.17 (m, 2H, ]CH2), 5.86e5.99
(m, 1H, ]CH), 7.26 (s, 7H, ArH), 7.39e7.41 (m, 4H, ]CH and ArH),
9.59 (s, 1H, CHO) ppm. 13C NMR (CDCl3, 75 MHz):
d
¼47.4, 57.1, 58.4,
ppm. 13C NMR (CDCl3, 75 MHz):
d¼18.0, 21.8, 25.7, 41.5, 46.7, 120.0,
118.0, 127.0, 128.1, 128.6, 129.3, 130.2, 131.4, 134.6, 135.5, 138.9,
139.3, 153.8, 195.4 ppm. MS (ES): m/z¼292.1 [Mþ1]þ. C20H21NO
(291.1623): calcd C 82.44, H 7.26, N 4.81; found C 82.36, H 7.33, N
4.92.
127.9, 129.1, 129.8, 130.9, 131.1, 133.9, 135.7, 135.8, 135.9, 143.6, 153.7,
194.2 ppm. MS (ES) m/z¼384.1 [Mþ1]þ. C22H25NO3S (383.1555):
calcd C 68.90, H 6.57, N 3.65; found C 68.97, H 6.52, N 3.61.
4.4.7. (E)-2-{[N-3-Methylbut-2-enyl-(N-tosyl)amino]methyl}-3-(2-
chlorophenyl)prop-2-enal (16b). This compound was isolated in
75% yield (0.75 g from 1.00 g) as a white solid, mp 95e96 ꢀC.
4.4.2. (E)-2-{[N-Allyl-(N-benzyl)amino]methyl}-3-(2-chlorophenyl)
prop-2-enal (8b). This compound was isolated in 87% yield (1.04 g
from 1.20 g) as brown oil. Rf¼0.38 (EtOAc/hexanes 1:4, v/v). IR
Rf¼0.29 (EtOAc/hexanes 1:4, v/v). IR (KBr): nmax¼1680 (CHO) cmꢂ1
.
(Neat): nmax¼1667 (CHO) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
d
¼3.00
1H NMR (CDCl3, 300 MHz):
d
¼1.50 (s, 3H, CH3), 1.52 (s, 3H, CH3),
(d, 2H, J¼6.5 Hz, CH2), 3.41 (s, 2H, CH2), 3.50 (s, 2H, CH2), 5.07e5.13
(m, 2H, ]CH2), 5.78e5.89 (m, 1H, ]CH), 7.22e7.46 (m, 8H, ArH),
7.72 (s,1H, ]CH), 8.13 (dd,1H, J1¼7.6 Hz, J2¼1.5 Hz, ArH), 9.67 (s,1H,
2.42 (s, 3H, CH3), 3.66 (d, 2H, J¼6.6 Hz, CH2), 4.12 (s, 2H, CH2),
4.74e4.78 (m, 1H, ]CH), 7.25e7.27 (m, 2H, ArH), 7.37e7.43 (m, 3H,
ArH), 7.44e7.50 (m, 2H, ArH), 7.71 (s, 1H, ]CH), 7.76e7.79 (m, 1H,
CHO) ppm. 13C NMR (CDCl3, 75 MHz):
d
¼47.4, 57.1, 58.6,118.2,126.9,
ArH), 9.56 (s, 1H, CHO) ppm. 13C NMR (CDCl3, 75 MHz):
d
¼17.9, 21.6,
127.2, 128.4, 129.4, 129.8, 131.1, 132.6, 135.6, 139.3, 140.6, 144.0,
148.9, 195.2 ppm. MS (ES): m/z¼326.1 [Mþ1]þ. C20H20ClNO
(325.1233): calcd C 73.72, H 6.19, N 4.30; found C 73.85, H 6.25, N
4.17.
25.7, 41.2, 46.6, 119.2, 127.1, 127.6, 129.65, 129.73, 131.3, 131.7, 132.1,
134.3,135.9,136.5,138.1,143.5,148.8,193.7 ppm. MS (ES) m/z¼418.1
[Mþ1]þ. C22H24ClNO3S (417.1165): calcd C 63.22, H 5.79, N 3.35;
found C 63.28, H 5.82, N 3.41.
4.4.3. (E)-2-{[N-Allyl-(N-benzyl)amino]methyl}-3-(4-fluorophenyl)
prop-2-enal (8c). This compound was isolated in 87% yield (0.43 g
from 0.50 g) as brown oil. Rf¼0.35 (EtOAc/hexanes 1:4, v/v). IR
4.5. General procedure for the formation of 10aed, 11a, 12a
and 13a as exemplified by 10a
(Neat): nmax¼1667 (CHO) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
d
¼3.04
A heterogeneous suspension of 8a (0.25 g, 0.86 mmol), methyl
proline ester hydrochloride (0.28 g, 1.72 mmol) and TEA (0.24 mL,
1.72 mmol) in 5 mL of toluene was irradiated in a sealed tube with
microwaves for 30 min at 120 ꢀC. After cooling to room tempera-
ture, the solvent was evaporated under reduced pressure and the
reaction mixture was diluted with 10 mL of water and extracted
with EtOAc (3ꢁ10 mL). The combined organic layers were dried
over anhyd Na2SO4 and concentrated under reduced pressure.
Further purification of the crude product by column chromatog-
raphy over silica gel over silica gel (230e400 mesh) using EtOAc/
hexanes (1:4, v/v) as the eluent furnished 10a (0.23 g, 68%) as
reddish brown oil.
(d, 2H, J¼6.5 Hz, CH2), 3.42 (d, 2H, J¼1.1 Hz, CH2), 3.52 (s, 2H, CH2),
5.10e5.26 (m, 2H, ]CH2), 5.85e5.93 (m, 1H, ]CH), 7.10e7.18 (m,
2H, ArH), 7.23e7.38 (m, 7H, ArH), 7.62 (s, 1H, ]CH), 9.62 (s, 1H,
CHO) ppm. 13C NMR (CDCl3, 75 MHz):
d
¼47.6, 52.1, 57.2, 118.3, 127.2,
128.4, 128.5, 129.0, 129.4, 132.2, 132.5, 132.8, 135.6, 135.9, 139.3,
139.5, 139.7, 192.7 ppm. MS (ES): m/z¼310.2 [Mþ1]þ. C20H20FNO
(309.1529): calcd C 77.64, H 6.52, N 4.53; found C 77.83, H 6.46, N
4.64.
4.4.4. (E)-2-{[N-Allyl-(N-benzyl)amino]methyl}-3-(4-methylphenyl)
prop-2-enal (8d). This compound was isolated in 88% yield (0.87 g
from 1.00 g) as brown oil. Rf¼0.42 (EtOAc/hexanes 1:4, v/v). IR
(Neat): nmax¼1679 (CHO) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
d
¼2.40
4.5.1. (cis)-Methyl (E) 2-benzyl-4-benzylidene-1,2,3,4,4a,6,7,8,9,9a-
decahydro-1H-pyrido[3,4-b]pyrrolizine-8a-carboxylate
(10a). Rf¼0.23 (EtOAc/hexanes 1:4, v/v). IR (Neat): nmax¼1725
(s, 3H, CH3), 3.06 (d, 2H, J¼6.5 Hz, CH2), 3.49 (s, 2H, CH2), 3.54 (s, 2H,
CH2), 5.11e5.17 (m, 2H, ]CH2), 5.87e6.00 (m, 1H, ]CH), 7.19e7.27
(m, 7H, ArH), 7.35 (s, 1H, ]CH), 7.77 (d, 2H, J¼8.1 Hz, ArH), 9.56 (s,
(CO2Me) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
CH2), 1.72e1.82 (m, 2H, CH2), 1.94 (d, 1H, J¼4.4 Hz, CH2), 2.01e2.09
(m, 1H, CH2), 2.44 (d, 2H, J¼8.8 Hz, CH2), 2.62e2.67 (m, 1H, CH),
2.76e2.80 (m, 1H, CH2), 3.09e3.16 (m, 2H, CH2), 3.20e3.25 (m, 1H,
d
¼1.56 (d, 1H, J¼11.2 Hz,
1H, CHO) ppm. 13C NMR (CDCl3, 75 MHz):
d¼21.8, 47.7, 57.3, 58.6,
76.9, 118.2, 127.1, 128.3, 128.5, 128.9, 129.5, 129.6, 130.3, 131.8, 132.1,
135.8, 138.2, 139.7, 141.1, 154.4, 195.7 ppm. MS (ES): m/z¼306.1

A. Mishra et al. / Tetrahedron 68 (2012) 2146e2154
2151
CH2), 3.51 (d, 2H, J¼13.3 Hz, CH2), 3.65 (d, 1H, J¼13.5 Hz, CH2), 3.72
(s, 3H, OCH3), 4.12 (d, 1H, J¼5.1 Hz, CH), 6.55 (s, 1H, ArH), 7.23e7.35
(m, 8H, ArH), 7.80 (d, 2H, J¼7.3 Hz, ArH) ppm. 13C NMR (CDCl3,
CH2), 2.88e2.93 (m, 1H, CH2), 3.01e3.05 (m, 1H, CH2), 3.37 (dd, 1H,
J1¼12.2 Hz, J2¼5.0 Hz, CH2), 3.65e3.73 (m, 4H, CH2 and OCH3),
4.12e4.16 (m, 2H, CH and CH2), 6.61 (s, 1H, ]CH), 7.24e7.35 (m, 5H,
ArH), 7.66e7.71 (m, 4H, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
75 MHz):
d
¼27.2, 38.2, 40.9, 41.4, 51.3, 52.0, 58.6, 61.5, 62.3, 75.6,
127.2, 127.3, 128.1, 128.4, 129.2, 129.6, 136.2, 177.7 ppm. MS (ES): m/
z¼403.3 [Mþ1]þ. DART-HRMS [ESþ]: calcd for C26H31N2O2
403.2386; found 403.2380.
d¼21.7, 27.2, 37.5, 40.3, 41.7, 47.9, 50.8, 52.3, 52.5, 58.2, 75.9, 127.8,
127.9, 128.4, 129.6, 129.8, 130.0, 133.1, 134.3, 135.6, 143.8, 177.1 ppm.
MS (ES) m/z¼467.3 [Mþ1]þ. DART-HRMS [ESþ]: calcd for
C26H31N2O4S 467.2005; found 467.2012.
4.5.2. (cis)-Methyl (E) 2-benzyl-4-(2-chlorobenzylidene)-1,2,3,4,4a,-
6,7,8,9,9a-decahydro-1H-pyrido[3,4-b]pyrrolizine-8a-carboxylate
(10b). This compound was isolated in 72% yield (0.48 g from 0.50 g)
as reddish brown oil. Rf¼0.20 (EtOAc/hexanes 1:4, v/v). IR (Neat):
4.5.6. (cis)-Methyl (E) 5-benzyl-7-benzylidene-2,3,3a,4,5,6,7,7a-oc-
tahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (12a). This com-
pound was isolated in 74% yield (0.23 g from 0.25 g) as brown oil.
Rf¼0.15 (EtOAc/hexanes 1:4, v/v). IR (Neat): nmax¼1725 (CO2Me),
nmax¼1724 (CO2Me) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
¼1.56 (d,1H,
d
J¼11.4 Hz, CH2), 1.76e1.83 (m, 1H, CH2), 1.93e1.98 (m, 2H, CH2),
2.07e2.14 (m, 1H, CH2), 2.38e2.45 (m, 2H, CH2), 2.58e2.64 (m, 1H,
CH), 2.75 (dd, 1H, J1¼11.6 Hz, J2¼4.2 Hz, CH2), 3.06e3.09 (m, 1H,
CH), 3.18e3.28 (m, 2H, CH2), 3.51 (d, 2H, J¼13.2 Hz, CH2), 3.64e3.71
(m, 4H, CH2 and OCH3), 4.00 (d,1H, J¼5.3 Hz, CH), 6.82 (s, 1H, ]CH),
7.17e7.23 (m, 2H, ArH), 7.28e7.36 (m, 6H, ArH), 8.41e8.44 (m, 1H,
3415 (NH) cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
d
¼1.61 (dd, 1H,
J1¼12.7 Hz, J2¼4.8 Hz, CH2), 1.91 (d, 1H, J¼10.8 Hz, CH2), 2.24 (t, 2H,
J¼9.7 Hz, CH2), 2.64 (dd, 1H, J1¼11.5 Hz, J2¼4.1 Hz, CH), 3.08 (d, 1H,
J¼14.1 Hz, CH2), 3.25e3.30 (m, 1H, CH), 3.50 (d, 1H, J¼12.7 Hz, CH2),
3.61 (d, 1H, J¼13.0 Hz, CH2), 3.77 (s, 3H, OCH3), 3.80 (s, 1H, CH), 3.88
(d, 1H, J¼3.7 Hz, CH), 6.54 (s, 1H, ]CH), 7.21e7.35 (m, 8H, ArH), 7.45
ArH) ppm. 13C NMR (CDCl3, 75 MHz):
51.6, 52.2, 56.6, 58.8, 61.5, 62.3, 76.0, 126.7, 127.4, 127.9, 128.6, 128.7,
d
¼27.4, 38.4, 41.3, 41.7, 49.2,
(d, 2H, J¼8.6 Hz, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
¼34.9, 38.8,
d
52.5, 54.9, 57.8, 58.2, 58.8, 62.6, 123.4, 127.2, 127.3, 127.4, 128.4,
128.5, 128.7, 129.0, 129.5, 130.1, 134.5, 136.7, 138.0, 175.7 ppm. MS
(ES): m/z¼363.4 [Mþ1]þ. DART-HRMS [ESþ]: calcd for C23H27N2O2
363.2073; found 363.2071.
129.3, 129.4, 131.8, 134.2, 134.4, 177.8 ppm. MS (ES): m/z¼437.3
[Mþ1]þ. DART-HRMS [ESþ]: calcd for C26H30ClN2O
437.1996;
2
found 437.2005.
4.5.3. (cis)-Methyl (E) 2-benzyl-4-(4-fluorobenzylidene) 1,2,3,4,4a,-
6,7,8,9,9a-decahydro-1H-pyrido[3,4-b]pyrrolizine-8a-carboxylate
(10c). This compound was isolated in 65% yield (0.31 g from 0.35 g)
as reddish brown oil. Rf¼0.23 (EtOAc/hexanes 1:4, v/v). IR (Neat):
4.5.7. (cis)-Methyl (E) 7-benzylidene-5-tosyloctahydro-2,3,3a,4,-
5,6,7,7a-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (13a). This com-
pound was isolated in 81% yield (0.29 g from 0.30 g) as a white
solid, mp 139e140 ꢀC. Rf¼0.10 (EtOAc/hexanes 1:4, v/v). IR (KBr):
nmax¼1725 (CO2Me), 3423 (NH) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
nmax¼1725 (CO2Me) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
¼1.57 (d, 2H,
d
J¼11.2 Hz, CH2), 1.76e1.83 (m, 2H, CH2), 2.03e2.11 (m, 2H, CH2),
2.39e2.46 (m, 2H, CH2), 2.60e2.65 (m, 1H, CH), 2.79 (dd, 1H,
J1¼10.2 Hz, J2¼3.0 Hz, CH2), 3.07e3.10 (m, 1H, CH2), 3.14e3.26 (m,
2H, CH2), 3.51 (d, 1H, J¼13.2 Hz, CH2), 3.62 (d, 1H, J¼17.8 Hz, CH2),
3.70 (s, 3H, OCH3), 4.06 (d, 1H, J¼4.9 Hz, CH), 6.73 (s, 1H, ]CH),
7.01e7.12 (m, 2H, ArH), 7.21e7.35 (m, 7H, ArH) ppm. 13C NMR
d
¼1.64 (dd, 1H, J1¼13.1 Hz, J2¼5.2 Hz, CH2), 2.16e2.30 (m, 2H,
CH2), 2.39e2.47 (m, 4H, CH and CH3), 3.44 (d, 1H, J¼12.7 Hz, CH2),
3.53 (dd, 1H, J1¼11.7 Hz, J2¼5.3 Hz, CH2), 3.68 (s, 3H, OCH3),
3.77e3.82 (m, 1H, CH), 3.87 (d, 1H, J¼4.7 Hz, CH), 4.11 (d, 1H,
J¼12.4 Hz, CH2), 6.66 (s, 1H, ]CH), 7.26e7.34 (m, 7H, ArH), 7.68 (d,
2H, J¼8.1 Hz, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
¼21.7, 33.3,
d
(CDCl3, 75 MHz):
d
¼22.9, 27.3, 29.5, 32.1, 38.4, 41.2, 52.2, 56.7, 58.8,
38.3, 47.0, 50.1, 52.4, 56.9, 58.4, 127.7, 127.9, 128.6, 128.8, 130.0,
131.6, 131.9, 134.1, 135.9, 143.8, 175.0 ppm. MS (ES): m/z¼427.1
[Mþ1]þ. DART-HRMS [ESþ]: calcd for C23H27N2O4S 427.1692;
found 427.1695.
62.4, 75.9, 115.1, 124.0, 127.4, 128.6, 129.0, 129.1, 129.4, 131.5,
177.8 ppm. MS (ES): m/z¼421.3 [Mþ1]þ. DART-HRMS [ESþ]: calcd
for C26H30FN2O2 421.2291; found 421.2295.
4.5.4. (cis)-Methyl (E) 2-benzyl-4-(4-methylbenzylidene) 1,2,3,4,4a,-
6,7,8,9,9a-decahydro-1H-pyrido[3,4-b]pyrrolizine-8a-carboxylate
(10d). This compound was isolated in 70% yield (0.57 g from
0.60 g) as reddish brown oil. Rf¼0.24 (EtOAc/hexanes 1:4, v/v). IR
4.6. General procedure for the formation of 14aeb as
exemplified by 14a
(Neat): nmax¼1731 (CO2Me) cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
To a stirred solution of 3a (1.00 g, 2.90 mmol) in anhyd DMF
(8 mL) was added K2CO3 (0.48 g, 3.48 mmol) and the mixture was
stirred for 10 min at room temperature. Then prenyl bromide
(0.40 mL, 3.48 mmol) was added and mixture was stirred at same
temperature for 2 h. When the reaction was complete, the mixture
was diluted with H2O (30 mL) and extracted with EtOAc (3ꢁ20 mL).
The combined organic layers were dried (anhyd Na2SO4) and con-
centrated to obtain the crude product, which was purified by col-
umn chromatography over silica gel (100e200 mesh) using EtOAc/
hexanes (1:9, v/v) as the eluent to yield 14a (0.96 g, 80%) as a white
solid.
d
¼1.56 (d, 1H, J¼11.2 Hz, CH2), 1.74e1.81 (m, 1H, CH2), 1.90e1.94
(m, 1H, CH2), 2.05 (d, 1H, J¼11.4 Hz, CH2), 2.34 (s, 3H, CH3), 2.42 (d,
2H, J¼11.0 Hz, CH2), 2.60e2.65 (m, 1H, CH2), 2.76e2.79 (m, 1H,
CH2), 3.11 (d, 2H, J¼13.8 Hz, CH2), 3.19e3.31 (m, 1H, CH), 3.49 (d,
2H, J¼13.1 Hz, CH2), 3.63 (d, 1H, J¼6.1 Hz, CH2), 3.67 (d, 1H,
J¼5.6 Hz, CH2), 3.73 (s, 3H, OCH3), 4.12 (d, 1H, J¼4.9 Hz, CH), 6.51 (s,
1H, ]CH), 7.13 (d, 2H, J¼7.9 Hz, ArH), 7.26e7.37 (m, 5H, ArH), 7.71
(d, 2H, J¼8.0 Hz, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
¼21.4, 27.4,
d
38.5, 41.0, 51.5, 52.3, 58.8, 75.8, 127.4, 128.5, 129.0, 129.4, 129.67,
129.72, 131.6, 133.6, 137.2, 178.0 ppm. MS (ES): m/z¼417.4 [Mþ1]þ.
DART-HRMS [ESþ]: calcd for C27H33N2O2 417.2542; found
417.2550.
4.6.1. (E)-Methyl 2-{[4-methyl-N-(3-methylbut-2-enyl)phenylsulfo-
namido]methyl}-3-phenylprop-2-enoate (14a). Mp 82e83 ꢀC.
Rf¼0.40 (EtOAc/hexanes 1:4, v/v). IR (KBr): nmax¼1711 (CO2Me)
4.5.5. (cis)-Methyl (E) 4-benzylidene-2-tosyl-1,2,3,4,4a,6,7,8,9,9a-
decahydro-1H-pyrido[3,4-b]pyrrolizine-8a-carboxylate (11a). This
compound was isolated in 78% yield (0.36 g from 0.35 g) as a white
solid, mp 141e142 ꢀC. Rf¼0.15 (EtOAc/hexanes 1:4, v/v). IR (KBr):
cmꢂ1. 1H NMR (CDCl3, 200 MHz):
d
¼1.49 (s, 6H, 2ꢁ CH3), 2.41 (s, 3H,
CH3), 3.74 (s, 3H, OCH3), 3.77 (s, 2H, CH2), 4.24 (s, 2H, CH2),
4.77e4.84 (m, 1H, ]CH), 7.21e7.27 (m, 2H, ArH), 7.39e7.45 (m, 5H,
ArH), 7.54 (d, 2H, J¼8.3 Hz, ArH), 7.79 (s, 1H, ]CH) ppm. 13C NMR
nmax¼1725 (CO2Me) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
¼1.65e1.75
d
(m, 2H, CH2), 1.77e1.92 (m, 2H, CH2), 2.35e2.41 (m, 1H, CH2), 2.44
(s, 3H, CH3), 2.48e2.57 (m, 2H, CH and CH2), 2.70e2.77 (m, 1H,
(CDCl3, 75 MHz):
128.5, 128.7, 129.3, 129.6, 130.0, 134.7, 136.0, 136.7, 143.2, 143.3,
d
¼17.9, 21.7, 25.8, 43.6, 46.5, 52.2, 119.9, 127.7,

2152
A. Mishra et al. / Tetrahedron 68 (2012) 2146e2154
168.1 ppm. MS (ES): m/z¼413.7 [Mþ1]þ. C23H27NO4S (413.1661):
4.7.3. (cis)-4-(E)-(2-Chlorobenzylidene)-10,10-dimethyl-2-tosyl-
1,2,3,4,4a,5,10,10a-octahydrobenzo[b][1,6]naphthyridine (17b). This
compound was isolated in 51% yield (0.15 g from 0.25 g) as a white
solid, mp 125e127 ꢀC. Rf¼0.30 (EtOAc/hexanes 1:4, v/v). IR (KBr):
calcd C 66.80, H 6.58, N 3.39; found C 66.74, H 6.65, N 3.33.
4.6.2. (E)-Methyl 3-(2-chlorophenyl)-2-{[4-methyl-N-(3-methylbut-
2-enyl)phenylsulfonamido]methyl}prop-2-enoate (14b). This com-
pound was isolated in 83% yield (1.96 g from 2.00 g) as a white
solid, mp 83e84 ꢀC. Rf¼0.38 (EtOAc/hexanes 1:4, v/v). IR (KBr):
nmax¼3361 (NH) cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
d
¼1.30 (s, 3H,
CH3), 1.41 (s, 3H, CH3), 1.93e1.97 (m, 1H, CH), 2.37 (s, 3H, CH3), 2.46
(d, 1H, J¼11.9 Hz, CH2), 3.31 (d, 1H, J¼13.0 Hz, CH2), 3.84 (dd, 1H,
J1¼11.7 Hz, J2¼3.8 Hz, CH2), 4.27 (d, 1H, J¼2.8 Hz, CH), 4.47 (d, 1H,
J¼12.8 Hz, CH2), 6.41 (d, 1H, J¼8.0 Hz, ArH), 6.64e6.69 (m, 2H, ]CH
and ArH), 6.95 (t, 1H, J¼7.3 Hz, ArH), 7.13 (d, 1H, J¼7.6 Hz, ArH),
7.20e7.35 (m, 4H, ArH), 7.41 (t, 2H, J¼5.0 Hz, ArH), 7.52 (d, 2H,
nmax¼1713 (CO2Me) cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
d
¼1.51 (s,
3H, CH3), 1.53 (s, 3H, CH3), 2.40 (s, 3H, CH3), 3.70 (s, 3H, OCH3), 3.74
(d, 2H, J¼6.6 Hz, CH2), 4.13 (s, 2H, CH2), 4.72e4.77 (m, 1H, ]CH),
7.21 (d, 2H, J¼8.1 Hz, ArH), 7.30e7.33 (m, 2H, ArH), 7.40e7.47 (m,
2H, ArH), 7.54 (d, 2H, J¼8.2 Hz, ArH), 7.85 (s, 1H, ]CH) ppm. 13C
J¼8.2 Hz, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
¼21.7, 26.0, 34.6,
d
NMR (CDCl3, 50 MHz):
d
¼18.0, 21.7, 25.8, 43.6, 46.5, 52.5, 119.4,
34.8, 42.5, 43.5, 45.5, 54.0, 114.1, 118.0, 126.3, 126.4, 127.1, 127.2,
127.7, 129.4, 129.7, 130.0, 131.2, 134.0, 134.1, 134.7, 136.9, 141.9,
143.6 ppm. MS (ES) m/z¼493.1 [Mþ1]þ. DART-HRMS [ESþ]: calcd
for C28H29ClFN2O2S 493.1717; found 493.1713.
126.9, 127.6, 129.6, 129.7, 130.2, 130.8, 131.2, 133.3, 134.2, 136.3,
136.9, 139.7, 143.1, 167.1 ppm. MS (ES): m/z¼448.1 [Mþ1]þ.
C23H26ClNO4S (447.1271): calcd C 61.67, H 5.85, N 3.13; found C
61.73, H 5.91, N 3.01.
4.7.4. (trans)-4-(E)-(2-Chlorobenzylidene)-10,10-dimethyl-2-tosyl-
1,2,3,4,4a,5,10,10a-octahydrobenzo[b][1,6]naphthyridine (17b). This
compound was isolated in 39% yield (0.13 g from 0.25 g) as
a white solid, mp 129e130 ꢀC. Rf¼0.30 (EtOAc/hexanes 1:4, v/v).
4.7. General procedure for the formation of 17e18(aeb) as
exemplified by 17a
IR (KBr): nmax¼3405 (NH) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
¼1.11
d
To a stirred solution of 16a (0.25 g, 0.65 mmol) in dry MeCN
(20 mL) was added aniline (0.06 mL, 0.65 mmol) at room temper-
ature under N2 atmosphere in the presence of molecular sieves. The
reaction mixture was stirred for 20 min and then to it BiCl3 (0.02 g,
0.065 mmol) was added and the reaction was continued at the
same temperature. After the completion of the reaction as moni-
tored by the TLC, the reaction mixture was filtered through a bed of
Celite. The filtrate was diluted with H2O (15 mL) and extracted with
EtOAc (2ꢁ10 mL). The combined organic layer was washed with
brine (20 mL), dried (anhyd Na2SO4) and evaporated to afford the
crude product as oil. Purification by column chromatography over
silica gel (230e400 mesh) using EtOAc/hexanes (3:97, v/v) as the
eluent furnished pure (cis)-17a (0.13 g, 43%) and (trans)-17a (0.09 g,
30%) as a white solid.
(s, 3H, CH3), 1.35 (s, 3H, CH3), 1.78e1.81 (m, 1H, CH), 2.40 (s, 3H,
CH3), 2.44 (d, 1H, J¼13.5 Hz, CH2), 3.67 (d, 1H, J¼12.4 Hz, CH2),
3.83 (dd, 1H, J1¼11.8 Hz, J2¼2.8 Hz, CH2), 4.24 (d, 1H, J¼12.8 Hz,
CH2), 4.39 (d, 1H, J¼2.4 Hz, CH), 6.38 (d, 1H, J¼7.9 Hz, ArH),
6.63e6.66 (m, 2H, ]CH and ArH), 6.90e6.95 (m, 1H, ArH),
7.07e7.12 (m, 2H, ArH), 7.19e7.29 (m, 4H, ArH), 7.39 (dd, 1H,
J1¼6.6 Hz, J2¼2.3 Hz, ArH), 7.67 (d, 2H, J¼8.1 Hz, ArH) ppm. 13C
NMR (CDCl3, 75 MHz)
d
¼21.8, 22.9, 26.2, 29.6, 29.9, 32.2, 34.7,
43.4, 44.7, 46.3, 48.6, 114.3, 118.2, 126.5, 126.8, 127.1, 127.8, 129.3,
129.9, 130.1, 130.3, 134.0, 134.2, 134.9, 136.6, 142.0, 143.7 ppm. MS
(ES) m/z¼493.0 [Mþ1]þ. DART-HRMS [ESþ]: calcd for
C28H29ClFN2O2S 493.1717; found 493.1715.
4.7.5. (cis)-4-(E) Benzylidene-8-fluoro-10,10-dimethyl-2-tosyl-1,2,3,-
4,4a,5,10,10a-octahydrobenzo[b][1,6]naphthyridine (18a). This com-
pound was isolated in 42% yield (0.13 g from 0.25 g) as a white solid,
mp 200e202 ꢀC. Rf¼0.29 (EtOAc/hexanes 1:4, v/v). IR (KBr):
4.7.1. (cis)-4-(E) Benzylidene-10,10-dimethyl-2-tosyl-1,2,3,4,4a,5,10,10a-
octahydrobenzo[b][1,6]naphthyridine (17a). Mp 193e195 ꢀC. Rf¼0.15
(EtOAc/hexanes 1:4, v/v). IR (KBr): nmax¼3389 (NH) cmꢂ1
.
1H NMR
nmax¼3409 (NH) cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
d
¼1.29 (s, 3H,
(CDCl3, 200 MHz):
d
¼1.29 (s, 3H, CH3), 1.41 (s, 3H, CH3), 1.87e1.97 (m,
CH3), 1.38 (s, 3H, CH3), 1.89e1.93 (m, 1H, CH), 2.39 (s, 3H, CH3), 2.45
(d, 1H, J¼12.0 Hz, CH2), 3.33 (d, 1H, J¼13.0 Hz, CH2), 3.56 (s, 1H, NH),
3.83 (dd, 1H, J1¼11.3 Hz, J2¼3.9 Hz, CH2), 4.15 (d, 1H, J¼2.7 Hz, CH),
4.70 (d, 1H, J¼12.5 Hz, CH2), 6.30e6.35 (m, 1H, ArH), 6.61e6.70 (m,
2H, ]CH and ArH), 6.84 (dd,1H, J1¼10.4 Hz, J2¼2.9 Hz, ArH), 7.22 (d,
2H, J¼7.9 Hz, ArH), 7.28e7.33 (m, 3H, ArH), 7.38e7.43 (m, 2H, ArH),
1H, CH), 2.38 (s, 3H, CH3), 2.43 (d, 1H, J¼12.0 Hz, CH2), 3.34 (d, 2H,
J¼13.2 Hz, CH2), 3.85 (dd, 1H, J1¼11.5 Hz, J2¼4.3 Hz, CH2), 4.19 (d, 1H,
J¼3.0 Hz, CH2\), 4.71 (d, 1H, J¼13.7 Hz, CH2), 6.40 (dd, 1H, J1¼7.9 Hz,
J2¼1.2 Hz, ArH), 6.63e6.70 (m, 2H, ]CH and ArH), 6.91e7.00 (m, 1H,
ArH), 7.14 (dd, 1H, J1¼7.9 Hz, J2¼1.4 Hz, ArH), 7.19e7.25 (m, 2H, ArH),
7.30e7.44 (m, 5H, ArH), 7.53 (d, 2H, J¼8.4 Hz, ArH) ppm. 13C NMR
7.53 (d, 2H, J¼7.9 Hz, ArH); 13C NMR (CDCl3, 75 MHz):
¼21.7, 25.9,
d
(CDCl3, 75 MHz):
d
¼21.7, 26.0, 34.6, 34.8, 42.3, 43.4, 45.3, 54.4, 114.0,
34.6, 34.8, 42.2, 43.2, 44.9, 54.3, 112.8, 113.6, 114.7, 127.7, 127.8,
128.8, 128.9, 129.1, 129.3, 129.9, 134.8, 135.1, 135.7, 138.1, 138.2,
143.6, 154.6, 157.7 ppm. MS (ES) m/z¼477.0 [Mþ1]þ. DART-HRMS
[ESþ]: calcd for C28H30FN2O2S 477.2012; found 477.2015.
117.9, 126.3, 127.1, 127.6, 127.7, 127.8, 128.8, 129.1, 129.3, 129.9, 134.9,
135.3, 135.8, 142.0, 143.5 ppm. MS (ES) m/z¼459.1 [Mþ1]þ. DART-
HRMS [ESþ]: calcd for C28H31N2O2S 459.2106; found 459.2103.
4.7.2. (trans)-4-(E) Benzylidene-10,10-dimethyl-2-tosyl-1,2,3,4,4a,5,10,-
10a-octahydrobenzo[b][1,6]naphthyridine (17a). Mp 191e192 ꢀC.
Rf¼0.15 (EtOAc/hexanes 1:4, v/v). IR (KBr): nmax¼3389 (NH) cmꢂ1. 1H
4.7.6. (trans)-4-(E)
Benzylidene-8-fluoro-10,10-dimethyl-2-tosyl-
1,2,3,4,4a,5,10,10a-octahydrobenzo[b][1,6]naphthyridine (18a). This
compound was isolated in 32% yield (0.10 g from 0.25 g) as a white
solid, mp 209e210 ꢀC. Rf¼0.28 (EtOAc/hexanes 1:4, v/v). IR (KBr):
NMR (CDCl3, 300 MHz):
d
¼1.15 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.79 (d,
1H, J¼11.9 Hz, CH), 2.40 (s, 3H, CH3), 2.47 (d, 1H, J¼11.9 Hz, CH2), 3.59
(d, 2H, J¼11.8 Hz, CH2 and NH), 3.82 (dd, 1H, J1¼11.4 Hz, J2¼3.2 Hz,
CH2), 4.15 (d, 1H, J¼12.1 Hz, CH2), 4.66 (d, 1H, J¼2.4 Hz, CH), 6.41 (d,
1H, J¼8.2 Hz, ArH), 6.62e6.68 (m, 2H, ]CH and ArH), 6.94 (t, 1H,
J¼7.3 Hz, ArH), 7.10 (d,1H, J¼7.7 Hz, ArH), 7.19e7.35 (m, 7H, ArH), 7.65
nmax¼3412 (NH) cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
d¼1.14 (s, 3H,
CH3), 1.33 (s, 3H, CH3), 1.77e1.81 (m,1H, CH), 2.40e2.43 (m, 4H, CH3
and CH2), 3.49e3.56 (m, 2H, CH2 and NH), 3.56 (s, 1H, NH), 3.80 (dd,
1H, J1¼11.7 Hz, J2¼3.3 Hz, CH2), 4.14 (d, 1H, J¼12.9 Hz, CH2), 4.62 (d,
1H, J¼2.6 Hz, CH), 6.30e6.35 (m, 1H, ArH), 6.65e6.67 (m, 2H, ]CH
and ArH), 6.80 (dd, 1H, J1¼10.1 Hz, J2¼2.7 Hz, ArH), 7.18 (d, 2H,
J¼7.0 Hz, ArH), 7.26e7.35 (m, 4H, ArH), 7.65 (d, 2H, J¼8.2 Hz, ArH)
(d, 2H, J¼8.1 Hz, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
¼21.7, 26.2,
d
34.58, 34.62, 43.6, 44.7, 46.0, 49.1, 114.1, 118.0, 126.5, 127.0, 127.7, 127.8,
128.7, 130.0, 130.2, 134.75, 134.82, 135.6, 142.0, 143.7 ppm. MS (ES) m/
z¼459.1 [Mþ1]þ. DART-HRMS [ESþ]: calcd for C28H31N2O2S 459.2106;
found 459.2103.
ppm. 13C NMR (CDCl3, 75 MHz):
d
¼21.8, 25.8, 26.1, 34.3, 35.0, 44.3,
45.4, 46.0, 49.0, 114.7, 119.1, 127.5, 127.8, 127.9, 128.7, 128.8, 129.1,
129.88, 129.94, 130.0, 130.2, 134.7, 135.3, 143.7, 146.0 ppm. MS (ES)

A. Mishra et al. / Tetrahedron 68 (2012) 2146e2154
2153
m/z¼477.1 [Mþ1]þ. DART-HRMS [ESþ]: calcd for C28H30FN2O2S
129.8, 132.3, 134.3, 137.3, 143.9, 170.0, 196.9 ppm. MS (ES) m/
z¼506.0 [Mþ1]þ. DART-HRMS [ESþ]: calcd for C30H36NO4S
506.2365; found 506.2360.
477.2012; found 477.2010.
4.7.7. (cis)-4-(E)-(2-Chlorobenzylidene)-8-fluoro-10,10-dimethyl-2-
tosyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[b][1,6]naphthyridine
(18b). This compound was isolated in 39% yield (0.12 g from 0.25 g)
as a white solid, mp 201e202 ꢀC. Rf¼0.30 (EtOAc/hexanes 1:4, v/v).
4.8.2. (cis)-1 (Z)-(2-Chlorobenzylidene)-5,5,8,8-tetramethyl-3-tosyl-
3,4,4a,5,7,8,9,10b-octahydro-1H-chromeno[3,4-c]pyridin-10(2H)-one
(19b). This compound was isolated in 74% yield (0.26 g from 0.25 g)
as a white solid, mp 241e242 ꢀC. Rf¼0.20 (EtOAc/hexanes 1:4, v/v).
IR (KBr): nmax¼3389 (NH) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
¼1.30
d
(s, 3H, CH3), 1.38 (s, 3H, CH3), 1.93e1.97 (m, 1H, CH), 2.38 (m, 3H,
CH3), 2.42 (d, 1H, J¼12.0 Hz, CH2), 3.29 (d, 1H, J¼13.0 Hz, CH2), 3.59
(s, 1H, NH), 3.83 (dd, 1H, J1¼11.5 Hz, J2¼3.5 Hz, CH2), 4.23 (d, 1H,
J¼2.6 Hz, CH), 4.46 (d, 1H, J¼12.9 Hz, CH2), 6.32e6.36 (m, 1H, ArH),
6.65e6.70 (m, 2H, ]CH and ArH), 6.84 (dd, 1H, J1¼10.1 Hz,
J2¼2.7 Hz, ArH), 7.21e7.33 (m, 4H, ArH), 7.41 (t, 2H, J¼7.3 Hz, ArH),
IR (KBr): nmax¼1658 (C]O) cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
d
¼0.51 (s, 3H, CH3), 0.96 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.34 (s, 3H,
CH3), 1.87e2.21 (m, 6H, CH and CH2), 2.40 (s, 3H, CH3), 2.74 (d, 1H,
J¼11.5 Hz, CH2), 3.62 (br s, 1H, CH), 3.80 (dd, 1H, J1¼11.2 Hz,
J2¼3.9 Hz, CH2), 4.09 (d, 1H, J¼12.1 Hz, CH2), 6.65 (s, 1H, ]CH),
7.15e7.17 (m, 2H, ArH), 7.26e7.38 (m, 3H, ArH), 7.52e7.55 (m, 1H,
ArH), 7.65 (d, 2H, J¼8.1 Hz, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
7.53 (d, 2H, J¼8.1 Hz, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
¼21.7,
d
26.0, 34.6, 34.9, 42.4, 43.3, 45.1, 54.1, 112.5, 112.8, 113.7, 114.0, 114.7,
114.8, 126.4, 127.2, 127.7, 128.86, 128.93, 129.4, 129.7, 130.0, 131.2,
134.0, 134.6, 136.8, 138.0, 143.7, 157.7 ppm. MS (ES) m/z¼511.1
[Mþ1]þ. DART-HRMS [ESþ]: calcd for C28H29ClFN2O2S 511.1622;
found: 511.1620.
d¼21.7, 26.0, 26.1, 30.2, 30.7, 31.5, 41.0, 42.9, 43.3, 50.8, 51.5, 78.5,
107.0, 126.0, 126.5, 128.2, 128.3, 129.5, 129.8, 131.3, 134.3, 135.6,
136.0, 143.8, 196.9 ppm. MS (ES) m/z¼540.2 [Mþ1]þ. DART-HRMS
[ESþ]: calcd for C30H35ClNO4S 540.1975; found 540.1978.
4.8.3. (cis)-1
(Z)-Benzylidene-5,5-dimethyl-3-tosyl-3,4,4a,5,7,8,9,-
4.7.8. (trans)-4-(E)-(2-Chlorobenzylidene)-8-fluoro-10,10-dimethyl-
2-tosyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[b][1,6]naphthyridine
(18b). This compound was isolated in 32% yield (0.10 g from 0.25 g)
as a white solid, mp 196e197 ꢀC. Rf¼0.29 (EtOAc/hexanes 1:4, v/v).
10b-octahydro-1H-chromeno[3,4-c]pyridin-10(2H)-one (20a). This
compound was isolated in 71% yield (0.22 g from 0.25 g) as a yellow
solid, mp 240e241 ꢀC. Rf¼0.17 (EtOAc/hexanes 1:4, v/v). IR (KBr):
nmax¼1649 (C]O) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
¼1.10 (s, 3H,
d
IR (KBr): nmax¼3389 (NH) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
d¼1.11
CH3), 1.25e1.33 (s, 4H, CH2 and CH3), 1.74e1.77 (m, 1H, CH2),
1.85e1.90 (m, 1H, CH2), 2.23e2.26 (m, 4H, CH2), 2.35 (s, 1H, CH),
2.44 (s, 3H, CH3), 2.91 (d, 1H, J¼10.8 Hz, CH2), 3.81 (dd, 1H,
J1¼9.9 Hz, J2¼4.3 Hz, CH2), 3.90 (br s, 1H, CH), 4.00 (d, 1H, J¼13.2 Hz,
CH2), 6.62 (s, 1H, ]CH), 7.26e7.34 (m, 7H, ArH), 7.67 (d, 2H,
(s, 3H, CH3), 1.33 (s, 3H, CH3), 1.77e1.81 (m, 1H, CH), 2.41 (s, 3H,
CH3), 2.47 (d, 1H, J¼12.0 Hz, CH2), 3.43 (s, 1H, NH), 3.66 (d, 1H,
J¼12.6 Hz, CH2), 3.81 (dd, 1H, J1¼11.7 Hz, J2¼3.6 Hz, CH2), 4.22 (d,
1H, J¼12.4 Hz, CH2), 4.35 (d, 1H, J¼2.1 Hz, CH), 6.28e6.33 (m, 1H,
ArH), 6.61e6.66 (m, 2H, ]CH and ArH), 6.79 (dd, 1H, J1¼10.1 Hz,
J2¼2.7 Hz, ArH), 7.08e7.11 (m, 1H, ArH), 7.20e7.30 (m, 4H, ArH),
7.38e7.41 (m, 1H, ArH), 7.67 (d, 2H, J¼8.2 Hz, ArH) ppm. 13C
J¼8.0 Hz, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
¼18.0, 20.7, 21.7,
d
25.9, 28.5, 36.6, 45.4, 49.6, 79.8, 111.1, 117.1, 118.5, 123.6, 127.4, 128.1,
129.0, 129.5, 129.8, 131.5, 136.96, 137.0, 138.3, 143.4, 171.5,
194.8 ppm. MS (ES) m/z¼478.0 [Mþ1]þ. DART-HRMS [ESþ]: calcd
for C28H32NO4S 478.2052; found 478.2049.
NMR (CDCl3, 75 MHz):
d
¼21.7, 26.1, 34.4, 34.9, 43.3, 44.3, 46.3, 48.5,
112.6, 112.9, 113.6, 114.0, 114.9, 115.0, 126.8, 127.1, 127.8, 129.1,
129.3, 129.9, 130.0, 130.3, 134.0, 134.1, 134.9, 136.6, 138.1, 143.7,
157.8 ppm. MS (ES): m/z¼511.0 [Mþ1]þ. DART-HRMS [ESþ]: calcd
for C28H29ClFN2O2S 511.1622; found 511.1615.
4.8.4. (cis)-1 (Z)-(2-Chlorobenzylidene)-5,5-dimethyl-3-tosyl-3,4,-
4a,5,7,8,9,10b-octahydro-1H-chromeno[3,4-c]pyridin-10(2H)-one
(20b). This compound was isolated in 70% yield (0.23 g from 0.25 g)
as a white solid, mp 204e205 ꢀC. Rf¼0.21 (EtOAc/hexanes 1:4, v/v).
4.8. General procedure for the formation of 19e20(aeb)
as exemplified by 19a
IR (KBr): nmax¼1657 (C]O) cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
¼1.08 (s, 3H, CH3),1.26e1.34 (s, 4H, CH and CH3), 1.82e1.88 (m, 2H,
d
A heterogeneous suspension of 16a (0.25 g, 0.65 mmol), 3,3-
dimethyl cyclohexane 1,3-dione (0.06 g, 0.46 mmol) and piperi-
dine (0.26 mL, 2.60 mmol) in 5 mL of toluene was irradiated in
a sealed tube with microwaves for 30 min at 120 ꢀC. After cooling to
room temperature, the solvent was evaporated under reduced
pressure and the reaction mixture was diluted with 10 mL of water
and extracted with EtOAc (3ꢁ10 mL). The combined organic layers
were dried over anhyd Na2SO4 and concentrated under reduced
pressure. Further purification of the crude product by column
chromatography over silica gel over silica gel (230e400 mesh)
using EtOAc/hexanes (1:4, v/v) as the eluent furnished 19a (0.26 g,
79%) as a white solid.
CH2), 2.22e2.26 (m, 4H, 2ꢁ CH2), 2.43 (s, 4H, CH and CH3), 2.98 (d,
1H, J¼12.5 Hz, CH2), 3.66 (br s, 1H, CH), 3.77 (d, 1H, J¼9.7 Hz, CH2),
4.04 (d, 1H, J¼12.2 Hz, CH2), 6.60 (s, 1H, ]CH), 7.16e7.18 (m, 2H,
ArH), 7.26e7.38 (m, 3H, ArH), 7.55 (d,1H, J¼7.5 Hz, ArH), 7.69 (d, 2H,
J¼9.0 Hz, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
¼20.7, 21.8, 25.8,
d
26.0, 29.7, 30.9, 37.9, 41.2, 42.6, 50.3, 78.3, 108.2, 125.8, 126.5, 128.0,
128.4, 129.5, 129.8, 131.3, 134.0, 134.2, 135.6, 136.0, 143.8, 171.7,
197.2 ppm. MS (ES) m/z¼512.1 [Mþ1]þ. DART-HRMS [ESþ]: calcd for
C28H31ClNO4S 512.1584; found 512.1587.
Acknowledgements
4.8.1. (cis)-1 (Z)-Benzylidene-5,5,8,8-tetramethyl-3-tosyl-3,4,4a,5,-
7,8,9,10b-octahydro-1H-chromeno[3,4-c]pyridin-10(2H)-one
(19a). Mp 223e224 ꢀC. Rf¼0.23 (EtOAc/hexanes 1:4, v/v). IR (KBr):
Two of the authors (A.M. and N.R.) gratefully acknowledges the
financial support from Council for Scientific and Industrial Re-
search, New Delhi. Authors gratefully acknowledge the SAIF Di-
vision of CDRI for recording all the spectroscopic and analytical
data. Authors also acknowledge the guidance extended by Prof.
Raja Roy, CBMR, SGPGI, Lucknow for elucidating the structures via
detailed NMR experiments. We acknowledge the help extended by
Prof. Sandeep Verma, IIT Kanpur and his student Mr. Rajneesh K.
Prajapati for the X-ray analysis of compound cis-18a. This work was
supported by a grant from Department of Science and Technology,
New Delhi.
nmax¼1650 (C]O) cmꢂ1. 1H NMR (CDCl3, 300 MHz):
¼0.49 (s, 3H,
d
CH3), 0.97 (s, 3H, CH3), 1.09 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.78e1.82
(m, 1H, CH2), 1.92e2.24 (m, 5H, CH and CH2), 2.40 (s, 3H, CH3), 2.69
(d,1H, J¼11.9 Hz, CH2), 3.81 (dd,1H, J1¼11.5 Hz, J2¼4.2 Hz, CH2), 3.87
(br s, 1H, CH), 4.02 (d, 1H, J¼11.5 Hz, CH2), 6.67 (s, 1H, ]CH),
7.26e7.37 (m, 7H, ArH), 7.63 (d, 2H, J¼8.1 Hz, ArH) ppm. 13C NMR
(CDCl3, 75 MHz)
d
¼21.7, 25.9, 26.0, 30.2, 30.4, 31.5, 41.1, 43.0, 43.3,
51.2, 51.5, 78.4, 107.1, 126.8, 128.1, 128.2, 128.4, 128.6, 129.0, 129.3,

2154
A. Mishra et al. / Tetrahedron 68 (2012) 2146e2154
5. Nag, S.; Batra, S. Tetrahedron 2011, 67, 8959e9061.
Supplementary data
6. (a) Portevin, B.; Torjman, C.; Pastoureau, P.; Bonnet, J.; Nanteuil, G. D. J. Med.
Chem. 2000, 43, 4582e4593 and references cited therein; (b) Rajaraman, S.;
Jimenez, L. S. Tetrahedron 2002, 58, 10407e10412; (c) Ulbrich, H.; Fiebich, B.;
Dannhardt, G. Eur. J. Med. Chem. 2002, 37, 953e959.
7. (a) Nag, S.; Yadav, G. P.; Maulik, P. R.; Batra, S. Synthesis 2007, 911e917; (b) Kim,
J. N.; Chung, Y. M.; Im, Y. J. Tetrahedron Lett. 2002, 43, 6209e6211.
8. (a) Snider, B. B.; Ahn, Y.; O’Hare, S. M. Org. Lett. 2001, 3, 4217e4220; (b) Pedrosa,
R.; Andres, C.; Heras, L. D. L.; Nieto, J. Org. Lett. 2002, 4, 2513e2516; (c) Pedrosa,
R.; Andres, C.; Nieto, J.; Perez-Cuadrado, C.; Francisco, I. S. Eur. J. Org. Chem.
2006, 3259e3265; (d) Garner, P.; Kaniskan, H. U. Tetrahedron Lett. 2005, 46,
5181e5185; (e) Poornachandran, M.; Raghunathan, R. Tetrahedron Lett. 2005,
46, 7197e7200; (f) Yang, X.; Luo, S.; Fang, F.; Liu, P.; Lu, Y.; He, M.; Zhai, H.
Tetrahedron 2006, 62, 2240e2246.
9. Neuschl, M.; Bogdal, D.; Potacek, M. Molecules 2007, 12, 49e59.
10. Sridharan, V.; Suryavanshi, P. A.; Menendez, J. C. Chem. Rev. 2011, web released
10 Aug., dx.doi.org/10.1021/cr100307m.
11. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115e136; (b) Maiti, S.; Panja, S. K.; Ban-
dyopadhyay, C. Tetrahedron 2010, 66, 7625e7632; (c) Jayagobi, M.; Poorna-
chandran, M.; Raghunathan, R. Tetrahedron Lett. 2009, 50, 648e650.
12. Hutait, S.; Singh, V.; Batra, S. Eur. J. Org. Chem. 2010, 6269e6276.
Copies of 1H and 13C NMR spectra and details of 2D experiments
of 11a and 19b are provided. Supplementary data associated with
this article can be found in the online version, at doi:10.1016/
j.tet.2012.01.016. These data include MOL files and InChiKeys of the
most important compounds described in this article.
References and notes
1. (a) Broggini, G.; Zecchi, G. Synthesis 1999, 905e917; (b) Novikov, M. S.;
Khlebnikov, A. F.; Besidina, O. V.; Kastokov, R. R. Tetrahedron Lett. 2001, 42,
533e535; (c) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765e2809; (d)
Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484e4517; (e)
Appukkuttan, P.; Mehta, V. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2010, 39,
1467e1477.
2. (a) Vedejs, E.; Piotrowski, D. W.; Tucci, F. C. J. Org. Chem. 2000, 65, 5498e5505;
(b) Pandey, G.; Sahoo, A. K.; Bagul, T. D. Org. Lett. 2000, 2, 2299e2301; (c)
Vedejs, E.; Klapers, A.; Naidu, B. N.; Piotrowski, D. W.; Tucci, F. C. J. Am. Chem.
Soc. 2000, 122, 5401e5402; (d) Coldham, I.; Crapnellk, M.; Moseley, J. D.; Rabot,
R. J. Chem. Soc., Perkin Trans. 1 2001, 1758e1763; (e) Shanmugam, P.; Vis-
wambharan, B.; Madhavan, S. Org. Lett. 2007, 9, 4095e4098.
3. (a) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511e4574 and references cited
therein; (b) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1e48
and references cited therein; (c) Gowrisankar, S.; Lee, H. S.; Kim, S. H.; Lee, K.
Y.; Kim, J. N. Tetrahedron 2009, 65, 8769e8780; (d) Basavaiah, D.; Reddy, B. S.;
Singh, B. S. Chem. Rev. 2010, 110, 5447e5674 and references cited therein; (e)
Zhong, W.; Liu, Y.; Wang, G.; Hong, L.; Chen, Y.; Chen, X.; Zheng, Y.; Zhang, W.;
Ma, W.; Shen, Y.; Yao, Y. Org. Prep. Proced. Int. 2011, 43, 1e66; (f) Jayashankaran,
J.; Durga, R.; Manian, R. S.; Sivaguru, M.; Raghunathan, R. Tetrahedron Lett.
2006, 47, 5535e5538; (g) Bakthadoss, M.; Sivakumar, N.; Sivakumar, G.;
Murugan, G. Tetrahedron Lett. 2008, 49, 820e823; (h) Ramesh, E.; Raghuna-
than, R. Tetrahedron Lett. 2008, 49, 1125e1128; (i) Kathiravan, S.; Vijayarajan,
D.; Raghunathan, R. Tetrahedron Lett. 2010, 51, 3065e3070; (j) Nagaiah, K.;
Venkatesham, A.; Srinivasa Rao, R.; Saddanapu, V.; Yadav, J. S.; Basha, S. J.;
Sarma, A. V. S.; Sridhar, B.; Addlagatta, A. Bioorg. Med. Chem. Lett. 2010, 20,
3259e3264.
13. Crystal data of compound 18a (crystallized from CHCl3): C28H29FN2O2S, M¼476.
ꢀ
59, Monoclinic, Pꢂ1, a¼33.877(7), b¼7.9404(15), c¼19.868(4) A,
a
¼90.00,
3
ꢂ3
ꢀ
b
¼95.989(7),
g
¼90.00, V¼5315.4(18) A , Z¼8, Dx¼1.191 g cm
, m
(Mo Ka
)¼0.
155 mmꢂ1, F (000)¼2016.0 colorless block, dimension 0.28ꢁ0.20ꢁ0.14 mm,
5212 reflections measured (Rint¼0.0605), 5212 unique, wR2¼0.1806, conven-
tional R¼0.0652 on F2 values of 3328 reflections with I>2
s
(I), (
D
/s
)
¼000),
max
S¼1.053 for all data and 307 parameters. Unit cell determination and intensity
data collection (2
q
¼50ꢀ) were performed on a Bruker P4 diffractometer at
293(2) K. Structure solutions by direct methods and refinements by full-matrix
least-squares methods on F2. Programs: XSCANS (Siemens Analytical X-ray
Instrument Inc.: Madison, WI, USA, 1996) for data collection and data pro-
cessing; SHELXTL-NT (Bruker AXS Inc.: Madison, Wisconsin, USA, 1997) for
structure determination, refinements and molecular graphics. Further details of
the crystal structure investigation can be obtained from the Cambridge Crys-
tallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK (CCDC de-
position no. 860024).
14. (a) Shanmugasundaram, M.; Manikandan, S.; Raghunathan, R. Tetrahedron
2002, 58, 997e1003; (b) Tietze, L. F.; Geissler, H.; Fennen, J.; Brumby, T.; Brand,
S.; Schulz, G. J. Org. Chem. 1994, 59, 182e191; (c) Lee, Y. R.; Hung, T. V. Tetra-
hedron 2008, 64, 7338e7346.
4. Sirisha, N.; Raghunathan, R. Tetrahedron Lett. 2010, 51, 2515e2518.