Synthesis and reactivity of hexahydropyrroloquinolines

Article abstract of DOI:10.1016/S0040-4020(01)00466-5

Formal [4+2] cycloaddition of cyclic enamides with imines derived from aromatic amines gave the 4-arylhexahydropyrroloquinoline skeleton in one step as mixtures of diastereoisomers. Aromatic imines derived from formaldehyde and methylglyoxalate also participated in this chemistry, with the latter favouring formation of the endo-cycloadduct. The cycloadducts derived from methylglyoxalate were unstable and fragmented to give highly substituted quinolines under both neutral and basic conditions. Imines derived from 3-cyanoacrolein also underwent cycloaddition and gave an advanced potential precursor to martinellic acid, albeit with poor diastereoselectivity.

Full text of DOI:10.1016/S0040-4020(01)00466-5

TETRAHEDRON
Pergamon
Tetrahedron 57 72001) 5615±5624
Synthesis and reactivity of hexahydropyrroloquinolines
Mark Hadden, Mark Nieuwenhuyzen, Deirdre Potts, Paul J. Stevensonp and Norris Thompson
School of Chemistry, The Queen's University of Belfast, Belfast BT9 5AG, Northern Ireland, UK
Received 12 February 2001; revised 9 April 2001; accepted 26 April 2001
AbstractÐFormal [412] cycloaddition of cyclic enamides with imines derived from aromatic amines gave the 4-arylhexahydropyrrolo-
quinoline skeleton in one step as mixtures of diastereoisomers. Aromatic imines derived from formaldehyde and methylglyoxalate also
participated in this chemistry, with the latter favouring formation of the endo-cycloadduct. The cycloadducts derived from methylglyoxalate
were unstable and fragmented to give highly substituted quinolines under both neutral and basic conditions. Imines derived from 3-cyano-
acrolein also underwent cycloaddition and gave an advanced potential precursor to martinellic acid, albeit with poor diastereoselectivity.
q 2001Elsevier Science Ltd. All rights reserved.
1. Introduction
martinellic acid, we15 and others16 reported a simple
synthesis of hexahydropyrroloquinolines based on an
imino Diels±Alder reaction. Imines derived from aromatic
amines behaved as the diene and cyclic enamides as the
dienophile component. The advantage of this approach
was that all three chiral centres present in the hexahydro-
pyrroloquinoline core were generated in one synthetic
operation. There was therefore potential to control both
the relative and absolute stereochemical outcome of this
reaction by judicial choice of catalyst. The symmetry of
the para-susbstituted aniline ensured the trisubstituted
aromatic product was obtained with the correct regio-
chemistry. We now report full details on this chemistry
and subsequent reactions of the hexahydropyrroloquinolines.
Pyrroloquinolines, Fig. 1, form the central core of a number
of biologically signi®cant molecules. Antineoplastic agent
1,1 gastric 7H1/K1) ATPase inhibitor 22,3 and natural
product, non-peptide Bradykinin inhibitor, martinellic acid
34 all contain pyrroloquinolines in various oxidation states.
Synthetic interest in martinellic acid has recently stimulated
many new approaches to hexahydropyrroloquinolines.5,6
Inter7 and intramolecular8±10 1,3-dipolar cycloaddition of
azomethine ylides, radical cyclisation11,12 and transition
metal catalysed cyclisation13 have all been employed to
give access to potential martinellic acid precursors. Despite
this activity, to date no synthesis of martinellic acid has
been accomplished. Hexahydropyrroloquinolines may be
considered to be a sub-grouping of tetrahydroquinolines
and a review on the synthesis of the latter class of
compounds has recently been published.14
2. Results and discussion
Scheme 1outlines the approach that was adopted. The
cyclic enamides 5 and 26 were readily available from the
In recent studies directed towards the synthesis of
Figure 1.
Keywords: martinellic acid; martinelline; imino Diels±Alder reaction; cyclic enamide; indium trichloride.
Corresponding author. Tel.: 112890-274426; fax: 112890-382117; e-mail: p.stevenson@qub.ac.uk
p
0040±4020/01/$ - see front matter q 2001Elsevier Science Ltd. All rights reserved.
PII: S0040-4020701)00466-5

5616
M. Hadden et al. / Tetrahedron 57 (2001) 5615±5624
Scheme 1.
trimer of 3,4-dihydro-2-H-pyrrole,17 but yields for this
procedure were variable and generally low. The most
reliable method for making these compounds was by
dehydration of the corresponding amido hemiacetal using
standard literature procedures.18±20 Of these, it was found
that the method of Correia was the most ef®cient. Reaction
of cyclic enamide 5 with imines 4a±d proceeded smoothly
at room temperature in acetonitrile as solvent in the
presence of 20 mol% indium trichloride and gave exo,
endo cycloadducts 6 and 7, respectively as mixtures of
stereoisomers 7Table 1, entries 1±4). The IUPAC number-
ing for pyrroloquinolines begins on the amide nitrogen and
goes clockwise around the ring. For clarity positions 3a 4
and 9b are depicted on exo-isomer 6, Scheme 1.
cycloaddition reactions.21 Due to the reliability and repro-
ducibility of indium trichloride this became the preferred
catalyst for the cycloadditions.
The stereochemistry at the ring junction in isomers 6a and
7a 7Table 1, entry 1) was readily assigned as cis due to the
axial±equatorial coupling constants JH3aH9b of 6.7 and
6.2 Hz, respectively. This was further con®rmed by nOe
difference spectroscopy, where saturation of proton H9b
gave enhancements of 6.0 and 6.8% onto H3a for the
endo and exo isomers, respectively. Assigning exo, endo
stereochemistry to each of the isomers 6a and 7a proved
more dif®cult than initially anticipated, by proton NMR
spectroscopy. This was because the exo isomers 6 adopted
an unexpected conformation where the aryl group and the
alkyl group of the pyrrolidine ring were trans-diaxial. Equa-
torial proton H3a, was antiperiplanar to the electronegative
secondary aromatic amine and this resulted in a further
decrease in the axial±equatorial vicinal coupling constant
The reaction was completely regioselective giving only the
isomers depicted in Scheme 1. In all cases investigated, the
desired exo-selectivity was poor, but fortuitously these
diastereoisomers were easily separated by ¯ash chromato-
graphy. Although we could not ®nd conditions to effect a
purely thermal reaction with imines derived from aromatic
aldehydes, other reagents such as scandium tri¯ate and
tri¯uoromethanesulphonic acid also catalysed this reaction.
In our hands scandium tri¯ate lost its catalytic activity on
standing after the bottle was opened. The tri¯uoromethane-
sulphonic acid catalysed reaction, using one drop of acid per
mmol of substrate, was as ef®cient as the indium catalysed
reaction, both in terms of yield and diastereoselectivity.
However, this procedure was always accompanied by
some hydrolysis of the imine making it less than ideal.
Protic acids have long been known to catalyse similar
JH3aH4.
22 As a result of these two effects, the vicinal coupling
constants JH3aH4 for the exo and endo isomers 6a and 7a
were remarkably similar at 2.7 and 2.5 Hz, respectively.
Clearly these isomers cannot be distinguished from
measurement of vicinal coupling constant JH3aH4. Obtaining
nOe difference experiments con®rmed the stereochemistry
of endo-adduct 7a. Hence, saturation of proton H9b gave an
enhancement onto H4 of 2% indicating these two protons
were cis and also 1,3-diaxial. With the corresponding exo-
isomer 6a saturation of proton H9b resulted in an nOe
enhancement onto the protons of the pendent aromatic
ring of 2.0%. This con®rmed the stereochemistry and indi-
cated that both proton H9b and the phenyl group were 1,3-
diaxial. This analysis of the stereochemistry and conforma-
tion in solution was further con®rmed in the solid state by
single crystal X-ray analysis of exo and endo-adducts 6a and
Table 1.
Entry
Product
R1
R2
R3
Ratio 6:7
Yield %
²
7b, respectively 7Fig. 2). It is clear from Fig. 2 that in the
exo-adduct 6a, two of the substituents are axial and one is
1a
2
3
4
5
H
H
OMe
H
MeO2C
H
H
H
NO2
H
H
:141
1
b
c
d
e
H
H
H
0.8:150
1:2
1:1
33a
48
0
²
OMe
A crystal structure of endo adduct 7d was also recorded and the re®ned
co-ordinates and bond distances have been deposited with the Cambridge
Crystallographic Data Centre.
a
Only the endo isomer 7c isolated.

M. Hadden et al. / Tetrahedron 57 (2001) 5615±5624
5617
Figure 2. X-ray structures of exo, endo adducts 6a and 7b, respectively.
equatorial. Due to the similarity of our NMR data to
that reported for martinelline,4 it is likely that martinelline
adopts a conformation similar to exo-adduct 6a. In the
crystal structure of the endo-adduct 7b two of the
substituents are equatorial and one is axial. This raises
the interesting question as to which of the two isomers is
thermodynamically more stable. It is noteworthy that
when the bulk of the phenyl group was increased by
introducing an o-nitro substituent 7Table 1, entry 3) then
the amount of endo-adduct substantially increased
suggesting that this was the thermodynamically most stable
isomer.
One example of an acyclic enamide was investigated.
2-Pyrrolidinone and heptanal condensed with azeotropic
removal of water and gave exclusively the E-enamide
8.23,24 Reaction of imine 4 with enamide 8 proceeded
smoothly at room temperature and gave a mixture of two
diastereoisomers, in the ratio 2:1and 67% combined yield,
Scheme 2. The numbering used for tetrahydroquinolines is
indicated on structure 9. The diastereoisomers were sepa-
rated by ¯ash chromatography and proton NMR analysis
con®rmed the major product was the exo-adduct 9, with
the stereochemistry of the enamide preserved, relative
stereochemistry-2Sp3Rp4Sp. In particular, the large pseudo
diaxial coupling constants JH3H4 and JH3H2 of 10.8 and
10.1 Hz, respectively, showed that all three substituents on
the saturated ring were pseudo equatorial. Assignment of
relative stereochemistry to the minor isomer 10 proved a
little more problematic. The coupling constant JH3H4 of
7.0 Hz is indicative of an equatorial±axial arrangement of
protons H3 and H4 and strongly suggests that the two
substituents attached at C3 and C4 are cis. Coupling
constant JH3H2 of 4.0 Hz seemed a little small to be an
In exo, endo isomers 6a and 7a the chemical shift of proton
H9b was 5.17 and 5.75 ppm, respectively and the 13C shifts
for C3 were 27.6 and 22.7 ppm, respectively. These large
differences in chemical shift for proton H9b and carbon C3
in exo, endo isomers 6 and 7 listed in Table 1are quite
general and could be reliably used to assign the stereo-
chemistry of all subsequent new hexahydropyrroloquino-
lines that were prepared.
Scheme 2.

5618
M. Hadden et al. / Tetrahedron 57 (2001) 5615±5624
Scheme 3.
axial±equatorial coupling. However, in a closely related
system 11, devoid of the 3-pentyl group, assignment of
the relative stereochemistry at C2 and C4 was trivial due
to the large pseudo diaxial couplings of JH3aH2 10.5 Hz and
JH3aH4 11.4 Hz, respectively.25 Of particular note was that
the axial±equatorial coupling constant JH3H2 in compound
11 was 4.2 Hz. This con®rms that our value for JH3H2 of
4.0 Hz is due to an axial±equatorial coupling and the
relative stereochemistry of the minor isomer is therefore
2Sp3Sp4Sp, i.e. endo with the stereochemistry of the
enamide reversed. This result indicates that adduct 10 was
formed by a non-concerted process.
ring A). However the reaction failed when a strong electron
releasing component was present on the aldehyde end of the
imine, ring B 7Table 1, entry 5). This effect has also been
noted in similar imino Diels±Alder reactions using enol
ethers as the dienophile.26 The imino Diels±Alder reactions
of aromatic imines with alkenes is well documented,27±32
and it is generally accepted that this is a stepwise process
involving ionic intermediates. In our case, the stepwise
mechanism is supported by the formation of adduct 10 in
which the stereochemistry of the double bond is not
conserved in the cycloadduct. The mechanism for the reac-
tion is depicted in Scheme 3. The ®rst step is co-ordination
of the imine to the Lewis acid to give the iminium salt 12.
This then reacts with the electron-rich enamide to give the
stabilised N-acyl iminium ion 13, hence controlling the
regioselectivity of the addition. Intramolecular cyclisation
The cycloaddition reaction appears to be general and both
electron-donating and electron-withdrawing groups are
tolerated on the amine component of the imine 7Scheme 3,
Scheme 4.

M. Hadden et al. / Tetrahedron 57 (2001) 5615±5624
5619
Scheme 5.
followed by proton transfer gave adducts 6 and 7 after
release of the indium catalyst. The fact that a strong
electron-releasing group on ring B gave no cycloadduct
7Table 1, entry 5) whilst electron-withdrawing groups on
ring A do not have any detrimental effect, suggests that
the ®rst carbon±carbon bond forming reaction, i.e. 12!13
is the slow step in the process.
aldehydes, with only intractable materials being produced.
However, when methoxymethylphenylamine 17a, a known
precursor of imine 18,34 was treated with a two fold excess
of cyclic enamide 5 in boiling methanol, the parent C4
unsubstituted hexahydropyrroloquinoline 19 was formed
in 43% yield, Scheme 5. Neither Lewis nor protic acid
was required to effect this transformation. When an
electron withdrawing carbomethoxy group was present at
the p-position of the imine 16b, this substrate failed to
participate in the cycloaddition, suggesting that this process
may be mechanistically different to the Lewis acid catalysed
reaction of the aromatic imines.
Given the biological importance of dihydropyrroloquino-
lines, oxidation of the hexahydropyrroloquinolines 6c and
7c to dihydropyrroloquinolines was attempted. It has
previously been shown that 4-aminodihydroquinolines of
the type 14 are unstable and will readily eliminate to give
the corresponding quinoline.33 Therefore, there are two
competitive pathways after initial oxidation to 14, namely
further oxidation to 15 or elimination of amide to give 16,
Scheme 4. Using a large excess of battery grade manganese
dioxide 750 equiv.) in re¯uxing benzene for 8 h gave
exclusively 15 in 80% yield. This indicated that the second
oxidation was indeed faster than the competing elimination.
When the reaction was repeated using 25 equiv. of manga-
nese dioxide and stopped after three hours, NMR analysis of
the crude reaction mixture revealed 37% starting material,
50% of adduct 15 and 13% of elimination product 16. These
experiments demonstrate that dihydroquinoline 14, in which
the nitrogen functionality at the 4-position is amide, is much
more stable than the corresponding amine derivatives.
For martinellic acid synthesis, a phenyl group at the
4-position is not particularly useful functionality. In order
to have the potential to chain extend at this position imine
20 derived from methyl glyoxalate was brie¯y investigated.
The cycloaddition of imine 20 was not as clean as the
previously investigated phenyl imines and a 2:1mixture
of endo, exo adducts 22 and 21 was produced as determined
by proton NMR spectroscopy, Scheme 6. However, ¯ash
chromatography gave only the endo-adduct 22 in a
miserable 6% isolated yield. This low yield can in part be
attributed to imine instability, but it soon became clear that
product 22 was also very unstable. On standing in deutero-
chloroform overnight adduct 22 was quantitatively
converted to quinoline 23. This process requires elimination
of amide and an oxidation, presumably by oxygen, though it
is not clear in which order these events occur. Synthesis of
The cycloaddition failed for imines derived from aliphatic
Scheme 6.

5620
M. Hadden et al. / Tetrahedron 57 (2001) 5615±5624
Scheme 7.
quinolines from 4-ethoxytetrahydroquinoline by loss of
ethanol and oxidation by oxygen is well known.35 The
instability of adducts 21 and 22 make them less than ideal
to work with.
coupling constants are given in Hertz. A 2 Hz line broad-
ening was used to process the proton NMR spectra. The
following abbreviations are used: sˆsinglet, dˆdoublet,
tˆtriplet, qˆquartet, mˆmultiplet and brˆbroad. Mass
spectra were recorded using Double Focusing Triple Sector
VG Auto Spec and accurate molecular masses were
determined by the peak matching method using per¯uoro-
kerosene as standard reference and were accurate to within
1/20.0006 a.m.u. Analytical TLC was carried out on
Merck Kielselgel 60254 plates and the spots visualised
using a Hanovia Chromatolite UV lamp. Flash chromato-
graphy was effected using Merck Kielselgel 60 7230±400
mesh).
When cyclic enamides were employed, in all cases in where
one of the cycloadducts predominated it was the endo
isomer. In an attempt to distinguish which isomer 21 or
22 was thermodynamically more stable, an attempt was
made to epimerise freshly prepared adduct 22 using sodium
methoxide as base. Hexahydropyrroloquinoline 21 proved
to be base sensitive and fragmented to give an unusual
tricyclic compound 24 in 85% yield. This elimination±
oxidation requires a carbomethoxy group at the 4-position
to proceed cleanly. The previously prepared 4-phenyl
substituted products 6 and 7 decomposed when treated
under both acidic and basic conditions.
3.2. General procedure for preparation of imines
All imines were prepared by mixing equimolar portions of
aldehyde and amine in dichloromethane over magnesium
sulphate or molecular sieves. When the reaction was
deemed to be complete by NMR spectroscopy, the drying
agent and solvent were removed to provide the imine which
was used crude for the next step. Imines derived from ethyl
gyloxalate and 3-cyanoacrolein were found to be unstable
and could not be stored.
It was clear from these feasibility studies that products
derived from glyoxalate esters were never going to be
suitable precursors to martinellic acid. The problem
remained as to how to modify this chemistry to put a
three carbon side chain at C4. To this end imine 25, derived
from 3-cyanoacrolein,36 was investigated, Scheme 7. There
are a number of possible sites of diene reactivity in substrate
25. It was therefore gratifying that reaction of imine 25 with
carbamate 26 produced the desired chemoselectivity and
gave a 1:3 mixture of exo, endo adducts 27 and 28 in 40%
combined yield. Despite the problems with this chemistry,
particularly the lack of exo-selectivity, it is remarkable that
the hexahydropyrroloquinoline skeleton 27, containing the
correct functionality for elaboration to martinellic acid can
be assembled in one step from very readily available starting
materials.
3.3. General procedure for indium trichloride catalysed
cycloadditions of imines to enamides
To a stirred solution of the imine 71mmol) and cyclic
enamide 71mmol) in dry acetonitrile 75 ml) under a nitro-
gen atmosphere was added indium trichloride 70.2 mmol).
After 30 min dichloromethane 710 ml) was added followed
by saturated sodium carbonate solution and stirring was
continued for 10 min. The organic layer was separated,
dried over magnesium sulphate and concentrated to provide
an exo, endo mixture of the cycloadducts. In all cases the
endo-isomer had a higher chemical shift for proton H9b than
the exo-isomer in the proton NMR spectra. The exo, endo
ratios were quanti®ed by comparing the integrations of these
signals. Solvents quoted with the Rf values were the ones
that were used for performing ¯ash chromatography.
3. Experimental
3.1. General
Melting points were recorded using a Ko¯er hot stage
apparatus and are uncorrected. IR spectra were recorded
on a Perkin±Elmer Model 983G instrument coupled to a
Perkin±Elmer 3700 Data Station as potassium bromide
3.3.1. exo-1-+4-Phenyl-2,3,3a,4,5,9b-hexahydropyrrolo[3,2-
c]quinolin-1-yl)propan-100-one 6a. Reaction according to
the general procedure gave the titled compound 764 mg,
21%), as a white solid mp 185±1868C Rf 0.38, 7ether:pet.
ether 90:10). 7C20H22N2O Requires M1 306.1732. Found
306.1735); nmax 7KBr)/cm21 3333.2, 2971.9, 1617.8. dH
7CDCl3, 500 MHz) 1.19 73H, t, Jˆ7.1Hz, C H3CH2), 2.13
72£1H, 2£m, 3-H), 2.24 72£1H, 2£m, CH3CH2), 2.47 71H,
1
7KBr) disks, or ®lms 7liquids). H nuclear magnetic reso-
nance 7NMR) spectra were recorded at 300 MHz using
General Electric QE300, Bruker DPX 300 and at
500 MHz using a Bruker DRX500 NMR spectrometers.
Chemical shifts are given in parts per million 7d) down
®eld from tetramethylsilane as internal standard and

M. Hadden et al. / Tetrahedron 57 (2001) 5615±5624
5621
m, 3a-H), 3.45 72£1H, 2£m, 2-H), 4.27 71H, br, NH), 4.35
71H, d, Jˆ2.5 Hz, 4-H), 5.17 71H, d, Jˆ6.7 Hz, 9a-H), 6.50
71H, d, Jˆ7.3 Hz, 6-H), 6.6171H, t, Jˆ7.3 Hz, 8-H), 7.04
71H, t, Jˆ7.3 Hz, 7-H), 7.10±7.30 75H, 5£m, PhH), 7.36
71H, d, Jˆ7.3 Hz, 9-H). dC 7CDCl3, 125 MHz) 9.37C300),
27.67C3), 28.77C200), 43.17C3a), 45.37C2), 51.77C4),
55.77C9b), 113.37C6), 117.97C8), 120.97C7), 125.77C9a),
127.27C40), 128.272£C30), 128.772£C20), 130.57C9),
142.37C5a), 144.87C10), 173.97C100). m/z 306 7M1, 30%),
277 711), 249 719), 206 7100), 91 716).
and 9-H). dC 7CDCl3, 125 MHz) 9.27C300), 22.77C3),
27.77C200), 44.17C3a), 45.67C2), 55.77OCH3), 56.17C9b),
56.87C4), 114.57C7), 115.67C9a), 115.87C6), 123.27C9),
126.672£C30), 127.77C40), 128.672£C20), 137.77C5a),
142.07C10), 153.07C8), 174.07C100). m/z 7M1, %); 336 7M1,
100%), 307 719), 279 738), 236 755), 91 724).
3.3.5. endo-1-[4-+20-Nitrophenyl)-2,3,3a,4,5,9b-hexahydro-
pyrrolo[3,2-c]quinolin-1-yl]propan-100-one 7c. Reaction
according to the general procedure followed by stirring
overnight resulted in precipitation of an orange solid
which was recrystallised from dichloromethane hexane to
give the titled compound 7117 mg, 33%) as a orange solid Rf
0.50, 7ether:hexane 90:10), mp .2708C. 7C20H21N3O3
Requires M1 351.1583. Found 351.1584). nmax 7KBr)/
cm21 3333.0, 2972.0, 1623.4, 1586.9. dH 7CDCl3,
500 MHz) 1.20 73H, t, Jˆ7.1Hz, C H3CH2), 1.62 71H, m,
3-H), 2.3173 £1H, 3£m, CH3CH2 and 3-H), 2.85 71H, m,
3a-H), 3.38 71H, dt, Jˆ9.9, 7.6 Hz, 2-H), 3.517H1 , t,
Jˆ9.9 Hz, 2-H), 3.73 71H, br, NH), 5.23 71H, d,
Jˆ2.8 Hz, 4-H), 5.8171H, d, Jˆ7.0 Hz, 9b-H) 6.57 71H,
d, Jˆ7.0 Hz, 6-H), 6.80 71H, t, Jˆ7.0 Hz, 8-H), 7.06 71H,
t, Jˆ7.0 Hz, 7-H), 7.48 71H, t Jˆ7.5 Hz, 50-H), 7.68 72£1H,
2£m, 30-H and 40-H), 7.95 71H, d, Jˆ7.5 Hz, 9-H), 8.05
71H, d, Jˆ7.5 Hz, 60-H). dC 7CDCl3, 125 MHz) 9.07C300),
23.27C3), 27.67C200), 41.37C3a), 45.57C2), 51.57C4),
55.77C9b), 115.07C6), 119.87C8), 122.77C9a), 124.87C30),
128.007C7), 128.67C40), 128.77C9), 131.17C60), 133.17C50),
136.47C10), 143.27C5a), 149.07C20), 174.07C100). m/z 7M1,
%), 3517M 1, 25%), 260 7100), 91 714).
3.3.2. endo-1-+4-Phenyl-2,3,3a,4,5,9b-hexahydropyrrolo-
[3,2-c]quinolin-1-yl)propan-100-one 7a. Reaction accord-
ing to the general procedure gave the titled compound
764 mg, 21%), as a white solid mp 153±1548C Rf 0.48,
7ether:pet. ether 90:10). 7C20H22N2O Requires M1
306.1732. Found 306.1735); nmax 7KBr)/cm21 3312.8,
2975.6, 1629.2. dH 7CDCl3, 500 MHz) 1.19 73H, t,
Jˆ7.4 Hz, CH3CH2), 1.64 71H, m, 3-H), 2.30 73£1H,
3£m, CH3CH2 and 3-H), 2.49 71H, m, 3a-H), 3.33 71H, dt,
Jˆ9.6 Hz, 7.7, 2-H), 3.48 71H, t, Jˆ9.6 Hz, 2-H), 3.90 71H,
br, NH), 4.73 71H, d, Jˆ2.7 Hz, 4-H), 5.77 71H, d,
Jˆ6.1Hz, 9b- H), 6.58 71H, d, Jˆ7.1Hz, 6- H), 6.74 71H,
t, Jˆ7.1Hz, 8- H), 7.06 71H, t, Jˆ7.1Jz, 7- H), 7.30±7.46
75H, m, Ph±H), 7.63 71H, d, Jˆ7.1Hz, 9- H). dC 7CDCl3,
125 MHz) 9.17C300), 22.07C3), 27.67C200), 44.07C3a),
45.27C2), 55.87C4), 56.47C9b), 114.77C6), 119.17C8),
122.27C7), 126.67C9a), 127.87C40), 128.072£C30), 128.772£
C20), 130.97C9), 141.87C5a), 143.77C10), 174.07C100). m/z
306 7M1, 100%), 277 760), 249 759), 206 795), 91 732).
3.3.3.
hydropyrrolo[3,2-c]quinolin-1-yl)propan-100-one
exo-1-+8-Methoxy-4-phenyl-2,3,3a,4,5,9b-hexa-
6b.
3.3.6. exo-4-Phenyl-1-propionyl-2,3,3a,4,5,9b-hexahydro-
1H-pyrrolo[3,2-c]quinoline-8-carboxylic acid methyl
ester 6d. Reaction according to the general procedure
gave the titled compound 787 mg, 24%) as a white solid Rf
0.18, 7ether), mp 170±1718C 7C22H24N2O3 Requires M1
364.1774. Found 364.1780). nmax 7KBr)/cm21; 3314.4,
2971.0, 1700.0, 1632.3, 1608.3. dH 7CDCl3, 500 MHz)
1.21 73H, t, Jˆ7.1Hz, C H3CH2), 2.18 72H, m, 3-H), 2.32
72H, q, Jˆ7.1Hz, CH 3CH2), 2.52 71H, m, 3a-H), 3.5172 £
1H, 2£m, 2-H), 3.8173H, s, C H3O), 4.32 71H, br, NH) 4.50
71H, br, 4-H), 5.26 71H, d, Jˆ6.4 Hz, 9b-H), 6.50 71H, d,
Jˆ8.2 Hz, 6-H), 7.24 75H, m, Ph±H), 7.80 71H, d,
Jˆ8.2 Hz, 7-H), 8.05 71H, s, 9-H). dC 7CDCl3, 125 MHz)
9.37C300), 27.77C3), 28.77C200), 42.87C3a), 45.27C2),
51.37C4), 51.67OCH3), 55.47C9b), 112.87C6), 119.57C9a),
119.77C8), 125.572£C30), 127.67C40), 129.072£C20),
Reaction according to the general procedure gave the titled
compound 774 mg, 22%) as a white solid. mp 153±1548C, Rf
0.48, 7ether). 7C21H24N2O2 Requires M1 336.1837. Found
336.1843). nmax 7KBr)/cm21 3345.7, 2937.9, 1625.1,
1503.5. dH 7CDCl3, 500 MHz) 1.18 73H, t, Jˆ7.1Hz,
CH3CH2), 2.19 72£1H, m, 3-H), 2.32 72£1H, 2£m,
CH3CH2), 2.56 71H, m, 3a-H), 3.53 72£1H, m, 2-H), 3.71
73H, s, CH3O), 3.72 71H, br, NH), 4.67 71H, br, 4-H), 5.21
71H, br, 9b-H), 6.70 71H, dd, Jˆ7.1Hz, 2.8, 6- H), 6.70 71H,
dd, Jˆ7.1Hz, 2.8, 7- H), 7.10 71H, d, Jˆ2.8 Hz, 9-H), 7.25
75H, m, Ph±H,). dC 7CDCl3, 125 MHz) 9.47C300), 27.87C3),
28.77C200), 43.47C3a), 45.57C2), 52.37OCH3), 55.77C4),
56.17C9b), 114.57C6), 114.67C7), 115.57C9), 121.57C9a),
125.97C40), 127.3 72£C30), 128.872£C20), 136.67C5a),
144.97C10), 152.47C8), 173.97C100). m/z 7M1, %), 336
7M1, 66%), 307 78), 279 715), 236 7100), 91 714).
130.47C7),
132.57C9),
144.17C10),
146.37C5a),
167.37COCH3), 173.97C100). m/z 7M1, %), 364 7M1, 7%),
264 715), 91 737), 57 7100).
3.3.4. endo-1-+8-Methoxy-4-phenyl-2,3,3a,4,5,9b-hexa-
hydropyrrolo[3,2-c]quinolin-1-yl)propan-100-one 7b. Reac-
tion according to the general procedure gave the titled
compound 793.4 mg, 28%) as a white solid mp 157.0±
158.28C, Rf 0.53, 7ether). 7C21H24N2O2 Requires M1
336.1837. Found 336.1844). nmax 7KBr)/cm21; 3360.7,
2974.0, 1638.8, 1504.0. dH 7CDCl3, 500 MHz) 1 .28 73H, t,
Jˆ7.1Hz, C H3CH2), 1.63 71H, m, 3-H), 2.3173 £1H, 3£m,
CH3CH2 and 3-H), 2.48 71H, m, 3a-H), 3.35 71H, dt,
Jˆ9.7 Hz, 7.3, 2-H), 3.49 71H, t, Jˆ9.7 Hz, 2-H), 3.72 73H,
s, CH3O), 3.73 71H, br, NH), 4.67 71H, d, Jˆ2.5 Hz, 4-H),
5.75 71H, d, Jˆ7.3 Hz, 9b-H), 6.5171H, d, Jˆ8.5 Hz, 6-H),
6.68 71H, dd, Jˆ8.5, 3.0 Hz, 7-H), 7.30-7.46 76H, m, Ph±H
3.3.7.
hydro-1H-pyrrolo[3,2-c]quinoline-8-carboxylic
endo-4-Phenyl-1-propionyl-2,3,3a,4,5,9b-hexa-
acid
methyl ester 7d. Reaction according to the general pro-
cedure gave the titled compound 787 mg, 24%) as a white
solid Rf 0.28, 7ether), mp 192±1938C. 7C22H24N2O3
Requires M1 364.1787. Found 364.1780). nmax 7KBr)/
cm21 3372.4, 2979.6, 1705.2, 1644.4, 1608.6. dH 7CDCl3,
300 MHz) 1.28 73H, t, Jˆ7.1Hz, C H3CH2), 1.64 71H, m,
3-H), 2.17 71H, m, 3-H), 2.32 72H, q, Jˆ7.1Hz, CH 3CH2),
2.50 71H, m, 3a-H), 3.35 71H, td, Jˆ10.2, 7.7 Hz, 2-H), 3.48
71H, m, 2-H), 3.89 73H, s, CH3O), 4.34 71H, br, NH), 4.82
71H, d, Jˆ2.7 Hz, 4-H), 5.76 71H, d, Jˆ7.3 Hz, 9b-H), 6.60

5622
M. Hadden et al. / Tetrahedron 57 (2001) 5615±5624
71H, d, Jˆ8.5 Hz, 6-H), 7.40 75H, m, Ph±H), 7.74 71H, d,
Jˆ8.5 Hz, 7-H), 8.19 71H, s, 9-H). dC 7CDCl3, 125 MHz)
9.27C300), 23.47C3), 27.67C200), 43.47C3a), 45.47C2),
51.77OCH3), 55.37C9b), 56.07C4), 114.17C6), 120.57C9a),
120.97C8), 126.572£C30), 128.37C40), 128.972£C20),
167.27COCH3), 174.17C100). m/z 7M1, %), 364 7M1, 17%),
307 710), 210 7100).
concentrated under reduced pressure and the residue puri-
®ed by ¯ash chromatography to yield the titled compound
780 mg, 82%) as clear oil Rf 0.3 7ether). 7C20H17N3O3
Requires M1 347.1270 Found 347.1256); nmax 7KBr)/
cm21 2963.9, 1680.0, 1527.6. dH 7CDCl3, 500 MHz) 1.34
73H, t, Jˆ7.2 Hz, CH3CH2), 2.65 72H, q, Jˆ7.2 Hz,
CH3CH2), 3.02 72H, t, Jˆ8.0 Hz, 3-H), 4.24 72H, t,
Jˆ8.0 Hz, 2-H), 7.52 71H, t, Jˆ8.0 Hz, 7-H), 7.55 71H, d,
Jˆ7.6 Hz, 60-H), 7.62 71H, t, Jˆ7.8 Hz, 40-H), 7.67 71H, t,
Jˆ8.0 Hz, 8-H), 7.74 71H, t, Jˆ7.6 Hz, 50-H), 8.04 72£1H,
2£d, Jˆ8.0 Hz, 6-H and 9-H), 8.14 71H, d, Jˆ7.8 Hz, 30-H);
dC 7CDCl3, 125 MHz) 8.6, 27.0, 29.0, 50.0, 119.3, 123.7,
124.3, 124.6, 125.2, 128.4, 2£128.6, 130.4, 132.4, 134.8,
147.8, 148.2, 149.1, 153.1, 173.4; m/z 7M1, %), 3477M1,
6%), 149 7100), 91 745), 57 797).
130.07C7),
132.77C9),
141.07C10),
147.57C5a),
3.3.8. 10-+3-Pentyl-2-p-tolyl-1,2,3,4-tetrahydroquinolin-
4-yl)pyrrolidin-20-ones
9 and 10. Imine 7500 mg,
2.56 mol, 1equiv.), and enamide 7460 mg, 2.54 mmol,
1equiv.) were reacted according to the general procedure
to give a 2:1mixture of 9 and 10 by proton NMR spectro-
scopy. Flash chromatography provided compound
9
7424 mg, 44%), as an oil which slowly solidi®ed to give a
white solid mp 145±1468C, Rf 0.44 7hexane:ether 1:4).
7C25H32N2O requires M1 376.2515 Found M1 376.2501).
3.3.10.
N-{20-+200-Nitrophenyl)quinolin-3-ylethyl}pro-
panamide 16. Battery grade manganese dioxide 7activated
by heating in an oven at 858C overnight) 7608 mg, 7 mmol),
was added to a mixture of precipitated endo/exo-1-[4-72-
nitrophenyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]-
quinolin-1-yl]-1-propanone 7100 mg, 0.28 mmol,) in dry
benzene 715 ml) and this was re¯uxed under a nitrogen
atmosphere for 3 h. The solution was then ®ltered through
celite and the residue washed with methanol 72£10 ml). The
methanol and benzene solutions were then combined and
concentrated under reduced pressure and the residue puri-
®ed by P.L.C 7ether). This provided a 1:1 mixture of two
compounds 710 mg, 10%), Rf 0.17ether), 16 and a compound
which may be the imine 14. On standing in CDCl3 overnight
the mixture became homogenous affording the titled
compound 16, 710 mg, 10%) as a clear oil Rf 0.17ether).
7C20H19N3O3 Requires M1 349.1426 Found 349.1428). nmax
7KBr)/cm21 3926.8, 2935.6, 1650.0, 1526.4. dH 7CDCl3,
300 MHz) 0.97 73H, t, Jˆ7.5 Hz, CH3CH2), 1.99 72H, m,
CH3CH2), 2.83 72H, t, Jˆ6.6 Hz, 10-H), 3.36 72H, m, 20),
5.48 71H, br, NH), 7.52 71H, d, Jˆ7.6 Hz, 600-H), 7.57 71H,
t, Jˆ7.8 Hz, 7-H), 7.60 71H, t, Jˆ7.6 Hz, 400-H), 7.70 71H, t,
Jˆ7.8 Hz, 6-H), 7.75 71H, t, Jˆ7.6 Hz, 500-H), 7.83 71H, d,
Jˆ7.8 Hz, 5-H), 8.0171H, d, Jˆ7.8 Hz, 8-H), 8.10 71H, s,
4-H), 8.18 71H, d, Jˆ7.6 Hz, 300-H). dC 7CDCl3, 125 MHz)
8.9, 28.7, 31.3, 37.7, 125.0, 125.15, 127.18, 127.6, 129.1,
129.5, 129.6, 129.9, 131.3, 133.5, 135.8, 136.7, 146.4,
148.4, 157.2, 174.0. m/z 7M1, %), 349, 7M1, 10%), 263
710), 149 764), 57 775), 28 7100).
n
max 7KBr)/cm21 3364, 2929, 1856, 1671, 1408, 1344, 1268.
dH 7500 MHz, CDCl3) 0.67 73H, t, Jˆ7.2 Hz, CH2CH3),
1.96 78H, m, methylene envelope), 1.94 72H, m,
CH2CH2CO), 2.0173H, s, ArC H3), 2.10 71H, ddt, Jˆ10.8,
10.4, 4.4 Hz, 3-H), 2.44 72H, m, CH2CH2CO), 3.09 72£1H,
2£m, NCH2CH2), 3.99 71H, s, NH), 4.34 71H, d, Jˆ10.1 Hz,
2-H), 5.37 71H, d, Jˆ10.8 Hz, 4-H), 6.55 71H, d, Jˆ8.0 Hz,
8-H), 6.66 71H, t, Jˆ7.4 Hz, 7-H), 6.77 71H, d, Jˆ7.8 Hz,
5-H), 7.20 71H, t, Jˆ7.6 Hz, 6-H), 7.55 72H, d, Jˆ8.6 Hz,
ArH), 8.15 72H, d, Jˆ8.4 Hz, ArH). dH 7125 MHz, CDCl3)
12.9, 16.4, 17.3, 21.3, 23.9, 27.4, 29.0, 31.0, 39.9, 41.4,
56.1, 60.7, 113.6, 115.3, 117.7, 122.7, 126.2, 2£126.9,
2£128.5, 144.1, 146.7, 148.3, 175.2. m/z 7M1, %)
3767M134), 291734), 2207100), 195740), 124783), 86751),
41751).
Collection of further fractions provided compound 10 as a
brown oil 7221mg, 23%). Rf 0.29 7hexane:ether 1:4) nmax
7KBr)/cm21 3410, 2928, 1671, 1345. dH 7500 MHz, CDCl3)
0.74 73H, t, Jˆ7.3 Hz, CH2CH3), 1.08 78H, m, methylene
envelope), 1.29 72£1H, 2£m, CH2CH2CO), 1.92 72£1H,
2£m, CH2CH2CO), 2.23 71H, qd, Jˆ6.8 Hz, 4.0, 3-H),
2.43 73H, s, ArCH3), 3.04 71H, ddd, Jˆ9.7, 7.8, 5.8 Hz,
NCHHCH2), 3.16 71H, ddd, Jˆ9.8, 7.9, 6. 0Hz,
NCHHCH2), 4.26 71H, s, NH), 4.60 71H, d, Jˆ4.0 Hz,
2-H), 4.97 71H, d, Jˆ7.0 Hz, 4-H), 6.58 71H, d, Jˆ7.3 Hz,
8-H), 6.70 71H, dd, Jˆ7.4 Hz, 7-H), 6.971H, d, Jˆ7.3 Hz,
5-H), 7.05 71H, d Jˆ7.3 Hz, 6-H), 7.35 72H, d, Jˆ10.0 Hz,
ArH), 8.10 72H, d, Jˆ10.0 Hz, ArH); dC 775 MHz, CDCl3)
12.9, 17.6, 21.5, 25.3, 25.8, 25.9, 30.5, 30.7, 40.3, 43.9,
49.4, 54.9, 113.6, 116.2, 117.4, 123.1, 126.3, 2£127.9,
2£128.7, 143.3, 146.3, 148.3, 174.4. m/z 7M1, %) 376
7M134), 291734), 2207100), 195740), 124783), 86751),
41751).
3.3.11. 1-+3,3a,4,5,9b-hexahydropyrrolo[3,2,c]quinolin-
1-yl)propan-10-one 19. A solution of methoxymethyl-
phenylamine 17a 755 mg, 0.4 mmol) and 1-72,3-dihydro-
pyrrol-1-yl)propan-1-one
5
7100 mg, 0.8 mmol) in
methanol 10 ml was boiled under re¯ux for 18 h. The
solvent was removed under reduced pressure and ¯ash
chromatography gave the titled compound 740 mg, 43%)
as a white solid mp 99±1018C Rf 0.35 7ether), C14H18N2O
requires M1 230.1419 found M1 230.1410. nmax. 7KBr)/
cm21 3334, 2925, 2855, 1734, 1371, 1300. dH7500 MHz,
CDCl3) 1.13 73H, t, Jˆ7.5 Hz, CH3), 1.94 72£1H, 2£m,
H3), 2.24 72£1H, 2£m, CH3CH2), 2.417H1 , m, H3a),
3.11 71H, dd, Jˆ11.8, 2.4 Hz, H40), 3.43 73£1H, 3£m,
H2, and H4), 5.46 71H, d, Jˆ7.4 Hz, H9b), 6.40 71H, d,
Jˆ7.7 Hz, H6), 6.59 71H, t, Jˆ7.7 Hz, H8), 6.93 71H, t,
Jˆ7.7 Hz, H7), 7.9171H, d, Jˆ7.7 Hz, H9). dC 775 MHz,
CDCl3) 8.17C30), 23.97C3), 25.27C20), 33.67C4) 40.87C3a),
3.3.9. 1-[4-+20-Nitrophenyl)-2,3-dihydropyrrolo[3,2-c]-
quinolin-1-yl]propan-100-one 15. Battery grade manganese
dioxide 7activated by heating in an oven at 858C overnight)
71.216 g, 14 mmol), was added to a mixture of precipitated
endo/exo-1-[4-720-nitrophenyl)-2,3,3a,4,5,9b-hexahydropyr-
rolo[3,2-c]quinolin-1-yl]-100-propanone 7100 mg, 0.14 mmol)
in dry benzene 715 ml) and re¯uxed under a nitrogen
atmosphere for 16 h. The solution was then ®ltered through
celite and the residue washed with methanol 72£10 ml). The
methanol and benzene solutions were then combined and

M. Hadden et al. / Tetrahedron 57 (2001) 5615±5624
5623
44.77C2), 53.37C9b), 113.37C6), 117.57C8), 121.47C9a),
126.87C7), 130.07C9), 142.67C5a), 172.97C10). m/z 7M1,
%) 230759), 201789), 173739), 145743), 1307100).
3.3.15.
hexahydropyrrolo[3,2-c]quinoline-1-carboxylic
endo-8-Bromo-4-+20-cyanovinyl)-2,3,3a,4,5,9b-
acid
methyl ester 28. General procedure gave titled compound
7108 mg, 30%) as a clear oil Rf 0.69 7ether). 7C16H16BrN3O2
requires M1 361.0425. Found 361.0438). nmax 7KBr)/cm21
3305.1, 2956.0, 2224.9, 1657.3. dH 7CDCl3, 300 MHz) 1.90
72£1H, br, 3-H), 2.4171H, br, 3a- H), 3.30 72£1H, br, 2-H),
3.70 73H, s, CH3O), 4.2171H, br, 4- H), 5.05 70.33H, br,
9b-H), 5.20 70.67H, br, 9b-H), 5.62 71H, d, Jˆ16.4 Hz,
20-H), 6.37 71H, d, Jˆ8.5 Hz, 6-H), 6.70 71H, dd, Jˆ16.4,
5.4 Hz, 10-H), 7.06 71H, d, Jˆ8.4 Hz, 7-H), 7.40 70.33H, br,
9-H), 7.63 70.67H, br, 9-H). dC 7CDCl3, 75 MHz) 22.7, 40.2,
44.4, 52.6, 53.1, 55.6, 101.1, 111.7, 116.3, 116.6, 131.1,
132.0, 132.8, 140.7, 153.1, 156.7. m/z 7M1, %) 3617M1,
35), 264 737), 128 7100).
3.3.12. endo-8-Methoxy-1-propionyl-2,3,3a,4,5,9b-hexa-
hydro-1H-pyrrolo[3,2-c]quinoline-4-carboxylic
acid
methyl ester 22. Imine 20 and enamide 5 reacted according
to the general procedure to give a 2:1 endo:exo mixture of
diastereoisomers by NMR spectroscopy. Separation by ¯ash
chromatography provided only the endo-isomer as an
orange oil 721mg, 6%), Rf 0.25, 7ether). As compound 22
rapidly aromatises, it could only be characterised by proton
NMR spectroscopy. dH 7CDCl3, 300 MHz) 1.23 73H, t,
Jˆ7.2 Hz, CH3CH2), 1.90 72H, m, 3-H), 2.40 73H, over-
lapping m, CH3CH2 and 3a-H), 3.35±3.50 72£1H, 2£m,
2-H), 3.8173H, s, C H3O), 4.08 74H, s overlapping with m,
CH3O and 4-H), 5.64 71H, d, Jˆ8.8 Hz, 9b-H), 6.88 71H, dd,
Jˆ8.8, 0.9 Hz, 7-H), 7.0171H, d, Jˆ0.9 Hz, 9-H), 7.60 71H,
d, Jˆ8.6 Hz, 6-H).
Collection of further fractions gave exo-8-bromo-4-720-
cyanovinyl)-2,3,3a,4,5,9b-hexahydropyrrolo[3,2-c]quino-
line-1-carboxylic acid methyl ester 27 736 mg, 10%) as a
clear oil Rf 0.27 7ether). 7C16H16BrN3O2 requires M1
361.0425. Found 361.0432). nmax 7KBr)/cm21 3305.1,
2956.0, 2224.9, 1657.3. dH 7CDCl3, 300 MHz) 2.05
72£1H, br, 3-H), 2.4171H, br, 3a- H), 3.30 71H, br, 2-H),
3.40 71H, br, 2-H), 3.75 73H, s, CH3O), 4.05 71H, br, 4-H),
4.16 71H, br, NH), 4.95 71H, br, 9b-H), 5.52 71H, d,
Jˆ16.3 Hz, 20-H), 6.40 71H, d, Jˆ8.6 Hz, 6-H), 6.75 71H,
dd, Jˆ16.3, 5.1 Hz, 10-H), 7.10 71H, d, Jˆ8.6 Hz, 7-H),
7.50 71H, br, 9-H). m/z 7M1, %), 3617M1, 35), 264 737),
128 7100).
3.3.13. 6-Methoxy-3-[2-+propionylamino)ethyl]quinoline-
2-carboxylic acid methyl ester 23. endo-8-Methoxy-1-
propionyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quino-
line-4-carboxylic acid methyl ester 22 780 mg, 0.25 mmol)
was allowed to stand overnight in deuterochloroform 71ml)
in a capped NMR tube. Proton NMR spectroscopy
showed complete consumption of the starting material.
The solvent was then removed under reduced pressure to
provide the pure titled compound 779 mg, 100%) as an
orange oil. 7C17H20N2O4 Requires M1 316.1423. Found
316.1422). nmax 7KBr)/cm21 2972.4, 1726.2, 1637.9,
1542.3. dH 7CDCl3, 500 MHz) 1.08 73H, t, Jˆ7.6 Hz,
CH3CH2), 2.14 72H, q, Jˆ7.6 Hz, CH3CH2), 3.23 72H, t,
Jˆ7.2 Hz, 10-H), 3.65 72H, q, Jˆ7.2 Hz, 20-H), 3.95 73H,
s, CH3O), 4.06 73H, s, CH3O), 6.2171H, br, N H), 7.03 71H,
d, Jˆ2.7 Hz, 5-H), 7.38 71H, dd, Jˆ9.4, 2.7 Hz, 7-H), 8.01
71H, s, 4-H), 8.07 71H, d, Jˆ9.4 Hz, 8-H). dC 7CDCl3,
125 MHz) 10.2, 30.0, 32.5, 41.4, 53.5, 56.1, 104.4, 123.8,
130.8, 131.8, 132.8, 137.7, 142.7, 146.2, 159.9, 167.8,
174.4. m/z 7M1, %), 316 7M1, 75%), 257 757), 231795),
171 7100).
References
1. Badawey, E. S. A. M.; Kappe, T. Eur. J. Med. Chem. 1997, 32,
815±822.
2. Leach, C. A.; Brown, T. H.; Ife, R. J.; Keeling, D. J.; Laing,
S. M.; Parsons, M. E.; Price, C. A.; Wiggall, K. J. J. Med.
Chem. 1992, 35, 1845±1852.
3. Brown, T. H.; Ife, R. J.; Keeling, D. J.; Laing, S. M.; Leach,
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3.3.14. 7-Methoxy-3,4-dihydro-2H-benzo[b][1,7]naph-
thyridin-1-one 24. Sodium methoxide 711 mg, 0.2 mmol)
was added to endo-8-methoxy-1-propionyl-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[3,2-c]quinoline-4-carboxylic acid
methyl ester 764 mg, 0.2 mmol) in methanol and the solu-
tion was re¯uxed for 3 h. The methanol was removed under
reduced pressure, the residue dissolved in DCM 710 ml)
washed with water 72£10 ml) dried over magnesium and
concentrated. The residue was puri®ed by ¯ash chromato-
graphy to afford the titled compound 739 mg, 85%) as a
white solid mp .2708C, Rf 0.5 7CHCl3:MeOH, 90:10).
7C13H12N2O2 requires M1 228.0899. Found 228.0907).
nmax 7KBr)/cm21 3205.2, 2950.2, 1676.8, 1619.8; dH
7CDCl3, 300 MHz) 3.22 72H, t, Jˆ6.3 Hz, 4-H), 3.68
72H, td, Jˆ6.3, 3.1Hz, 3- H), 3.95 73H, s, CH3O),
7.07 71H, d, Jˆ2.6 Hz, 6-H), 7.16 71H, br, NH), 7.38
71H, dd, Jˆ9.3, 2.6 Hz, 8-H), 7.92 71H, s, 5-H), 8.27
71H, d, Jˆ9.3 Hz, 9-H). dC 7CDCl3, 125 MHz) 28.6,
40.0, 56.6, 104.0, 122.8, 130.6, 131.6, 132.6, 133.0,
143.9, 144.3, 159.4, 164.9. m/z 7M1, %), 2287M1,
94%), 199 716), 171 7100), 128 722).
4. Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard,
A. M.; Salvatore, M. J.; Lumma, W. C.; Anderson, P. S.;
Pitzenberger, S. M.; Varga, S. L. J. Am. Chem. Soc. 1995,
117, 6682±6685.
5. Nieman, J. A.; Ennis, M. D. Org. Lett. 2000, 2, 1395±1397.
6. Frank, K. E.; Aube, J. J. Org. Chem. 2000, 65, 655±666.
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