Scope and limitations of the T-reaction employing some functionalized C-H-acids and naturally occurring secondary amines

Article abstract of DOI:10.3987/COM-07-11260

Scope and limitations of the T-reaction with emphasis on using chiral, natural products as starting materials to prepare novel chiral heterocycles is studied and the diastereoselective introduction of newly formed stereocenters is explained via proposed mechanisms.

Full text of DOI:10.3987/COM-07-11260

HETEROCYCLES, Vol. 75, No. 4, 2008
799
HETEROCYCLES, Vol. 75, No. 4, 2008, pp. 799 - 838. © The Japan Institute of Heterocyclic Chemistry
Received, 17th October, 2007, Accepted, 25th Decemebr, 2007, Published online, 28th Decemebr, 2007. COM-07-11260
SCOPE AND LIMITATIONS OF THE T-REACTION EMPLOYING SOME
FUNCTIONALIZED C-H-ACIDS AND NATURALLY OCCURRING
SECONDARY AMINES
Constantin Rabong,a Christian Hametner,a Kurt Mereiter,b Victor G.
Kartsev,c and Ulrich Jordisa*
a) Institute of Applied Synthetic Chemistry, Vienna University of Technology,
Getreidemarkt 9/163, 1060 Vienna, Austria.
e-mail: ujordis@pop.tuwien.ac.at
b) Institute of Chemical Technologies and Analytics,
c) InterBioScreen Ltd., 142432 Chernogolovka, Moscow Region, Russian
Federation.
e-mail: vkartsev@ibscreen.chg.ru
Abstract - Scope and limitations of the T-reaction with emphasis on using chiral,
natural products as starting materials to prepare novel chiral heterocycles is studied and
the diastereoselective introduction of newly formed stereocenters is explained via
proposed mechanisms.
INTRODUCTION
The T-reaction is currently being used with increased frequency for the creation of new C-C bonds in
[1,2-a]-fused quinoline-type heterocycles. The key feature of the T-reaction encompasses a thermal
isomerization leading to cyclization, a sequence governed by the tert-amino-effect,1 i.e. interaction of a
tertiary aromatic amine substituted with its unsaturated ortho-substituent having electron-withdrawing
substituents Y,Y’ in a conjugated arrangement (Scheme 1). The transformation was explained by virtue of
a chiral, helical [1,5]-dipolar intermediate2, generated upon a suprafacial [1,5]-hydrideshift3 from an α-
amino-carbon to the benzylic position as the rate-determining step taking place upon heating. The transfer
being accompanied by charge separation in the molecule, subsequent intramolecular addition of the carb-
anion to the iminium-doublebond is brought about, accomplishing C-C-bond formation from a practically
nonactivated NCH-moiety.

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HETEROCYCLES, Vol. 75, No. 4, 2008
N+
H
N+
N+
∆
N
N
[1,5]-H
H
{
{
H
fast
{
{
HH
H
{
suprafacial
Y'
Y
C
-
Y
Y'
-
Y
Y'
Y
Y'
Y
Y'
Scheme 1: The tert-amino-effect operative in the T-reaction.
As is to be described in this paper, we investigated this protocol for the economical and yield-efficient
preparation of structurally diverse heterocycles, ultimately allowing for the straightforward generation
and isolation of orthogonally functionalized products bearing stereoselectively introduced centers of
chirality.
RESULTS AND DISCUSSION
The two-step-procedure towards 1,2,3,4-tetrahydroquinolines consisted first of aryl amination (see
Schemes 2, 3) of secondary amines with ortho-halo-substituted aromatic aldehydes, either via
nucleophilic aromatic substitution or Pd-catalyzed Buchwald-Hartwig crosscoupling4 followed by the
tandem2,5 T-reaction in protic solvents (see schemes). We examined variations on the C-H-acid moiety,
namely employing mono- (X = NO2, Y = H), disubstituted (X, Y= COR, COOR, CONHR, NCOR or
CN)6 and heterocyclic7 active methylene compounds 2,2-dimethyl-[1,3]-dioxane-4,6-dione (Meldrum’s
acid, 11, see Scheme 4) and 1,3-dimethylpyrimidine-2,4,6-trione (N,N-dimethylbarbituric acid, 12). When
X ≠ Y, new stereogenic centers are formed. With X = Y, follow-up transformations8 still lead to
stereochemically defined products.
R'
R'
R'
X
R
R
X
R
X
Y
N
, ∆
N
N
Y
O
H
O
Scheme 2: Synthesis of 1,2,3-substituted tetrahydroquinolines in the T-reaction.
Preferably the condensation and cyclization is performed as a one pot procedure5 and with 11 and 12,
isolation and characterisation of the benzylidenic intermediates was unsuccessful in all but one case. Thus,
the description of the corresponding reaction rates as “anomalously”7 high in comparison to open-chain
active methylene compounds with similar electron-withdrawing properties is validated.9,10

HETEROCYCLES, Vol. 75, No. 4, 2008
801
Method I
CHO
CHO
HNR3R4
+
Scaffold
I / II / III/ IV
{
{
NR3R4
X
9
Method II
CHO
R1
R2
CHO
S
CHO
Cl
R1
CHO
O
N
N
Cl
N
Cl
N
X
IV
I
II
III
R2
X = F / Br
R1, R2 = H / F
R1 = H / OMe; R2 =H.
Or R1, R2 = -O-CH2-O-
HNR3R4 =
O
O
z
O
O
O
O
O
N
NH
N
H
H
O
H
Z = - / CH2
/ O / NMe
5a-5d
N
(S)
(S)
8
7
6
Scheme 3: Methods of N-Arylation
Method I: X = Br, R1 = R2 = H , 1 eq. HNR3R4 (6 / 7 / 8), 0.01-0.05 eq. Pd(OAc)2 cat., 0.03-0.15 eq. (±)-
BINAP cat., 1.4 eq. Cs2CO3, C6H5CH3, ∆, Ar. Method II: X = F (Scaffold I), X = Cl (Scaffold II, III,
IV), R1, R2 = H / F, 1 eq. HNR3R4 (5), 1.5 eq. K2CO3, DMF or DCE, ∆.
The introduction of a variety of nucleophilic secondary amines 5-8 into aromatic cores I-IV is
summarized in Scheme 3. The reaction was carried out either via nucleophilic aromatic substitution of
ortho-fluoro or ortho-chloro11,12 substituted aldehydes or Buchwald-Hartwig Pd-catalyzed aryl
amination13-16 employing ortho-bromo aromatic aldehydes as starting materials towards the coupling of
sensitive or sterically hindered nucleophiles. The latter was found to be advantageous for achieving C-N
bond formation, giving access to substituted products in generally better yield and shorter reaction times
compared to SNAr2- type reactions. Beyond that, the Pd-mediated coupling presented no significant
advantage over the conventional base-catalyzed reaction in the case of unsubstituted or otherwise
insensititive nucleophiles (5a-d). Both methods allowed for the preparation of non-racemic arylated tert-
anilines (HNR3R4= 6, 8). The inferior yield of the reaction employing 8 in respect to its closely related
open-chain analog 7 may illustrate the points made above.

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HETEROCYCLES, Vol. 75, No. 4, 2008
Table 1: Reaction conditions and yields for N-Arylation, as depicted in Scheme 2
Product
Scaffold
Method
HNR3R4
Temp [°C], Time [h],
isolated yield [%]
95, 20, 79
R1, R2
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
9r
9s
I
I
I
I
I
I
I
I
I
I
I
I
H, H
H, H
H, H
H, H
H, H
F, H
H, F
F, H
H, F
6
7
8
90, 60, 67
90, 110, 36
150, 16, 87
150, 16, 93
60, 200, 63
100, 20, 76
120, 52, 79
100, 20, 57
120, 52, 56
60, 14, 63
80, 20, 56
80, 20, 54
80, 40, 93
70, 20, 60
80, 40, 75
80, 20, 66
80, 50, 88
100, 20, 76
80, 3, quant.a
100, 20, 51
100, 16, 75
II
II
II
II
II
II
II
II
II
II
II
II
II
II
II
II
II
II
II
5a
5b
5a
5b
5b
5c
5c
5a
5c
5c
5d
5a
5b
5c
5d
5a
5c
5c
5d
I
F, H
H, H
H, H
II
II
II
II
II
II
II
II
III
III
IV
IV
OCH3, H
OCH3, H
-O-CH2-O-
-O-CH2-O-
-O-CH2-O-
-O-CH2-O-
-
9t
9u
9v
-
-
-
a Reaction performed in DCE.
Table 2: Reaction conditions and yields for T-reactions, as depicted in Scheme 3
Entry
Scaffold
Z
Y-Y’-Y
Temp. [°C], Time [h],
isolated yield [%]
75, 2, 97
75, 1, 96
75, 6, 93
100, 6, quant.
75, 30, quant.
75, 20, 99
75, 20, 51
75, 45, 88
R1, R2
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
13l
13m
13n
13o
I
I
I
I
H, H
H, H
H, F
H, F
H, H
-O-CH2-O-
-O-CH2-O-
-O-CH2-O-
-O-CH2-O-
-O-CH2-O-
-O-CH2-O-
-
-
-
-
-
A
A
B
B
B
A
A
B
A
B
B
A
B
A
B
CH2
CH2
O
-
-
II
II
II
II
II
II
II
III
IV
IV
IV
O
O
CH2
CH2
NCH3
O
CH2
O
75, 4, 99
100, 6, 92
75, 30, quant.
75, 100, 95
100, 24, 88
100, 100, 75
100, 90, 60
O
Employing cyclic C-H acids 11 and 12 (Scheme 4) furnished correspondding racemic spiro-substituted
fused heterocycles 13 in good to excellent yields, providing derivatives of novel heterocycles
[1,3]thiazolo[5',4':5,6]pyrido[2,1-c][1,4]oxazinone (13l), 1,3-benzodioxolo[5,6-g]pyrido[1,2-a]-1,8-naph-
thyridine (13i,j), 1,3-benzodioxolo[5,6-g][1,4]oxazino[4,3-a]-1,8-naphthyridine (13g,h), 1,3-benzo-
dioxolo[5,6-g]pyrazino[1,2-a]-1,8-naphthyridine (13k) and derivatives of known heterocycles pyrazolo-

HETEROCYCLES, Vol. 75, No. 4, 2008
803
O
Y
Y'
O
N
O
N
O
O
O
O
Y
N
O
O
or
1 eq.
Scaffold
I / II /
III / IV
11
12
{
{
O
N
+
( )
n-BuOH,
∆
- 13
z
z
With 11: Y = (C=O), Y' = C(Me)2
with 12: Y = NMe, Y'= (C=O)
(A) or
(B)
Z = - , CH2, O, NMe
Scheme 4: Tandem-cyclizations of ortho-cycloalkylamino substituted aromatic aldehydes
via tert-amino-effect using Meldrum’s or N,N-dimethylbarbituric acid
[4',3':5,6]pyrido[2,1-c][1,4]oxazine (13n,o), pyrazolo[4,3-c]quinolizine (13m) and 1,3-benzodioxolo[5,6-
g]pyrrolo[1,2-a]-1,8-naphthyridine (13f). In the case of condensation-cyclization using 11, prolonged
heating often led to decompositon of the spiro-heterocycle in situ, furnishing the corresponding free
carboxylic acid (see also Scheme 7).
O
O
N
N
N
O
N
O
O
O
O
N
*
12
O
CHO
O
O
∆
N
n-BuOH, 75 °C, 22 h
69%
O
14
(S)
9b (S)
O
O
O
N
CHO
N
N
O
N
N
N
O
12
O
O
∆
n-BuOH, 75 °C, 30 h
9c
+
15
( )
88%
-
O
O
O
O
O
O
Scheme 5: Stereo- and regioselective T-reactions on N-[(2-formyl)phen-1-yl] arylated derivatives of
natural products
Derivatives of naturally occuring 2-phenylethylamines from Lophophora williamsii were subjected to the
T-reaction using 1 eq. of N,N-dimethylbarbituric acid. With the derivative 9b of (-)-anhalonine, the only
isolated product was characterized as 14 where ring closure had taken place regio- and stereoselectively
on the more substituted α-amino carbon.8,17 The N-methylmescaline derivative 9c cyclizes regioselective-
ly to yield 15.

804
HETEROCYCLES, Vol. 75, No. 4, 2008
O
O
CO2H
H
H
O
CO2H
H2O, HCl, pH = 1
H
H
O
∆
, 95 °C, 16 h
N
+
N
N
n
n
n
13a,b
n = 0, 1
16
17
+ -
+ -
(l)
( )
( )
(u)
-
-
Yield (%)
isomer ratiob
>
n
0
(3a,4-u) :
(4a,5-u) :
82
95
(3a,4-l) 5:1
16a,17a
=
>
(4a,5-l) 7:1
=
16b,17b 1
Scheme 6: Diastereoselective ring-opening of spiro-fused 1,3-dioxane-4,6-diones.
b isomers not adequately separable on SiO2; isomer ratio determined via 1H-NMR.
Spirofused 1,3-dioxane-4,6-diones 13a,b, easily accessible by a T-reaction with Meldrum’s acid, were
converted into corresponding carboxylic acids in excellent yields, either by hydrolysis and
decarboxylation under acidic conditions, or upon prolonged heating. In compliance with earlier results,18
the preferred diastereomer 16 is that in which the vicinal protons at the two stereocenters are related trans
to each other, furnishing the -(u) diastereomer.19 This was deduced from the value of the vicinal coupling
3
1
constants J of protons in H-NMR at the stereogenic phenylethylenic and bridgehead α-amino carbon,
observed to be 9.8-10 (16a) and 9.4-9.6 (16b) Hz, respectively, and assigned using 400 MHz HC- and
HH-COSY of 16 and 17. Moreover, formation of novel carboxylic acids occurred upon prolonged heating
of the reaction mixture. Thus, [1,3]dioxolo[6,7]isoquino[2,1-a]quinoline-13-carboxylic acids 19, 20 and
hexahydrobenzo[g]pyrrolo[1,2-a]-1,8-naphthyridine-4-carboxylic acid 21 are available in acceptable
yields (Scheme 7).
As it was known that the T-reaction is capable of inducing stereocenters in high selectivity,2,3,7,8 we
decided to further investigate this reaction using unsymmetrical active methylene compounds.The
reaction of 2-piperidine-1-yl-benzaldehyde 9e with 3-oxo-3-phenylpropionitrile 23 proceeds in favor of
the (4a,5–u) isomer 24 with the cyano moiety located trans to the bridgehead hydrogen (Scheme 8) as
determined by single crystal XRD (Figure 2). Two conformers of the pure (4a,5-u)-isomer co-crystallized
from MeOH in a 1:1 ratio (together with their respective mirror images). The unit cell thus contains four
distinguishable structures in this racemic compound.

HETEROCYCLES, Vol. 75, No. 4, 2008
805
9k
9b
O
O
O
O
∆
∆
O
O
O
O
11
n-BuOH, 75 °C, 110 h
n-BuOH, 75 °C, 30 h
11
O
O
O
O
O
O
O
O
O
O
N
O
N
N
59 %
77 %
H
CO2H
H
O
O
CO2H
H
O
4
H
+
O
3a
N
N
N
N
O
N
21
22
( )- (3a,4-l)
d
O
18
>
+ -
( )
(3a,4-u)
+
21 : 22
6 : 1
-
=
-
O
+
CO2H
H
H
CO2H
13
O
O
+
O
O
N
12
N
20
(12R,13S)
19
19 : 20c
6 : 5 or 5 : 6
O
=
(12R,13R) O
Scheme 7: T-reactions using Meldrum’s acid. c Configuration of major isomer unassigned. d Ratio
assessed via 1H-NMR.
O
N
O
O
H
H
4a
N
N
23
5
CN
CN
24
+
n-BuOH, 75 °C, 40 h
66 %
25
+ -
( ) (4a,5-u)
+
( )-
(4a,5-l)
3 : 1
-
-
9e
N
S
O
O
O
S
O
NH
O
H
O
O
H
N
O
N
N
H
26
N
+
O
NH
28
1 eq. NH4OAc
S
EtOH, 78 °C, 65 h
99 %
27
N
+ -
( ) (4a,5-u)
1 : 2
+ -
( ) (4a,5-l)
-
-
Scheme 8: Stereochemical outcome of T-reactions employing unsymmetrical active methylene
compounds

806
HETEROCYCLES, Vol. 75, No. 4, 2008
A similar outcome was observed for the reaction of 9e with 26, the structure of the major diastereomer
determined by single crystal XRD and shown to be the (4a,5-l) isomer 28 (Scheme 8 and Figure 1).
Figure 1: XRD of compound 28. (50% probability thermal ellipsoids crystallographic numbering, non-
stereogenic hydrogens omitted for clarity, dashed lines on right model indicate H-bonding between N1-N2
and S1-O1.)
Figure 2: XRD of two conformers of compound 24 (ORTEP drawing, 50 % probability, crystallographic
numbering, non-stereogenic hydrogens omitted for clarity). In below: Asymmetric unit cell, hydrogens
omitted.

HETEROCYCLES, Vol. 75, No. 4, 2008
807
We explain the formation of the major (4a,5-u)-isomer of 24 as follows: There is good evidence that the
T-reaction proceeds via a suprafacial [1,5]-hydride transfer3 of the two possible Knoevenagel
intermediates 29 (Scheme 9). Assuming that there is no equilibration in the zwitterionic intermediate2
generated after hydride migration, 8 possible cyclization products have to be considered. It is further
known that the vinyl double bond preferably points out of the steric congestion with the amine
substituent.2 As Ha and Hb are indistinguishable, the stereochemical outcome is determined by the E to Z
ratio of intermediates 29. These considerations also explain the preferred formation of 28 from 9e and 26.
Ha
Ha
Hb
N
O
H
Hb
N
N
H
O
N
E - 29
Z - 29
Ha migrates
Hb migrates
Hb migrates
Ha migrates
N+
Ha
N+
Ha
N+
N+
Hb
Hb
Hb
C
Hb
C
Ha
C
Ha
C
H
H
H
H
COPh
CN
CN
NC
PhOC
PhOC
NC
COPh
Hb
Hb
Ha
Ha
4a
CN
COPh
H
COPh
COPh
CN
N
N
N
N
5
CN
H
CN
Hb
COPh
Hb
Ha
Ha
H
H
(4aS,5S)
(4aR,5R)
minor isomer
(4aS,5R)
(4aR,5S)
major isomer
(4a,5-u)
(4a,5-l)
Scheme 9: Overall scheme of supposedly viated pathways of cyclization via tert-amino-effect,
compounds 23 and 24
Scheme 10 depicts the product ratios arising from the T-reactions of optically pure 9a. Here, the
diastereomer distribution was principally concluded from NOESY experiments (Figure 3) and supported
by 400 MHz HH-COSY, HSQC and HMBC experiments.
Unexpectedly, we failed to locate any NOE interactions between H1 and H3a or between H3a and CO2-
CH3 in isomers 30-33. Proceeding from the known configuration of H1 onward along the pyrrolidine ring

808
HETEROCYCLES, Vol. 75, No. 4, 2008
resulted in the determination of the configuration of the stereogenic protons at C3a. Elucidating signal
enhancements between H1 and H2u, further H3a and H3d were observed whereas H3a showed no NOE
with H3u in the main isomer. In contrast, H3a interacted with H5u in the minor isomer.
O
O
O
O
O
O
N
N
MeO2C
3a
1
N
N
MeO2C
N
N
N
H
N
H
12
H
H
O
+
O
O
∆
n-BuOH, 75 °C, 45 h
73 %
30
31
(1S,3aS)
(1S,3aR)
5 : 2
9a (S)
O
O
O
O
O
O
MeO2C
MeO2C
O
O
O
O
N
H
H
N
H
H
+
11
O
O
∆
32
33
n-BuOH, 75 °C, 30 h
69 %
9 : 1
(1S,3aS)
(1S,3aR)
Scheme 10: Diastereoselective T-reactions of L-proline substituted benzaldehydes
H
H
H
H2d
O
H2d
H2u
H3u
H
H
H3d
H
H
N
H2u
O
H3d
H3a
H
H
N
O
O
H1
H
O
*
O
H3u
*
H
*
H1
N
H
*
N
H3a
H9
O
N
O
H5u
H5d
H9
H
H8
O
H5u
H6
H
H5d
H
H6
(1S,3aS)
H7
N
H
H8
H
H
O
(1S,3aR)
H7
Figure 3: Selected NOE correlations for 30, 31. 32, 33 generate analogous signals.
In Scheme 11, a possible mechanism accounting for this stereopreference is hypothesized. Assuming a
transient destabilizing interaction2 occurs in the unsaturated intermediate between the chiral α-amino
proton and H9 in the phenyl ring in 34, such an interaction would disfavor the placement of Hb in a
coplanar orientation for subsequent hydride-migration. Conversely, the migration of Ha does not suffer
from a comparable sterical hindrance.

HETEROCYCLES, Vol. 75, No. 4, 2008
809
O
O
MeO2C
H
H
N+
N
30, 32
Ha
Hb
Hb
O
Ha
H
Y
C
O
H
O
O
Y
Y
Y'
Y
Y'
O
M
H
O
H
H
MeO2C
N+
N
Hb
31, 33
Ha
Hb
H
Ha
C
O
H
O
O
O
34
Y
Y
Y
Y
Y'
Y'
P
Scheme 11: Explanation of the diastereomeric preference in T-reactions using prolines
Further, we studied the T-reaction using nitromethane. Using 9d (Table 1), a mixture of separable nitro
compounds 35-38 (Scheme 12) was obtained. 9e did not give rise to any cyclized compounds.
Comparable relative rates of cyclization for pyrrolidine vs. piperidine as the tert-amino substituent were
reported earlier.8 Lewis acid catalysis using AlCl3 only slightly improves the yield and does not
considerably shorten the time required to reach the thermodynamic equilibrium of the four main
compounds present in the reaction mixture at that stage. This underscores the surprising inertness of T-
substrates towards catalysis probably owing to the concerted nature of hydride transfer and fast
subsequent C-C bond formation. The relative configuration at the stereogenic centers in the major isomer
3
isolated upon cyclization (35) was assigned to be (3a,4-u) from J = 9.6 Hz at these positions and
confirmed by 400-MHz HC- and HH-COSY-experiments.
A side product from the preparation of the ortho-piperidinyl-nitrostyrene 37 was isolated, and its structure
was assigned to be 39 via single crystal XRD (Figure 4). It may be worthy of note that a 2,4-disubstituted
1,3,5-trinitropentane fragment in an open chain arrangement has not yet been reported to date in the
literature.

810
HETEROCYCLES, Vol. 75, No. 4, 2008
n
n
n
n
O
N+
n
H
H
H
NO2
H
N
iv)
or
v)
N
N
N
O
N
NO2
CHO
Z
E
+
O
+
N+
O
+
35
- (u)
37
36
38
i)
ii)
or
iii)
+
+ - (l)
( )
( )
-
-
9d, e
O
n
n
O2N
NO2
n
N+
O
N
N
N
E
39
+
n = 0: 59 %
n = 1: 66 %
n = 0: - (not isolated)
n = 1: 30 %
NO2
Scheme 12: Nitro-functionalized [1,2-a]fused hexahydroquinolines via tert-amino-effect. i) MeNO2, 0.2
eq. KF, 2 eq. HNMe2.HCl; C6H5Me, ∆, 110 °C, 2-3 h, Dean-Stark trap.20 ii) n-BuOH, ∆, 118 °C; 80 h
(n=0) or 220 h (n=1). iii) n-BuOH, ∆, 118 °C, 90 h, AlCl3 cat./ stoich. iv) 1 eq. NH4OAc, 1.1 eq. MeNO2,
∆, 118 °C, 120 h. v) 1 eq. NH4OAc, 1.1 eq. MeNO2, ∆, 118 °C, 60 h, AlCl3 cat.
Figure 4: XRD of compound 39 (20 % thermal ellipsoids, hydrogens omitted for clarity, crystallographic
numbering, view from two opposite sides)
Table 3: Yields of 35-38, as depicted in scheme 11
n
0
0
0
Path
ii)
iv)
v)
Isolated yield of 35 and 36 (%)
39; (3a,4-u): (3a,4-l) ≥ 12:1.
25; (3a,4-u): (3a,4-l) ≥ 23:2
27; (3a,4-u): (3a,4-l) ≥ 25:2
Isolated yield of 37 and 38 (%)
37a: <1; 38a: 11.
37a: 16; 38a: 20.
37a: 8; 38a: 19.
1
ii), iii)
tracese
37b: 40, 38b: not determined.
Attempts to utilize methyl nitroacetate, N-methylhydantoin or ethyl acetoacetate as C-H acids gave the T-
products only in low yield (Scheme 13, Table 4).
e detectable by TLC-staining in molybdatophosphate, compound stains characteristically cherry-red to purple, as was found to
be a general phenomenon with all [1,2-a]-quinolines covered in this paper.

HETEROCYCLES, Vol. 75, No. 4, 2008
811
n
n
n
H
X
Y
N
N
N
1 eq. NH4OAc
X-CH2-Y
+
+
CHO
Y
∆, EtOH, 78 °C
V
VI
X
n = 0, 1
+
( )- (u) or (l)
E/Z
-
Scheme 13: Further T-reactions employing unsymmetrically substituted C-H-acids
Table 4: Reaction conditions and yields for T-reactions, as depicted in Scheme 12. f Nature of major
diastereomer unassessed.
Reaction
time [h]
n
X
Y
Yield of V (%)
Yield of VI (%)
40
41
42
1
0
1
NO2
MeCO
MeCO
60
220
250
15 (ratio ≥ 10:1)f 59 (E/Z-mixture)
7 (ratio ≥ 7:1)f
3 (ratio ≥ 4:1)f
CO2Me
CO2Me
CO2Me
60 (E/Z-mixture)
49 (E/Z-mixture)
O
59 (E:Z
= 2:3)
43
0
290
tracese
X-Y =
N
O
N
CONCLUSION
We have successfully employed the T-reaction in the synthesis of derivatives of natural products. In
introducing a Pd-catalyzed cross-coupling, an extension in scope regarding secondary amine nucleophiles
has been realized. Efficient domino processes using the tert-amino-effect allowed for the selective
formation of functionalized stereogenic centers. Thus, novel valuable quinolines as promising building
blocks have become readily available.
EXPERIMENTAL
1
Melting points (°C) were determined in a BUCHI B-545 and are uncorrected. H-NMR spectra were
recorded on 200-MHz-spectra Bruker AVANCE 200 and 400-MHz-spectra on a Bruker AVANCE 400,
13
respecttively, with tetramethylsilane as internal standard. C-NMR were recorded on the AVANCE 200
at 50 MHz. Chemical shifts are given in ppm and coupling constants in Hz. 1H-1H-spin decoupling and
13
DEPT Θ 45° were used. In case of C-NMR, additional indication from J-modulated measurements is
given after the chemical shift and is either (J), (2J) or (-) meaning νres ~ J (CH/CH3), νres ~ J/2 (CH2) or no
signal for Cquart in the DEPT experiment. Mass spectra were obtained by electron impact via GC-MS with
an FID-detector (240 °C) on a ThermoQuest Trace GC 2000 using a DB5 capillary column (30 m x 0.32
mm i.d.).MALDI-MS/MS was performed on a MALDI IV Benchtop TOF mass spectrometer equipped
with ESI trap, ion source 337 nm N2-Laser (3 ns pulse duration) and curved field reflectron, in low energy
CID. Optical rotations were obtained using a Perkin-Elmer 241 polarimeter (1dm cell); specific optical

812
HETEROCYCLES, Vol. 75, No. 4, 2008
rotation
was
calculated
using
the
equation:
α [wavelength[nm]temperature[°C]]= α [589
nm]*100/(L[dm]*c[g/100mL]).
Single crystal X-ray data were collected on a Bruker Smart APEX CCD area detector diffractometer
using graphite-monochromated Mo Kα radiation (λ= 0.71073 Å, sealed X-ray tube) and 0.3 -scan
frames covering complete spheres of the reciprocal space, detector distance: 50 mm, 512x512 pixels.
Corrections for absorption (multi-scan (SADABS; Bruker, 2003) Tmin = 0.92, Tmax = 0.99), λ/2 effects, and
crystal decay were applied.21 The structures were solved by direct methods using the program
SHELXS97.22 Structure refinement on F2 was carried out with the program SHELXL97, as well. All non-
hydrogen atoms were refined anisotropically. Hydrogen atoms were inserted in idealized positions and
were refined riding with the atoms to which they were bonded.
Reactions were monitored a) by thin-layer chromatography on Merck silica gel 60 F254 TLC- plates;
detection was either by UV-irradiation at 254/336 nm on untreated silica or by staining with
ammoniummolybdatophosphate, ninhydrine, 2,4-dinitrophenylhydrazine, I2/SiO2 or vanilline in H2SO4,
accompanied by gentle heating; b) by UV-HPLC on a WATERS 2695 ( Elutants: Solvent A= 0.1%
CF3CO2H + 3 % MeCN + 97 % H2O; Solvent B= 0.1 % CF3CO2H + 97 % MeCN + 3 % H2O; flow in the
range of 0.1 mL/min) using a Chromolith Performance PDA column (100mm length, 3mm diameter) at
220-380nm. Purity by HPLC of ≥ 98 % (at 254nm) was achieved for all samples (unless indicated
otherwise) and considered to be sufficient.
Column chromatography was performed using a BUCHI MPLC consisting of two C-605 pump modules,
a C-615 pump manager, a C-630 UV-monitor and a C-660 fraction collector on flash-type 40-63µm silica.
Petroleum ether (PE) refers to a boiling range of 40-60 °C. EE refers to acetic acid ethyl ester. When
solvent gradients were employed, the polarity was increased parabolically with respect to the mixture
percentage of the more polar eluent.
Solvents were obtained commercially, then dried by and stored over 3Å-molsieves before use. Absolute
solvents were prepared in the usual ways.
K2CO3 was thoroughly dried by heating the finely ground commercially available material in a crucible
over a Bunsen burner for at least 30 min and subsequently allowing to cool down to rt in an evacuated
desiccator.
Preparation of single-crystals for XRD by diffusion and slow evaporation: The sample was dissolved in a
minimum amount of CH2Cl2 in an oversized glass tube and then placed in a closed vessel under an almost
saturated atmosphere of Et2O; after standing at rt for an appreciable amount of time or when the solvent
level in the sample tube had risen to near the edge, the vessel was opened and the solvent mixture allowed
to slowly evaporate.

HETEROCYCLES, Vol. 75, No. 4, 2008
813
General procedure for the preparation of ortho-amino substituted aromatic aldehydes via
nucleophilic aromatic substitution:
General procedures 1a and 1b: To a mixture of 1 eq. of ortho-haloaldehyde in the reaction solvent, there
were added subsequently 1.1-6 eq. of secondary amine and 1.4 eq. of dry K2CO3 (respective to the
amount of secondary amine nucleophile added; for additionally introduced acidic mixture components,
e.g. hydrohalogenide salts of those secondary amines, there was further added a stoichiometrically equal
increased amount of K2CO3 to compensate for the excess of acid in the reaction mixture) (variation 1a) or
1 eq. of secondary amine and 1.4 eq. of dry K2CO3 (variation 1b).
The resulting mixture was heated under reflux for the time indicated. The suspension was cooled to rt and
poured into a half-saturated K2CO3-solution, extracted with CH2Cl2 (three times using 10 mL/ 100 mg of
expected product). The organic phases were combined, washed once with 10 mL brine, the brine re-
extracted with 10 mL CH2Cl2 and the combined organic phases dried (Na2SO4), the solvent roto-
evaporated to yield the crude product that was dissolved in CH2Cl2. There was added an appropriate
amount of 40-63 µm silica gel and the resultant mixture was concentrated on a rotavapor until no more
solvent was distilled off. The adsorbed mixture was then loaded as such into an MPLC cartridge for
chromatographic separation.
General procedure for the preperation of ortho-amino substituted aromatic aldehydes via Pd-
mediated coupling:
General procedure 2: To 1 eq. of ortho-halo-aldehyde I-IV there were added 0.01 eq. of Pd(OAc)2, 0.03
eq. of rac-BINAP to 1 eq. of secondary amine 5-8 and 1.4 eq. of Cs2CO3 (respective to the amount of
secondary amine nucleophile added; for additionally introduced acidic mixture components, e.g.
hydrohalogenide salts of those secondary amines, there was further added a stoichiometrically equal
increased amount of Cs2CO3 to compensate for the excess of acid in the reaction mixture) in toluene. The
mixture was purged with argon for 15 min and then heated under reflux and argon atmosphere for the
time indicated (see experimental details).The resulting suspension was cooled to rt and poured into a half-
saturated K2CO3-solution, extracted with CH2Cl2 (three times using 10 mL/ 100 mg of expected product).
The organic phases were combined, washed once with 10 mL brine, the brine re-extracted with 10 mL
CH2Cl2 and the combined organic phases dried (Na2SO4), the solvent roto-evaporated to yield the crude
product that was dissolved in CH2Cl2. There was added an appropriate amount of 40-63 µm silica gel and
the resultant suspension was concentrated on a rotavapor until no more solvent was distilled off. The
adsorbed mixture was then loaded as such into an MPLC cartridge for chromatographic separation.

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HETEROCYCLES, Vol. 75, No. 4, 2008
Methyl 1-(2-formylphenyl)-L-prolinate; (S)-1-(2-Formylphenyl)-pyrrolidine-2-carboxylic acid
methyl ester (9a). Prepared following general procedure 2 from 2-bromobenzaldehyde (794 mg, 4.29
mmol) and (S)-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (711 mg, 4.29 mmol). Toluene,
10 mL, 20 h, 95 °C. MPLC gradient PE to PE:EE=80:20. Yield 790 mg (79 %), yellow oil, [α]D20 - 365.7
(c 1.17, CHCl3).1H-NMR (200MHz, CDCl3) δ 9.94 (s, 1H, CHO), 7.52 (dd, 1H, J=7.6, J=7.2 Hz, Ar-H-5),
7.21 (dd, 1H, J=7.6, J=6.6 Hz, Ar-H-4), 6.76-6.69 (m, 2H, Ar-H), 4.37 (dd, 1H, J=6.8, J=6.6Hz, α-
amino-CH), 3.62-3.51 (br.m, 1H, J=8.4, J= 7, J=6.6 Hz, α-amino-CH2), 3.44 (s, 3H, CH3), 3.22-3.12
(br.m, 1H, J=6.8 Hz, α-amino-CH2), 2.31-2.20 (m, 1H, J=7 Hz, β-amino-CH2), 1.98-1.70 (br.m, 3H, β-
amino-CH2).13C-NMR (50MHz, CDCl3) δ 190.2 (J), 173.3 (-), 149 (-), 134.3 (J), 132.6 (J), 124.4 (-),
118.3 (J), 115.7 (J), 62.6 (J), 54.5 (2J), 51.8 (J), 30.1 (2J), 24.6 (2J).GC-MS, m/z (Irel, (%)):174.07 (100),
156.12 (27), 76.95 (20), 233.13 [M+] (12), 175.23 (12), 129.11 (12), 116.91 (10), 51.1 (8), 103.91 (7),
154.06 (7), 146.1 (6), 128.08 (6), 91.1 (6), 118.12 (5), 130.15 (5), 155.14 (5), 105.1 (5), 132.07 (4),
144.12 (4), 65.17 (3).
2-{Methyl[2-(3,4,5-trimethoxyphenyl)ethyl]amino}benzaldehyde (9b). Prepared following general
procedure 2 from 2-bromobenzaldehyde (322 mg, 1.74 mmol) and methyl[2-(3,4,5-trimethoxy-phenyl)-
ethyl]amine (391 mg, 1.74 mmol). Toluene, 10 mL, 60 h, 90 °C. MPLC gradient PE to PE:Et2O=80:20.
Yield 350 mg (67 %), yellow oil. 1H-NMR (200MHz, CDCl3) δ 10.14 (s, 1H, CHO), 7.70 (dd, 1H, J=7.6,
J=1.8 Hz) 7.44-7.36 (m, 1H, J=8.8, J=7.2, J=1.8 Hz), 7.04-6.94 (m, 2H, J=8.2, J=7.4 Hz), 6.27 (s, 2H,
(OCH3)3-Ar-H), 3.75 (s, 6H, m-O-CH3), 3.74 (s, 3H, p-O-CH3), 3.37-3.29 (m, 2H, J=15.4, J=8, J=7.4 Hz,
β-phenylethylamine-CH2), 2.89 (s, 3H, N-CH3), 2.81-2.73 (m, 2H, J=15.4, J=8, J=7.4 Hz, benzyl-
CH2).13C-NMR (50MHz, CDCl3) δ 191.4 (J), 155.4 (-), 153.1 (-), 136.4 (-), 134.9 (-), 134.5 (J), 130.1 (J),
128.3 (-), 121.5 (J), 119.3 (J), 105.5 (J), 60.8 (J), 60 (2J), 56 (J), 42.3 (J), 34.2 (2J). GC-MS, two main
peaks, m/z (Irel, (%)): 7.32 min:106.03 (100), 135.12 (70), 76.9 (49), 51.07 (30), 79.08 (22), 78.13 (22),
91.09 (19), 118.18 (16), 107.18 (15), 9.29 min: 194.1 (100), 179.11 (81), 64.95 (46), 151.06 (38), 90.95
(35), 135.95 (32), 76.92 (29), 121.04 (17), 51.09 (17).
2-[(9S)-4-Methoxy-9-methyl-6,9-dihydro[1,3]dioxolo[4,5-h]isoquinolin-8(7H)-yl]benzaldehyde (9c).
Prepared following general procedure 2 from 2-bromobenzaldehyde(569 mg, 3.08 mmol) and (S)-4-
methoxy-9-methyl-6,7,8,9-tetrahydro[1,3]dioxolo[4,5-h]isoquinoline (680 mg, 3.08 mmol). Toluene, 10
mL, 110 h, 90 °C. MPLC gradient PE to PE:EE=90:10. Yield 359mg (36 %), yellow crystals, mp
129.3 °C, [α]D20 + 460.3 (c 0.86, CHCl3).1H-NMR (200MHz, CDCl3) δ 10.27 (s, 1H, CHO), 7.78-7.74 (m,
1H, J=8, J=7.4, J=1.8 Hz), 7.46-7.38 (m, 1H, J=8, J=7.6, J=7.4, J=1.8 Hz), 7.09-7.01 (m, 2H, J=8.2,
J=7.6 Hz), 6.25 (s, 1H), 5.93 (d, 1H, J=1.4 Hz, -O-CH2-O-), 5.88 (d, 1H, J=1.4 Hz, -O-CH2-O-), 4.49 (q,
1H, J=6.6 Hz, α-amino-CH), 3.82 (s, 3H, O-CH3), 3.56 (ddd, 1H, J=12.7, J=11, J=4.2 Hz, α-amino-CH2),

HETEROCYCLES, Vol. 75, No. 4, 2008
815
3.25 (ddd, 1H, J=12.7, J=6.1, J=5.5 Hz, α-amino-CH2), 2.92-2.75 (m, 1H, J=16.2, J=11, J=5.5 Hz,
benzyl-CH2), 2.66-2.55 (dd, 1H, J=16.2, J=4.2 Hz, benzyl-CH2), 1.25 (d, 3H, J=6.6 Hz, α-amino-CH3).
13C-NMR (50MHz, CDCl3) δ 191.8 (J), 154.8 (-), 144.6 (-), 142.4 (-), 134.6 (J), 133.2 (-), 129.5 (-), 128.9
(J), 128.3 (-), 122.7 (J), 122.1 (J), 115.3 (-), 106.9 (J), 101.5 (2J), 56.4 (J), 54.7 (J), 45.9 (2J), 27.8 (2J),
17.9 (J). MALDI-MS/MS: m/z (Irel, %) TIC, MS2: 306.1 (100): 306.1 (100), 234 (36), 263.1 (17), 278.1
(8); 322.1(3).
2-Pyrrolidin-1-ylbenzaldehyde (9d). Prepared following general procedure 1a from 2-
fluorobenzaldehyde (21300 mg, 171.5 mmol) and pyrrolidine (15000 mg, 207 mmol). DMF, 100 mL, 16
h, 150 °C. Distilled in a Kugelrohr apparatus at 0.01 mbar and 120 °C, Yield 26300 mg (87 %), purity by
HPLC >99.6 % (254nm), yellow oil. 1H-NMR (200MHz, CDCl3) δ 10.05 (s, 1H, CHO), 7.69-7.59 (m (dd
and dd), 2H, J=8, J=7.4, J=7.2 Hz), 6.93-6.69 (m, 2H), 3.52-3.4 (m, 4H, J~6 Hz, α-amino-CH2), 1.88-1.6
(br.m, 4H, β-amino-CH2).
2-Piperidin-1-ylbenzaldehyde (9e). Prepared following general procedure 1b from 2-
fluorobenzaldehyde (3280 mg, 26.5 mmol) and piperidine (2250 mg, 26.5 mmol). DMF, 50 mL, 16 h,
150 °C. Crude yield 4903 mg (98 %, reddish oil). Purity by HPLC 96.2 % (254 nm). Distilled in a
Kugelrohr apparatus at 0.01 mbar and 120 °C, Yield 4644 mg (93 %), purity by HPLC >99.9 %, yellow
oil, Rf=0.84 (PE:EE=75:25).1H-NMR (200MHz, CDCl3) δ 10.27 (s, 1H, CHO), 7.76 (d, 1H, J=6.6 Hz,
Ar-H-6), 7.45 (m, 1H, Ar-H-4), 7.11-6.98 (m, 2H, Ar-H-3, Ar-H-5), 3.01 (br.d, 4H, J~6 Hz, α-amino-
CH2), 1.79-1.65 (br.m, 4H, β−amino-CH2), 1.65-1.57 (br.m, 2H, γ−amino-CH2).13C-NMR (50MHz,
CDCl3) δ 191.3 (J), 156.9 (-), 134.7 (J), 129 (J), 128.5 (-), 121.9 (J), 118.9 (J), 55.5 (2J), 26.1 (2J), 24
(2J).GC-MS, m/z (Irel, (%)):105.9 (100), 189.2 [M+] (69), 172.04 (41), 188.17 (38), 131.99 (35), 76.94
(30), 103.96 (30), 146 (26), 118.09 (18), 160.04 (17).
5-Fluoro-2-pyrrolidin-1-ylbenzaldehyde (9f). Prepared following general procedure 1b from 2,5-
difluorobenzaldehyde (1110 mg, 7.8 mmol) and pyrrolidine (554 mg, 7.8 mmol). DMF, 10 mL, 200 h,
60 °C. MPLC gradient PE to PE:EE=80:20, Yield 946 mg (63 %), yellow oil.1H-NMR (200MHz,CDCl3)
δ 10.05 (s, 1H, CHO), 7.33 (dd, 1H, J=9.2, J=3.3 Hz), 7.11-7.05 (m, 1H), 6.74 (dd, 1H, J=9.2, J=4.3 Hz),
3.3-3.23 (br.m, 4H, α-amino-CH2), 1.94-1.88 (br.m, 4H, β-amino-CH2).13C-NMR (50MHz, CDCl3)
δ 189.4 (J), 167.2 (-), 140.5 (-), 135.8 (-), 122.2 (J), 120.1 (J), 116.4 (J), 53.4 (2J), 23.9 (2J).
3-Fluoro-2-piperidin-1-ylbenzaldehyde (9g). Prepared following general procedure 1a from 2,3-
difluorobenzaldehyde (138 mg, 0.97 mmol) and piperidine (248 mg, 2.91 mmol). DMF, 5 mL, 20 h,
1
100 °C. MPLC gradient PE to PE:EE=80:20. Yield 152 mg (76 %), yellow oil. H-NMR (200MHz,
CDCl3) δ 10.35 (s, 1H, CHO), 7.45 (dd, 1H, J=7.4, J=7.1 Hz, Ar-H-6), 7.2-6.9 (m, 2H, J=7.4 Hz, Ar-H-4,
Ar-H-5), 3.18-3.01 (m, 4H, α−amino-CH2), 1.77-1.45 (br.m, 6H, β−, γ−amino-CH2).13C-NMR

816
HETEROCYCLES, Vol. 75, No. 4, 2008
(50MHz,CDCl3) δ 191.6, 162.6, 151.6, 143.3, 133.9, 124.6, 122.3, 54.1, 26.4, 24.
5-Fluoro-2-piperidin-1-ylbenzaldehyde (9h). Prepared following general procedure 1a from 2,5-
difluoro-benzaldehyde (138 mg, 0.97 mmol) and piperidine (248 mg, 2.91 mmol). DMF, 5 mL, 52 h,
1
120 °C. MPLC gradient PE to PE:EE=90:10. Yield 157 mg (79 %), yellow oil. H-NMR (200MHz,
CDCl3) δ 10.2 (s, 1H, CHO), 7.42 (dd, 1H, J=8.6, J=3.1 Hz, Ar-H-3), 7.2-6.95 (m, 2H, J=8.9, J=8.6,
J=3.1 Hz, Ar-H-4, Ar-H-6), 2.96-2.83 (m, 4H, J=5.4 Hz, α-amino-CH2), 1.8-1.6 (br.m, 4H, β-amino-
CH2), 1.59-1.4 (br.m, 2H, γ-amino-CH2). 13C-NMR (50MHz,CDCl3) δ 190.1, 155.9, 130.2, 121.8, 121.4,
121.1, 114.1, 55.9, 26.1, 23.8. GC-MS, m/z (Irel, (%)): 211.05 (100), 91.02 (71), 84.12 (13), 64.97 (13),
212.19 (11), 182.99 (8), 55.13 (6), 125.9 (6).
3-Fluoro-2-morpholin-4-ylbenzaldehyde (9i). Prepared following general procedure 1a from 2,3-
difluorobenzaldehyde (157 mg, 1.04 mmol) and morpholine (288 mg, 3.12 mmol). DMF, 5 mL, 20 h,
1
100 °C. MPLC gradient PE:EE=9:1 to PE:EE=85:15. Yield 115 mg (57 %), yellow oil. H-NMR
(200MHz, CDCl3) δ 10.47 (s, 1H, CHO), 7.55 (br.d, 1H, J=7.2 Hz, Ar-H-6), 7.35-7.05 (m, 2H, J=7.2 Hz,
Ar-H-4, Ar-H-5), 3.82-3.69 (m, 4H, O-CH2), 3.22-3.09 (m, 4H, N-CH2).13C-NMR (50MHz, CDCl3)
δ 191.2, 157.8, 141.5, 134.1, 125.9, 124.2, 122.6, 67.3, 52.7.
5-Fluoro-2-morpholin-4-ylbenzaldehyde (9j). Prepared following general procedure 1a from 2,5-
difluorobenzaldehyde (157 mg, 1.04 mmol) and morpholine (288 mg, 3.12 mmol). DMF, 5 mL, 52 h,
1
120 °C. MPLC gradient PE to PE:EE=80:20. Yield 112 mg (56 %), yellow oil. H-NMR (200MHz,
CDCl3) δ 10.31 (s, 1H, CHO), 7.45 (dd, 1H, J=7.7, J=7.4 Hz, Ar-H-3), 7.25-7.01 (m, 2H, Ar-H-4, Ar-H-
6) 3.88-3.79 (m, 4H, O-CH2), 3.01-2.89 (m, 4H, N-CH2).13C-NMR (50MHz,CDCl3) δ 190.1, 161.3, 151.9,
130.5, 122.1, 121.7, 115.4, 66.8, 54.5.
2-Pyrrolidin-1-ylquinoline-3-carbaldehyde (9k). Prepared following general procedure 1b from 2-
chloroquinoline-3-carbaldehyde (1270 mg, 6.64 mmol) and pyrrolidine (472 mg, 6.64 mmol). DMF, 15
1
mL, 14 h, 60 °C. MPLC in PE to PE:EE=80:20. Yield 948 mg (63 %), orange oil. H-NMR (200MHz,
CDCl3) δ 9.94 (s, 1H, CHO), 8.12 (s, 1H, Ar-H-4), 7.61-7.43 (m, 3H), 7.05 (dd, 1H, J=7.6, J=7 Hz), 3.54-
3.41 (m, 4H, α-amino-CH2), 1.82-1.76 (m, 4H, β-amino-CH2).13C-NMR (50MHz, CDCl3) δ 189.5, 154.5,
149.9, 143.5, 133.3, 132.9, 128.2, 126.7, 122.3, 121.1, 50.6, 25.9. GC-MS, m/z (Irel, (%)):168.79 (100),
128.08 (99), 226.33 [M+] (93), 101.28 (90), 197.50 (80), 156.49 (75), 142.82 (61), 70.06 (61), 75.08 (36),
115.15 (27), 89.14 (17).
2-Morpholin-4-ylquinoline-3-carbaldehyde (9l). Prepared following ge-neral procedure 1a from 2-
chloroquinoline-3-carbaldehyde (198 mg, 1.03 mmol) and morpholine (270 mg, 3.1 mmol). DMF, 5 mL,
1
20 h, 80 °C. MPLC gradient PE:EE=88:12 to PE:EE=84:16. Yield 140 mg (56 %), amber oil. H-NMR
(200MHz, CDCl3) δ 10.11 (s, 1H, CHO), 8.45 (s, 1H, Ar-H-4), 7.85-7.5 (m, 2H, Ar-H-5, Ar-H-8), 7.41-

HETEROCYCLES, Vol. 75, No. 4, 2008
817
7.25 (m, 2H, Ar-H-6, Ar-H-7), 3.93-3.87 (m, 4H, O-CH2), 3.55-3.42 (br.m, 4H, N-CH2). 13C-NMR
(50MHz, CDCl3) δ 189.9 (J), 158.7 (-), 149.2 (-), 143.1 (J), 132.6 (J), 129.2 (J), 127.5 (-), 124.8 (-), 124.0
(J), 121.9 (J), 66.8 (2J), 51.4 (2J). GC-MS, m/z (Irel, (%)): 129.12 (100), 127.92 (79), 242.01 [M+] (77),
207.03 (71), 183.07 (45), 100.9 (44), 157.15 (39), 102.11 (28), 156.14 (26), 74.8 (26), 144.14 (24),
169.13 (20), 77.13 (20), 195.06 (19), 185.14 (18), 213.13 (17), 85.97 (17), 13.19 (16), 184.18 (16), 225.1
(15).
6-Methoxy-2-morpholin-4-ylquinoline-3-carbaldehyde (9m). Prepared following general procedure 1a
from 2-chloro-6-methoxyquinoline-3-carbaldehyde (204 mg, 0.92 mmol) and morpholine (240 mg, 2.76
mmol). DMF, 5 mL, 20 h, 80 °C. MPLC gradient PE:EE=80:20 to PE:EE=60:40. Yield 135 mg (54 %),
red oil. 1H-NMR (200MHz, CDCl3) δ 10.2 (s, 1H, CHO), 8.46 (s, 1H, Ar-H-4), 8.02 (s, 1H, Ar-H-5), 7.85
(d, 1H, J=8.8 Hz, Ar-H-8), 7.41 (br.d, 1H, J=8.8 Hz, Ar-H7), 3.90-3.85 (m, 4H, O-CH2), 3.44-3.34 (m,
4H, N-CH2), 2.91 (s, 3H, CH3).13C-NMR (50MHz, CDCl3) δ 190.3 (J), 162.5 (-), 156.6 (-) 145.2 (-),
141.0 (J), 129.1(J), 125.1 (J), 124.9 (-), 122.2 (-), 106.5 (J), 66.8 (2J), 51.7 (2J), 36.4 (J). GC-MS, m/z (Irel,
(%)): 272.14 [M+] (100), 159.14 (56), 187.16 (44), 116.1 (39), 213.07 (39), 199.15 (31), 73.3 (28), 158.18
(25), 174.15 (23), 214.16 (21), 215.18 (20), 115.08 (19), 243.18 (19), 171.16 (17), 186.3 (16).
6-Methoxy-2-(4-methylpiperazin-1-yl)quinoline-3-carbaldehyde (9n). Prepared following general
procedure 1a from 2-chloro-6-methoxyquinoline-3-carbaldehyde (222 mg, 1 mmol) and 1-methyl-
piperazine (301 mg, 3 mmol). DMF, 5 mL, 40 h, 80 °C. MPLC gradient PE to PE:EE=80:20. Yield 266
mg (93 %), yellow oil that crystallized upon standing, yellow needles, mp 114.2 °C. 1H-NMR (200MHz,
CDCl3) δ 10.12 (s, 1H, CHO), 8.31 (s, 1H, Ar-H-4), 7.68 (d, 1H, J=9.2 Hz, Ar-H-8), 7.28 (dd, 1H, J=9.2,
J=2.8 Hz, Ar-H-7), 6.98 (d, H, J=2.8 Hz, Ar-H-5), 3.82 (s, 3H, O-CH3), 3.42-3.37 (m, 4H, J=4.8 Hz,
13
ArN-CH2), 2.6-2.55 (m, 4H, J=4.8 Hz, CH3N-CH2), 2.31 (s, 3H, N-CH3). C-NMR (50MHz, CDCl3)
δ 190 (J), 157.7 (-), 155.9 (-), 144.7 (-), 139.7 (J), 128.5 (J), 124.3 (J), 124.2 (-), 121.6 (-),106 (J), 55 (J),
54.4 (2J), 50.8 (2J), 45.6 (J). GC-MS, m/z (Irel, (%)): 282.16 (100), 162.04 (80), 208.15 (51), 121.98 (35),
57.11 (34), 178.11 (29), 192.14 (28), 123.08 (25), 226.1 (25), 124.09 (20), 207.11 (19), 150.09 (17),
164.11 (16), 283.25 (14), 108.87 (13), 136.09 (12), 135.07 (11), 147.96 (11), 266.22 (10), 94.82 (10).
6-Pyrrolidin-1-yl[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde (9o). Prepared following general
procedure 1a from 6-chloro[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde (1000 mg, 4.25 mmol) and
pyrrolidine (907 mg, 13 mmol). DMF, 10 mL, 20 h, 70 °C. MPLC gradient PE to PE:EE =80: 20.Yield
634 mg (60 %), yellow oil. 1H-NMR (200MHz, CDCl3) δ 10 (s, 1H, CHO), 8.1 (s, 1H, Ar-H-4), 6.95 (s,
1H, Ar-H-8), 6.8 (s, 1H, Ar-H-5), 5.95 (s, 2H, -O-CH2-O-), 3.6-3.45 (m, 4H, α−amino-CH2), 2-1.7 (m,
4H, β−ami-no-CH2). 13C-NMR (50MHz, CDCl3) δ 189.5 (J),154.5 (-), 153.3 (-), 149.1 (-), 145 (-), 141.6
(J), 133.2 (-), 117.9 (J), 105.3 (-), 103.6 (J), 101.5 (2J), 50.9 (2J), 25.7 (2J).

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6-Piperidin-1-yl[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde (9p). Prepared following general
procedure 1a from 6-chloro[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde (40 mg, 0.17 mmol) and
piperidine (20 mg, 0.34 mmol). DMF, 2 mL, 40 h, 80 °C. MPLC gradient PE to PE:EE=70:30. Yield 36
1
mg (75 %), yellow oil, crystals from n-BuOH, yellow needles, mp 103 °C. H-NMR (200MHz, CDCl3)
δ 10.05 (s, 1H, CHO), 8.20 (s, 1H, Ar-H-8), 7.05 (s, 1H, Ar-H-9), 6.96 (s, 1H, Ar-H-4), 6.01 (s, 2H, -O-
CH2-O-), 3.30-3.22 (m, 4H, α-amino-CH2), 1.8-1.55 (br.m, 6H, β−, γ−amino-CH2). 13C-NMR (50MHz,
CDCl3) δ 191.8 (J), 155 (-), 151.5 (-), 145.8 (J), 131.5 (-), 129.3 (-), 126.5 (-), 122 (-), 124.0 (J), 121.9 (J),
101.6 (2J), 54.6 (2J), 28.6 (2J), 26.5 (2J). GC-MS, two main peaks, m/z (Irel, (%)): 283.9 [M+] (100), 84.0
(74), 172 (70), 200 (66), 188.1 (62),113.8 (53), 227 (52), 212.9 (50), 267(23), 240.9 (21), 141.8 (18), 255
(16). 148.08 (100), 149.18 (8), 90.95 (7), 76.97 (6), 120.09 (6), 117.95 (5), 105.09 (4).
6-Morpholin-4-yl[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde (9q).
Prepared following general procedure 1a from 6-chloro[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde (206
mg, 0.87 mmol) and morpholine (228 mg, 2.61 mmol). DMF, 5 mL, 20 h, 80 °C. MPLC in PE to
PE:EE=90:10. Yield 166 mg (66 %), orange oil. 1H-NMR (200MHz, CDCl3) δ 10.05 (s, 1H, CHO), 8.25
(s, 1H, Ar-H-4), 7.1 (s, 1H, Ar-H-5), 6.96 (s, 1H, Ar-H-8), 6.02 (s, 2H, -O-CH2-O-), 3.88-3.83 (m, 4H, O-
CH2), 3.40-3.33 (m, 4H, N-CH2).
13C-NMR (50MHz, CDCl3) δ 189.8 (J), 153.3 (-), 146.7 (-), 141 (J), 125.9 (-), 125.2 (-), 120.4 (-), 119.7
(-), 104.7 (J), 103.9 (J), 101.9 (2J), 66.8 (2J), 51.7 (2J).
6-(4-Methylpiperazin-1-yl)[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde (9r). Prepared following
general procedure 1a from 6-chloro[1,3]dio-xolo[4,5-g]quinoline-7-carbaldehyde (197 mg, 0.97 mmol)
and 1-methyl-piperazine (251 mg, 2.9 mmol). DMF, 5 mL, 50 h, 80 °C. MPLC gradient PE to
PE:EE=80:20. Yield 230 mg (88 %), yellow oil that crystallized upon standing, yellow needles, mp
1
114.5 °C. H-NMR (200MHz, CDCl3) δ 1H-NMR (200MHz, CDCl3) δ 9.96 (s, 1H, CHO), 8.19 (s, 1H,
Ar-H-4), 7.17 (s, 1H, Ar-H-5), 6.88 (s, 1H, Ar-H-8), 5.98 (s, 2H, -O-CH2-O-), 3.09-3.03 (m, 4H, ArN-
13
CH2), 2.44-2.36 (m, 4H, CH3N-CH2), 2.2 (br.s, 3H, CH3). C-NMR (50MHz, CDCl3) δ 190.1 (J), 158.8
(-), 153.1 (-), 148.3 (-), 146.5 (-), 140.1 (J), 120.2 (-), 119.9 (-), 104.7(J), 103.9 (J), 101.8 (2J), 55.0 (2J),
51.2 (2J), 46.1 (J). GC-MS, 2 main peaks, m/z (Irel, (%)):14.55 min: 104.95 (100), 76.97 (91), 211.18 (68),
316.23 (51), 172.17 (49), 171.17 (25), 315.18 (22), 50.92 (18), 130.07 (14). 15.24 min: 185.04 (100),
70.05 (47), 83.11 (43), 127.9 (38), 129.1 (23), 173.04 (21), 100.91 (14), 255.1 (13), 198.17 (13), 186.19
(11).
3-Benzyl-2-oxo-4-pyrrolidin-1-yl-2,3-dihydro-1,3-thiazole-5-carbaldehyde (9s). Prepared following
general procedure 1a from 3-benzyl-4-chloro-2-oxo-2,3-dihydrothiazole-5-carbaldehyde (196 mg, 0.7
mmol) and pyrrolidine (150 mg, 2.2 mmol). DMF, 5 mL, 20 h, 100 °C. MPLC gradient EE to
1
EE:acetone=80:20. Yield 152 mg (76 %), amber oil. H-NMR (200MHz, CDCl3) δ 9.64 (s, 1H, CHO),

HETEROCYCLES, Vol. 75, No. 4, 2008
819
7.33-7.14 (m, 3H, phenyl Ar-H-3, H-4, H-5), 7.09-6.94 (m, 2H, phenyl Ar-H-2, H-6), 5.01 (s, 2H, benzyl-
CH2), 3.43-3.20 (br.m, 4H, J~6 Hz, pyrrolidinyl-α-amino-CH2) 1.99-1.67 (bm, 4H, J=8.8, J~6 Hz,
pyrrolidinyl-β-amino-CH2).13C-NMR (50MHz, CDCl3) δ 180.5, 169.2, 151.6, 135.3, 128, 124.2, 123.6,
105.1, 56.8, 48.4, 24.8. GC-MS, m/z (Irel, (%)): 98.1 (100), 55.2 (14.5), 84.0 (7.5), 70.1 (7).
3-Benzyl-4-morpholin-4-yl-2-oxo-2,3-dihydro-1,3-thiazole-5-carbaldehyde (9t). Prepared following
general procedure 1a from 3-benzyl-4-chloro-2-oxo-2,3-dihydrothiazole-5-carbaldehyde (168 mg, 0.22
mmol) and morpholine (112 mg, 1.32 mmol). 1,2-dichloroethane, 3 mL, 3 h, 80 °C. MPLC gradient PE to
PE:EE=80:20. Yield 200 mg (quant.), amber oil, crystals from CH2Cl2/Et2O by diffusion and slow
evaporation, mp 215.6 °C. 1H-NMR (200MHz, CDCl3) δ 9.8 (s, 1H, CHO), 7.3-7.05 (m, 5H, Ar-H), 4.84
(s, 2H, benzyl-CH2), 3.12-3.01 (m, 4H, J=5.5 Hz, O-CH2), 2.99-2.87 (br.m, 4H, N-CH2).13C-NMR
(50MHz, CDCl3) δ 177.1, 167.6, 152.2, 133.2, 126.4, 125.3, 123.8, 105.4, 52.1, 45.1, 23.6. GC-MS, m/z
(Irel, (%)): 98.1 (100), 55.2 (14.6), 84.0 (7.7), 70.1 (7.1).
3-Methyl-5-morpholin-4-yl-1-phenyl-1H-pyrazole-4-carbaldehyde (9u). Prepared following general
procedure 1a from 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (163 mg, 0.74 mmol) and
morpholine (193 mg, 2.22 mmol). DMF, 5 mL, 20 h, 100 °C. MPLC gradient PE to PE:EE=80:20. Yield
110 mg (51 %), grey oil. 1H-NMR (200MHz, CDCl3) δ 9.89 (s, 1H, CHO), 7.50-7.33 (m, 5H, Ar-H), 3.62
(br.d, 4H, J=4.8 Hz, O-CH2), 3.07 (br.d, J=4.8 Hz, N-CH2), 2.41 (s, 3H, CH3).13 C-NMR (50MHz,
CDCl3) δ 182, 151.1, 150.5, 137.8, 128.1, 127.2, 123.7, 110.8, 65.5, 49.6, 12.4. GC-MS, m/z (Irel, (%)):
211.8 (100), 240 (85), 271 [M+] (80), 90.9 (74), 252.1 (67.5), 225.9 (66), 103.9 (60), 51 (56), 184.1(55),
144.1 (53), 115.9 (46), 198.1 (36).
3-Methyl-5-(4-methylpiperazin-1-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (9v). Prepared following
general procedure 1a from 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (155 mg, 0.7 mmol)
and 1-methyl-piperazine (210 mg, 2.1 mmol). DMF, 5 mL, 16 h, 100 °C. MPLC gradient PE to
1
PE:EE=70:30. Yield 149 mg (75 %), yellow oil. H-NMR (200MHz, CDCl3) δ 9.85 (s, 1H, CHO), 7.41-
6.94 (m, 5H, Ar-H), 3.22-3.05 (m, 4H), 2.40-2.25 (m, 4H), 2.22 (s, 3H, N-CH3), 2.2 (s, 3H, Ar-CH3). 13C-
NMR (50MHz, CDCl3) δ 184.5, 152.1, 148.7, 136.7, 125.7, 124.6, 123.9, 108, 69.3, 48, 45.5, 15.5.GC-
MS, m/z (Irel, (%)): 70.1 (100), 77.0 (20), 284.1 [M+] (18.5), 83.2 (16.5), 91.0 (14.5), 212 (14), 58.2 (13).
General procedure for the preperation of heterocycles via cyclization by tert-amino-effect:
General procedure 3 To 1 eq. of ortho-aminoaldehyde in n-BuOH there were added 1-1.08 eq. of C-H-
acidic compound. The mixture was refluxed on a silicon oil bath with good stirring at a temperature and
for the time given, subsequently cooled to rt and the solvent roto-evaporated to yield the crude product
that was dissolved in CH2Cl2. There was added an appropriate amount of 40-63 µm silica gel and the
resultant suspension was concentrated on a rotavapor until no more solvent was distilled off. The

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HETEROCYCLES, Vol. 75, No. 4, 2008
adsorbed mixture was then loaded as such into an MPLC cartridge for chromatographic separation.
General procedure 3a: Analogous to procedure 3, but before chromatographic separation, the resultant
crude product was washed with dH2O (two times using 2 mL/ 100 mg of expected product) and once with
5 mL brine, the aqueous phases washed once again with CH2Cl2 (using 2 mL/mL of dH2O) and the
combined organic phases dried (Na2SO4), the solvent roto-evaporated to yield the crude product that was
dissolved in CH2Cl2. There was added an appropriate amount of 40-63 µm silica gel and the resultant
mixture was concentrated on a rotavapor until no more solvent was distilled off. The adsorbed mixture
was then loaded as such into an MPLC cartridge for chromatographic separation.
General procedure 3b: Analogous to procedure 3, but the crude product was triturated from the least
amount of cold 96 % EtOH.
General procedure 3c: Analogous to procedure 3, but the crude product was obtained in a state where
further purification was unnecessary.
General procedure 3d: Analogous to procedure 3, but to the reaction mixture there was added 1 eq. of
anhydrous NH4OAc before refluxing.
General procedure 3e: Analogous to procedure 3a, but upon solvent-solvent-extraction, the aqueous
phase was adjusted to a pH near the ionization point of the expected product and the aqueous phase
continuosly extracted with CH2Cl2 to yield the crude product in a state where further chromatographic
purification was unnecessary.
(±)-2,2-Dimethyl-1',2',3',3a'-tetrahydro-5'H-spiro[1,3-dioxane-5,4'-pyrrolo[1,2-a]quinoline]-4,6-
dione (13a). Prepared following general procedure 3c from 2-pyrrolidine-1-yl-benzaldehyde 9d (2326 mg,
13.29 mmol) and 2,2-dimethyl-[1,3]dioxane-4,6-dione 11 (1913 mg, 13.29 mmol). n-BuOH, 20 mL,
75 °C, 2 h. Evaporation of solvent and recrystallization from 96 % EtOH. Yield: 2899 mg (97 %), white
solid, mp 187 °C (EtOH, decomp.); single crystals for XRD from abs. EtOH/DMF=5:1, colorless prisms,
1
mp 189 °C (decomp). H-NMR (200MHz, CDCl3) δ 7.19 (dd, 1H, J=7.9, J=7.6 Hz), 7.05 (d, 1H, J=7.4
Hz), 6.72-6.61 (m, 2H, J=7.9, J=7.4 Hz), 3.99 (dd, 1H, J=8.8, J=3 Hz), 3.70-3.60 (m, 1H), 3.57 (d, 1H,
J=16.4 Hz, benzyl-CH2), 3.33 (dd, 1H, J=16, J=4.2 Hz), 3.19 (d, 1H, J=16.4 Hz, benzyl-CH2), 2.29-2.15
(br.m, 1H), 2.12-1.98 (br.m, 2H), 1.8 (s, 3H, CH3), 1.77 (s, 3H, CH3), 1.74-1.64 (br.m, 1H).13C-NMR
(50MHz, CDCl3) δ 170 (-), 164.1 (-), 143.1 (-), 128.2 (J), 127.8 (J), 117 (-), 116.2 (J), 111.6 (J), 104.7 (-),
64.6 (J), 48 (2J), 47.3 (-) 36.5 (2J), 30 (J), 28.5 (2J), 28.2 (J), 23.2 (2J).
(±)-2,2-Dimethyl-2',3',4',4a'-tetrahydro-1'H,6'H-spiro[1,3-dioxane-5,5'-pyrido[1,2-a]quinoline]-4,6-
dione (13b). Prepared following general procedure 3b from 2-piperidin-1-yl-benzaldehyde 9e (180 mg,
0.95 mmol) and 2,2-dimethyl[1,3]dioxane-4,6-dione 11 (135 mg, 0.97 mmol). n-BuOH, 5 mL, 1 h, 75 °C.
Trituration from 5 mL cold 96 % EtOH. Yield 288 mg (96 %), white solid, mp 151.6 °C (decomp.), Rf =
1
0.46 (PE:EE=75:25). H-NMR (200MHz, CDCl3) δ 7.17 (dd, 1H, J=7.8, J=7.2 Hz), 7.01-6.93 (m, 2H,

HETEROCYCLES, Vol. 75, No. 4, 2008
821
J=8, J=6.4 Hz), 6.75 (dd, 1H, J=7.4, J=7.2 Hz), 4.12 (br.d, 1H, J=12.3 Hz), 3.54 (d, 1H, J=16.5 Hz,
benzyl-CH2), 3.48-3.44 (m, 1H, J=8.2Hz), 3.14 (d, 1H, J=16.5 Hz, benzyl-CH2), 2.80 (m, 1H, J=12.2,
13
J=11.7 Hz), 1.89-1.82 (br.m, 1H), 1.78 (br., 6H, CH3), 1.74-1.68 (bm, 2H), 1.67-1.35 (br.m, 3H). C-
NMR (50MHz, CDCl3) δ 169.3, 164.8, 144.8, 128.7, 127.6, 119.3, 118.2, 113.3, 105, 61.7, 52.1, 48.6,
34.3, 30.3, 28.1, 28, 24.5, 23.9. GC-MS, two peaks, intensity ratio (rel.%): 35 (15.5 min), 100 (16.7 min);
m/z (Irel, (%)): Signal 15.5 min.: 213.2 (100), 156.1 (70), 184.2 (65), 129.2 (42), 143.2 (20), 170.2 (19),
77.2 (16). Signal 16.7 min.: 184.2 (100), 213.2 (91), 156.2 (66), 130.2 (60), 144.2 (45), 55.1 (45), 77.2
(34), 170.2 (27), 115.1 (20).
(±)-10-Fluoro-1',3'-dimethyl-2,3,4,4a-tetrahydro-1H,2'H,6H-spiro[pyrido[1,2-a]quinoline-5,5'-
pyrimidine]-2',4',6'(1'H,3'H)-trione
(13c). Prepared following general procedure 3 from 3-fluoro-2-piperidin-1-yl-benzaldehyde 9g (50 mg,
0.24 mmol) and 1,3-dimethylpyrimidine-2,4,6-trione 12 (38 mg, 0.25 mmol). n-BuOH, 2 mL, 6 h, 75 °C.
1
MPLC gradient PE to PE:EE=80:20. Yield 77 mg (93 %), whitish solid. H-NMR (200MHz, CDCl3)
δ 6.92 (dd, 1H, J=7.5, J=1.6 Hz), 6.79-6.50 (m, 2H), 4.14-4.01 (m, 1H), 3.44 (d, 1H, J=17.4 Hz, benzyl-
CH2), 3.46-3.39 (m, 1H), 3.31 (s, 3H, N-CH3), 3.19 (s, 3H, N-CH3), 2.95 (d, 1H, J=17.4 Hz, benzyl-CH2),
13
2.91–2.79 (br.m, 1H), 1.7-1.1 (br.m, 6H). C-NMR (50MHz, CDCl3) δ 170.3 (-), 167.5 (-), 151.1 (-),
150.2 (-), 133.8 (-), 130.8 (J), 124.5 (-), 123.9 (J), 119.2 (J), 64.6 (J), 53.1 (-), 51.5 (2J), 35.6 (2J), 29.1 (J),
28.6 (J), 26.8 (2J), 24.9 (2J), 24.1 (2J).GC-MS, m/z (Irel, (%)): 345.3 [M+] (100), 189.2 (99), 57.9 (88),
148.2 (68), 83.2 (56), 174.2 (52), 161.2 (33), 135.2 (22).
(±)-10-Fluoro-1',3'-dimethyl-1,2,4,4a-tetrahydro-2'H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5'-
pyrimidine]-2',4',6'(1'H,3'H)-trione (13d). Prepared following general procedure 3 from 3-fluoro-2-
morpholin-4-yl-benzaldehyde 9i (38 mg, 0.18 mmol) and 1,3-dimethylpyrimidine-2,4,6-trione 12 (29 mg,
0.19 mmol). n-BuOH, 2 mL, 6 h, 100 °C. MPLC gradient PE to PE:EE=50:50. Yield 63 mg (quant.),
1
white solid. H-NMR (200MHz, CDCl3) δ 6.93 (dd, 1H, J=7.6, J=1.2 Hz), 6.89-6.72 (m, 2H), 3.83-3.53
(br.m, 6H), 3.34 (d, 1H, J=15.8 Hz, benzyl-CH2), 3.21 (s, 3H, N-CH3), 3.2 (s, 3H, N-CH3), 3.1-3.01 (m,
1H), 2.95 (d, 1H, J=15.8 Hz, benzyl-CH2).13C-NMR (50MHz, CDCl3) δ 170.2 (-), 169.9 (-), 150.8 (-),
134.5 (-), 126.9 (-), 124.1 (J), 121.8 (J), 121.6 (-), 114.2 (J), 67.1 (2J), 66.6 (2J), 62.5 (J), 50.1 (-), 45.8
(2J), 35.1 (2J), 29 (J), 28.9 (J).GC-MS, m/z (Irel, (%)): 347.2 [M+] (100), 174.0 (87), 303.2 (80), 147.2
(67), 316.2 (65), 58.1 (51), 260.2 (48).
(±)-1',3'-Dimethyl-1,2,3,3a-tetrahydro-2'H,5H-spiro[benzo[g]pyrrolo [1,2-a]-1,8-naphthyridine-4,5'-
pyrimidine]-2',4',6'(1'H,3'H)-trione (13e). Prepared following general procedure 3 from 2-pyrrolidin-1-
yl-quinoline-3-carbaldehyde 9k (249 mg, 1.01 mmol) and 1,3-dimethylpyrimidine-2,4,6-trione 12 (172
mg, 1.01 mmol). n-BuOH, 10 mL, 30 h, 75 °C. MPLC gradient PE to PE:EE=80:20. Yield 400 mg
1
(quant.), whitish solid. H-NMR (200MHz, CDCl3) δ 7.69 (d, 1H, J=8.3 Hz), 7.54 (br.s, 1H, Ar-H-4),

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7.48-7.37 (m, 2H, J=8.3, J=7.7, J=1.5 Hz), 7.11 (ddd, 1H, J=7.9, J=6.8, J=1.1 Hz), 4.12-3.96 (m, 2H,
J=7.6, J=5.8, J=4.3, J=3.2 Hz, α-amino-CH2, α-amino-CH), 3.66-3.57 (br.m, 2H, J=16.4, J=1.9 Hz,
benzylic-H, α-amino-CH2), 3.33 (s, 3H, CH3), 3.14 (s, 3H, CH3), 3.01 (d, 1H, J=16.4 Hz, benzylic-H),
2.07-1.86 (m, 2H, J=5.8, J=4.3, J=2.6 Hz, β-amino-CH2), 1.52-1.33 (m, 2H, J=9.8, J=7.1, J=1.5 Hz, β-
amino-CH2).13C-NMR (50MHz, CDCl3) δ 169.9 (-), 166.6 (-), 152.4 (-), 150.8 (-), 147.1 (-), 133.9 (J),
128.8 (J), 126.8 (J), 125.9 (J), 122.9 (-), 121.9 (J), 117.1 (-), 64.2 (J), 49 (-), 47.1 (2J), 36.8 (2J), 29.1 (J),
28.5 (2J), 28.4 (J), 23 (2J).
(±)-2',2'-Dimethyl-1,2,3,3a-tetrahydro-5H-spiro[1,3-benzodioxolo[5,6-g]pyrrolo[1,2-a]-1,8-
naphthyridine-4,5'-[1,3]dioxane]-4',6'-dione (13f). Prepared following general procedure 3 from 6-
pyrrolidin-1-yl-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde 9o (448 mg, 1.66 mmol) and 2,2-dimethyl-
[1,3]dioxane-4,6-dione 11 (239 mg, 1.66 mmol). n-BuOH, 10 mL, 20 h, 75 °C. MPLC gradient PE to
PE:EE=80:20. Yield 650 mg (99 %), white solid, mp 232.8 °C. 1H-NMR (200MHz, CDCl3) δ 7.42 (s, 1H,
Ar-H-4), 7.09 (s, 1H, Ar-H-8), 6.79 (s, 1H, Ar-H-5), 5.93 (s, 2H, -O-CH2-O-), 4.15-3.9 (m, 2H, α-amino-
CH2, α -amino-CH), 3.55 (d, 1H, J=17.2 Hz, benzylic-CH2), 3.6-3.42 (br.m, 1H, α-amino-CH2), 3.15 (d,
1H, J=17.2 Hz, benzylic-CH2), 2.2-2.03 (br.m, 1H, β-amino-CH2), 2-1.5 (br.m, 3H, β-amino-CH2), 1.66
(br.s, 6H, CH3).13C-NMR (50MHz, CDCl3) δ 169.3 (-), 163.9 (-), 151.1 (-), 150 (-), 144 (-), 133.7 (J), 136
(-), 118.1 (-), 113 (-), 105 (-), 103.9 (J), 102.8 (J), 101 (2J), 64.5 (J), 49.8 (-), 47.4 (2J), 36.2 (2J), 30.1 (J),
28.9 (2J), 28.1 (J), 22.9 (2J).
(±)-2',2'-Dimethyl-1,2,4,4a-tetrahydro-6H-spiro[1,3-benzodioxolo[5,6-g][1,4]oxazino[4,3-a]-1,8-
naphthyridine-5,5'-[1,3]dioxane]-4',6'-dione (13g). Prepared following general procedure 3 from 6-
morpholin-4-yl-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde 9q (140 mg, 0.53 mmol) and 2,2-dimethyl-
[1,3]dioxane-4,6-dione 11 (75 mg, 0.53 mmol). n-BuOH, 5 mL, 20 h, 75 °C. MPLC gradient PE to
1
PE:EE=80:20. Yield 110 mg (51 %), white solid. H-NMR (200MHz, CDCl3) δ 7.59 (s, 1H, Ar-H-4),
7.06 (s, 1H, Ar-H-5), 6.85 (s, 1H, Ar-H-8), 5.98 (s, 2H, -O-CH2-O-), 4.94 (d, 1H, J=13 Hz), 4.02-3.89 (m,
2H), 3.71-3.49 (m, 3H), 3.21-2.92 (br.m, 3H), 1.76 (s, 3H, CH3), 1.75 (s, 3H, CH3).13C-NMR (50MHz,
CDCl3) δ 170.2 (-), 168.9 (-), 149.7 (-), 144.2 (-), 141.8 (-), 133.8 (J), 123.9 (-), 122.6 (-), 111 (-), 104.8
(J), 103.8 (-), 102.2 (J), 101.8 (2J), 68 (2J), 66.5 (2J), 60.8 (J), 49 (-), 46.4 (-), 44 (2J), 36.2 (2J), 24.5 (J),
23.2 (J).
(±)-1',3'-Dimethyl-1,2,4,4a-tetrahydro-2'H,6H-spiro[1,3-benzodioxolo[5,6-g][1,4]oxazino[4,3-a]-1,8-
naphthyridine-5,5'-pyrimidine]-2',4',6'-(1'H,3'H)-trione (13h). Prepared following general procedure
3 from 6-morpholin-4-yl-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde 9q (50 mg, 0.175 mmol) and 1,3-
dimethylpyrimidine-2,4,6-trione 12 (27.5 mg, 0.18 mmol). n-BuOH, 5 mL, 45 h, 75 °C. MPLC gradient
1
PE to PE:EE=50:50. Yield 65 mg (88 %), nearly colorless solid. H-NMR (200MHz, CDCl3) δ 7.41 (s,

HETEROCYCLES, Vol. 75, No. 4, 2008
823
1H, Ar-H-4), 7.01 (bs, 1H, Ar-H-5), 6.77 (s, 1H, Ar-H-8), 5.96 (s, 2H, -O-CH2-O-), 4.97 (d, 1H, J=13.5
Hz), 3.99-3.84 (m, 2H), 3.66-3.42 (br.m, 3H), 3.31 (s, 3H, N-CH3), 3.2 (s, 3H, N-CH3), 3.19-2.91 (br.m,
3H).13C-NMR (50MHz, CDCl3) δ 169.4 (-), 166.2 (-), 150.5 (-), 141.9 (-), 140.4 (-), 133.7 (J), 120.3 (-),
119.3 (-), 114.1 (-), 109.3 (-), 104.2 (J), 102.4 (J), 101.1 (2J), 66.9 (2J), 66.4 (2J), 59.4 (J), 49.4 (-), 44.0
(2J), 35.1 (2J), 29.2 (J), 28.6 (J).GC-MS, m/z (Irel, (%)):149.1 (100), 57.2 (37), 167.1 (28), 71.2 (24),
113.2 (12), 83.2 (9).
(±)-2',2'-Dimethyl-2,3,4,4a-tetrahydro-1H,6H-spiro[1,3-benzodioxo-lo[5,6-g]pyrido[1,2-a]-1,8-
naphthyridine-5,5'-[1,3]dioxane]-4',6'-dione (13i). Prepared following general procedure 3 from 6-
piperidin-1-yl-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde 9p (75 mg, 0.27 mmol) and 2,2-dimethyl-
[1,3]dioxane-4,6-dione 11 (39 mg, 0.28 mmol). n-BuOH, 5 mL, 4 h, 75 °C. MPLC gradient PE to
PE:EE=80:20. Yield 108 mg (99 %), white solid.1H-NMR (200MHz, CDCl3) δ 7.36 (s, 1H, Ar-H4), 7.05
(s, 1H, Ar-H-5), 6.8 (s, 1H, Ar-H-8), 5.96 (s, 2H, -O-CH2-O-), 4.9-4.83 (d, 1H, J=12.8 Hz, α−amino-
CH2), 3.58-3.53 (m, 1H, α−amino-CH), 3.52-3.09 (m, 4H, J=16.6, J=12.8 Hz, α−amino-CH2, benzyl-CH2,
β−amino-CH), 2.88-2.72 (br.m, 1H), 1.82 (br.s, 6H, CH3), 1.8-1.2 (br.m, 4H, β−, γ−amino-CH2).
2,2-Dimethyl-5-[(6-piperidin-1-yl[1,3]dioxolo[4,5-g]quinolin-7-yl)methy-lene]-1,3-dioxane-4,6-dione
(13i-1). Prepared from 6-piperidin-1-yl-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde 9p (75 mg, 0.27
mmol) and 2,2-dimethyl-[1,3]dioxane-4,6-dione 11 (39 mg, 0.28 mmol) in 2 mL n-BuOH. The mixture
was stirred for 30 min at rt until a thick orange to brownish precipitate had developed; the precipitate was
filtered off, washed with 3x 0.5 mL n-BuOH and once with 0.5 mL cold MeOH yielding 71 mg (65 %) as
an orange solid which was dried under vaccuum and exhibited spectroscopic properties exhibited by the
proposed Knoevenagel-type benzylidenic intermediate as well as a little of an impurity, supposedly 13i.
Upon standing in CDCl3 at rt overnight the sample turned colorless. NMR-measurements were repeated
and showed only signals corresponding to the cyclized product (characterisation see 13i).1H-NMR
(200MHz, CDCl3) δ 8.52 (s, 1H, benzylidene-H), 8.50 (s, 1H, Ar-H-4), 7.06 (s, 1H, Ar-H-8), 6.91 (s, 1H,
Ar-H-5), 6.01 (s, 2H, -O-CH2-O-), 3.29-3.13 (br.m, 4H, α -amino-CH2), 1.81-1.54 (br.m, 12H, CH3, β-, γ-
amino-CH2).
(±)-1',3'-Dimethyl-2,3,4,4a-tetrahydro-1H,2'H,6H-spiro[1,3-benzodioxolo[5,6-g]pyrido[1,2-a]-1,8-
naphthyridine-5,5'-pyrimidine]-2',4',6'(1'H,-3'H)trione (13j). Prepared following general procedure 3
from 6-piperidin-1-yl-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde 9p (31 mg, 0.11 mmol) and 1,3-
dimethylpyrimidine-2,4,6-trione 12 (17 mg, 0.11 mmol). n-BuOH, 2 mL, 6 h, 100 °C. MPLC gradient PE
to PE:EE=70:30. Yield 43 mg (92 %), white solid.1H-NMR (200MHz, CDCl3) δ 7.38 (s, 1H, Ar-H-4),
7.01 (s, 1H, Ar-H-5), 6.79 (s, 1H, Ar-H-8), 5.93 (s, 2H, -O-CH2-O-), 4.97 (d, 1H, J=14 Hz), 3.66-3.60 (m,
1H, J=11.4, J=2.2 Hz), 3.42-3.16 (m, 4H), 3.29 (s, 3H, N-CH3), 3.23 (s, 3H, N-CH3), 2.68-2.62 (br.m,
1H), 1.8-1.2 (br.m, 4H).13C-NMR (50MHz, CDCl3) δ 169.5 (-), 166 (-), 150.3 (-), 141.6 (-), 140 (-), 133.5

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HETEROCYCLES, Vol. 75, No. 4, 2008
(J), 120.3 (-), 119.6 (-), 114.5 (-), 109.6 (-), 104.2 (J), 102.4 (J), 100.6 (2J), 64.7 (2J), 62.8 (J), 45.9 (-),
39.9 (2J), 35.1 (2J), 29.8 (J), 29 (J), 25.8 (2J), 24 (2J). GC-MS, m/z (Irel, (%)): 149.1 (100), 57.2 (51),
167.1 (37), 71.2 (30).
(±)-1',3,3'-Trimethyl-2,3,4,4a-tetrahydro-1H,2'H,6H-spiro[1,3-benzodioxolo[5,6-g]pyrazino[1,2-a]-
1,8-naphthyridine-5,5'-pyrimidine]-2',4',6'-(1'H,3'H)-trione (13k). Prepared following general
procedure 3 from 6-(4-methyl-piperazin-1-yl)[1,3]dioxolo[4,5-g]quinoline-7-carbal-dehyde 9r (50 mg,
0.17 mmol) and 1,3-dimethylpyrimidine-2,4,6-trione 12 (27 mg, 0.18 mmol). n-BuOH, 5 mL, 30 h, 75 °C.
1
MPLC gradient PE to PE:EE= 70:30. Yield 73 mg (quant.), white solid. H-NMR (200MHz, CDCl3)
δ 7.38 (s, 1H, Ar-H-4), 7.02 (s, 1H, Ar-H-8), 6.78 (s, 1H, Ar-H-5), 5.93 (s, 2H, -O-CH2-O-), 5.17-5.09 (m,
1H, J=12.5 Hz), 3.89 (dd, 1H, J=10.7, J=2.7 Hz), 3.45 (m, 1H, J=16.8, J=1.2 Hz, benzylic-CH2), 3.40 (s,
1H), 3.30 (s, 3H, (CO)N-CH3), 3.22 (s, 3H, (CO)N-CH3), 3.12 (d, 1H, J=16.8 Hz, benzylic-CH2), 2.97
(br.m, 1H, J=12.6, J=3.1 Hz), 2.8 (d, 1H, J=11.5 Hz), 2.55 (br.d, 1H, J=10.2 Hz), 2.21 (s, 3H, N-CH3),
2.11-2.06 (br.m, 1H, J=11.7, J=3.1 Hz).13C-NMR (50MHz, CDCl3) δ 169.5 (-), 167 (-), 152.1 (-), 150.8 (-
), 149.9 (-), 144.9 (-), 144.3 (-), 133.6 (J), 119.2 (-), 114.5 (-), 104.2 (J), 102.4 (J), 101 (2J), 59.6 (J), 55.7
(2J), 53.7 (2J), 50.8 (-), 44.2 (2J), 34 (2J), 29.9 (J), 28.7(J), 26.9 (J).GC-MS, m/z (Irel, (%)): 91.1 (100),
146.1 (94), 202.2 (34), 65.1 (29), 250.3 (27), 293.3 (19).
(±)-1'-Benzyl-2,2-dimethyl-1',4',5a',6',8',9'-hexahydro-2'H-spiro[1,3-dioxane-5,5'-
[1,3]thiazolo[5',4':5,6]pyrido[2,1-c][1,4]oxazine]-2',4,6-trione (13l). Prepared following general
procedure 3 from 3-benzyl-4-morpholin-4-yl-2-oxo-2,3-dihydrothiazole-5-carbaldehyde 9t (25 mg, 0.09
mmol) and 2,2-dimethyl-[1,3]dioxane-4,6-dione 11 (12.8 mg, 0.09 mmol). n-BuOH, 2 mL, 100 h, 75 °C.
1
MPLC gradient PE to PE:EE=90:10.Yield 36 mg (95 %), greyish solid. H-NMR (200MHz, CDCl3)
δ 7.31-7.05 (m, 5H, Ar-H), 4.99-4.95 (m, 2H, N-CH2Ph), 4.16-4.09 (bs, 1H, α−amino-CH), 3.69-3.59 (m,
2H), 3.44 (d, 1H, J=16.1 Hz, benzylic-CH2), 3.29 (d, 1H, J=16.1 Hz, benzylic-CH2), 2.92-2.85 (m, 2H),
2.84-2.77 (m, 2H), 1.38 (s, 3H, CH3), 1.37 (s, 3H, CH3).13C-NMR (50MHz, CDCl3) δ 166.7, 165.5, 165.2,
131.4, 129.8, 127.9, 127.8, 125.5, 121.8, 103, 67.1, 65.4, 55.7, 51.4, 50.3, 44.1, 37.7, 28.4, 28.1. GC-MS,
two major peaks of rel. int. 51 %, 100 %; m/z (Irel, (%)):100 % rel. int. peak, 16 min, m/z (Irel, (%)): 242.9
(100), 184 (76), 77 (64), 186.2 (56), 51 (48). 51 % rel. int. peak, 22 min, m/z (Irel, (%)): 149 (100), 167
(82), 57.1 (72), 70.2 (63), 150.1 (40).
(±)-1',3,3'-Trimethyl-1-phenyl-1,4,6,7,8,9-hexahydro-2'H,5aH-spiro[pyrazolo[4,3-c]quinolizine-5,5'-
pyrimidine]-2',4',6'(1'H,3'H)-trione (13m). Prepared following general procedure 3 from 3-methyl-1-
phenyl-5-piperidin-1-yl-1H-pyrazole-4-carbaldehyde (27 mg, 0.1 mmol) and 1,3-dimethylpyrimidine-
2,4,6-trione 12 (16 mg, 0.11 mmol). n-BuOH, 2 mL, 24 h, 100 °C. MPLC gradient PE to PE:EE=80:20.
Yield 41 mg (88 %), white solid.1H-NMR (200MHz, CDCl3) δ 7.33-7.22 (m, 5H, Ar-H), 4.30 (bs, 1H),
3.91-3.87 (m, 1H), 3.50-3.46 (m, 1H), 3.34 (s, 3H, N-CH3), 3.33 (s, 3H, N-CH3), 3.31 (d, 1H, J=17 Hz),

HETEROCYCLES, Vol. 75, No. 4, 2008
825
3.29-3.25 (m, 2H), 3.19 (d, 1H, J=17 Hz), 3.01-2.93 (m, 1H), 2.35 (s, 3H, Ar-CH3), 1.9-1.81 (br.m, 1H),
13
1.6-1.4 (br.m, 2H). C-NMR (50MHz, CDCl3) δ 171.7, 169.4, 150, 133.3, 132.5, 129.2, 128.7, 128.3,
127.7, 126.2, 66.2, 52.7, 54.7, 44.4, 37.4, 30.3, 29.9, 28.1, 25.2, 13.4. GC-MS, m/z (Irel, (%)): 240.8 (100),
77 (57), 84 (56), 158.2 (43), 117.1 (42), 212.2 (42), 184.2 (41).
(±)-2,2,3'-Trimethyl-1'-phenyl-1',4',5a',6',8',9'-hexahydrospiro[1,3-dio-xane-5,5'-
pyrazolo[4',3':5,6]pyrido[2,1-c][1,4]oxazine]-4,6-dione (13n). Prepared following general procedure 3
from 3-methyl-5-morpholin-4-yl-1-phenyl-1H-pyrazole-4-carbaldehyde 9u (25 mg, 0.09 mmol) and 2,2-
dimethyl-[1,3]dioxane-4,6-dione 11 (14 mg, 0.1 mmol). n-BuOH, 2 mL, 100 h, 100 °C. MPLC gradient
PE to PE:EE=50:50. Yield 27 mg (75 %), colorless solid.1H-NMR (200MHz, CDCl3) δ 7.29-7.15 (m, 5H,
Ar-H), 4.23 (br.s, 1H), 4.02-3.95 (m, 2H), 3.88-3.79 (m, 2H), 3.59-3.54 (m, 2H), 3.30 (d, 1H, J=16.9 Hz,
benzylic-CH2), 3.12 (d, 1H, J=16.9 Hz, benzylic-CH2), 2.41 (s, 3H, Ar-CH3), 1.39 (s, 3H, CH3), 1.38 (s,
3H, CH3).13 C-NMR (50MHz, CDCl3) δ 171.5, 166.4, 135.3, 133.3 129.2, 128.9, 128.3, 127.5, 126.3,
103.3, 65.3, 54.7, 52.7, 45.3, 41.7, 30.4, 23.5, 22.7, 13.8. GC-MS, two major peaks, m/z (Irel, (%)): 56.1
(100), 104.9 (63), 86.9 (51), 143 (50), 161.1 (38), 217.2 (33); 91 (100), 132 (90), 178.9 (88), 104 (77), 65
(73), 77 (68), 146.1 (66).
(±)-1',3,3'-Trimethyl-1-phenyl-1,4,5a,6,8,9-hexahydro-2'H-spiro[pyrazolo[4',3':5,6]pyrido[2,1-
c][1,4]oxazine-5,5'-pyrimidine]-2',4',6'(1'H, 3'H)-trione (13o). Prepared following general procedure 3
from 3-methyl-5-morpholin-4-yl-1-phenyl-1H-pyrazole-4-carbaldehyde 9u (27 mg, 0.1 mmol) and 1,3-
dimethylpyrimidine-2,4,6-trione 12 (16 mg, 0.1 mmol). n-BuOH, 2 mL, 90 h, 100 °C. MPLC gradient PE
to PE:EE=60:40. Yield 24 mg (60 %), white solid.1H-NMR (200MHz, CDCl3) δ 7.33-7.22 (m, 5H, Ar-H),
4.14 (br.s, 1H), 3.75-3.71 (m, 2H), 3.60-3.54 (m, 2H), 3.59-3.54 (m, 2H), 3.51 (d, 1H, J=15.8 Hz), 3.41 (d,
13
1H, J=15.8 Hz), 3.31-3.28 (br.s, 6H, N-CH3), 2.4 (s, 3H, Ar-CH3). C-NMR (50MHz, CDCl3) δ 169.5,
168.4, 151.3, 134.4, 133.2, 129.2, 128.9, 128.3, 127.5, 126.3, 66.2, 57.8, 52.7, 50.7, 44, 38.1, 28.5, 28.2,
13.8. GC-MS, two major peaks, rel. int. 49 %, 100 %., m/z (Irel, (%)):100 % rel. int. peak, 16 min: 184.1
(100), 242.3 (98), 77 (92), 186.2 (78), 51.1 (63). 21 min: 149 (100), 167.1 (86), 57.1 (82), 70.2 (75),
150.1 (38).
(12bS)-8-Methoxy-1',3',12b-trimethyl-7,12b-dihydro-2'H,6H,14H-spiro[1,3-
dioxolo[6,7]isoquino[2,1-a]quinoline-13,5'-pyrimidine]-2',4',6'-(1'H,3'H)-trione
(14).
Prepared
following general procedure 3b from 2-((S)-9-methoxy-5-methyl-7,8-dihydro-5H-[1,3]dioxolo[4,5-
g]isoquinolin-6-yl)benzaldehyde 9c (100 mg, 0.307 mmol) and 1,3-dimethylpyrimidine-2,4,6-trione 12
(51 mg, 0.33 mmol). n-BuOH, 5 mL, 22 h, 75 °C. Trituration from 5 mL cold 96 % EtOH. Yield 98 mg
20
(69 %), amber solid, mp 215.9 °C, [α]D + 13.7 (c 0.93, CHCl3). 1H-NMR (200MHz, CDCl3) δ 7.4 (bd,
1H, J=6.6 Hz), 7.2-6.99 (m, 2H, J=7.6, J=7.2, J=6.3 Hz), 6.77 (bd, 1H, J=7.6 Hz), 6.35 (s, 1H), 6.06 (d,
1H, J=1 Hz, -O-CH2-O-), 5.86 (d, 1H, J=1 Hz, -O-CH2-O-), 4.37-4.25 (m, 1H, J=18, J=11.4, J=5.5 Hz,

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HETEROCYCLES, Vol. 75, No. 4, 2008
α-amino-CH2), 3.9 (s, 3H, O-CH3), 3.7 (d, 1H, J=16.2 Hz, benzyl-CH2), 3.56-3.38 (m, 1H, J=18, J=10,
J=4.5 Hz), 3.34 (d, 1H, J=16.2 Hz, benzyl-CH2), 3.05 (br.s, 6H, N-CH3), 2.93-2.86 (m, 1H, J=15.8, J=10,
J=5.5 Hz), 2.81-2.67 (m, 1H, J=15.8, J=11.4, J=4.5 Hz), 1.93 (s, 3H, Cquart-CH3).13C-NMR (50MHz,
CDCl3) δ 166.4 (-), 165.1 (-), 151.9 (-), 148.6 (-), 146.7 (-), 141.5 (-), 134.5 (-), 131.5 (-), 130.8 (J), 129.7
(-), 126.7 (J), 123.8 (J), 118.1 (J), 109.2 (-), 107.6 (J), 102.2 (2J), 56.9 (J), 47.5 (2J), 29.8 (2J), 28.8 (2J),
28.3 (J), 28.2 (J), 20.1 (J). GC-MS, m/z (Irel, (%)): Fragmentation, 2 main peaks: broad, 13.73-13.85 min:
380.13 (100), 306.09 (60), 395.19 (45), 322.14 (23), 294.13 (17), 76.99 (15), 352.13 (11), 204.14 (10),
292.14 (10); 14.15 min: 378.12 (100), 304.11 (59), 72.98 (56), 281.05 (50), 95.86 (48), 320.09 (38), 191
(36), 393.11 (32).
(±)-1,1',3-Trimethyl-2'-(3,4,5-trimethoxybenzyl)-1',4'-dihydro-2H,2'H-spiro[pyrimidine-5,3'-
quinoline]-2,4,6(1H,3H)-trione (15). Prepared following general procedure 3 from 2-{methyl-[2-(3,4,5-
trimethoxy-phenyl)ethyl]amino}benzaldehyde 9b (100 mg, 0.304 mmol) and 1,3-dimethylpyrimidine-
2,4,6-trione 12 (50 mg, 0.32 mmol). n-BuOH, 5 mL, 30 h, 75 °C. MPLC gradient PE:CH2Cl2=88:12 to
PE:CH2Cl2:Et2O=70:10:20. Yield 125 mg (88 %), yellow oil that upon standing spontaneously crystal-
lized to a white solid, mp 256.7 °C.1H-NMR (200MHz, CDCl3) δ 7.19-7.03 (m, 2H, J=8, J=7.4, J=0.8
Hz), 6.72 (dd, 1H, J=7.4, J=0.8 Hz), 6.46 (d, 1H, J=8 Hz), 6.03 (br.s, 2H), 3.77-3.63 (br.m, 2H, J=17.6
Hz), 3.76 (s, 3H, O-CH3), 3.69 (br.s, 6H, O-CH3), 3.25 (s, 3H, (CO)2N-CH3), 3.15 (s, 3H, (CO)2N-CH3),
2.99 (d, 1H, J=17.6 Hz, benzyl-CH2), 2.57 (dd, 1H, J=13.6, J=9.6 Hz), 2.48 (s, 3H, N-CH3), 2.42 (dd, 1H,
J=13.7, J=4.7 Hz).13C-NMR (50MHz, CDCl3) δ 169.7 (-), 169.1 (-), 153.1 (intense, -), 151.7 (-), 142 (-),
136.8 (-), 133.2 (-), 128.7 (J), 127 (J), 120.3 (-), 117.9 (J), 112.7 (J), 106.4 (intense, J), 68.7 (J), 60.8 (J),
56.1 (intense, J), 55.1 (-), 40.3 (J), 36.1 (2J), 29.4 (J), 29 (J), 26.4 (2J). GC-MS, m/z (Irel, (%)): 380.12
(100), 306.09 (73), 395.18 (53), 322.11 (42), 76.88 (25), 294.13 (25), 95.84 (21), 281.08 (18).
(±)-(3aR*,4S*)-1,2,3,3a,4,5-Hexahydropyrrolo[1,2-a]quinoline-4-car-boxylic
acid
(16a). (±)-
(3aR*,4R*)-1,2,3,3a,4,5-Hexahydropyrrolo[1,2-a]-quinoline-4-carboxylic acid (17a). Prepared
following general procedure 3e from (±)-2,2-dimethyl-1',2',3',3a'-tetrahydro-5'H-spiro[1,3-dioxane-5,4'-
pyrrolo[1,2-a]quinoline]-4,6-dione 13a (752mg, 2.56 mmol). H2O/HCl, 20 mL, pH 1, 95 °C, 50 h. The
resultant aqueous suspension was basified to pH 4.2 and extracted continuously with CH2Cl2. The organic
phases were once washed with 2 mL dH2O, dried (Na2SO4) and rotoevaporated to yield 457 mg (82 %),
purity by HPLC 97.6 % (254 nm), slightly brown solid, recrystallization from 96 % EtOH, blackish to
violet plates, mp 116-121°C (decomp.); diastereomer ratio is u:l ≥ 7:1 (de ≥ 75 %) via integration in 1H-
NMR. Main isomer (3a,4-u): 1H-NMR (200MHz, CDCl3) δ 9.97 (bs, 1H, COO-H), 7.03 (dd, 1H, J=8,
J=7.4 Hz), 6.94 (d, 1H, J=7.8 Hz), 6.55 (br.d, 1H, J=7.4 Hz), 6.36 (d, 1H, J=7.8 Hz), 3.51-3.38 (ddd, 1H,
J=10, J=5, J=2.4 Hz), 3.36-3.27 (br.dd, 1H, J=8.9, J=2.2 Hz), 3.20- 3.08 (ddd, 1H, J=9.9, J=8.9, J=1.6
Hz), 2.98-2.88 (m, 2H, J=15.8, J=12.3, J=4.4 Hz), 2.37-2.24 (m, 1H, J=9.8, J=7.6, J=2.4 Hz), 2.24-2.16

HETEROCYCLES, Vol. 75, No. 4, 2008
827
(br.m, 1H, J=12.3, J=5.4 Hz), 2.03-1.79 (br.m, 2H, J=11.7, J=9.2, J=6.9, J=4.9, J=2.3 Hz), 1.61-1.45
(ddd, 1H, J=11.5, J=10, J=7.8 Hz). 13C-NMR (50MHz, CDCl3) δ 180.8 (-), 143.7 (-), 128.5 (J), 127.7 (J),
1
119.4 (-), 115.4 (J), 110.4 (J), 59.3 (J), 47.2 (2J), 43.5 (J), 31.9 (2J), 28.5 (2J), 23.7 (2J). H-NMR
(400MHz, CDCl3) δ 7.01-6.95 (m, 2H, J=7.6 Hz), 6.5-6.46 (dd, 1H, J=7, J=7.1 Hz), 6.39-6.37 (br.d, 1H,
J=7.9 Hz), 3.4-3.34 (m, 1H, J=9.8, J=5.3, J=4.7 Hz), 3.33-3.29 (br.m, 1H, J=8.8 Hz), 3.13-3.07 (m, 1H,
J=8.8, J=8.5, J=7.6 Hz), 2.89 (br.dd, 1H, J=15.8, J=4.4 Hz, benzyl-CH2), 2.8 (br.dd, 1H, J=15.8, J=12 Hz,
benzyl-CH2), 2.17-2.11 (br.m, 2H, J=12, J=9.8, J=6.9, J=4.7, J= 4.4 Hz, α-keto-H, β-amino-CH2), 2.04-
1.95 (br.m, 1H, J=12.6, J=6.1 Hz), 1.91-1.81 (br.m, 1H, J=10, J=8.5, J=6.4 Hz), 1.56-1.45 (m, 1H, J=10,
J=7.6 Hz). Minor isomer 17a, (3a,4-l): 1H-NMR (200MHz, CDCl3) δ 10.2-9.8 (m (br.s), 1H, COO-H),
7.11 (m, 1H), 6.79 (m, 1H), 6.55 (br.d, 1H, J=7.4 Hz), 6.3 (m, 1H), 3.67-3.61 (br.m, 1H); other signals
are not resolved properly.13C-NMR (50MHz, CDCl3) δ 177.2 (-), 144.5 (-), 128.8 (J), 127.3 (J), 120.2 (-),
117.6 (J), 112.3 (J), 58.7 (J), 47.3 (2J), 40 (J), 31.1 (2J), 28.8 (2J), 22.9 (2J).GC-MS, m/z (Irel, (%)): u/l-
mixture, 2 main peaks: 12.91 min: 223.15 (100), 221.07 (72), 195.13 (49), 167.12 (44). 13.07 min: 223.01
(100), 221.1 (54), 195.16 (41), 167.15 (31). MALDI-MS/MS: m/z (Irel, %) TIC, MS2: 170.1 (100); 385.1
(33): 341.1 (100), 196.1 (67), 385.1 (51), 170 (9), 216 (8); 186 (9); 212.1 (7); 357.1 (6); 401.1 (5); 337.1
(4); 415.1 (4).
(±)-(4aR*,5S*)-2,3,4,4a,5,6-Hexahydro-1H-pyrido[1,2-a]quinoline-5-carboxylic acid (16b). (±)-
(4aR*,5R*)-2,3,4,4a,5,6-Hexahydro-1H-pyri-do[1,2-a]quinoline-5-carboxylic acid (17b). Prepared
following general procedure 3e from (±)-2,2-dimethyl-2',3',4',4a'-tetrahydro-1'H,6'H-spiro[1,3-dioxane-
5,5'-pyrido[1,2-a]quinoline]-4,6-dione 13b (850 mg, 2.7 mmol). H2O/HCl, 20 mL, pH 1, 95 °C, 16 h. The
resultant aqueous suspension was basified to pH 5.4 and continuously extracted with CH2Cl2. The organic
phases were once washed with 2 mL dH2O, dried (Na2SO4) and rotoevaporated to yield 588 mg (95 %),
purity by HPLC 97.9 % (254 nm), slightly brown semi-solid, diastereomer ratio is u:l ≥ 5:1 (de ≥ 67 %)
via integration in 1H-NMR (~7:1 via integration in 13C-NMR). Main isomer (4a,5-u): 1H-NMR (200MHz,
CDCl3) δ 11.2-10.7 (br.s, 1H, COO-H), 7.03 (dd, 1H, J=7.8, J=7.6 Hz), 6.91 (d, 1H, J=7.4 Hz), 6.81-6.68
(m, 1H, J=8.2, J=7.6 Hz), 6.65-6.58 (m, 1H, J=7.2 Hz), 3.85 (d, 1H, J=13.1 Hz, α-amino-CH2), 3.14 (dd,
1H, J=9.6, J=7.8 Hz, α-amino-CH), 3.01- 2.59 (m, 4H, J=16.4, J=15.2, J=12.8, J=9.6, J=7.2 Hz), 1.73-
1
1.18 (br.m, 6H). H-NMR (400MHz, CDCl3) δ 6.98 (dd, 1H, J=8.9, J=7.3 Hz), 6.89 (d, 1H, J=7.3 Hz),
6.7 (d, 1H, J=8.2 Hz), 6.55 (dd, 1H, J=7.6, J=7.3 Hz), 3.85 (bd, 1H, J=12.9 Hz, α-amino-CH2), 3.15 (ddd,
1H, J=9.4, J=8.5, J=5.6 Hz, α-amino-CH), 2.95 (dd, 1H, J=15, J=8.5 Hz, benzyl-CH2), 2.8-2.61 (m, 2H,
J=15, J=12.9, J=5 Hz benzyl-CH2, α-amino-CH2), 2.54-2.48 (ddd, 1H, J=9.4, J=9.1, J=5.1 Hz), 1.80-1.63
13
(br.m, 3H), 1.57-1.27 (br.m, 3H). C-NMR (50MHz, CDCl3) δ 180.2 (-), 145.5 (-), 129.9 (J), 127.5 (J),
122.8 (-), 118.3 (J), 113.2 (J), 58 (J), 48.5 (2J), 46 (J), 31.1 (2J), 29.7 (2J), 24.7 (2J), 24.5 (2J). Minor

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HETEROCYCLES, Vol. 75, No. 4, 2008
isomer 17b, (4a,5-l): 1H-NMR (200MHz, CDCl3) δ 11.2-10.7 (br.s, 1H, COO-H), 7.07- 6.90 (m, 2H),
6.81-6.57 (m, 2H), 3.97 (d, 1H, J=14.3 Hz), 3.51-3.44 (br.m, 1H), 3.01- 2.59 (m, 4H), 1.73-1.18 (br.m,
6H), other signals not resolved properly.1H-NMR (400MHz, CDCl3) δ 7-6.5 (4 Ar-H), 3.99 (d, 1H,
J=14.3 Hz), 3.61-3.49 (ddd,1H, J=8.2, J=4.5, J=4.2 Hz, α-amino-CH), 2.99-2.89 (m, 1H, J=12 Hz), other
signals not resolved.13C-NMR (50MHz, CDCl3) δ 178.4 (-), 144.1 (-), 129.9 (J), 127.5 (J), 121.9 (-),
118.3 (J), 113.5 (J), 57.3 (J), 53.5 (2J), 42.6 (J), 26.9 (2J), 24.7 (2J), 24.6 (2J), 22.9 (2J).
(12bR,13R)-8-Methoxy-12b-methyl-7,12b,13,14-tetrahydro-6H-[1,3]dioxolo[6,7]isoquino[2,1-
a]quinoline-13-carboxylic acid (19). (12bR,13S)-8-Methoxy-12b-methyl-7,12b,13,14-tetrahydro-6H-
[1,3]dioxolo[6,7]isoquino[2,1-a]quinoline-13-carboxylic acid (20).
Prepared following general procedure
3
from 2-((S)-4-methoxy-9-methyl-6,9-dihydro-7H-
[1,3]dioxolo[4,5-h]isoquinolin-8-yl)-benzaldehyde 9c (100 mg, 0.43 mmol) and 2,2-dimethyl-
[1,3]dioxane-4,6-dione 11 (70 mg, 0.45 mmol). n-BuOH, 5 mL, 30 h, 75 °C. MPLC gradient
PE:CH2Cl2=88:12 to PE:CH2Cl2:Et2O=70:10:20. Yield of parent spiro compound 18 13 mg (16 %),
1
yellow solid, yield of carboxylic acids 61 mg (61 %), de ≥ 9 %, red oil. Main isomer, 33 mg: H-NMR
(200MHz, CDCl3) δ 7.03 (dd, 1H, J=7.2, J=6.7 Hz), 6.99-6.95 (m, 1H, J=6.4 Hz), 6.73 (d, 1H, J=8.2 Hz),
6.62 (dd, 1H, J=7.2, J=0.8 Hz), 6.22 (s, 1H), 5.91 (d, 1H, J=1.4 Hz, -O-CH2-O-), 5.88 (d, 1H, J=1.4 Hz, -
O-CH2-O-), 3.97-3.87 (m, 1H, J=9.7, J=6, J=3, J=2.9 Hz), 3.81 (br.s, 3H, O-CH3), 3.68-3.62 (m, 2H,
J=12.3, J=7, J=5.3, J=3.5 Hz), 3.12-2.94 (m, 2H, J=15.2, J=12.3, J=9.5, J=3, J=2.9 Hz, α-carboxy-
benzyl-CH2, benzyl-CH2), 2.81-2.73 (m, 1H, J=12.3, J=11.9 Hz, α-carbo-xy-benzyl-CH2), 2.65-2.55 (m,
1H, J=15.2, J=10, 2.9 Hz, benzyl-CH2), 1.39 (s, 3H, CH3). 13C-NMR (50MHz, CDCl3) δ 172.5 (-), 144.9
(-), 144.2 (-), 142.3 (-), 133.6 (-), 129.5 (-), 129.1 (J), 126.9 (J), 121 (-), 118.6 (-), 117 (J), 111.6 (J), 106.4
(J), 101.1 (2J), 59.6 (2J), 56.4 (J), 46.1 (-), 44.5 (J), 38.9 (2J), 28.4 (2J), 21.6 (J).GC-MS, m/z (Irel, (%)):
Fragmentation, main peaks: 8.11 min: 76.91 (100), 83.87 (92), 79.09 (82), 85.87 (58), 51.06 (56), 106.98
(43), 187.92 (28), 28. (26). 8.83 min: 56.95 (100), 70.93 (68), 85.15 (32), 83.86 (30), 54.98 (16), 86.19
(10). 9.73 min: 56.98 (100), 70.95 (68), 85.14 (32). 11.33 min: 57.07 (100), 219.18 (31), 177.09 (30),
163.08 (23), 91 (10), 267.19 (10), 135.11 (8). 11.7 min: 69.87 (100), 81.03 (80), 99.02 (77), 168.94 (57).
12.08 min: 54.96 (100), 68.93 (88), 57.12 (84), 83.12 (83), 97.15 (70). 12.35 min: 126.98 (100), 155.04
(86), 174.09 (37), 128.14 (21), 99.06 (17), 199.03 (17), 173.07 (17), 227.08 (16), 84.01 (13), 301.15 (14).
13.39 min: 149 (100), 72.99 (17), 281.04 (11). 13.49 min: 54.94 (100), 57.09 (83), 68.98 (77), 83.12 (76),
97.14 (72). Minor isomer, 28 mg: 1H-NMR (200MHz, CDCl3) δ 7.05 (dd, 1H, J=7.6, J=6.8 Hz), 6.94-6.9
(m, 2H, J=9 Hz), 6.68 (dd, 1H, J=7.2, J=6.8 Hz), 6.2 (s, 1H), 5.86 (d, 1H, J=1.2 Hz, -O-CH2-O-), 5.8 (d,
1H, J=1.2 Hz, -O-CH2-O-), 3.97-3.87 (m, 1H, J=9, J=7.2, J=2.9Hz), 3.78 (bs, 3H, OCH3), 3.74-3.7 (m,
1H, J=9, J=5.5, J=3.3 Hz), 3.64-3.57 (m, 1H, J=7.2, J=3.5 Hz), 3.12-2.94 (m, 2H, J=14.4, J=12.7, J=11.5,
J=9.5, J=3, J=2.9 Hz, α-carboxy-benzyl-CH2, benzyl-CH2), 2.94-2.87 (br.m, 2H, J=14.4, J=11.5, J=3.3