Synthesis and conformational analysis of tetrahydroisoquinoline- and piperidine-fused 1,3,4,2-oxadiazaphosphinanes, new ring systems

Article abstract of DOI:10.1016/j.tet.2006.01.018

Through cyclization of tetrahydroisoquinoline and piperidine 1,2-hydrazino alcohols with phenylphosphonic dichloride and phenyl dichlorophosphate, P-epimeric diastereomers of 1,6,7,11b-tetrahydro-4H-1,3,4,2-oxadiazaphosphino[5, 4-a]isoquinoline-3-oxides (

Full text of DOI:10.1016/j.tet.2006.01.018

Tetrahedron 62 (2006) 2883–2891
Synthesis and conformational analysis of tetrahydroisoquinoline-
and piperidine-fused 1,3,4,2-oxadiazaphosphinanes,
new ring systems
a
Zita Zal a´ n, Tam a´ s A. Martinek, L a´ szl o´ L a´ z a´ r, Reijo Sillanp a¨ a¨ and Ferenc F u¨ l o¨ p
a
a
b
a,
*
a
Institute of Pharmaceutical Chemistry, University of Szeged, PO Box 121, H-6701 Szeged, Hungary
b
Department of Chemistry, University of Jyv a¨ skyl a¨ , PO Box 35, 40351 Jyv a¨ skyl a¨ , Finland
Received 6 October 2005; revised 28 November 2005; accepted 5 January 2006
Available online 19 January 2006
Dedicated to Professor G e´ za St a´ jer on his 70th birthday
Abstract—Through cyclization of tetrahydroisoquinoline and piperidine 1,2-hydrazino alcohols with phenylphosphonic dichloride and
phenyl dichlorophosphate, P-epimeric diastereomers of 1,6,7,11b-tetrahydro-4H-1,3,4,2-oxadiazaphosphino[5,4-a]isoquinoline-3-oxides
(
13 and 14), 1,6,11,11a-tetrahydro-4H-1,3,4,2-oxadiazaphosphino[4,5-b]isoquinoline-3-oxides (15 and 16) and 1,6,7,8,9,9a-hexahydro-4H-
pyrido[1,2-d][1,3,4,2]oxadiazaphosphinane-3-oxides (17 and 18), the first representatives of these ring systems, were prepared. NMR and
X-ray diffraction studies revealed that, independently of the P-substituent and the relative configuration of the phosphorus atom, 13, 14, 17
and 18 could be characterized by trans-connected hetero rings and the chair conformation of the 1,3,4,2-oxadiazaphosphinane moiety, while
the stereochemistry of the connection of the hetero rings in the 1,3,4,2-oxadiazaphosphinanes linearly fused to tetrahydroisoquinoline
(15 and 16) was found to be dependent on the P-configuration relative to that of the carbon at the annelation.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
containing an additional nitrogen atom in the heterocyclic
7
–10
ring.
The first representatives of this ring system were
In consequence of their valuable pharmacological effects
and wide-ranging potential for synthetic applications,
considerable interest has been focused towards 1,3,
prepared with the aim of identifying potential antitumour
agents. However, despite the close structural analogy,
cyclophosphamide-analogue 1,3,4,2-oxadiazaphosphinane-
2-oxides, and the homologous 1,3,4,2-oxadiazaphosphepin-
1
2
-O,N,P heterocycles. The 1,3,2-oxazaphosphinane ring
system is found in alkylating anticancer drugs (cyclophos-
phamide and ifosfamide), numerous derivatives of which
have been prepared to determine their structure–activity
2
activity.
-oxides, proved to exhibit negligible antileukaemic
9
,10
Furthermore, there has been only one stereo-
chemical investigation of this ring system: 4-methyl-2-
phenoxy-1,3,4,2-oxadiazaphosphinane-2-oxide proved to
exist predominantly in the chair conformation, with the
2
relationships. Compounds containing a 1,3,2-oxazaphos-
phinane moiety were recently reported to possess matrix
3
metalloproteinase-inhibitory, pesticidal and antimicrobial
4
5
8
P]O group occupying an axial position.
activities. Phosphorus-stabilized carbanions derived from
chiral 1,3,2-oxazaphosphinane 2-oxides have been widely
used in the diastereoselective formation of carbon–carbon
As a continuation of our previous stereochemical studies
on 1,2,3,4-tetrahydroisoquinoline-condensed 1,3- and 1,2,
6
bonds.
11
3
2
-heterocycles, our present aim was to prepare 1,3,4,
-oxadiazaphosphinane-2-oxides attached angularly or line-
In contrast with the thoroughly investigated 1,3,2-oxaza-
phosphinane-2-oxide derivatives, less attention has been
paid to the preparation and transformations of the
corresponding 1,3,4,2-oxadiazaphosphinane-2-oxides
arly to the tetrahydroisoquinoline ring in order to investigate
the effects of the substituents and the configurations of the
substituted atoms on the predominant conformations of the
nitrogen-bridged tricyclic system. To determine the effects
of the attached aromatic ring on the stereochemistry of the
ring junction, a further aim was to synthesise the parent
piperidine-condensed derivatives. To the best of our
knowledge, nitrogen-bridged 1,3,4,2-oxadiazaphosphinane-
Keywords: Hydrazino alcohols; Isoquinolines; Phosphorus heterocycles;
Conformation.
*
Corresponding author. Tel.: C36 62 545564; fax: C36 62 545705;
e-mail: fulop@pharm.u-szeged.hu
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.018

2884
Z. Zal a´ n et al. / Tetrahedron 62 (2006) 2883–2891
2-oxides with a condensed skeleton have not been reported
previously in the literature.
The amino alcohols 7a,b necessary for the linearly fused
model compounds were prepared by LiAlH4 reduction
of the corresponding 1,2,3,4-tetrahydroisoquinoline-
3
-carboxylic acids (TIC: 6a and 6,7-diMeO-TIC: 6b)
1
5,16
(Scheme 2).
2-amino-3-(3,4-dimethoxyphenyl)propanoic acid, an
The lengthy hydrolysis step of 9 towards
1
5
2
. Results and discussion
intermediate of 6b, proved to be a tedious reaction on a
1
7
0.1 mol scale. Accordingly, an alternative procedure,
based on a change in the sequence of the transformation
2
.1. Syntheses
of the functional groups of 9, was applied for the synthesis
of larger quantities of 7b. LiAlH reduction of 9 resulted
Most of the methods applied earlier to the synthesis of
,3,4,2-oxadiazaphosphinanes were based on the ring
closures of the corresponding hydrazino alcohols with the
4
1
in N-benzyl amino alcohol 10, which was converted to
the corresponding tetrahydroisoquinoline derivative 11 by
Pictet-Spengler cyclization with formaldehyde. Removal of
the benzyl group of 11 by catalytic hydrogenation in the
presence of Pd/C led to 6,7-dimethoxy-1,2,3,4-tetrahydro-3-
isoquinolinylmethanol (7b) (Scheme 2).
7
–9
appropriate phosphorus-containing fragments.
This
methodology was also applied for the preparation of our
target compounds.
Regioisomeric tetrahydroisoquinoline hydrazino alcohols 5
and 8a,b, starting materials for the phosphorus-containing
model compounds, were prepared from the corresponding
amino alcohol derivatives 4 and 7a,b by using a two-step
1
Hydrazino alcohols 5, 8a,b and 12 were cyclized with
8
phenylphosphonic dichloride, and phenyl dichlorophosphate
at room temperature in THF in the presence of Et N, resulting
procedure (N-nitrosation and a subsequent LiAlH reduction)
4
3
in 1,6,7,11b-tetrahydro-4H-1,3,4,2-oxadiazaphosphino-
[5,4-a]isoquinoline-3-oxides (13 and 14), 1,6,11,11a-tetra-
usually applied for the preparation of N-substituted
hydrazines or hydrazino alcohols from secondary amines
or amino alcohols, respectively (Schemes 1 and 2).
1
2
hydro-4H-1,3,4,2-oxadiazaphosphino[4,5-b]isoquinoline-3-
oxides (15 and 16) and 1,6,7,8,9,9a-hexahydro-4H-pyr-
ido[1, 2-d][1,3,4,2]oxadiazaphosphinane-3-oxides (17 and
18), which are the first representatives of these ring systems
(Scheme 3). In most cases, two P-2 epimeric diastereomers,
differing in the cis or trans position of the P-substituent and
the hydrogen at the annelation (H-an), were formed and
separated by column chromatography. A significant
Due to its natural occurrence, many procedures have been
developed for the preparation of the tetrahydroisoquinoline
amino alcohol derivative calycotomine (4), which was
1
3
obtained by LiAlH reduction of the corresponding amino
4
ester 3. Compound 3 was prepared using a three-step process
starting from homoveratrylamine (1) (Scheme 1).
1
4
MeO
MeO
MeO
MeO
MeO
ii
i
NH2
N
NH
MeO
COOEt
COOEt
1
2
3
iii
MeO
MeO
MeO
MeO
iv
N
NH
OH
NH2
OH
5
4
Scheme 1. Reagents and conditions: (i) 1. (COOOEt)
(iii) LiAlH , THF, D, 3 h, 66%; (iv) 1. NaNO , AcOH, H
2
, 140 8C, 6 h, 2. POCl
3
, PhMe, EtOH, D, 3.5 h, 49% (1C2); (ii) H
, THF, rt, 2 h, 52%.
2
, 5% Pt/C, EtOH, rt, 1 atm, 6 h, 82%;
4
2
2
O, rt, 8 h, 2. LiAlH
4
R
R
COOH
NH
R
R
R
R
i
OH
ii
OH
NH
7a,b
N
NH2
6a,b
8a,b
v
R = OMe
MeO
MeO
COOMe
MeO
MeO
MeO
MeO
iii
OH
Ph
iv
OH
Ph
HN
Ph
O
HN
N
9
10
11
R = H: a; R = MeO: b
Scheme 2. Reagents and conditions: (i) LiAlH
8b); (iii) LiAlH , THF, D, 5 h, 78%; (iv) CH
4
, THF, D, 8 h, 51% (for RZMeO); (ii) 1. NaNO
2
, AcOH, H
2
O, rt, 8 h, 2. LiAlH
4
, THF, rt, 2 h, 45% (8a), 67%
(
4
2
O, HCl, H O, D, 6 h, 92%; (v) H , 10% Pd/C, MeOH, 30 bar, 40 8C, 30 h, w100%.
2
2

Z. Zal a´ n et al. / Tetrahedron 62 (2006) 2883–2891
2885
MeO
MeO
MeO
MeO
i
11b
.
N
O
N
O
5
HCl
+
NH
P
O
NH
P
Ph
H
3
H
Ph
O
1
1
3
14
H
1
H
N
R1
R1
R1
R1
.
i
11a
O
P
O
P
O
8
a HCl
or 8b
3
+
Ph
O
Ph
N
N
H
N
H
15a,b
16a,b
H
1
H
OH
NH2
i
9a
O
P
O
R2
3
O
R2
+
N
N
N
N
H
P
N
H
O
12
17a,b
18a,b
1
2
Diastereomeric ratio
in the crude product
Compound
R
R
1
3:14
5a:16a
5b:16b
7a:18a
7b:18b
–
–
48:52
1
H
–
–
50:50
~0:~100
21:79
1
OMe
1
–
–
Ph
1
OPh
50:50
2 2 3
Scheme 3. Reagents and conditions: (i) Cl POPh or Cl PO(OPh), Et N, THF, rt, 48 h, 34–51%.
difference in the ratios of the P-2 epimers, was found for 17a
and 18a, the trans isomer (18a) being the main product,
while in the ring closure of 8b, the minor oxadiazapho-
sphinane diastereomer (15b) could not be detected, even in
The phosphorus-containing 1,2,3-heterocycles are prone to
participate in a conformational equilibrium involving chair,
twisted chair and other distorted conformations.
1
,20
1
the crude product (by H NMR spectroscopy).
The stereochemistry of the model compounds was
determined in two steps. First, the predominant confor-
mation was assigned on the basis of the characteristic J
3
2
.2. Structure
couplings and NOE interactions. Second, the relative
configuration of the P-phenyl substituent was observed by
using the NOEs from the P-phenyl group to the annelation
protons (where applicable) and/or the significant differences
in the chemical shifts for certain indicator nuclei.
In keeping with the nitrogen-bridged saturated bi- or
polycyclic heterocycles, the stereo-structures of the pre-
pared 1,3,4,2-oxadiazaphosphinanes (13–18) can be
1
described by a conformational equilibrium of cis –trans–
2
19
cis type. In the trans structure, the B/C hetero rings are
trans-connected, with a trans-diaxial arrangement of H-an
and the nitrogen lone pair. In the two other configurations,
the hetero rings are cis-connected: for the cis-1 confor-
mation, C-1 is in the inside, while for the cis-2
conformation, C-1 is in the outside position (Fig. 1).
The orientation of H-an (i.e., H-11b for 13 and 14; H-11a for
15 and 16; and H-9a for 17 and 18) and the protons
connected to the carbons adjacent to the annelation (H-1 and
H-X; H-X: H-11 for 15 and 16, and H-9 for 17 and 18) or
the protons connected to the carbons adjacent to the
R1
R1
H
H
N
N
H
N
P
R2
N
P
N
R2
H
N
R1
O
O
P
O
H
R2
H
cis-1
trans
cis-2
Figure 1. Possible ring connections of 1,6,7,8,9,9a-hexahydro-4H-pyrido[1,2-d]-[1,3,4,2]oxadiazaphosphinanes.

2886
Z. Zal a´ n et al. / Tetrahedron 62 (2006) 2883–2891
a
Table 1. Characteristic vicinal coupling constants in Hz
Compound
H-1ax-H-an
H-1eq-H-an
H-Xax-H-an
H-Xeq-H-an
H-1ax-P
H-1eq-P
1
1
1
1
1
1
1
1
1
3
4
9.3
10.6
4.0
9.8
8.2
4.3
2.8
2.5
4.0
3.8
3.3
3.0
3.5
3.5
—
—
—
—
5.5
4.8
4.8
2.8
3.1
3.0
5.3
1.3
3.8
7.3
8.1
3.5
2.0
1.6
2.3
17.1
18.6
20.0
18.4
18.1
18.9
20.4
19.9
26.4
5a
6a
6b
7a
8a
7b
8b
11.8
10.6
10.3
10.1
10.0
10.1
Overlap
9.8
10.3
10.6
9.0
Overlap
a
For the meanings of H-an and H-X, see the text.
NOE
H
MeO
H
NOE
H
NOE
H
6
H
H
1
1
1b
R
R
N
1
O
9a
O
11a
MeO
NH
3
H
H
3
3P
O
6
O
Ph
6 N
H
N
P
P
N
H
N
1
O
Ph
R
H
H
O
H
14
16a,b
17a,b; 18a,b
Figure 2. Detected NOEs.
nitrogen-bridge (H-6) were assigned by using the vicinal
coupling constants (Table 1) and the detected NOESY
cross-peaks (Fig. 2).
ring. These findings are in accord with two possible
conformations: a cis-2-connected chair–chair and a trans-
connected chair-boat. In order to establish the most
stable conformer, ab initio calculations were performed at
the HF/6-31* level. The calculations revealed that confor-
mation cis-2 is 5.3 kcal/mol more stable, and we therefore
believe that the hetero rings are predominantly cis-
connected (cis-2 conformation; Fig. 3).
The data in Table 1 show that H-an for 16a,b, 17a,b and 18a
has two high vicinal couplings to the axial protons
connected to the carbons adjacent to the annelation (H-X,
i.e., H-11 for 15a,b and 16a,b; and H-9 for 17a,b and
1
hetero rings are trans-connected. The vicinal couplings of
8a,b), indicating that H-an is in an axial position and the
Concerning the orientation of the P-substituent, P-Ph-H-1ax
NOE interactions could readily be detected in 14 and 16a,b
(Fig. 2), which indicates the axial arrangement of the
P-phenyl group and its position trans to H-an (H-11b or
H-11a, respectively).
H-11b for 13 and 14 correspond to a trans diaxial position
for H-11b and H-1 , which excludes the hetero ring
ax
connection of cis-2 type. The NOESY cross-peaks detected
for H-11b and H-6ax indicate the trans connection of the
hetero rings for both compounds.
P-Ph-H-1ax or P-OPh-H-1ax NOE interactions could not be
determined unambiguously for compounds 17a and 18a,
and the P-configuration was therefore deduced from the
chemical shifts calculated by using the GIAO method at the
HF/6-31G* level and the geometrical constraints obtained
by means of NMR. It is a trend that H-1ax exhibits an upfield
shift in compounds containing an axial P-phenyl group
3
For 15a, the J (H-1 -H-11a) and J (H-1 -H-11a) values
3
ax
eq
were 4.0 and 2.5 Hz, respectively, which suggest that H-an
is equatorial to the oxadiazaphosphinane ring. This is
supported by a strong NOE from H-11a to both H-1 protons.
The vicinal couplings between H-11a and H-11 show an
axial orientation of H-11a with respect to the isoquinoline
(i.e., trans to H-an), due to the ring current shielding.
The comparison of the experimental and theoretical
chemical shifts (Table 2) unambiguously corroborated
the assignment. Unfortunately, the phenoxy derivatives
Table 2. Experimental and calculated characteristic chemical shifts in ppm
TMSZ0)
(
d
Compound
H-1ax
Calcd
H-1eq
Calcd
Exp.
Exp.
1
1
1
1
1
1
1
1
1
3
4
4.72
4.05
4.44
3.99
3.97
4.42
3.78
4.23
4.26
4.09
3.29
3.27
3.04
3.01
3.97
3.02
3.69
3.73
4.58
4.72
4.32
4.51
4.46
4.13
4.16
4.17
4.31
3.91
3.87
3.48
3.53
3.49
3.45
3.39
3.18
3.50
5a
6a
6b
7a
8a
7b
8b
Figure 3. Ab initio geometry obtained for 15a.

Z. Zal a´ n et al. / Tetrahedron 62 (2006) 2883–2891
2887
Figure 4. X-ray crystal structures of 18a and 18b. The thermal displacement ellipsoids are drawn at a probability level of 30%.
(
17b and 18b) did not allow utilization of the shielding
1,6,7,8,9,9a-hexahydro-4H-pyrido[1,2-d][1,3,4,2]oxadiaza-
phosphinane-3-oxides (17 and 18), have been prepared via
cyclization of the corresponding tetrahydroisoquinoline or
piperidine hydrazino alcohols. The NMR spectroscopic and
X-ray diffraction data allowed the preferred conformation of
13–18 to be identified. This revealed that, independent of
the P-substituent and the relative configuration of the
phosphorus atom, 13, 14, 17 and 18 could be characterized
by trans-connected hetero rings and the chair conformation
of the 1,3,4,2-oxadiazaphosphinane moiety, while the
stereochemistry of the connection of the hetero rings
effect because of the flexible aromatic substituent; the
stereochemical assignment is therefore based purely on the
X-ray data. The steric assignment of the P-2 epimers of 17
and 18, based on the results of NMR experiments and
theoretical calculations, was in accordance with the X-ray
crystal structures of 18a and 18b (Fig. 4).
The stereochemical assignments for 13–18 are presented in
Table 3.
(
trans or cis-2) was found to be dependent on the
Table 3. Stereochemical assignments for 13–18
P-configuration relative to that of the carbon at the
annelation site for 1,3,4,2-oxadiazaphosphinanes linearly
fused to tetrahydroisoquinoline (15 and 16).
Com-
pound
Steric position of H-
an and the P-sub-
stituent
Stereochemistry of
the junction of the
hetero rings
Oxadiazapho-
sphinane ring
conformation
1
1
1
1
1
1
1
1
1
3
4
cis
trans
cis
trans
trans
cis
trans
cis
trans
trans
cis
trans
trans
trans
trans
trans
trans
chair
chair
chair
chair
chair
chair
chair
chair
chair
4
. Experimental
5a
6a
6b
7a
8a
7b
8b
4.1. General
The NMR spectra were recorded in CDCl3 or in D O
2
solutions at 300 K on a Bruker AVANCE DRX 400
spectrometer. Chemical shifts are given in d (ppm) relative
to TMS (CDCl ) or to TSP (D O) as internal standards;
trans
3
2
multiplicities were recorded as s (singlet), br s (broad
singlet), d (doublet), dd (double doublet), ddd (double
double doublet), td (triple doublet), dtd (double triple
doublet), dddd (double double double doublet), t (triplet), dt
The chair conformation found for 1,3,4,2-diazaphosphi-
nanes angularly fused to tetrahydroisoquinoline (13, 14) is
substantially different from the steric structures of the
analogous 1,3,2-oxazaphosphino[4,3-a]isoquinolines,
which could be characterized by distorted conformations
(double triplet), tt (triple triplet), q (quartet), dq (double
2
0
quartet), tq (triple quartet) and m (multiplet). IR spectra
were run in KBr discs on a Perkin-Elmer Paragon 1000 PC
FT-IR spectrometer controlled by GRAMS Analyst for PE
of the 1,3,2-oxazaphosphinane ring.
1000 3.01A software. Melting points were recorded on a
3
. Conclusions
Kofler hot-plate microscope apparatus and are uncorrected.
For column chromatography, silica gel 60 (0.063–
0.200 mm) was used.
The first representatives of the new ring systems, which are
P-epimeric diastereomers of 1,6,7,11b-tetrahydro-4H-
1
,3,4,2-oxadiazaphosphino[5,4-a]isoquinoline-3-oxides (13
X-ray crystallographic study. Crystallographic data were
collected at 173 K with a Nonius Kappa CCD area-detector
diffractometer, with the use of graphite-monochromatized
and 14), 1,6,11,11a-tetrahydro-4H-1,3,4,2-oxadiazaphos-
phino[4,5-b]isoquinoline-3-oxides (15 and 16) and

2888
Z. Zal a´ n et al. / Tetrahedron 62 (2006) 2883–2891
˚
Mo-K radiation (lZ0.71073 A). The data collection was
81.5–83 8C). [Found: C, 63.95; H, 6.60; N, 5.30.
C H NO requires C, 63.87; H, 6.51; N, 5.32%]; n
max
1719, 1518, 1277, 1198, 1135 cm ; d (CDCl ) 1.44 (t,
H 3
a
performed with f and u scans. The data were processed
with DENZO-SMN n 0.93.0.
1
4
17
4
2
1
K1
3
3.89 (m, 2H, NCH ), 3.90 (s, 3H, OCH ), 3.93 (s, 3H,
H, JZ7.1 Hz, CH CH ), 2.67–2.74 (m, 2H, ArCH ), 3.83–
2 3 2
The structures were solved by direct methods with use of the
SIR92 program, and full-matrix, least-squares refinements
2
3
2
2
OCH ), 4.43 (q, 2H, JZ7.1 Hz, OCH ), 6.70 (s, 1H, C H ),
3
2
6 2
2
23
on F were performed with the SHELXL-97 program. In
both cases, all heavy atoms were refined anisotropically.
The CH hydrogen atoms were included at fixed distances
from their host atoms, with fixed displacement parameters.
The NH hydrogen atoms were refined with isotropic
displacement parameters. Figures were drawn with
7.39 (s, 1H, C H ).
6
2
4.1.2. Ethyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line-1-carboxylate (3). To a solution of dihydroisoquino-
line 2 (22.0 g, 83.6 mmol) in EtOH (200 mL), 5% platinum
on activated charcoal catalyst (1.00 g) was added and the
mixture was stirred under hydrogen at atmospheric pressure
and ambient temperature. When the hydrogen uptake had
ceased (approx 6 h), the catalyst was filtered off and the
filtrate was evaporated. The oily product was dissolved in
EtOH (30 mL) and treated with 22% ethanolic HCl (20 mL)
2
4
ORTEP-3 for Windows. CCDC-284666 (18a) and
CCDC-284667 (18b) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge at www.ccdc.cam.ac.uk/conts/retrieving.html
[
or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: (Internet) C44
223 336 033; e-mail: deposit@ccdc.cam.ac.uk].
and Et O (100 mL) to yield crystalline 3$HCl. The crystals
2
1
were filtered off and washed with a 1:4 mixture of EtOH
and Et O (100 mL). Yield: 20.7 g (82%). For the further
2
1
Compounds 6b, 7a,
6
15
16
18
and 12 were prepared
9
according to known procedures.
transformations, the free base 3 was liberated from the
above hydrochloride salt in the usual manner (Na CO and
EtOAc).
2
3
4
.1.1. Ethyl 6,7-dimethoxy-3,4-dihydroisoquinoline-1-
carboxylate (2). A mixture of 2-(3,4-dimethoxyphenyl)-
ethylamine (1) (54.4 g, 0.3 mol) and diethyl oxalate
(131.5 g, 0.9 mol) was stirred at 140 8C for 6 h. The ethanol
formed and the excess of diethyl oxalate were distilled off in
vacuo, and the oily residue was treated with Et O, resulting
2
in ethyl N-[2-(3,4-dimethoxyphenyl)ethyl]oxamate as a
crystalline product. The crystals were filtered off, washed
with Et O and used in the next step without further
2
purification. Yield: 68.7 g (81%).
An analytical sample of 3$HCl was recrystallized from
EtOH–Et O to give yellowish-white crystals. Mp: 202–
204 8C. [Found: C, 55.48; H, 6.37; N, 4.60. C14 20ClNO
requires C, 55.72; H, 6.68; N, 4.64%]; nmax 1740, 1522,
2
H
4
K1
1264, 1238, 1027 cm ; d
CH CH ), 3.02–3.18 (m, 2H, ArCH
NCH ), 3.88 (s, 3H, OCH ), 3.90 (s, 3H, OCH
2H, JZ7.1 Hz, OCH ), 5.40 (s, 1H, NCH), 6.95 (s, 1H,
), 7.17 (s, 1H, C ).
(D
O) 1.34 (t, 3H, JZ7.1 Hz,
), 3.59–3.72 (m, 2H,
), 4.38 (q,
H
2
2
3
2
2
3
3
2
C
H
2
H
6 2
6
An analytical sample of the product was recrystallized from
iPr O to give shining white plates. Mp: 68–70 8C (lit. mp:
4.1.3. (6,7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolyl)-
methanol (4). To a stirred and ice-cooled suspension of
2
5
2
7
requires C, 59.78; H, 6.81; N, 4.98%]; n
3–74 8C). [Found: C, 59.89; H, 6.75; N, 5.03. C H NO
5
LiAlH (3.10 g, 81.7 mmol) in dry THF (100 mL), a
4
solution of compound 3 (12.0 g, 39.8 mmol) in dry THF
(35 mL) was added dropwise. The mixture was stirred and
1
4
19
1746, 1683,
max
K1
1
516, 1238, 1023 cm ; d (CDCl ) 1.38 (t, 3H, JZ7.2 Hz,
H
3
CH CH ), 2.82 (t, 2H, JZ6.8 Hz, ArCH ), 3.58 (q, 2H, JZ
refluxed for 3 h and then cooled, and the excess of LiAlH
4
2
3
2
6
4
6
.8 Hz, NCH ), 3.87 (s, 3H, OCH ), 3.88 (s, 3H, OCH ),
.33 (q, 2H, JZ7.2 Hz, OCH ), 6.70–6.76 (m, 2H, C H ),
was decomposed by the addition of a mixture of water
(6.2 mL) and THF (50 mL). After stirring at room
temperature for 1 h, the inorganic salts were filtered off
and washed with hot EtOAc (3!120 mL). The combined
2
3
3
2
6 3
.82 (d, 1H, JZ8.1 Hz, C H ), 7.14 (br s, 1H, NH).
6
3
To a stirred solution of ethyl N-[2-(3,4-dimethoxyphenyl)
ethyl]oxamate (40.0 g, 0.142 mol) in abs toluene (350 mL)
and abs EtOH (30 mL), POCl (120.0 g, 0.783 mol) was
3
organic filtrate and washings were dried (Na SO ) and
2 4
evaporated under reduced pressure to give the crude amino
alcohol 4 as a crystalline product, which was filtered off,
added. The resulting mixture was stirred and refluxed for
washed with Et
O and recrystallized from EtOAc. Yield:
2
2
5.87 g (66%). Mp: 138–139 8C (lit. mp: 134–135 8C). nmax
6
3
.5 h, and then evaporated under reduced pressure. The oily
residue was carefully dissolved in warm 96% ethanol
100 mL) and the solution was added to a mixture of ice-
K1 1
3316, 1517, 1259, 1225, 1060 cm . The H NMR
spectrum of 4 was in accordance with the literature data
on the (S) enantiomer of 4.
2
7
(
cold water (500 mL) and EtOAc (250 mL). The resulting
mixture was made alkaline with concd NH OH under
4
vigorous stirring and external cooling on an ice-water bath.
The organic layer was separated and the aqueous layer was
extracted with EtOAc (2!250 mL). The combined organic
extracts were dried (Na SO ) and evaporated. The oily residue
was treated with Et O to give 2 as a beige crystalline product,
2
which was filtered off, washed with Et O and used in the next
2
4.1.4. (6,7-Dimethoxy-1,2,3,4-tetrahydro-3-isoquinolyl)-
methanol (7b). Method A. To a stirred and ice-cooled
suspension of LiAlH4 (5.85 g, 154 mmol) in dry THF
(300 mL), compound 6b (10.50 g, 38.4 mmol) was added in
small portions. The mixture was stirred and refluxed for 8 h,
which was followed by the usual work-up (see the previous
procedure), resulting in the crude amino alcohol 7b as a
crystalline product. Recrystallization from EtOAc gave
analytically pure 7b as white needles. Yield: 4.4 g (51%).
Mp: 146–147 8C. [Found: C, 64.73; H, 7.52; N, 6.33.
2
4
step without any further purification. Yield: 22.4 g (60%).
An analytical sample of 2 was recrystallized from iPr O
2
1
4b
to give pale-beige crystals. Mp: 76–78 8C (lit.
mp:

Z. Zal a´ n et al. / Tetrahedron 62 (2006) 2883–2891
2889
C H NO requires C, 64.55; H, 7.67; N, 6.27%]; n
max
An analytical sample of 11$HCl was recrystallized from
MeOH–Et O to give white needles. Mp: 209–211 8C.
1
2
17
3
K1
286, 1522, 1239, 1227, 1079 cm ; d (CDCl ) 2.50 (dd,
3
1
1
H
3
2
H, JZ10.5, 16.0 Hz, 4-CH ), 2.61 (dd, 1H, JZ4.4,
6.0 Hz, 4-CH ), 3.00–3.08 (m, 1H, NCH), 3.52 (dd, 1H,
[Found: C, 65.48; H, 7.03; N, 3.91. C H ClNO requires
19 24
2
3
C, 65.23; H, 6.91; N, 4.00%]; n
3220, 1525, 1225, 1193,
max
2
K1
JZ8.0, 10.8 Hz, OCH ), 3.77 (dd, 1H, JZ3.7, 10.8 Hz,
1092 cm ; dH (D O) 3.04 (dd, 1H, JZ6.9, 17.6 Hz,
2
2
OCH ), 3.83 (s, 3H, OCH ), 3.84 (s, 3H, OCH ), 3.98 (s, 2H,
1
4-CH ), 3.21 (dd, 1H, JZ2.8, 17.6 Hz, 4-CH ), 3.84 (s, 3H,
2
3
3
2
2
-CH ), 6.53 (s, 1H, C H ), 6.57 (s, 1H, C H ).
2
OCH ) 3.85–3.99 (m, 5H, OCH , OCH , NCH), 4.02–4.11
(m, 1H, OCH ), 4.16–4.49 (m, 4H, 2!NCH ) 6.80 (s, 1H,
2
6
2
6
3 2 3
2
2
Method B. A mixture of compound 11$HCl (35.0 g,
.1 mol), 10% Pd/C catalyst (2.0 g) and MeOH (500 mL)
was hydrogenated in an autoclave at 40 8C and 30 bar for
0 h. The catalyst was removed by filtration, and the filtrate
C H ), 6.98 (s, 1H, C H ), 7.42–7.62 (m, 5H, C H ).
6 2 6 2 6 5
0
4.2. General procedure for the preparation of the
hydrazino alcohols 5, 8a and 8b
3
was evaporated to dryness to give 7b$HCl as a crystalline
product. The crystals were filtered off and washed with
A solution of NaNO (1.38 g, 20 mmol) in H O (10 mL) was
2
2
Et O. Yield: 25.8 g (w100%). For the further transform-
added dropwise to a suspension of the corresponding amino
alcohol (4 or 7a or 7b, 10 mmol) in H O (50 mL) with
2
ations, free base 7b was liberated from the above
hydrochloride salt in the usual manner (Na CO and
EtOAc).
2
2
3
vigorous stirring on an ice-cold bath, and AcOH (0.90 g,
15 mmol) wasthenaddeddropwise. Themixturewasstirredat
room temperature for 8 h and then extracted with EtOAc (4!
50 mL). The combined organic extracts were dried (Na SO )
An analytical sample of 7b$HCl was recrystallized from
5% MeOH–Et O to give a white powder. Mp: 280–282 8C.
2
4
9
and evaporated under reduced pressure to give the N-nitroso
derivatives of 4, 7a and 7b in nearly quantitative yields.
According to TLC, the products were pure enough to be used
in the next step without further purification.
2
[
C, 55.49; H, 6.99; N, 5.39%]; n
Found: C, 55.24; H, 6.81; N, 5.37. C H ClNO requires
12 18 3
3374, 2911, 2765, 1522,
max
K1
1
230, 1130 cm ; dH (D O) 2.92–3.07 (m, 2H, 4-CH ),
2 2
3
.60–3.68 (m, 1H, NCH), 3.78–3.90 (m, 7H, 2!OCH3,
OCH ), 4.03 (dd, 1H, JZ3.5, 12.5 Hz, OCH ), 4.32–4.43
The solution of the corresponding crude N-nitroso derivative
of 4 or 7a or 7b in THF (15 mL) was added dropwise to a
stirred and ice-cooled suspension of LiAlH4 (0.76 g,
20 mmol) in THF (30 mL). The mixture was stirred at room
temperature for 2 h, after which the usual work-up (see above)
resulted in the crude hydrazino alcohols as oily (5, 8a) or
crystalline (8b) products. The crystalline 8b was filtered off,
2
2
(
m, 2H, 1-CH ), 6.86 (s, 1H, C H ), 6.89 (s, 1H, C H ).
2 6 2 6 2
4
.1.5.
2-Benzylamino-3-(3,4-dimethoxyphenyl)-1-
propanol (10). To a stirred and ice-cooled suspension of
LiAlH (12.0 g, 316 mmol) in dry THF (400 mL), compound
4
9 (23.0 g, 67 mmol) was added in small portions. The mixture
wasstirredandrefluxedfor5 h.Theusualwork-up(seeabove)
washed with n-hexane and recrystallized from iPr O–EtOAc.
2
resulted in crude amino alcohol 10 as a crystalline product.
The crystals were filtered off, washed with Et O and used in
the next step without further purification. Yield: 15.8 g (78%).
The oily products (5 and 8a) were converted to the crystalline
hydrochlorides bytreatmentoftheir solution inMeOHwithan
excess of 22% ethanolic HCl and Et O.
2
2
An analytical sample of the product was recrystallized from
iPr O–EtOAc to give white needles. Mp: 115–115.5 8C
4.2.1. Compound 5$HCl. Yield: 1.95 g (71%). Mp:
210–215 8C (95% MeOH–Et O). [Found: C, 52.13; H,
2
1
2
7
(
lit. mp: 114–116 8C). [Found: C, 71.44; H, 7.49; N, 4.50.
C H NO requires C, 71.73; H, 7.69; N, 4.65%]; n
max
6.85; N, 10.01. C H ClN O requires C, 52.46; H, 6.97;
2 3
1
2
19
K1
N, 10.20%]; nmax 3335, 3289, 1524, 1269, 1230 cm
dH (D O) 3.13–3.19 (m, 2H, 4-CH ), 3.56–3.62 (m, 1H,
;
1
8
23
3
K1
3
2
286, 2837, 1517, 1264, 1238, 1136 cm ; dH (CDCl3)
.70–2.77 (m, 2H, ArCH C), 2.88–2.96 (m, 1H, NCH), 3.36
2
2
3-CH ), 3.82–3.89 (m, 1H, 3-CH ), 3.90 (s, 3H, OCH ),
2 2 3
2
0
3.91 (s, 3H, OCH ), 3.99 (dd, 1H, JZ8.0, 12.8 Hz, 1 -CH ),
3 2
(
dd, 1H, JZ4.9, 10.7 Hz, OCH ), 3.66 (dd, 1H, JZ3.9,
2
0
1
OCH ), 3.87 (s, 3H, OCH ), 6.63–6.67 (m, 1H, C H ), 6.70
0.7 Hz, OCH ), 3.72–3.82 (m, 2H, NCH ), 3.83 (s, 3H,
4.26 (dd, 1H, JZ3.2, 12.8 Hz, 1 -CH ), 4.57 (m, 1H, 1-CH),
2
2
2
6.94 (s, 1H, C H ), 6.98 (s, 1H, C H ).
3
3
6
3
6
2
6 2
(
dd, 2H, JZ1.6, 8.0 Hz, C H ), 6.77–6.82 (m, 5H, C H ).
6 3 6 5
4
.2.2. Compound 8a$HCl. Yield: 1.42 g (66%). Mp: 195–
197 8C. [Found: C, 55.63; H, 6.79; N, 12.98. C10 15ClN
requires C, 55.94; H, 7.04; N, 13.05%]; nmax 3341, 2980,
4.1.6. (2-Benzyl-6,7-dimethoxy-1,2,3,4-tetrahydro-3-
isoquinolyl)methanol (11). A mixture of compound 10
H
O
2
K1
(
(
13.8 g, 45.8 mmol), water (500 mL), 36% formalin
55 mL) and concd HCl (28 mL) was stirred and refluxed
2752, 1449, 1086, 766 cm ; d
JZ10.5, 17.5 Hz, 4-CH ), 3.13 (dd, 1H, JZ5.2, 17.5 Hz,
4-CH ), 3.68–3.76 (m, 1H, 3-CH), 3.79 (dd, 1H, JZ6.8,
12.4 Hz, 1 -CH
4.46 (s, 2H, 1-CH
(D O) 3.04 (dd, 1H,
H 2
2
for 6 h. The solution was left to cool to ambient temperature,
then made alkaline (under ice-bath cooling) with 10%
NaOH solution and extracted with CHCl (4!150 mL).
2
0
0
), 4.01 (dd, 1H, JZ3.6, 12.4 Hz, 1 -CH
),
2
2
), 7.24–7.37 (m, 4H, C ).
H
6 4
3
2
The combined organic extracts were dried (Na SO ) and
2
4
evaporated under reduced pressure to give crude 11 as a
yellow oil. The oily product was dissolved in MeOH
4.2.3. Compound 8b. Yield: 1.60 g (67%). Mp: 91–93 8C.
[Found: C, 59.62; H, 7.70; N, 11.51. C H N O requires
1
2 18 2 3
(
1
50 mL) and converted to the crystalline hydrochloride of
1 by adding an excess of 22% ethanolic HCl (20 mL) and
Et O (300 mL). The crystals were filtered off, washed with a
C, 60.49; H, 7.61; N, 11.76%]; n
1520, 1255, 1228, 1120,
max
K1
1049 cm ; dH (CDCl ) 2.59 (dd, 1H, JZ4.2, 16.1 Hz,
3
4-CH ), 2.67–2.88 (m, 2H, 4-CH , 3-CH), 3.73–3.88 (m,
9H, OCH , 2!OCH , 1-CH ), 3.98 (d, 1H, JZ14.5 Hz,
2
2
2
1
without further purification. Yield: 14.8 g (92%).
:10 mixture of MeOH and Et O and used in the next step
2
2 3 2
1-CH ), 6.51 (1H, s, C H ), 6.59 (1H, s, C H ).
2 6 2 6 2

2890
Z. Zal a´ n et al. / Tetrahedron 62 (2006) 2883–2891
4
2
2
.3. General procedure for the preparation of the 1,3,4,
-oxadiazaphosphino[5,4-a]isoquinolines (13, 14), 1,3,4,
-oxadiazaphosphino[4,5-b]isoquinolines (15a,b; 16b)
1H, JZ5.5, 17.6 Hz, H-5eq), 3.19 (m, 1H, H-4a), 3.48 (dd,
1H, JZ11.8, 17.6 Hz, H-5ax), 4.09 (d, 1H, JZ16.1 Hz,
H-10eq), 4.28 (dd, 1H, JZ2.5, 6.5 Hz, H-10ax), 4.32 (ddd,
1H, JZ2.5, 11.3, 17.9 Hz, H-4eq), 4.44 (ddd, 1H, JZ3.3,
4.0, 11.3 Hz, H-4ax), 7.09 (dd, 1H, JZ2.8, 6.3 Hz, H-9),
and pyrido[1,2-d]1,3,4,2-oxadiazaphosphinanes (17a,b;
8a,b)
1
7
.16–7.26 (m, 3H, H-6, H-7, H-8), 7.52 (dt, 2H, JZ4.0,
To a solution of the corresponding hydrazino alcohol (8b or
7.3 Hz, m-Ar), 7.59 (dt, 1H, JZ1.3, 7.5 Hz, p-Ar), 7.96
1
8
2, 10 mmol) or hydrazino alcohol hydrochloride (5$HCl or
a$HCl, 10 mmol) and Et N (2.02 g, 20 mmol; in the case
(ddd, 2H, JZ1.3, 8.3, 13.6 Hz, o-Ar); dC (CDCl ) 23.4
3
(C-5), 53.9 (C-4a), 58.2 (C-10), 70.8 (C-4), 127.2 (C-7,
C-8), 127.4 (C-6), 129.0 (C-9), 130.5 (C-5a), 131.2 (C-9a),
127.3 (CP), 129.0 (m-Ar), 131.3 (o-Ar), 132.3 (p-Ar).
3
of 5$HCl and 8a$HCl: 3.04 g, 30 mmol) in anhydrous THF
100 mL) at room temperature, a solution of phenylphos-
(
phonic dichloride or phenyl dichlorophosphate (10 mmol)
in anhydrous THF (20 mL) was added dropwise over a
period of 30 min. The mixture was stirred at room
temperature for 48 h and then filtered, and the filtrate was
evaporated in vacuo to afford a yellow oil containing a
mixture of the corresponding oxadiazaphosphinane diaster-
eomers. The diastereomeric ratios were determined from the
Compound 16a. A white solid; yield: 0.42 g (14%). Mp:
209–211 8C. [Found: C, 64.15; H, 5.68; N, 9.21.
C H N O P requires C, 64.00; H, 5.71; N, 9.33%]; n
max
1
6
17
2
2
K1
3108, 1450, 1238, 1004, 817 cm ; d (CDCl ) 2.71 (dd,
H
3
1H, JZ10.3, 16.1 Hz, H-5ax), 2.84 (dd, 1H, JZ4.8,
16.2 Hz, H-5eq), 3.07 (tt, 1H, JZ4.0, 10.8 Hz, H-4a),
3.78 (d, 1H, JZ14.9 Hz, H-10ax), 3.99 (ddd, 1H, JZ7.3,
9.8, 11.6 Hz, H-4ax), 4.36 (d, 1H, JZ14.6 Hz, H-10eq),
4.51 (ddd, 1H, JZ4.0, 11.6, 18.38 Hz, H-4eq), 7.09 (dd, 2H,
JZ3.3, 5.3 Hz, H-6, H-9), 7.19 (dd, 2H, JZ3.5, 5.3 Hz, H-
7, H-8), 7.48 (dt, 2H, JZ4.0, 7.5 Hz, m-Ar), 7.55 (dt, 1H,
JZ1.3, 7.3 Hz, p-Ar), 7.98 (ddd, 2H, JZ1.5, 8.3, 13.6 Hz,
o-Ar); d (CDCl ) 31.1 (C-5), 58.6 (C-4a), 58.9 (C-10), 70.7
1
H NMR spectra of the crude products. Purification of the
crude products by column chromatography gave 14, 15a,
1
7b and 18a as the more mobile, and 13, 16a, 17a and 18b
as the less mobile diastereomers. Compound 16b was the
only product in the ring closure.
Compounds 13:14Z48:52. Eluent: EtOAc.
C
3
(C-4), 126.2 (C-6), 126.7 (C-7, C-8), 128.1 (C-9), 128.5
Compound 13. A white solid; yield: 0.44 g (12%). Mp: 173–
1
(m-Ar), 131.1 (C-9a), 131.4 (C-5a), 126.5 (CP), 131.5
(o-Ar), 132.4 (p-Ar).
76.5 8C (iPr O–EtOAc). [Found: C, 59.95; H, 5.91; N, 7.82.
2
C H N O P requires C, 60.00; H, 5.87; N, 7.77%]; n
max
1
8
21
2
4
K1
122, 1513, 1228, 1128, 797 cm ; d (CDCl ) 2.79 (dt, 1H,
3
Compound 16b. Eluent: EtOAc/MeOHZ9:1.
H
3
JZ4.0,15.4 Hz, H-9eq), 3.10(dd,1H, JZ4.5,8.8 Hz, H-9ax),
3
1
4
1
.15 (td, 1H, JZ4.0, 8.8 Hz, H-10ax), 3.6 (dd, 1H, JZ4.5,
Compound 16b. Transparent crystals; yield: 1.43 g (40%).
Mp: 201–205 8C (iPr O–EtOAc). [Found: C, 60.10; H,
0.3 Hz, H-10eq), 3.88 (s, 3H, OCH ), 3.89 (s, 3H, OCH ),
.25 (dd, 1H, JZ4.3, 9.3 Hz, H-4a), 4.58 (ddd, 1H, JZ4.3,
1.6, 17.1 Hz, H-4eq), 4.72 (ddd, 1H, JZ5.3, 9.3, 11.6 Hz,
3
3
2
5.74; N, 7.86. C H N O P requires C, 60.00; H, 5.87; N,
8 21 2 4
1
K1
7.77%]; nmax 3092, 1519, 1236, 1028, 804 cm ; dH
H-4ax), 6.55 (s, 1H, H-5), 6.64 (s, 1H, H-8), 7.52 (dt, 2H, JZ
.0, 7.5 Hz, m-Ar), 7.63 (dt, 1H, JZ1.5, 7.3 Hz, p-Ar), 8.0
ddd, 2H, JZ1.5, 8.3, 13.0 Hz, o-Ar); d (CDCl ) 26.7 (C-9),
(CDCl ) 2.61 (dd, 1H, JZ10.3, 16.3 Hz, H-5ax), 2.74 (dd,
3
4
(
1H, JZ4.8, 16.4 Hz, H-5eq), 3.06 (tt, 1H, JZ4.0, 10.8 Hz,
H-4a), 3.75 (d, 1H, JZ14.1 Hz, H-10ax), 3.82 (s, 3H,
OCH ), 3.84 (s, 3H, OCH ), 3.97 (td, 1H, JZ8.1, 11.6 Hz,
C
3
5
1.9 (C-10), 56.0 (C-6, C-7), 60.5 (C-4a), 67.6 (C-4), 108.5
3
3
(
1
C-5), 112.1 (C-8), 123.2 (C-4b), 125.6 (C-8a), 128.1 (CP),
28.6 (m-Ar), 132.1 (o-Ar), 133.0 (p-Ar).
H-4ax), 4.23 (d, 1H, JZ14.4 Hz, H-10eq), 4.46 (ddd, 1H,
JZ3.8, 11.6, 18.1 Hz, H-4eq), 6.53 (s, 2H, H-6, H-9), 7.47
(dt, 2H, JZ4.0, 7.5 Hz, m-Ar), 7.55 (dt, 1H, JZ1.3, 7.5 Hz,
Compound 14. A white foam; yield: 0.80 g (22%). [Found: C,
p-Ar), 7.96 (ddd, 2H, JZ1.3, 8.3, 13.6 Hz, o-Ar); dC
5
5
9.92; H, 5.89; N, 7.80. C H N O P requires C, 60.00; H,
1
(CDCl ) 30.6 (C-5), 55.9 (C-7, C-8), 58.4 (C-4a), 58.5
(C-10), 70.7 (C-4), 110.2 (C-6, C-9), 123.0 (C-5a), 124.2
(C-9a), 127.7 (CP), 128.6 (m-Ar), 132.0 (p-Ar), 132.1 (o-Ar).
8
21
2
4
3
K1
.87; N, 7.77%]; nmax 2933, 1522, 1235, 1129, 799 cm ; dH
(
CDCl ) 2.67 (dt, 1H, JZ3.0, 15.4 Hz, H-9eq), 2.93 (td, 1H,
3
JZ2.8, 10.3 Hz, H-10ax), 3.01 (ddd, 1H, JZ5.0, 10.8,
5.9 Hz, H-9ax), 3.26–3.31 (m, 1H, H-10eq), 3.84 (s, 3H,
OCH ), 3.85 (s, 3H, OCH ), 4.01 (d, 1H, JZ11.0 Hz, H-4a),
1
Compounds 17a:18aZ21:79. Eluent: EtOAc/MeOHZ9:1.
3
3
4.05 (td, 1H, JZ1.3, 10.6 Hz, H-4ax), 4.72 (ddd, 1H, JZ2.8,
10.3, 18.6 Hz, H-4eq), 6.48 (s, 1H, H-5), 6.58 (s, 1H, H-8),
7.48 (dt, 2H, JZ4.0, 7.5 Hz, m-Ar), 7.55 (dt, 1H, JZ1.5,
7.3 Hz, p-Ar), 7.93 (ddd, 2H, JZ1.5, 8.3, 13.6 Hz, o-Ar); dC
Compound 17a. Transparent needles; yield: 0.50 g (20%).
Mp: 178–181 8C (EtOAc). [Found: C, 57.11; H, 6.81; N,
11.13. C H N O P requires C, 57.14; H, 6.79; N, 11.11%];
1
2 17 2 2
K1
nmax 3109, 2933, 1439, 1224, 801 cm ; d (CDCl ) 1.31 (tq,
3
H
(
7
(
CDCl ) 29.6 (C-9), 52.8 (C-10), 56.2 (C-6,C-7), 63.1 (C-4a),
3.4 (C-4), 108.0 (C-5), 111.7 (C-8), 122.8 (C-4b), 126.6
C-8a), 130.1 (CP), 128.5 (m-Ar), 131.1 (o-Ar), 132.0 (p-Ar).
1H, JZ3.5, 12.3 Hz, H-6ax), 1.42 (dq, 1H, JZ3.5, 12.8 Hz,
H-5ax), 1.54–1.75 (m, 4H, H-5eq), 1.75–1.83 (m, 2H, H-6eq,
H-7), 2.33 (dt, 1H, JZ3.0, 11.3 Hz, H-8ax), 2.58 (tt, 1H, JZ
3
3.0, 13.4 Hz, H-4a), 3.29 (td, 1H, JZ3.5, 10.8 Hz, H-8eq),
Compounds 15a:16aZ50:50. Eluent: EtOAc.
4.17 (ddd, 1H, JZ3.3, 11.3, 18.9 Hz, H-4eq), 4.49 (ddd, 1H,
JZ3.5, 9.8, 11.3 Hz, H-4ax), 7.5 (dt, 2H, JZ4.0, 7.8 Hz,
m-Ar), 7.6(dt, 1H, JZ1.3, 7.5 Hz, p-Ar), 7.9(ddd, 2H, JZ1.3,
8.3, 12.8 Hz, o-Ar); d (CDCl ) 22.9 (C-6), 24.1 (C-7), 26.2
(C-5), 58.2 (C-8), 63.5 (C-4a), 70.2 (C-4), 126.7 (CP), 128.5
(m-Ar), 132.0 (o-Ar), 133.0 (p-Ar).
Compound 15a. A white solid; yield: 0.81 g (27%). Mp:
1
45–148 8C [Found: C, 63.82; H, 5.55; N, 9.46.
C H N O P requires C, 64.00; H, 5.71; N, 9.33%]; n
max
C
3
1
6
17
2
2
K1
3
118, 1390, 1241, 1130, 950 cm ; d (CDCl ) 2.73 (dd,
H
3

Z. Zal a´ n et al. / Tetrahedron 62 (2006) 2883–2891
2891
Compound 18a. White crystals; yield: 0.54 g (21%). Mp:
46–148 8C (EtOAc). [Found: C, 57.20; H, 6.84; N, 11.09.
C H N O P requires C, 57.14; H, 6.79; N, 11.11%]; n
max
3. (a) Sørensen, M. D.; Blæhr, L. K. A.; Christensen, M. K. Int.
Patent Appl. WO 02/06293; Chem. Abstr. 2002, 136, 118577.
(b) Christensen, M. K.; Blæhr, L. K. A. Int. Patent Appl. WO
03/059921; Chem. Abstr. 2003, 139, 117538.
1
1
2
17
2
2
K1
3
1
1
2
112, 2944, 1456, 1225, 810 cm ; d (CDCl ) 1.06 (dtd,
H 3
H, JZ3.8, 11.3, 13.4 Hz, H-5ax), 1.19–1.32 (m, 1H, H-6),
.48–1.8 (m, 4H, H-5eq, H-6eq, H-7), 2.29 (ddd, 1H, JZ
.3, 10.3, 12.6 Hz, H-8ax), 2.46 (tt, 1H, JZ3.0, 10.8 Hz,
4. Shipov, A. E.; Genkina, G. K.; Artyushin, O. I.; Mndzhoyan,
Z. O.; Gushchin, B. E.; Chumakova, E. I.; Roslavtseva, S. A.;
Eremina, O. Y.; Bakanova, E. I.; Kagan, Y. S.; Ershova, E. A.;
Mastryukova, T. A.; Kabachnik, M. I. Russ. Chem. Bull. 1995,
44, 2147–2156.
H-4a), 3.26 (td, 1H, JZ2.3, 11.0 Hz, H-8eq), 3.53 (d, 1H JZ
1
4
0.6 Hz, NH), 3.81 (ddd, 1H, JZ2.0, 10.3, 11.3 Hz, H-4ax),
.18 (ddd, 1H, JZ3.0, 11.3, 20.4 Hz, H-4eq), 7.46 (dt, 2H,
5. Reddy, P. V. G.; Kiran, Y. B. R.; Reddy, C. S.; Reddy, C. D.
Chem. Pharm. Bull. 2004, 52, 307–310.
JZ4.0, 7.3 Hz, m-Ar), 7.53 (dd, 1H, JZ1.3, 7.3 Hz, p-Ar),
.9 (ddd, 2H, JZ1.3, 7.8, 12.8 Hz, o-Ar); d (CDCl ) 22.7
7
6. (a) Molt, O.; Schrader, T. Synthesis 2002, 2633–2670.
(b) Pedrosa, R.; Maestro, A.; P e´ rez-Encabo, A.; Raliegos, R.
Synlett 2004, 1300–1302.
C
3
(
(
C-6), 26.1 (C-7), 26.6 (C-5), 58.1 (C-8), 62.5 (C-4a), 73.13
C-4), 128.3 (CP), 128.6 (m-Ar), 131.3 (o-Ar), 132.0 (p-Ar).
7
. (a) Cates, L. A. J. Heterocycl. Chem. 1973, 10, 111–112.
(b) Cates, L. A.; Li, V.-S.; Basrur, J. P.; Saddawi, B. H.;
Alkadhi, K. A. J. Heterocycl. Chem. 1985, 22, 183–185.
Compounds 17b:18bZ50:50. Eluent: EtOAc.
Compound 17b. Transparent needles; yield: 0.54 g (20%).
Mp: 153–154.5 8C (iPr O–EtOAc). [Found: C, 53.80; H, 6.36;
8. Arshinova, R.; Kraemer, R.; Majoral, J.-P.; Navech, J. Org.
Magn. Reson. 1975, 7, 309–312.
2
N, 10.41. C H N O P requires C, 53.73; H, 6.39; N,
1
9. Gadzhiev, G. Y.; Koroteev, M. P.; Budagov, V. A.; Ibragimov,
S. I. Zh. Obshch. Khim. 1986, 56, 2648–2649.
2 17 2 3
K1
0.44%];nmax 3129, 2943, 1263, 1010, 942 cm ;d (CDCl )
1
1
1
H 3
.2 (dddd, 1H, JZ3.8, 11.1, 13.6, 16.9 Hz, H-5ax), 1.31 (tq,
H, JZ4.0, 13.1 Hz, H-6ax), 1.56–1.81 (m, 4H, H-5eq,
10. Takamizawa, A.; Matsumoto, S.; Iwata, T.; Sakai, S.; Makino,
I. Chem. Pharm. Bull. 1977, 25, 1582–1590.
H-6eq, H-7), 2.26 (dt, 1H, JZ2.8, 11.8 Hz, H-8ax), 2.45 (tt,
H, JZ3.0, 10.6 Hz, H-4a), 3.20 (dt, 1H, JZ3.5, 10.8 Hz,
H-8eq), 3.75 (d, 1H, JZ9.8 Hz, NH), 4.17 (ddd, 1H, JZ3.5,
1.0, 19.9 Hz, H-4eq), 4.21–4.27 (m, 1H, H-4ax) 7.19 (t, 1H,
JZ7.05 Hz, p-Ar), 7.29–7.38 (m, 4H, Ar); d (CDCl ) 22.6
11. (a) Zal a´ n, Z.; Martinek, T. A.; L a´ z a´ r, L.; F u¨ l o¨ p, F. Tetrahedron
2003, 59, 9117–9125. (b) Zal a´ n, Z.; Het e´ nyi, A.; L a´ z a´ r, L.;
F u¨ l o¨ p, F. Tetrahedron 2005, 61, 5287–5295.
1
1
12. (a) Ragnarsson, U. Chem. Soc. Rev. 2001, 30, 205–213.
(b) Zal a´ n, Z.; L a´ z a´ r, L.; F u¨ l o¨ p, F. Curr. Org. Chem. 2005, 9,
357–376.
C
3
(
C-6), 25.0 (C-7), 25.8 (C-5), 57.6 (C-8), 62.1 (C-4a), 74.1
C-4), 150.5 (CP), 120.8 (m-Ar), 124.9 (p-Ar), 129.7 (o-Ar).
(
13. Kauffman, T. S. Synthesis 2005, 339–360.
1
4. (a) Gr u¨ ssner, A.; Jaeger, E.; Hellerbach, J.; Schnider, O. Helv.
Chim. Acta 1959, 42, 2431–2439. (b) Shamma, M.; Hillman,
M. J. Tetrahedron 1971, 24, 1363–1374. (c) Czarnocki, Z.;
MacLean, D. B.; Szarek, W. A. Bull. Soc. Chim. Belg. 1986,
95, 749–770.
Compound 18b. A pale yellow solid; yield: 0.37 g (14%).
Mp: 123–125 8C (iPr O–EtOAc). [Found: C, 53.69; H, 6.41;
2
N, 10.39. C H N O P requires C, 53.73; H, 6.39; N,
2 17 2 3
1
K1
0.44%]; nmax 3129, 2940, 1251, 1209, 957 cm ; dH
1
(
4
CDCl ) 1.26–1.44 (m, 2H, H-5ax, H-6ax), 1.44–1.84 (m,
3
H, H-5eq, H-6eq, H-7), 2.64 (td, 1H, JZ2.8, 12.3 Hz,
15. Grunewald, G. L.; Sall, D. J.; Monn, J. A. J. Med. Chem. 1988,
31, 824–830.
H-8ax), 2.75 (m, 1H, H-4a), 3.23 (td, 1H, JZ3.1, 11.8 Hz,
H-8eq), 4.26 (dd, 1H, JZ8.6, 11.6 Hz, H-4ax), 4.31 (ddd,
16. O’Reilly, N. J.; Derwin, W. S.; Lin, H. C. Synthesis 1990,
550–556.
1
p-Ar), 7.23–7.38 (m, 4H, Ar); d (CDCl ) 22.7 (C-7), 23.1
H, JZ3.5, 11.6, 26.4 Hz, H-4eq), 7.19 (t, 1H, JZ7.3 Hz,
17. Burri, K.; Schmitt, L.; Islam, K. Int. Patent Appl. WO
03/018017; Chem. Abstr. 2003, 138, 221474.
18. Rosling, A.; F u¨ l o¨ p, F.; Sillanp a¨ a¨ , R.; Mattinen, J. Heterocycles
1997, 45, 95–106.
C
3
(
(
C-6), 24.4 (C-5), 57.8 (C-8), 60.5 (C-4a), 72.9 (C-4), 150.5
CP), 120.5 (m-Ar), 124.9 (p-Ar), 129.8 (o-Ar).
1
9. Crabb, T. A. In Cyclic Organonitrogen Stereodynamics;
Lambert, J. B., Takeuchi, Y., Eds.; VCH: New York, 1992;
pp 253–287.
Acknowledgements
20. Martinek, T.; Forr o´ , E.; G u¨ nther, G.; Sillanp a¨ a¨ , R.; F u¨ l o¨ p, F.
J. Org. Chem. 2000, 65, 316–321.
The authors’ thanks are due to the Hungarian Research
Foundation (OTKA No. T049407) for financial support.
21. Otwinowski, Z.; Minor, W. In Methods in Enzymology; Carter,
C. V., Jr., Sweet, R. M., Eds.; Macromolecular Crystallography;
Academic: New York, 1997; Vol. 276, pp 307–326; Part A.
2
2. Altomare, A.; Cascarano, M.; Giacovazzo, C.; Guagliardi, A.;
Burla, M. C.; Pilodori, G.; Camalli, M. J. Appl. Crystallogr.
1994, 27, 435.
References and notes
2
3. Sheldrick, G. M. SHELX-97, University of G o¨ ttingen:
Germany, 1997.
24. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
1
2
. Kivel a¨ , H.; Zal a´ n, Z.; T a¨ htinen, P.; Sillanp a¨ a¨ , R.; F u¨ l o¨ p, F.;
Pihlaja, K. Eur. J. Org. Chem. 2005, 1189–1200 and
references cited therein.
25. Schneider, W.; Schilken, K. Arch. Pharm. 1963, 296,
389–395.
26. Rozwadowska, M. D.; Br o´ zda, D. Pharmazie 1984, 39,
387–388.
. (a) Colvin, O. M. Curr. Pharm. Des. 1999, 5, 555–560. (b)
Ludeman, S. M. In From Nerve Agent to Anticancer Drug: The
Chemistry of Phosphoramide Mustard; Torrence, P. F., Ed.;
Biomedical Chemistry; Wiley-Interscience: New York, 2000;
pp 163–187.
27. Pedrosa, R.; Andres, C.; Iglesias, J. M. J. Org. Chem. 2001, 66,
243–250.