1H and 13C NMR spectral assignments and X-ray crystallography of 4,5,8,12b-TETrahydro-isoindolo[1,2-a]isoquinoline and derivatives

Article abstract of DOI:10.4067/S0717-97072012000100004

12b-Hydroxy-5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-8-one (4), 5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinoline (5) and 12b-hydroxy-5,6,8,12b- tetrahydroisoindolo[1,2-a]isoquinoline (6) were obtained by reduction of 4,5,8,12b-tetrahydroisoindolo[1

Full text of DOI:10.4067/S0717-97072012000100004

J. Chil. Chem. Soc., 57, Nº 1 (2012)
1H AND 13C NMR SPECTRAL ASSIGNMENTS AND X-RAY CRYSTALLOGRAPHY OF 4,5,8,12b-
TETRAHYDRO-ISOINDOLO[1,2-a]ISOQUINOLINE AND DERIVATIVES
VICENTE CASTRO-CASTILLO,a,b* ANTONIO GALDÁMEZ,b, MARCO REBOLLEDO-FUENTES,b
BRUCE K. CASSELS b,c
a Faculty of Basic Sciences, Metropolitan Educational Sciences University, Santiago, Chile,
bDepartment of Chemistry, Faculty of Sciences, University of Chile, Santiago, Chile,
c Institute for Cell Dynamics and Biotechnology, University of Chile, Santiago, Chile
(Received: December 10, 2010 - Accepted: December 19, 2011)
ABSTRACT
12b-Hydroxy-5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-8-one (4), 5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinoline (5) and 12b-hydroxy-5,6,8,12b-
tetrahydroisoindolo[1,2-a]isoquinoline (6) were obtained by reduction of 4,5,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-8-one (3) with LiAlH4/THF/N2. The
precursor and products were characterized by NMR spectroscopy and the X-ray crystal structure of 5 hydrochloride monohydrate (5a) was determined. 1H and
13C NMR spectra were completely assigned for compounds 3, 4, and 5a, using two-dimensional experiments (H-H COSY, HMQC, HMBC and H-H NOESY).
INTRODUCTION
The isoindolo[1,2-a]isoquinoline structure (1) is a rigid tetracyclic ring
system that has been poorly investigated. This system, as the 5,6-dihydro-
8(12bH)one derivative, was first reported in 1968,1 and later found in a natural
product named nuevamine (2), isolated from an extract of Berberis darwinii
Hook., native to south-central Chile and Argentina.2,3 Several syntheses of 2
and, generally, the isoindolo[1,2-a]isoquinoline skeleton have been reported,
but a systematic study of its analogues has been lacking in spite of the likelihood
of some of these products having interesting pharmacological properties.3-5
Scheme 1. Reagents and conditions: a) LiAlH4/THF, reflux, N2, 72 h.
RESULTS AND DISCUSSION
Reduction of 4,5,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-8one (3)
with LiAlH /THF for 48
h under N2 generated, in moderate yield,
12b-hydroxy4-5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-8-one (4, 55%),
plus small amounts of 5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinoline
(5, 6%) and a previously undocumented product,6 12b-hydroxy-5,6,8,12b-
tetrahydroisoindolo[1,2-a]isoquinoline (6) in 3% yield. Walker and Kempton
carried out this reduction under slightly different conditions, reporting 23%
and 18% yields of 4 and 5, respectively.6 Compound 5 oxidizes rapidly in the
presence of air, and therefore its hydrochloride 5a was prepared and studied.
The complete 1H and 13C NMR assignments of compounds 3-5a, based on one-
and two-dimensional NMR experiments (e.g. Figures 1 and 2; Figure 1 gives
the atom numbering), are shown in Tables 1-3.
The synthesis of a series of (±)-5,6,8,12b-tetrahydroisoindolo[1,2-a]
isoquinoline-8-ones (3) bearing one to three methoxyl groups, a methylenedioxy
group, a methoxyl and a hydroxyl, or two hydroxyl groups on ring A was
reported a couple of years ago,4 following a general route that involved
acid-catalyzed cyclization of the corresponding 3-hydroxy-2-(substituted
phenyl)ethylisoindol-1-ones. The reactivity of these systems has been poorly
investigated.1 A particularly surprising observation was that attempts to obtain
the corresponding tertiary amine (5) from 3 by treatment with LiAlH4 in THF
generated the 12b-hydroxy derivative (4) of 3 as the major product, plus a very
low yield of 5 (Scheme 1).6
We have now confirmed that the LiAlH4 reduction of lactam 3 generates
the expected 5 and a high yield of 4, together with the previously unreported
6. In particular, we have provided convincing proof of the structure of 5 (as its
1
hydrochloride monohydrate 5a) based on a complete study of its H and 13C
NMR spectra, those of 3 and 4, and an X-ray crystallographic analysis of 5a. In
addition, 6 was found to participate in a ring-breaking tautomeric equilibrium
that hindered its spectral assignments. Tertiary amines related to 5 and 6 have
not been found in nature, and to the best of our knowledge only one direct
synthesis of such compounds has been reported very recently.7
Figure1.a)Numberingschemesofthe5,6,8,12b-tetrahydroisoindolo[1,2-a]
isoquinolin-8-one skeleton and b) COSY correlations in 3.
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e-mail: vicente.castro@umce.cl

J. Chil. Chem. Soc., 57, Nº 1 (2012)
Figure 2. a) COSY and b) NOESY correlations for 5a.
Table 1. 1H chemical shifts (d) [H-X, multiplicity, J(H,H) (Hz)]a and 13Ca chemical shifts (d) of 5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-8-one (3).
3
Carbon
d 1H
d
13C
HMBCb
3, 4a, 12b
4, 12c
COSYc
2, 12b
1, 3
NOESYd
1
2
7.75 [H-1, d, J(1,2) = 7.5]
7.28 [H-2, t, J(2,3) = J(2,1) = 7.5]
7.22 [H-3, t, J(3,4) = J(3,2) = 7.5]
7.19 [H-4, d, J(3,4) = 7.5]
-
125.7
126.5
127.1
129.1
134.4
28.79
12, 12b
-
3
1, 4a
2, 4
-
4
2, 5, 12c
1, 3, 6, 12b
4, 4a, 6, 12c
3
5 (both)
-
4a
5
-
2.83 [H-5α, m], 2.98 [H-5β, m]
3.56 [H-6α, ddd, J = 12.9, 11.5, 4.5 Hz, 1H], 4.32
[H-6β, ddd, J = 13.0, 6.1, 2.2 Hz, 1H]
-
6α, 6β
4, 6 (both)
6
37.58
4a, 5, 8, 12b
6 (both), 5
5, 12b(α)
7
8
-
-
6, 9, 12b
-
-
-
166.7
132.1
131.7
128.5
122.9
124.3
144.6
58.48
134.5
-
-
-
8a
9
-
10, 12, 12b
8, 11, 12a
-
7.67 [H-9, d, J(9,10) = 7.5]
10
-
10
11
12
12a
12b
12c
7.53 [H-10, t, J(10,9) = J(10,11) = 7.3]
8a, 12
9, 11
10, 12
11,12b
-
-
7.72 [H-11, t, J(11,10) = J(11,12) = 7.5]
9, 12a
-
8.10 [H-12, d, J(12,11) = 7.6]
8a, 10, 12b
9, 11, 12b
1, 12b
-
-
1, 12
-
5.85 [H-12b, s]
-
1, 4a, 6, 8a, 12, 12a, 12c
2, 4, 5, 12b
1,12
-
a In ppm from TMS; b H,C HMBC, c H-H COSY and d H-H NOESY connectivities.
Table 2. 1H chemical shifts (d) [H-X, multiplicity, J(H,H) (Hz)]a and 13Ca chemical shifts (d) of 12b-hydroxy-5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-
8-one (4).
4
Carbon
d 1H
d
13C
HMBCb
3, 4a, 12b
4, 12c
COSYc
1
2
8.02 [H-1, d, J(1,2) = 7.6]
7.29 [H-2, t, J(2,3) = J(2,1) = 7.5]
7.23 [H-3, t, J(3,4) = J(3,2) = 7.5]
7.16 [H-4, d, J(3,4) = 7.5]
-
127.9
126.4
128.0
129.0
134.4
28.77
2
1, 3
2, 4
3
3
1, 4a
4
2, 5, 12c
1, 3, 6
4a
5
-
2.81 [H-5α], 2.96 [H-5β, m]
3.60 [H-6α, ddd, J = 13.0, 11.5, 4.5 Hz, 1H], 4.31 [H-
6β, ddd, J = 13.0, 6.2, 2.3 Hz, 1H]
-
4, 4a, 6, 12c
6α, 6β
6
34.33
4a, 5, 8, 12b
6 (both), 5
7
8
-
-
-
-
166.0
130.5
132.4
129.3
122.5
124.0
148.5
85.67
137.4
6, 9
-
8a
9
-
10, 12
8, 11, 12a
8a, 12
-
7.70 [H-9, d, J(9,10) = 8]
10
10
11
12
12a
12b
12c
7.53 [H-10, t, J(10,9) = J(10,11) = 7.2]
9, 11
7.63 [H-11, t, J(11,10) = J(11,12) = 7.6]
9, 12a
10, 12
8.17 [H-12, d, J(12,11) = 7.6]
8a, 10, 12b
9, 11
11
-
-
-
-
1, 6, 12
2, 4, 5
-
-
a In ppm from TMS; b H,C HMBC and c H-H COSY connectivities.
973

J. Chil. Chem. Soc., 57, Nº 1 (2012)
Table 3. 1H chemical shifts (d) [H-X, multiplicity, J(H,H) (Hz)]a and 13Ca chemical shifts (d) of 5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinoline hydrochloride
(5a).
5a
e
d 1H
HMBCb
3, 4a, 12b
4
COSYc
NOESY
d
13C
CN°
1
7.55 [H-1, d, J(1,2) = 7.6]
7.36 [H-2, t, J(2,3) = J(2,1) = 7.3]
7.30 [H-3, t, J(3,4) = J(3,2) = 7.6]
7.26 [H-4, d, J(3,4) = 7.6]
-
127.5
127.6
128.3
129.3
132.2
24.25
46.10
-
2, 12b
12, 12b
2
1, 3
-
3
1, 4a
2, 4
-
4
2, 5
3
5 (both)
4a
5
1, 3, 6, 12b
4, 4a, 6
4a, 5, 8, 12b
-
-
6α, 6β
6 (both), 5
-
-
3.10 [H-5α, H-5β, m]
4
6
3.31 [H-6α, m], 3.59 [H-6β, m]
8 (both), 12b(α)
7
-
-
4.82 [H-8α, d, J (a,b) = J (b,a) = 14.7], 4.67 [H-
8
56.70
6, 9, 12b
8 (both), 9
6 (both), 9, 12b(α)
8β, d, J (a,b) = J (b,a) = 14.9]
8a
9
-
130.7
124.2
129.3
128.0
124.1
137.6
64.52
134.1
10, 12, 12b
-
8 (both), 10
9, 11
10, 12
11,12b
-
-
7.45 [H-9, dd, J = 8.3, J’= 2.9]
8, 11, 12a
8 (both),
10
7.40 [H-10, t, J(10,9) = J(10,11) = 8.0]
8a, 12
-
11
7.38 [H-11, t, J(11,10) = J(11,12) = 8.1]
9
8a, 10, 12b
9, 12b
-
12
7.53 [H-12, dd, J = 8.3, J’=2.9]
1, 12b
12a
12b
12c
-
-
1, 12
-
6.12 [H-12b, s]
-
1, 4a, 6, 8a, 12, 12a, 12c
12b
1,12
-
a In ppm from TMS; b H,C HMBC, c H-H COSY and d H-H NOESY connectivities.
The hydroxyl group on doubly benzylic carbon atom C12b of compounds
3 and 4 is associated with small downfield shifts of the H1 and H12 resonances.
The same effect is seen for the signals of the C5 and C6 methylene protons. In
contrast, the H11 resonance undergoes a slight upfield shift, and the remaining
aromatic proton signals are practically unchanged.
8-one (3) to its 12b-hydroxy derivative (4) and several analogous reactions,
extending a report of a similar process undergone by 10,11-dimethoxy-
4,5,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-8-one.1,8 The formation of 4
and its analogues is probably due to the doubly benzylic character of C12b
which should therefore generate a highly stabilized free radical upon hydrogen
abstraction. However, the strongly basic environment required suggests that
the mechanism of autoxidation in this case might proceed via ionization to
afford a carbanion capable of reducing molecular oxygen, and thus becoming
oxidized to the stabilized free radical.1
In the 1H NMR spectrum of 5a, the H1 and H12 resonances appear at 7.55
and 7.53 ppm, respectively, suggesting that the molecule is considerably less
planar than those of the lactams. The other ring A proton resonances are shifted
downfield by almost 1 ppm, while the ring D proton signals appear further
upfield due to the replacement of the C8 carbonyl by a methylene group. The
positively charged nitrogen atom deshields H12b, but this effect is not manifest
on H5, suggesting that in the cases of 3 and 4 the magnetic anisotropy of the C8
carbonyl group is dominant.
The mass spectra of 3 and 4 are dominated by the ions presumably
formed by loss of the hydrogen atom or the hydroxyl group, respectively,
from C12b. The subsequent formation of a C=C double bond, necessarily at
C5-C6, is another highly likely process, apparently followed in both cases by
decarbonylation, generating a four-membered ring.
1
The H NMR spectra of 3 and 4 are quite similar. In these, the H6a and
H6b resonances appear at 3-55-3.53 and 4.32-4.31 ppm, respectively, with
practically identical coupling constants for their doublets of doublets of
doublets. H5a and –b resonate at 2.99-2.97 and 2.83-2.81 ppm, respectively,
also with very similar coupling constants. This may be taken as an indication
that both compounds have the same time-averaged conformation in spite of
the conformational mobility inferred from the X-ray structures of different
isoindolo[1,2-a]isoquinolin-8-ones (vide infra) and the possible steric bias
due to the presence of the 12b-hydroxy group in 4. In 5a the pattern is rather
different, with H6a and H6b as multiplets at 3.59 and 3.32, and H5a and
H5b very poorly resolved and centred near 3.12 and 3.07 ppm. The lack of a
downfield (i.e. 4.3 ppm) H6 resonance might be attributed to the absence of a
carbonyl group at C8, although the change from an sp2 lactam nitrogen to an sp3
ammonium group might also be a determining factor. More significantly, the
almost identical resonance frequencies of the H5 protons in 5a suggests that the
time-averaged conformation of this compound in solution bears both hydrogen
atoms almost symmetrically with regard to ring A, while in the isoindolo[1,2-a]
isoquinolin-8-ones the shielding of these atoms by the neighboring aromatic
ring is quite different.
Thecrystalstructureof5awasdeterminedbysinglecrystalX-raydiffraction.
The asymmetric unit consists of 5,6,8,12b-tetrahydroisoindolo[1,2-a]
isoquinoline hydrochloride and a solvent water molecule (Figure 3). The
crystal contains a single enantiomer, as found previously by Wakchaure
et al. for nuevamine (2),9 and by us for 5,6,8,12b-tetrahydrodioxolo[4,5-g]
isoindolo[1,2-a]isoquinolin-8-one,10 indicating that these racemic synthetic
compounds crystallize as conglomerates of both enantiomers.
The 13C NMR spectra of 3 and 4 only show significant differences for
the unhydroxylated or hydroxylated C12b and the neighboring C12a and
C12c. The ring A carbon resonances are very similar for all three compounds.
Replacement of the C8 carbonyl group in 3 by an ammonium-substituted
methylene group in 5a leads to strong deshielding of the para-carbon atom and
strong shielding of the ortho atoms in ring C.
Figure 3. A view of the asymmetric unit of 5a, showing the organic
and solvent water molecules (atom numbering scheme) and the chloride ion.
Displacement ellipsoids are drawn at the 50% probability level and H atoms are
shown as small spheres of arbitrary radius.
Castro-Castillo et al.4 recently reported the extremely facile and
quantitative autoxidation of 4,5,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-
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J. Chil. Chem. Soc., 57, Nº 1 (2012)
Ring
B
(N7/C5-C6/C4a/C12B/C12C) has
a
distorted envelope
of the lactone [116.3(2)º] are very similar. However, the C8-N7-C6-C5 torsion
angles are quite different [178.5(2)º and 100.3(4)º, respectively]. Nevertheless,
this torsion angle in 5a is similar to the corresponding angle in the synthetic
intermediate iso - 12b-methoxycarbonyl-5,6,8,12b-tetrahydrodioxolo[4,5-g]
isoindolo[1,2-a]isoquinolin-8-one.9 This suggests that the latter ring is quite
conformationally mobile and that the difference between ammonium salt 5a
and the corresponding lactone is largely dictated by crystal packing forces.
conformation. Two sp2 carbon atoms (C12C/C4a) of the benzene ring are
almost coplanar with the base of the distorted envelope. The Cremer and Pople
puckering parameters of ring B are QT = 0.477(3)Å, θ = 130.1(4)° and φ =
227.8(4)º.11 The value of φ is appropriate for either an envelope or skew-
boat.12 Ring C (N7/C8/C8a/C12B/C12A) adopts an envelope conformation
on N7 with puckering parameters q2 = 0.323(3) Å and φ2 = 178.1(4)º. The
geometry at N7 is distorted pyramid (sp3 hybridization). The sum of the three
angles formed by N7, C6, C8 and H7N is 332.6º. Torsion angles C8-N7-C6-C5
and C12A-C12B-C12C-C1 are 178.5(2)º and 70.1(3)º, respectively. The C12a-
C12b-C12C bond angle is 118.14(18)º.
In the crystal of 5a, molecules are linked by O1W—HW···Cl, N7—
H7N···Cl, C—H···O1W and C—H···p intermolecular interactions forming a
supramolecular network (Table 4). The solvent water molecule plays a dual
role as both donor and acceptor in the hydrogen-bonding interactions, which
R21( 6 )
motifs.13 The H
2
Comparison of the crystal structure of 5a with that of the related lactone
5,6,8,12b-tetrahydrodioxolo[4,5-g]isoindolo[1,2-a]isoquinolin-8-one
(C17H13NO3),10 shows that the C12a-C12b-C12c angles of 5a [118.15(18)º] and
consecutively generate the graph-set
and
R4 (8)
atoms of the water molecule (H1W and H2W) link each chloride anion forming
2
a four-center
motif (Figure 4, top, Table 4).
R4 (8)
Table 4. Hydrogen-bond and intermolecular contact interaction geometry of 5a (Å, º).
D-X...A
d(D-X)
d(X...A)
d(D...A)
<(DXA)
O1W—H1W···Cli
O1W—H2W···Clii
N7—H7N···Cliii
0.97 (4)
0.97 (1)
2.26 (4)
2.28 (1)
3.222 (2)
3.248 (2)
3.018 (2)
3.298 (4)
3.430 (4)
3.351 (3)
176 (3)
174 (3)
0.99 (1)
2.03 (1)
174 (2)
C1—H1···O1W
C9—H9···O1Wii
0.947 (19)
0.94 (2)
2.602 (19)
2.51 (2)
130.6 (15)
164.5 (18)
137.0 (13)
C12B—H12B···O1W
0.974 (17)
2.572 (17)
Symmetry codes: (i) x, y, z+1; (ii) −x+1, −y, −z+1; (iii) x, −y+1/2, z+1/2.
The C8—H8···Cg1 distance is 2.81(2) Å and Cg1 is the centroid of the C8a/
C9-C12/C12a ring. The C6—H6B···Cg2 distance is 2.83(3) Å and Cg2 is the
centroid of the C1-C4/C4a/C12c ring.
Figure 5. Part of the crystal structure of 5a, showing the formation of
the C—H···p intermolecular interactions built from C8—H8···Cg1 [symmetry
code: 1-x, −y, 1−z] and C6—H6B···Cg2 [symmetry code: x, 1/2−y, -1/2+z].
Dashed lines represent intermolecular interactions.
Figure 4. A partial packing scheme of 5a. Top: A view of the hydrogen-
bonded channels running parallel to the ab plane. Bottom: A view of the
hydrogen bonds of the water molecules that are involved in the C1—H1···O1W
and C12B—H12B···O1W centers. Dashed lines represent hydrogen bonds.
The half-chair crystal conformations of ring B in nuevamine (2),9
The molecules are linked via intermolecular N7—H7N···Cliii interactions
[symmetry code: (iii) x, −y+1/2, z+1/2] between the chloride anions and the
organic molecules (Table 4). Thus, the combination of O1W—HW···Cl and
N—H···Cl hydrogen bonds leads to the formation of 3-dimensional channels
running along the [010] direction (Figure 2, top). The hydrogen bonds of the
watermoleculesthatare involvedin C1—H1···O1W andC12B—H12B···O1W
generate two graph-set descriptor R21( 6 )motifs (Figure 2, bottom, Table 4).
The packing structure contains an additional C9—H9···O1Wii intermolecular
contact [symmetry code: (ii) −x+1, −y, −z+1] with a bond distance of 2.51(2)
Å and an angle of 164.5(18)º.
and
5,6,8,12b-tetrahydrodioxolo[4,5-g]isoindolo[1,2-a]isoquinolin-8-one
(C17H13NO3),10 and the half-boat conformation of the corresponding ring in
the crystals of 12b-methoxycarbonyl-5,6,8,12b-tetrahydrodioxolo[4,5-g]
isoindolo[1,2-a]isoquinolin-8-one,9 and now 5a, reveal that the conformational
difference between these pairs of compounds is unrelated to the sp2 lactam or sp3
tertiary ammonium character of the nitrogen atom. However, the presence of a
large substituent at C12b in the 8-oxo compounds, as in 12b-methoxycarbonyl-
5,6,8,12b-tetrahydrodioxolo[4,5-g]isoindolo[1,2-a]isoquinolin-8-one, might
determine a preference for a half-boat conformation. In view of the flexibility
1
of these molecules, the conformational data that can be gleaned from the H
NMR spectra cannot be related directly to either one of these basic X-ray
conformational types, as both are presumably in equilibrium in solution.
The hydrogen bond network is reinforced by two C—H···p interactions.14
H8 on the five-membered ring is oriented toward the face of an aromatic ring
of the neighboring molecule, leading to the formation of dimers (Figure 5).
As stated in the introduction, the isoindolo[1,2-a]isoquinoline scaffold is
975

J. Chil. Chem. Soc., 57, Nº 1 (2012)
of potential pharmacological interest, and it may be viewed as a “privileged”
structure. Our results constitute the groundwork for a better understanding of
the dynamics of this unusual system and for the interpretation of its interactions
with proteins and/or nucleic acids. This is of particular interest in relation to
the likely DNA interactions of the planar isoindolo[1,2-a]isoquinolin-8-ones
and the effect of unprecedented tertiary amines like 5 on enzymes, receptors,
structural or transporter proteins. We have now proved beyond all doubt the
identity of the latter compound, whose structure has only been reported with
some uncertainty in the older literature,6 and which holds much promise for
future elaboration.
The spectral widths were 5 and 17 Hz in the F2 (1H) and F1 (13C) domains,
respectively, with 4 scans x F and 3 ms increments in t1. The data were
processed using Qsine functions2for weighting in both dimensions. The HMBC
spectra were obtained using the inv4gplrndqf pulse sequence in Bruker software
with 1024 ´ 128 data points, acquiring 16 scans ´ F and 3 ms increments in
t1. They were acquired with spectral widths of 5 (F )2and 17 kHz (F1), and the
delays D1 and D2 were 3.5 and 65 ms, respectively.2
X-ray Crystallography
Single crystal analysis data were collected on a Bruker SMART CCD
diffractometer with MoKa radiation. Data collection: Bruker SMART
(BRUKER 1996); cell refinement: Bruker SAINTPLUS V6.02 (BRUKER
1997); data reduction: Bruker SHELXTL V6.10 (BRUKER 2000); program
used to solve structure: SHELXS97 (Sheldrick, 1990); program used to
refine structure: SHELXL97 (Sheldrick, 1997).15,16 Molecular graphics:
DIAMOND (Brandenburg, 1999); software used to prepare material for
publication: PLATON (Spek, 2003).17,18 Crystal dimensions of C16H16N.H2O.
EXPERIMENTAL SECTION
General Procedures. Commercially available, laboratory grade reagents
were used without further purification. Melting points were determined on a
Reichert Galen III hot plate with a DUAL JTEK Dig – Sense thermocouple
thermometer, and are uncorrected. Analytical TLC was performed on Merck
silica gel 60 F254 chromatofoils.
Cl
0.26×0.21×0.06 mm; Mr = 275.76; Monoclinic P21/c; a = 11.3465 (14)
The synthesis of 3 has been reported,1 based on the partial reduction with
NaBH4 of N-(2-phenylethyl)phthalimide to 3-hydroxy-2-(2-phenylethyl)
isoindolin-1-one and the cyclization of this compound in 37% HCl.
Å; b = 11.0603(14) Å; c = 11.3638 (14) Å;b = 94.698 (2)°; V = 1421.3 (3)
Å3 Z = 4; m = 0.26 mm-1. 9997/1568 measured/unique reflections with I >
;
2s(I) [ Rint = 0.070]; R [(F2> 2s (F2)] = 0.044; wR(F2) = 0.086; S = 1.08; 244
parameters; Drmax =0.40e Å-3 and Drmim = -0.15 e Å-3. All H atoms were located
in difference maps and their positions and isotropic displacement parameters
were refined freely. Supplementary information: crystallographic data
(excluding structure factors) for the structural analysis have been deposited in
the Cambridge Crystallographic Data Centre, CCDC 802469. These data can
be obtained free of charge from the Cambridge Crystallographic Data Centre;
Postal Address: CCDC, 12 Union Road, Cambridge CB21EZ, UK, Telephone:
(44) 01223 762910, Fax: (44) 01223 336033, e-mail: deposit@ccdc.cam.ac.uk.
3-Hydroxy-2-(2-phenylethyl)isoindolin-1-one. Colorless needles from
1
MeOH (96 %), mp 170-172 °C (lit.4 170-172 °C). H NMR: δ 2.98 (m, 2H,
CH2), 3.63 (m, 2H, CH ), 5.52 (s, 1H, CH), 6.43 (s, 1H, OH) 7.22 (m, 5H,
ArH), 7.60 (m, 4H, ArH2).
5,6,8,12b-Tetrahydroisoindolo[1,2-a]isoquinolin-8-one (3). Colorless
plates from EtOAc (77%), mp 115-117 °C (lit.1,4,6,8 114-116, 115-117, 116-118,
114-116 °C), HREIMS m/z 235.0605 (calcd for C16H NO, 235.0997), EIMS
m/z (rel. int.) 235.10 (19 %), 234.06 (85 %), 232.05 (11030 %), 204.06 (31 %).
ACKNOWLEDGEMENTS
12b-Hydroxy-5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinolin-8-one
(4), 5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinoline hydrochloride (5a)
and 12b-hydroxy-5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinoline (6). A
suspension of 5.0 g LiAlH4 in 250 mL anhydrous THF was placed under an
inert atmosphere (dry N ) and stirred. A solution of 2 (5.0 g, 21.2 mmol) in
THF (15 mL) was added2dropwise and the reaction mixture was maintained at
reflux for 48 h. After returning to room temperature, the excess hydride was
destroyed by adding water-THF (1:1, 20 mL) followed by 15 % NaOH (15
mL) and then again water (10 mL). The solids were removed by filtration and
washed with additional THF. The combined filtrate and washes were stripped
of solvent under vacuum, and the residue was chromatographed on silica gel
(EtOAc) to afford 4 (2.9 g, 55 %) as colorless prisms from MeOH, 5 (yellow
oil, 297 mg, 6%) and 6 (yellow oil, 154 mg, 3%). Mp (4) 197-198 °C (lit.4,6
mp 197-198, 200-203 °C), HREIMS m/z (4) 251.0756 (calcd for C16H13NO2,
251.0946), EIMS m/z (rel. int.) 251.07 (16 %), 234.07 (100 %), 232.05 (88 %),
204.06 (31 %). Mp (5a) 219-221 °C (lit.6 mp 221-225 °C), HREIMS m/z (5a)
221.1016 (calcd for C16H N, 221.1205). 1H NMR (6) (400 MHz): δ 3.27 (t, J
= 7.4 Hz, 2H, CH2), 3.831(5s, 2H, CH2), 4.34 (s, 2H, CH2), 7.21 (d, J = 7.8 Hz,
1H, ArH), 7.26 (d, J = 7.6 Hz, 1H, ArH), 7.32 (t, J = 7.5 Hz, 1H, ArH), 7.35
(m, 3H, ArH), 7.60 (t, J = 7.5 Hz, 1H, ArH), 7.63 (t, J = 7.6 Hz, 1H, ArH).
13C NMR (6) (400 MHz): δ 24.46 (CH2), 45.88 (CH2), 56.35 (CH2), 83.02 (C),
123.48 (C), 123.83 (CH), 126.75 (CH), 126.89 (C), 127.27 (CH), 127.57 (CH),
127.86 (CH), 129.31 (CH), 131.81 (CH), 136.75 (CH), 138.22 (C), 139.02 (C),
HREIMS m/z (6) 237.1096 (calcd for C16H15NO, 237.1154).
This work was supported by CONICYT grant AT-23070040 and ICM grant
P05-001-F. V. C.-C. is the recipient of a MeceSup (UMC-0204) fellowship.
M. T. Garland and A. Ibáñez are thanked for the X-ray measurements and
FONDAP Grant Nº 11980002 for the purchase of the Bruker SMART CCD
single crystal diffractometer.
REFERENCES
1. M. Winn, H.E. Zaugg. J. Org. Chem. 1968, 33, 3779.
2. E. Valencia, A.J. Freyer, M. Shamma, V. Fajardo. Tetrahedron Lett.,
1984, 25, 599.
3. R. Alonso, L. Castedo, D. Domínguez. Tetrahedron Lett., 1985, 26, 2925.
4. V. Castro-Castillo, M. Rebolledo-Fuentes, B.K. Cassels. J. Chil. Chem.
Soc. 2009, 54, 417.
5. E.V. Boltukhina, F.I. Zubkov, A.V. Varlamov. Chem. Heterocycl. Comp.
2006, 42, 971.
6. G.N. Walker, R.J. Kempton. J. Org. Chem. 1971, 36, 1413.
7. E. Sobarzo-Sánchez, E. Uriarte, L. Santana, R.A. Tapia.; P. Pérez-Lourido.
Helv. Chim. Acta. 2010, 93, 1385.
8. A.R. Katritzky, S. Mehta, H-Y. He. J. Org. Chem. 2001, 66, 148.
9. P.B. Wakchaure, S. Easwar, V.G. Puranik, N.P. Argade. Tetrahedron
2008, 64, 1786.
10. A. Galdámez, V. Castro-Castillo, B.K. Cassels. J. Chil. Chem. Soc. 2009,
54, 327.
11. D. Cremer, J.A. Pople. J. Am. Chem. Soc. 1975, 97, 1354.
12. J. Bernstein, R.E. Davis, L. Shimoni, N-L. Chang. Angew. Chem. Int. Ed.
Engl. 1995, 34, 1555.
1
NMR studies. H and 13C NMR spectra were recorded using a Bruker
Avance 400 spectrometer with a Bruker inverse 5 mm Z gradient probe
operating at 400.13 MHz and 100.62 MHz, respectively. All experiments
were carried out at a probe temperature of 300 K, using solutions in DMSO-d6
containing tetramethylsilane as an internal standard. Proton spectra were
obtained with a spectral width of 5 kHz, a 30° flip angle (9.20 ms) and 1.0 s
relaxation delay in 32 scans. 13C spectra were recorded with a spectral width
of 20 kHz with 256 ns between transients, and the 30° flip angle pulse lasted
13.50 ms.
13. G.R. Desiraju. Acc. Chem. Res., 2002, 35, 565.
14. J.A.C. Boeyens. J.Cryst. Mol. Struct., 1978, 8, 317.
15. SMART, SAINTPLUS V6.02, SHELXTL V6.10 and SADABS; Bruker
Analytical X-ray Instruments Inc., Madison, Wisconsin, USA.
16. G. M. Sheldrick, 1997. SHELXL-97. Program for the Refinement of
Crystal Structures. University of Göttingen, Germany.
17. K. Brandenburg, DIAMOND. Visual Crystal Structure Information
System. Version 2.1e Crystal Impact GbR, Bonn, Germany 1999.
18. PLATON Program: A. L. Spek, J. Appl. Cryst. 2003, 36, 7.
The homonuclear H-1H shift-correlated 2D spectra were acquired with
1
spectral widths of 5 kHz using the cosygpqf pulse sequence in the Bruker
software. The spectra were collected with 1024 ´ 256 data points. Other
parameters were the following: number of increments in t , 3 ms; number of
scans, 4; relaxation delay, 1.0 s. The HSQC spectra were 1recorded using the
invietgpsi pulse sequence in Bruker software with 1024 x 256 data points.
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