Amine exchange and unexpected ring-opening reactions of pyranone derivatives: Synthesis of 3-amino-substituted oxonaphthopyran-carbaldehydes and tetrahydropyrimidinethanones as new potential oligonucleotide stabilization agents

Article abstract of DOI:10.1002/1522-2675(200206)85:6<1698::AID-HLCA1698>3.0.CO;2-B

3-[(3-Aminopropyl)amino]-1-oxo-1H-naphtho[2,1-b]pyran-2-carbaldehyde (10) was synthesized by nucleophilic substitution reaction of 2-(3-dimethylamino)-1-oxo-1H-naphtho[2,1-b]pyran-2-carbaldehyde (9) and the monoprotected propane-1,3-diamine. The reaction

Full text of DOI:10.1002/1522-2675(200206)85:6<1698::AID-HLCA1698>3.0.CO;2-B

1
698
Helvetica Chimica Acta ± Vol. 85 (2002)
Amine Exchange and Unexpected Ring-Opening Reactions of Pyranone
Derivatives: Synthesis of 3-Amino-Substituted Oxonaphthopyran-
carbaldehydes and Tetrahydropyrimidinethanones as New Potential
Oligonucleotide Stabilization Agents
a
a
a
1
b
b
by Enzo Sottofattori ), Maria Anzaldi ), Alessandro Balbi* ) ), Roberto Artali ), and Gabriella Bombieri )
a) Dipartimento di Scienze Farmaceutiche, Universit a¡ degli Studi di Genova, Viale Benedetto XV 3,
I-16132 Genova
b) Istituto di Chimica Farmaceutica, Universit a¡ di Milano, Viale Abruzzi 42, I-20131 Milano
3-[(3-Aminopropyl)amino]-1-oxo-1H-naphtho[2,1-b]pyran-2-carbaldehyde (10) was synthesized by nu-
cleophilic substitution reaction of 2-(3-dimethylamino)-1-oxo-1H-naphtho[2,1-b]pyran-2-carbaldehyde (9) and
the monoprotected propane-1,3-diamine. The reaction with the unprotected reagent led to the unexpected 1-(2-
hydroxynaphthalen-1-yl)-2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone (6). Extension of this reaction to
chromone 16 gave 1-(2-hydroxy-3-isopropyl-6-methylphenyl)-2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone
(
7). The X-ray crystal structures of 6 and 7 were also determined.
Introduction. ± While developing new strategies to synthesize chromone deriva-
tives, which can be linked to oligonucleotides to form conjugates with enhanced
stabilization ability [1], we exploited the peculiar behavior of 3-nitrochromones, which
can be summarized as follows: a) 2-(dialkylamino)chromones 1 undergo amine
exchange when treated with mono- or diamines if position 2 is activated from a suitable
substituent in position 3 [2]; b) the nitro group in position 3 can be displaced by an
amino group (2 and 3) or, unexpectedly, by a cyano group (see 4) [2].
R1
O
R1
R1
O
O
O
X
NO2
NR2
X
CN
X
Y
O
NR2
O
NHR3
R2
R1
R2
R1
R2
1
4
5
O
O
O
O
H
N
O
X
NHR3
NHR3
Cl
N
H
O
NR2
R2
R2
2
3
8
1
2
3
X = H, Cl, NO2 Y= NO2, CHO R = Me
R = i-Pr
R = (CH2)nNH2, (CH2)nMe
1)
Tel.: ‡390103538368; fax: ‡390103538358; e-mail: balbi@unige.it

Helvetica Chimica Acta ± Vol. 85 (2002)
1699
We took advantage of the above behavior by developing, inter alia, simple synthetic
pathways to 2-[(3-aminoalkyl)amino][1]benzopyran-4(4H)-one derivatives 5. These
compounds, which are able to stabilize the complementary oligonucleotide complexes
[
3], have also demonstrated the ability to interact and inhibit HIV-1 reverse
transcriptase (RT) [4][5]. Since these studies pointed out the primary role of
formylchromone derivatives that interact with the RT site involved with tRNA [5], we
focused our efforts on synthesizing new derivatives with a pyran carbaldehyde structure
as a fixed moiety. The present report describes the synthesis of the carbaldehyde
derivatives and the serendipitous preparation of the tetrahydropyrimidines 6 and 7 that
have been characterized also by X-ray analysis.
Results and Discussion. ± For the synthesis of the carbaldehyde derivatives, we used
the tricyclic 3-(dimethylamino)-1H-naphtho[2,1-b]pyran 8 as a starting molecule. The
reason for selecting a naphthopyran instead of a chromone derivative was that the
naphtho better than the benzo moiety might improve lipophilicity and cell penetration
[
6].
Vilsmeier formylation of 8 gave the 2-formyl derivatives 9 [7], which, by exploiting
our amine-exchange method [2], should have given the desired aminoalkylamino
derivatives 10. However, in this case, we obtained tetrahydropyrimidine derivative 6 as
a main product instead of the expected compound 10 (Scheme 1).
The synthesis of the 3-aminonaphtho derivative 10 was then accomplished via the
protected derivative 11, which was easily obtained from 9 by amine exchange with N-
Scheme 1
8
O
HN
CHO
a)
N
H
O
NHPr
O
O
12
e)
CHO b)
OH
f )
6
O
O
NMe2
9
O
O
c)
CHNPr
NHPr
CHO
CHO
d)
O
O
N(CH2)3NHCPh3
H
11
13
O
N(CH2)3NH2
·HCl
10 ·HCl H
b)
10
6
a) Vilsmeier formylation. b) 9 (0.75 mmol), propane-1,3-diamine (7.5 mmol), toluene, 1108. c) 9 (1.5 mmol), N-
triphenylmethyl)-1,3-propanediamine (1.5 mmol), toluene, r.t. d) Aq. HCl, 608, 2 h. e) 9 (1.5 mmol),
propanamine (1.5 mmol), toluene, reflux, 2 h. f) 9 (1.5 mmol), propanamine (15 mmol), toluene, reflux, 2 h.
(

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Helvetica Chimica Acta ± Vol. 85 (2002)
(triphenylmethyl)propane-1,3-diamine at room temperature. Detritylation with HCl
gave 10, which was isolated and purified as the hydrochloric acid salt.
The concomitant presence of the carbaldehyde substituent and the diamine reagent
is the most plausible explanation for the formation of the pyrimidine derivative 6. In
fact, reactions involving 9 and 1 mol of propanamine essentially gave the 1-oxo-3-
(
propylamino)-1H-naphtho[2,1-b]pyran-2-carbaldehyde (12), while 2 mol of propan-
amine gave the 3-(propylamino)-2-[(propylimino)methyl]naphtho[2,1-b]pyran-
(1H)-one (13). Furthermore, 10 was converted to 6 by treatment with propane-1,3-
1
diamine under the same conditions used to convert 9 to 6 (Scheme 1). The highly
hindered monoprotected diamine cannot yield compound 14 due to the obvious steric
impediment; consequently, it gives compound 11. On the contrary, the propane-1,3-
diamine could form 14, which is the key intermediate of the reaction. After elimination
of 1,4,5,6-tetrahydropyrimidine, 14 is then converted to 15, which is the source of 6.
Moreover, the reaction seems to be generally applicable; in fact, the extension to
chromone 16 succeeded, and tetrahydropyrimidine 7 was then obtained.
Scheme 2
H
OH
O
O
N
2
H2N(CH2)3NH2
-THPy
H
N
H
N
N
H
9
or 10
6
O
HN
HN
14
15
THPy ˆ 1,4,5,6-tetrahydropyrimidine
Scheme 3
R1
O
O
OH
O
HN
CHO
R2
H2N(CH2)3NH2
N
H
NMe2
toluene, 110°
R1
R2
16
7
1
2
R ˆ Me; R ˆ i-Pr
All new compounds gave satisfactory combustion-analysis and spectroscopic data,
in accordance with the given structures (see Exper. Part).
X-Ray Structures of 6 and 7. Fig. 1 shows an ORTEP [8] view of 6 with the atom-
numbering scheme, while selected bond distances and angles for both 6 and 7 are
reported in Table 1.
The molecular structure of 6 is characterized by the presence of intramolecular H-
bonds between the carbonyl O(1)-atom as acceptor and the adjacent H-atom belonging
to the pyrimidine N-atom and the H-atom of the OH-group of the naphthalene moiety.
The length of the latter H-bond O(1) ¥¥¥ HÀO(2) is 1.67(4) ä with an O(1) ¥¥¥ O(2)
distance of 2.549(3) ä and an O(1) ¥¥¥ HÀO(2) angle of 151(4)8, the first one,

Helvetica Chimica Acta ± Vol. 85 (2002)
1701
Fig. 1. ORTEP [8] Drawing of the crystal structure of 6 (ellipsoids at 50% probability)
Table 1. Significant Bond Distances [ä] and Angles [8] for 6 and 7
6
7
N(1)ÀC(13)
1.326(3)
1.338(3)
1.468(3)
1.464(3)
1.509(5)
1.501(5)
1.429(3)
1.383(3)
1.292(3)
1.502(3)
1.332(3)
1.325(3)
1.452(4)
1.452(4)
1.512(5)
1.499(5)
1.427(4)
1.369(3)
1.305(3)
1.500(3)
N(2)ÀC(13)
N(1)ÀC(14)
N(2)ÀC(16)
C(14)ÀC(15)
C(15)ÀC(16)
C(12)ÀC(13)
C(12)ÀC(11)
C(11)ÀO(1)
C(1)ÀC(11)
N(1)ÀC(13)ÀN(2)
C(13)ÀN(1)ÀC(14)
C(13)ÀN(2)ÀC(16)
C(13)ÀC(12)ÀC(11)
C(12)ÀC(11)ÀC(1)
119.5(2)
123.5(2)
122.8(2)
123.6(2)
120.0(2)
119.7(2)
123.7(2)
123.3(2)
124.7(2)
120.3(2)
N(1)ÀH ¥¥¥ O(1), is 1.97(3) ä with an N(1) ¥¥¥ O(1) distance of 2.695(3) ä and an
N(1)ÀH ¥¥¥ O(1) angle of 138(3)8 (Fig. 1). In addition, an intermolecular contact
involving the H-atom of N(2) points to the direction of O(1)' of an adjacent
molecule ('at 1/2 ‡ x, 1/2 À y, 1/2 ‡ z) with an N(2) ¥¥¥ O(1)' distance of 2.996(3) ä,
N(2)ÀH ¥¥¥ O(2)' distance of 2.14(3) ä and an N(2)ÀH ¥¥¥ O(2)' angle of 172(3)8. The
tetrahydropyrimidine moiety deserves some comment. The protonation of both N-
atoms, N(1)ÀC(13) and N(2)ÀC(13) bond distances of 1.326(3) and 1.328(3) ä,
respectively, associated with the values of C(13)ÀC(12) 1.429(4) ä, C(12)ÀC(11)
1
.382(2) ä and C(11)ÀO(1) 1.292(3) ä, could be justified by the presence of the
resonance forms shown in Scheme 4.
In fact, the CÀN bonds in the ring show some double-bond character, as well
C(13)ÀC(12) and C(12)ÀC(11), while C(11)ÀO is longer than a usual CˆO group,
which is on the order of 1.24 ä, indicating a delocalized p-system.

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Helvetica Chimica Acta ± Vol. 85 (2002)
Scheme 4
-
-
O
O
O
11
1
1
11
+
N
C
N
N
C
N
C
C C
12
C
C12
C
C12
13
1
3
13
+
N
N
The conformation of the heterocycle is that of a half chair with the C(15)-atom
.676(4) ä out of plane. The overall molecular conformation is characterized by the
0
torsion angle O(1)ÀC(11)ÀC(1)ÀC(2) of 141.58 that avoids contact between
HÀC(12) and HÀC(3). The molecular structure of 7 is reported in Fig. 2.
Fig. 2. ORTEP [8] Drawing of the crystal structure of 7 (ellipsoids at 50% probability)
The molecular skeleton is rather similar to that of 6, apart from a missing benzene
nucleus and the presence of Me and i-Pr groups at C(2) and at C(5), respectively. The
values of the common bond distances are in agreement, as shown in Table 1. The two
intramolecular contacts N(1)ÀH ¥¥¥ O(2) (1.92(3) ä) and its angle (141(3)8; N(1) ¥¥¥
O(1) 2.690(3) ä) and O(2)ÀH ¥¥¥ O(1) (1.76(4) ä; O(1) ¥¥¥ O(2) 2.603(3) ä) and its
angle (150(3)8) are as in 6. The crystal packing in this case is characterized by an
intermolecular contact N(2)ÀH ¥¥¥ O(1)' ('at x, 1/2 À y, 1/2 ‡ z; 1.87(3) ä; 171(3)8; N(2)
¥
¥¥ O(1) 2.771(3) ä) with the carbonyl O(1)-atom in addition to the two intramolecular
contacts previously described. These results could account for the difference in the
NMR spectra of the two compounds in the d values for NH and OH. The half-chair
conformation of the pyrimidine ring is again confirmed from the out-of-plane distance
of C(15) of 0.630(4) ä as in 6.
Conclusions. ± The present study has highlighted the capability of our amine-
exchange method [2] to be applied to naphthopyran derivatives. We were then able to
obtain compound 10, which can easily be linked to DNA (data not shown). This meets
our particular requirements for ongoing studies on selective inhibitors of RT. This
synthetic strategy could also be suitable in the preparation of pyran or naphthopyran

Helvetica Chimica Acta ± Vol. 85 (2002)
1703
derivatives with amino side chains that are more complex and of different lengths. On
the other hand, the addition-elimination stages, which give rise to the opening of the
pyrone ring, thus giving the new tetrahydropyrimidines 6 and 7, could open a new route
in the preparation of not easily accessible derivatives. The formation of intramolecular
H-bonds O(1) ¥¥¥ HÀO(2) and O(1) ¥¥¥ HÀN(1) could be important for the elucidation
of the enzymatic reaction mechanisms in future applications of these products as
stabilizing-intercalating agents.
ExperimentalPart
General. All commercially available reagents were used without further purification. The reactions were
monitored by TLC. M.p.s: Fisher-Johns apparatus; uncorrected. IR Spectra: Perkin-Elmer 398 spectrometer; n
À1
1
13
1
13
in cm
200 MHz, H; 50 MHz, C) spectrometers; with Me
were performed on a Carlo-Erba 1106 Elemental Analyser in the Microanalysis Laboratory in our department.
N-(Triphenylmethyl)propane-1,3-diamine. Propane-1,3-diamine (25 g, 0.3 mmol) and Ph CCl (5.6 g,
.02 mol) in CHCl (150 ml) were kept at r.t. for 2 h. The reaction was quenched with H O (150 ml), the org.
layer separated, dried (MgSO ), and evaporated. The resulting solid was purified by CC (SiO , CHCl /EtOH/
Et N 90 :7:3) giving the title compound as a white solid (5 g, 79%): M.p. 59 ± 618 ([9]: 59 ±618).
-(Dimethylamino)-1-oxo-1H-naphtho[2,1-b]pyran-2-carbaldehyde (9). In a flask cooled in an ice bath and
protected from moisture by a CaCl trap, POCl (0.92 g, 6 mmol) was added dropwise to 2 ml of DMF. The
. H- and C-NMR spectra: Bruker AC-300 (300 MHz, H; 75 MHz, C) or Varian Gemini-200
1
13
(
4
Si as internal standard (d ˆ 0 ppm). Elemental analyses
3
0
3
2
4
2
3
3
3
2
3
resulting soln. was stirred for 30 min at r.t. A suspension of 0.96 g (4 mmol) of 3-(dimethylamino) naphtho[2,1-
b]pyran-1(1H)-one in DMF (10 ml) was added, and the mixture was heated at 958. After 90 min, the mixture
was cooled and poured onto crushed ice. The soln. was alkalinized (Na CO ), and 9 precipitated immediately.
2 3
The colorless solid was collected, washed with H
compound (0.9 g, 84%). M.p. 218 ± 2198 (EtOH) [10]: 218 ± 2198. H-NMR (200 MHz, CDCl
2
O, dried, and crystallized from AcOEt, giving the title
1
3
): 3.37 (s, 2 Me);
7
(
.34 (d, 1 arom. H); 7.56 (m, 1 arom. H); 7.66 (m, 1 arom. H); 7.75 (d, 1 arom. H); 8.05 (d, 1 arom. H); 10.02
d, 1 arom. H); 10.31 (d, CHO).
-(2-Hydroxynaphthalen-1-yl)-2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone (6). A suspension of
0.2 g, 0.75 mmol) and propane-1,3-diamine (0.63 ml, 7.5 mmol) in toluene (5 ml) was stirred at 1108 for 2 h.
, AcOEt/EtOH 8 :2) to give 0.10 g (50%) of 6
O. M.p. 226 ± 2278 (AcOEt/EtOH 8 :2) IR (KBr): 3320, 1620,
); 3.33 (d, 2 CH N); 5.05 (m, CH); 7.03
1
9
(
The solvent was evaporated and the residue purified by CC (SiO
as a brownish yellow oil, which solidified with Et
2
2
1
1
580, 1510, 1460, 1380, 1370. H-NMR (200 MHz, DMSO): 1.88 (t, CH
2
2
(
(
(
m, 1 arom. H); 7.27 (m, 1 arom. H); 7.45 (m, 1 arom. H); 7.76 (m, 2 arom. H); 8.30 (d, 1 arom. H); 9.25
1
3
2 NH); 13.12 (OH). C-NMR (50 MHz, (D
CH);118.10 (C); 119.15 (CH); 122.48 (CH); 124.70 (CH); 126.40 (CH); 128.31 (C); 128.63 (CH); 130.71 (CH);
31.00 (C); 157.24 (C); 159.36 (C); 179.58 (C). Anal. calc. for C16 (268.31): C 71.62, H 6.01, N 10.44;
found: C 71.96, H 6.18, N 10.76.
6 2 2 2
)DMSO): 19.94 (CH ); 37.72 (CH ); 37.83 (CH ); 85.36
1
16 2 2
H N O
By the above procedure, 6 was prepared from 3-[(3-aminopropyl)amino]-1-oxo-1H-naphtho[2,1-b]pyran-
-carbaldehyde (10; 0.25 g, 0.75 mmol) and propane-1,3-diamine (0.63 ml, 7.5 mmol) in toluene (5 ml). After
2
purification of the residue, 0.7 g (28%) of 6 were obtained.
-(2-Hydroxy-3-isopropyl-6-methylphenyl)-2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone (7). Analo-
gously to the preparation of 6, 0.2 g (0.75 mmol) of 2-(dimethylamino)-8-isopropyl-5-methyl-4-oxo-4H-
1]benzopyran-3-carbaldehyde 16 and propane-1,3-diamine (0.63 ml, 7.5 mmol) in toluene (5 ml) was heated at
1
[
1
108 for 3 h. After cooling, the yellow precipitate was filtered off and crystallized from AcOEt (0.12 g, 58%).
1
M.p. 2408 (AcOEt). IR (KBr): 3320, 1620, 1580, 1510, 1460, 1380, 1370. H-NMR (200 MHz, CDCl
3
): 1.19
, CH); 4.68 (s, CH); 6.62
)DMSO): 20.79 (CH ); 22.56
); 86.01 (CH); 121.77 (CH); 125.91 (C); 126.41 (CH); 132.60 (C);
33.58 (C); 155.97 (C); 159.99 (C); 184.02 (C). Anal. calc. for C16 (274.36): C 70.04, H 8.08, N 10.21;
found: C 69,63, H 8.31, N 10.35.
-[(3-Aminopropyl)amino]-1-oxo-1H-naphtho[2,1-b]pyran-2-carbaldehyde Hydrochloride (10 ¥ HCl). A
soln. of 9 (0.4 g, 1.5 mmol) and 0.47 g (1.5 mmol) of N-(triphenylmethyl)propane-1,3-diamine in 15 ml of
toluene was stirred at r.t. for 3 h. Evaporation of the solvent and purification of the residue by CC (SiO
(
(
(
s, Me); 1.22 (s, Me); 1.6 (2 NH); 2.00 (m, CH
d, 1 arom. H); 7.02 (d, 1 arom. H); 11.25 (s, 1 OH). C-NMR (50 MHz, (D
Me); 23.10 (2 Me); 26.91 (CH); 38.70 (2 CH
2 2
); 2.4 (s, Me); 3.38 (m, 2 CH
1
3
6
2
2
1
22 2 2
H N O
3
2
,

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704
Helvetica Chimica Acta ± Vol. 85 (2002)
AcOEt) yielded 0.65 g of crude 1-oxo-3-{3-[(triphenylmethyl)amino]propylamino}-1H-naphtho[2,1-b]pyran-2-
carbaldehyde (11), which was hydrolyzed with diluted HCl at 608 for 2 h. H O was removed by co-evaporation
2
with toluene and the residue crystallized with EtOH to give 10 ¥ HCl (0.3 g, 60%) as colorless crystals. M.p. 210 ±
1
2
138 (EtOH). IR (KBr): 3400, 2900, 2000, 1660, 1630, 1610, 1560, 1490. H-NMR (200 MHz,(D
6
)DMSO): 2.05
); 8.35
)DMSO): 27.15
); 100.67 (C); 114.48 (C); 117.46 (CH); 126.43 (CH); 126.54 (CH); 128.87 (CH);
29.26 (CH); 130.36 (C); 131.05 (C); 135.78 (CH); 154.36 (C); 163.05 (C);177.94 (C); 188.74 (CHO). Anal. calc.
for C17 Cl (332.78): C 61.36, H 5.15, N 8.42, Cl 10.35; found: C 60.96, H 5.35, N 8.26, Cl 10.95.
-Oxo-3-(propylamino)-1H-naphtho[2,1-b]pyran-2-carbaldehyde (12). A soln. of 0.4 g (1.5 mmol) of 9
and propanamine (0.12 ml, 1.5 mmol) in toluene (15 ml) was refluxed for 2 h. The mixture was allowed to cool to
r.t., and the precipitate was collected by filtraton and purified by CC (SiO , AcOEt) to give 0.29 g (69%) of 12
as yellow crystals. M.p. 147 ± 1488 (EtOH; [11]: 147 ± 1488). 1H-NMR (200 MHz, CDCl
): 1.07 (t, Me); 1.79
); 7.35 (d, 1 arom. H); 7.57 (m, 1 arom. H); 7.68 (m, 1 arom. H); 7.75 (d, 1 arom. H);
.02 (d, 1 arom. H); 10.00 (d, 1 arom. H); 10.30 (d, CHO); 10.40 (NH). 13C-NMR (50 MHz, CDCl
): 11.85
); 42.95 (CH ); 101.21 (C); 115.80 (C); 116.65 (CH); 126.92 (CH); 127.71 (CH); 128.66 (CH);
29.76 (CH); 131.45 (C); 131.60 (C); 134.79 (CH); 154.64 (C); 163.87 (C); 178.93 (C); 190.58 (CHO).
-(Propylamino)-2-[(propylimino)methyl]naphtho[2,1-b]pyran-1-(1H)-one (13). A mixture of 0.48 g
1.5 mmol) of 9 and propanamine (1.23 ml, 15 mmol) in toluene (15 ml) was refluxed for 2 h. The solvent
(
(
(
m, CH
d, 1 arom. H); 9.90 (d, 1 arom. H); 10.13 (s, CHO); 10.25 (NH). C-NMR (50 MHz, (D
CH ); 36.46 (CH ); 37.82 (CH
2 2 2 3
); 2.90 (m, CH N); 3.72 (m, CH N); 7.73 (m, 3 arom. H); 8.07 (d, 1 arom. H); 8.20 (NH
1
3
6
2
2
2
1
17 2 3
H N O
1
2
3
(
2 2
m, CH ); 3.53 (m, CH
8
3
(
Me); 23.25 (CH
2
2
1
3
(
was evaporated, and the residue treated with petroleum ether. The resulting yellow solid, which was crystallized
with EtOH, gave 13 (0.32 g, 66%). M.p. 76 ± 778 (EtOH). IR (KBr): 3100, 2980, 2960, 2740, 1650, 1630, 1590,
1
1
570. H-NMR (200 MHz, CDCl
3
): 0.96 (t, Me); 1.05 (t, Me); 1.70 (m, 2 CH
2
); 3.52 (m, 2 CH
2
); 7.30
(
(
(
d, 1 arom. H); 7.54 (m, 1 arom. H); 7.68 (m, 1 arom. H); 7.80 (d, 1 arom. H); 7.95 (d, 1 arom. H); 8.80
1
3
s, CHN); 10.10 (d, 1 arom. H); 11.50 (NH). C-NMR (50 MHz, CDCl
3
): 12.15 (Me); 12.26 (Me); 24.00
CH ); 25.00 (CH) ); 44.38 (CH ); 59.13 (CH ); 97.50 (C); 114.93 (C); 117.19 (CH); 126.10 (CH); 127.80 (CH);
2
2
2
2
Table 2. Crystal and Refinement Data for 6 and 7
6
7
Formula
C
16
H
16
N
2
O
2
C
16 22 2 2
H N O
M
r
268.31
monoclinic
P2 /n
274.36
monoclinic
P2 /c
11.721(2)
11.024(3)
11.965(3)
101.07(2)
1517.3(6)
4
Crystal system
Space group
a [ä]
1
1
9.829(2)
b [ä]
c [ä]
b [8]
V/[ä ]
12.042(3)
11.762(3)
102.65(2)
1358.4(6)
4
1.312
293
0.088
3
Z
À3
D
c
/[g cm
Temp./K
m(MoK
]
1.201
293
0.080
À1
a
) [mm
]
Crystal size [mm]
Scan technique
Data collected
q [8]
Refls. collected
Unique refls.
0.11 Â 0.13 Â 0.08
0.10 Â 0.12 Â 0.10
w/2q
w/2q
(À 12,0,0) to (12,15,15)
3.05 ± 28.00
2949
2819 (Rint ˆ 0.011)
2819,0,245
1.318
(À 15, À2,0) to (15,14,15)
3.28 ± 28.00
3232
3098 (Rint ˆ 0.016)
3098,0,269
1.280
Data, restraints, parameters
2
Goodness-of-fit (F )
a
R (I ꢀ 2s(I) )
0.069 (2722 refls.)
0.1520
0.0790 (3000 refls.)
0.1625
b
Rw
F
)
a) S[ j F
j . b) {S[w(F2
2
c
)2]/S[w(F2 )2]}1/2
.
o
o
j À j F
c
j ]/S j F
o
o
À F

Helvetica Chimica Acta ± Vol. 85 (2002)
1705
1
(
28.51 (CH); 129.12 (CH); 131.18 (C); 131.89 (C); 134.78 (CH); 155.00 (C); 157.80 (CHN); 159.40 (C); 178.59
C). Anal. calc. for C20 (332.40): C 74.51, H 6.88, N 8.69; found: C 74.10, H 6.78, N 8.77.
X-Ray Crystallography. The crystal data are given in Table 2. The intensity data were collected on a CAD4
diffractometer with graphite-monochromated MoK radiation (l 0.71073 ä). The cell parameters were
22 2 2
H N O
a
determined and refined by least-squares fit of 20 high-angle reflections. The structures were solved by direct
methods using Sir-92 [12] and conventional Fourier synthesis [13]. The refinement of the structures was made by
2
full-matrix least-squares on F . All non-H-atoms were refined anisotropically. The H-atom positions were
detected in a difference Fourier synthesis and refined with isotropic thermal factors. The supplementary
crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as deposition Nos.
CCDC-172504 and -172505). Copies of the data can be obtained, free of charge, on application to the CCDC, 12
Union Road, Cambridge CB2 1EZ UK (fax: ‡ 44(1223) 336033; e-mail: deposit@ccdc.cam.ac.uk).
We would like to thank M.U.R.S.T. for their financial support.
REFERENCES
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1994, 50, 4009.
[2] E. Sottofattori, T. Grandi, A. Balbi, Tetrahedron Lett. 1995, 36, 1331.
[
3] A. Balbi, E. Sottofattori, T. Grandi, M. Mazzei, D. S. Pyshnyi, S. G. Lokhov, A. V. Lebedev, Bioorg. Med.
Chem. 1997, 5, 1903.
[
[
4] I. V. Martyanov, O. D. Zakharova, E. Sottofattori, G. A. Maksakova, D. S. Pyshnyi, M. Mazzei, A. Balbi, S.
Litvak, L. Tarrago-Litvak, G. A. Nevinskii, Biochem. Mol. Biol. Int. 1998, 45, 857.
5] I. V. Martyanov, O. D. Zakharova, E. Sottofattori, D. S. Pyshnyi, E. Y. Yurchenko, P. Babbi, M. Mazzei, A.
Balbi, M. L. Andreola, S. Litvak, L. Tarrago-Litvak, G. A. Nevinskii, Antisense Nucleic Acid Drug Dev.
1999, 9, 473.
[
[
[
[
6] M. Mazzei, E. Sottofattori, M. Ibrahim, A. Balbi, Nucleotides Nucleosides, 1998, 17, 1885.
7] G. Roma, A. Ermili, A. Balbi, J. Heterocycl. Chem. 1975, 12, 1103.
8] C. K. Johnson, ORTEP 11, Report ORNL-5138, Oak Ridge National Laboratory, TN, 1976.
9] R. J. Bergeron, Y. Feng, W. R. Weimar, J. S. McManis, H. Dimova, C. Porter, B. Raisler, O. Phanstiel, J.
Med. Chem. 1997, 40, 1475.
[10] G. Roma, A. Ermili, M. Mazzei, J. Heterocycl. Chem. 1975, 12, 31.
[11] A. Balbi, M. Di Braccio, G. Roma, A. Ermili, A. Ambrosini, N. Passerini, Farmaco Ed. Sci. 1979, 34, 595.
[12] A. Altomare, M. C. Burla, M. Camalli, G. Cascarano, C. Giacovazzo, A. Gagliardi, G. Polidori, J. Appl.
Crystallogr. 1994, 27, 435.
[13] G. M. Sheldrick, SHELX-97, University of Gˆttingen, Germany.
Received January 8, 2002