Benzo[b]fluorenes formed in the thermal cyclization of 3-ene-1,6-diynes

Article abstract of DOI:10.1515/znb-1998-0913

A three-step preparation of the benzofluorene core is presented. The last step involves thermal cyclization of 3-ene-1,6-diyne (7) leading to the formation of four benzofluorene derivatives, one of which has been investigated by X-ray analysis. The harsh thermal conditions indicate that the cyclization of 7 might not proceed via a biradical intermediate as would be anticipated by a mechanistic proposal from Ueda.

Full text of DOI:10.1515/znb-1998-0913

Benzo[6]fluorenes Formed in the Thermal Cyclization of 3-Ene-l,6-diynes
Michael Schmittei *, Marc Strittm atter3, W olfdieter A. Schenkb, Michael Hagelb
3
a Institut für Organische Chem ie der Universität Würzburg, Am Hubland,
D-97074 Würzburg
b Institut für Anorganische Chem ie der Universität Würzburg, Am Hubland,
D-97074 Würzburg, Germany
Z. Naturforsch. 53b, 1015-1020 (1998); received June 9, 1998
Enediyne, Cyclization, Fluorene, X-R ay Data, Biradical
A
three-step preparation of the benzofluorene core is presented. The last step involves
thermal cyclization of 3-ene-l,6-diyne (7) leading to the formation of four benzofluorene
derivatives, one of which has been investigated by X-ray analysis. The harsh thermal condi-
tions indicate that the cyclization of 7 might not proceed via a biradical intermediate as
would be anticipated by a mechanistic proposal from Ueda.
Recent work by Ueda et al. [1] has indicated
that the thermal cyclization of bis-diyne can be
exo biradical cyclization via B2 6 equally leading to
five-membered ring systems.
1
used for the construction of polycyclic ring sys-
tems, in particular fluorenes (Scheme 1). The mild
conditions (room tem perature, 48 h) and the sim-
plicity of the procedure posed to us the question
whether this synthetic strategy could equally be
applied to other substrates.
POPh2
POPh2
™s
Schem e 2. Biradical cyclization of 3 according to Schmit-
tel et al. [2, 4],
R =H (45%)
Since the C
2
-C
6
biradical cyclization was trig-
R =CH3(38%)
gered when using radical stabilizing groups at the
alkynyl terminus (in particular aryl groups) we
w ondered whether the bis-diyne 1 of Ueda could
be simplified for more convenient preparative use.
As a consequence we have studied the thermal re-
actions of the simple 3-ene-l,6-diynes 7 and 16,
which will be described in the following.
Scheme 1. Biradical cyclization of 1 according to U eda
et al. [1],
As a key interm ediate the authors have pos-
tulated a biradical formed in a bis-exo-dig cycliza-
tion between two alkynyl moieties. Such a motif
3
-Ene-l,6-diyne 7 could be easily prepared in
is reminescent of the recently established C
2
-C
6
two steps. The Pd°-catalyzed coupling of phenyl-
acetylene with o-bromobenzaldehyde (5) afforded
biradical cyclization of enyne-allenes [ ], where an
2
alkynyl and an allenyl group are involved in a bis-
the alkynylated coupling product
6
in 92% yield.
Reaction of with sodium diethyl-bis(phenylacet-
6
ylene)aluminate, prepared from the reaction of
SDDA (sodium diethyldihydroaluminate) with
phenylacetylene, resulted in the formation of 3-
Reprint requests to Prof. Dr. M. Schmittel.
Fax: + 49 931 888 4606.
E-mail: mjls@chemie.uni-wuerzburg.de
en e-l, -diyne 7 (76%).
6
0
932-0776/98/0900-1015 $06.00 © 1998 Verlag der Zeitschrift für Naturforschung. Tübingen ■www.znaturforsch.com
D
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016
M. Schmittei et al. - Benzo(b)fluorenes Formed in the Thermal Cyclization of 3-Ene-l,6-diynes
Ph
Pd(0)/Cul
Ph ----------------.
NEt3, 18 h, 80 °C
„
+
H
=
O
5
H
6 (92%)
-Ph)2
H
1
,4-CHD
toluene
reflux,
8
1
(13%)
9 (44%)
Ph
Na AI'Et2( —
benzene, 1 h, 0 °C
Scheme 3. Synthesis of propargyl alcohol 7.
0(11%)
11(18%)
Scheme 4. Thermolysis of propargyl alcohol 7.
The heat evolvement at 160 °C in a DSC experi-
m ent indicated that 7 cyclizes at much higher tem -
perature than U eda’s system 1, but on the same
For this reason the proton at C- 6 resides in the
time at much lower tem peratures than phenyl sub- shielding region of the adjacent phenyl ring and
stituted 3-ene-l,5-diynes [3]. Heating 7 in toluene
10~ 2 M) to reflux for 10 d in presence of an excess
of 1,4-cyclohexadiene (1,4-CHD) afforded the
appears upfield (d = 6.34 in 10 and d = 6.45 in 8
respectively). Analogously, a shift of 6.34 ppm has
been reported for compound 4 [4]. With this
(
four benzo[
6
]fluorenes 8 - 1 1 in an overall yield of knowledge we were able to assign unambiguously
8
6
% (after isolation by chromatography).
As we were able to obtain a X-ray analysis of
the position of the phenyl group in the benzo-
[bjfluorenes 8-11 by their characteristic !H NMR
and 13C NM R data.
the benzo[
6
]fluorenone 10 the assignment of the
various structures can be taken as conclusive. The
Two mechanistic pathways can be envisaged to
phenyl group at C-9 in 10 is placed nearly perpen- account for the course of the cyclization, one of
dicular to the benzo[b]fluorene skeleton as de- which involves a concerted [4+2] cycloaddition
m onstrated by a dihedral angel of 100.46° (C23-
C18-C9-C10).
generating the 1,2,4-cyclohexatriene moiety in 12
and 13. Alternatively, 7 could undergo a cycliza-
C21
C4
Fig. 1. ORTEP representation of the
crystal structure of 10
.
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M. Schmittei et al. ■Benzo(b)fluorenes Formed in the Thermal Cyclization of 3-Ene-l,6-diynes
1017
Table I. Characteristic spectroscopic data of benzo[6]-
fluorenes 8- 11.
8
9
10
*
11
*
*
1
6
9
1
-H [ppm]
-H [ppm]
-H [ppm]
6-H [ppm]
5.80
6.45
-
5.80
*
6.34
-
8.07
-
7.93
-
8.16
74.0
-
8.24
187.1
1714
C l [ppm]
73.8
-
192.8
1719
(
(
C = 0 ) [cm-1]
O -H ) [cm -1]
3354
3594
-
-
Schem e 6. Preparation of 3-ene-l,6-diyne 16.
*
Signal cannot be unambiguously identified as it is lo-
cated among the resonances of various other aromatic
protons.
diate 14. However, if both cyclizations, i.e. of 1 and
would involve biradical interm ediates one
7
,
would definitively expect that the transformation
of 7 should take place at milder conditions be-
cause of the roughly similar radical stabilizing ef-
fect of the phenyl and the alkynyl group [5]. A ddi-
tional steric effects should not be present in 7 vs.
tion to form the biradical 14, which then ring
closes to 12 and 13. A subsequent hydrogen shift
should then lead to the corresponding alcohols
8
and 9 that under the thermolysis conditions were
partly oxidized to the benzo[b]fluorenones 10 1. But as mentioned before, the thermolysis of 7
and 11
-Ene-l,6-diyne 16 was prepared analogously to
. Pd°-catalyzed coupling of terr-butylacetylene
with o-bromobenzaldehyde (5) afforded 15 in 84%
yield, which upon reaction with sodium diethyl-
.
(toluene, 1 0 d, reflux) needed much more drastic
reaction conditions than that of 1 (rt, 48 h). Hence,
further mechanistic studies are certainly war-
ranted to ascertain biradicals as interm ediates in
this reaction.
3
7
bis(phenylacetylene)aluminate
furnished
16
As a prerequisite for the therm al cyclization,
two aryl groups seem to be helpful at the two alky-
nyl termini, a limitation which should still allow
for many variations. Although the cyclization of 7
afforded two constitutionally different benzofluor-
enols (and benzofluorenones as oxidation pro-
ducts) the simple, two-step preparation of 7 is ex-
pected to make this thermal, high yield pathway
(
67%). However, thermolysis of 16 under various
conditions (toluene, 1 0 d, reflux; mesitylene,
reflux) didn’t provide any cyclization product but
only unreacted 16.
A t present we are unable to distinguish between
the two alternative pathways, i.e.
6
d,
a concerted
[
4+2]-cycloaddition and that via biradical interme-
Scheme 5. Formation of the benzo[6]-
fluorenes.
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1
018
M. Schmittei et al. ■Benzo(b)fluorenes Formed in the Thermal Cyclization of 3-Ene-l,6-diynes
attractive for the combinatorial [
6
] preparation of
1.33 (s, 9H, CH3), 7.31 (m, 1H), 7.46 (m, 2H), 7.84
(
(
d, V (H,H) = 6.7 Hz, 1H), 10.51 (s, 1H); 13C NMR
63 MHz, CDC13): (3 = 28.9, 31.2, 74.8, 106.0, 126.7,
substituted benzofluorenones, since such com-
pounds quite often exhibit interesting biological
activity [7-10] (cf. Kinafluorenone [11,12] and Ki-
nobscurinone [13, 14]).
1
27.7, 127.8, 133.0, 133.5, 136.2, 192.0; HRMS
calcd for C 13H ]40 [M+]: 186.1045, found 186.1041.
C om pound 16: As described above for the syn-
thesis of 7, phenylacetylene (860 [A, 7.89 mmol),
SDDA (1.92 ml, 3.84 mmol) and 15 (625 mg.
3.50 mmol) were brought to reaction. Purification
of the crude product by column chromatography
(trichloromethane, Rf = 0.68) afforded 16 (627 mg,
67%) as a colorless oil. IR (neat): v = 3384 (OH),
Experimental Section
C om pound 7: Phenylacetylene (1.55 g, 15.2
mmol) was added dropwise to a solution of 2 M
SDDA (sodium diethyldihydroaluminate) (3.80
ml, 7.60 mmol) in benzene ( 8 ml). The mixture was
stirred for 3 h until gas evolution ceased. The mix- 3060, 2968, 2896, 2232 (C =C ), 2218 (C=C ), 1598,
ture was then cooled to 0 °C and a solution of o-
1484, 1448, 1365, 1291, 1203, 1096, 1031, 961, 821,
phenylethinyl)benzaldehyde [4] (1.55 g, 7.50 757, 690 cm "1; ’H NM R (250 MHz, CDC13): (3 =
(
mmol) in benzene (5 ml) was added. A fter being
1.29 (s, 9H, C H 3), 2.90 (brs, 1H, OH), 5.95 (s, 1H),
7.19 (m, 1H), 7.22-7.30 (m, 4H), 7.35-7.42 (m,
3H), 7.63 (dd, 3J (H, H) = 7.5 Hz, 4J (H, H) = 1.4
stirred for
with saturated aqueous NH
was separated and the aqueous layer extracted
with ethyl acetate (3x50 ml). The combined or- 30.9, 64.0, 76.5, 86.3, 88.3,104.7, 122.0,122.6,126.6,
ganic layers were dried (M gS04) and filtered.
128.1, 128.1, 128.2, 128.4, 131.8, 132.4, 142.1;
Concentration furnished (1.78 g, 5.81 mmol,
6%) as colorless crystalls. M.p. 71 °C; IR (neat)
v = 3549, 3385 (OH), 3060, 2878, 2221 ( O C ) ,
1
h at 0 °C the mixture was quenched
4
C1. The organic layer
Hz, 1H); 13C-NM R (63 MHz, CDC13):
6
= 28.3,
7
HRM S calcd for C
288.1505.
2
,H 20O [M+]: 288.1514, found
7
Thermoylsis o f 7: A mixture of 7 (308 mg,
1.00 mmol) and 1,4-cyclohexadiene (1.60 g,
2 0 . 0 mmol) in toluene was heated to reflux for
10 d. A fter evaporation of the solvent, the crude
residue was purified by column chromatography
1
8
599, 1493, 1380, 1267, 1184, 1096, 1030, 960, 916,
10, 757, 691 cm“ 1; ]H NMR (250 MHz, CDC13):
<3 = 3.17 (s, 1H, OH ), 6.25 (s, 1H), 1.26-7.46 (m,
8
H), 7.49-7.54 (m, 2H), 7.56-7.67 (m, 3H), 7.86
(
d, 3J (H, H) = 7.6 Hz, 1H); 13C-NMR (63 MHz,
(cyclohexane/ethyl acetate
1
:
1
) to afford four
CDC13):
1
1
6
= 63.8, 8 6
23.0, 126.9, 128.4, 128.5, 128.6, 128.8,129.9, 131.7,
31.8, 131.9, 132.6, 142.4.
.
6
,
8 6
.
8
,
8 8
.
6
, 95.2,121.6,122.7,
benzo[ ]fluorenes 8-11: 8 (39.4 mg, 128 /miol,
13%, Rf = 0.46); IR (neat): v = 3354 (OH), 3063,
3032, 2922, 1598, 1496, 1453, 1361, 1206, 1018,914,
6
8
1
24, 749 cm “ 1; !H NM R (250 MHz, CDC13): (3 =
.26 (s, 1H), 5.79 (s, 1H), 6.45 (d, 3J (H, H) = 7.8
Hz, 1H). 7.13 (dd, V (H, H) = 7.5 Hz, 3J (H, H) =
.5 Hz, 1H), 7.32-7.52 (m, 4H), 7.56-7.65 (m,
H), 7.70 (d, 3J (H, H) = 7.5 Hz, 1H), 7.91 (d,
C
23H 160 (308.1)
Calcd C 89.58 H 5.23% ,
Found C 90.00 H 5.14% .
7
5
Com pound 15: A solution of o-bromobenzalde-
3
7 (H , H) = 7.0 Hz, 1H), 8.16 (s, 1H); 13C NMR
hyde (10.7 g, 57.6 mmol) and 3,3-dimethylbutyne
(63 MHz, CDC13): (3 = 74.0, 123.9, 125.6, 126.9,
127.3, 127.5, 127.8, 128.3, 128.4, 128.8, 128.9, 129.0,
129.4, 129.5, 129.9, 134.4, 135.8, 138.3, 140.4, 143.3,
[
15] (5.50 g, 66.9 mmol) in N Et (200 ml) was
3
treated with dichloro-bis(triphenylphosphine)pal-
ladium(II) (586 mg, 835 /xmol) and copper(I)io-
146.2; HRMS calcd for
C
23H 130
[M+-3H]:
dide (268 mg, 1.40 mmol). A fter the reaction mix- 305.0966, found 305.0970. 9 (135 mg, 439 //mol,
ture had been stirred at 40 °C for 24 h, saturated
aqueous NH C1 was added. The organic layer was
then separated and the aqueous layer extracted
44%, R f = 0.48); IR (CC14): v = 3594 (OH), 3061,
3031, 2928, 2852, 1628, 1586, 1494, 1471, 1443,
1365, 1316, 1254, 1206, 1174. 1100, 1037 cm "1; ]H
4
with n-pentane (3 x 100 ml). The combined or- NM R (250 MHz, CDC13): d = 1.89 (s, 1H), 5.80 (s,
ganic layers were dried (M gS04), filtered and
concentrated. The resulting crude product was
purified by column chromatography (trichloro-
methane, R f = 0.74) to afford 15 (9.00 g, 84%) as
a brown oil. IR (neat): v = 2970, 2903, 2896, 2743
1H), 7.35 (ddd, 3J (H, H) = 7.3 Hz, 3J (H, H) - 7.3
Hz, 4J (H, H) = 1.2 Hz, 1H), 7.36-7.50 (m, 4H),
7.54-7.63 (m,
6
H), 7.83 (d, 3J (H, H) = 7.0 Hz,
1H), 7.94 (d, 3J (H, H) = 7.6 Hz, 1H), 8.07 (s, 1H);
I3C NM R (63 MHz, CDC13): (3 = 73.8,117.9, 120.4,
125.4, 125.8, 126.1, 126.2, 127.7, 128.3, 128.4, 128.9,
129.0, 129.1, 130.6, 131.7, 132.6, 134.4, 137.4, 139.5,
141.1, 145.3.
(
CHO), 2234 (C =C ), 1698 (C = 0), 1651, 1595,
472, 1450, 1387,1283, 1264, 1203, 1158, 826, 761,
69, 635 c m -1; ‘H NMR (250 MHz, CDC13): (3 =
1
6
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M. Schmittei et al. • Benzo(b)fluorenes Formed in the Thermal Cyclization of 3-Ene-l,6-diynes
1019
C
23H 160 (308.1)
Table II. Crystal data and experimental details of 10
(recrystallized from chloroform).
Calcd
C 89.58 H 5.23% ,
Found C 88.95 H 5.22% .
Formula (M F)
Space group
C23H 140 (306.34)
P-l
Lattice constants [A]
a = 9.269(3)
b = 9.344(3)
c = 10.381(3)
a = 70.04(2)°
ß = 68.78(2)°
y = 75.39(2)°
2
320
779.3(4)
293(2) K
1.306
Enraf-Nonius-CAD4
M oK a,
Graphite monochromator,
A = 0.70930 A
0 < h < 11
1
0 (33.4 mg, 109 |imol, 11%, Rf = 0.73); IR
(
1
1
CC14): v = 3062, 2962, 2928, 1714 (C = 0), 1626,
601, 1514, 1495, 1470, 1444, 1362, 1314, 1262,
110, 1046, 946, 909 cm "1; *H NMR (250 MHz,
CDCI
3
): (3 = 6.34 (m, 1H), 7.18-7.23 (m, 2H),
.38-7.48 (m, 5H), 7.47 (m, 1H), 7.52-7.62 (m,
H). 7.73 (m, 1H), 7.93 (m, 1H), 8.24 (s, 1H); 13C
Z
7
2
F(000)
Cell volum e [A 3]
Temperature
D ensity [g em -1] calc.
Diffractom eter
Radiation
NMR (63 MHz, CDC13): d = 123.8, 124.2, 125.2,
26.8, 127.1, 128.3, 128.6, 128.7, 128.9, 129.3, 129.7,
30.7, 133.3, 134.7, 136.5, 136.9, 137.4, 153.7, 187.1.
In accordance with the literature [16]; 11 (55.3 mg,
81 //mol, 18%, Rf = 0.76); IR (CC14): v = 3060,
961, 2855, 1719 (C = 0), 1625, 1605, 1584, 1471,
336, 1278, 1261, 1185, 1036, 954, 908 c m '1; !H
NMR (250 MHz, CDC13): (3 = 7.29 (ddd, 3J (H,
H) = 7.3 Hz, 3J (H, H) = 7.3 Hz, 4J (H, H) = 0.9
Hz, 1H), 7.36-7.41 (m, 3H), 7.54-7.58 (m, 5H),
.62 (m, 2H), 7.76 (d, 3J (H, H) = 7.6 Hz, 1H), 7.86
d, 3J (H, H) = 8.2 Hz, 1H), 7.93 (s, 1H); 13C NM R
63 MHz, CDCI ): Ö = 118.6, 120.7, 124.1, 126.8,
28.0, 128.1, 128.8, 128.8, 129.0, 129.2, 129.5, 129.5,
33.8, 134.6, 135.5, 136.2, 136.6, 138.4, 141.2,
44.0, 192.8.
1
1
1
2
1
Index range
-
1 1 < k < 11
-
1 2 < / < 12
0
-R an ge
2° - 26°
3249
Total reflections
Symmetry independent
R eflections (N )
Parameters (P)
N/P
7
(
(
1
1
1
3049
274
11.13
0.0661
0.1379
3
/
?-value
R m-\alu e
block-matrix least-squares method (SHELXL 96
program) [18].
Crystallographic data for the structure reported
in this paper have been deposited with the Cam-
bridge Crystallographic D ata Centre as supple-
m entary material.
C 3H140 (306.3)
2
Calcd
C 90.17 H 4.61% ,
Found C 89.84 H 4.59% .
In accordance with the literature [17].
Acknow ledgem ents
Crystal data o f 10: The structure of 10 was estab-
lished by an X-ray structural analysis. Crystal data
and the details of the procedure are compiled in
We gratefully acknowledge financial support
from the Stiftung Volkswagenwerk, the Deutsche
Table II. The structure was solved by direct m eth- Forschungsgemeinschaft (SFB 347) and the Fonds
ods (SHELXS 96 program) [18] and refined by the
der Chemischen Industrie.
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1
020
M. Schmittei et al. ■Benzo(b)fluorenes Formed in the Thermal Cyclization of 3-Ene-l,6-diynes
[
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[
8
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