Intramolecular dehydro Diels-Alder reactions of diarylacetylenes: Synthesis of 5H-benzo[j]phenanthridine and 6H-naphtho[2,3-c]chromene skeletons

Article abstract of DOI:10.1055/s-2003-40839

Intramolecular dehydro Diels-Alder reactions of aniline and phenol diarylacetylene derivatives lead to the formation of 5H-henzo[j]phenanthridine and 6H-naphtho[2,3-c]chromene skeletons.

Full text of DOI:10.1055/s-2003-40839

1524
LETTER
Intramolecular Dehydro Diels–Alder Reactions of Diarylacetylenes: Synthesis
of 5H-Benzo[j]phenanthridine and 6H-Naphtho[2,3-c]chromene Skeletons
Intramolecular
D
eh
a
ydro
D
iels
v
–Alder Reac
i
tions
o
d
f
D
iarylacetylene
s
Rodríguez, M. Fernanda Martínez-Esperón, Luis Castedo, Domingo Domínguez, Carlos Saá*
Departamento de Química Orgánica y Unidad Asociada al CSIC, Facultad de Química, Universidad de Santiago de Compostela,
15782 Santiago de Compostela, Spain
Fax +34(981)595012; E-mail: qocsaa@usc.es
Received 29 April 2003
OH
Abstract: Intramolecular dehydro Diels–Alder reactions of aniline
and phenol diarylacetylene derivatives lead to the formation of 5H-
benzo[j]phenanthridine and 6H-naphtho[2,3-c]chromene skeletons.
1) n-BuLi 2) CeCl3
Ph
Ph
CHO
Key words: arenynes, aromatic polycycles, benzo[j]phenanth-
ridines, dehydro Diels–Alder reactions, naphtho[2,3-c]chromenes
1
2 (30%)
Intramolecular dehydro Diels–Alder reactions between
O
alkynes and arenynes (or enynes) have been known since
the 19th century.1 The [4+2] cycloaddition of an alkyne
MnO2
unit and an arylacetylene involves the formation of a
CH2Cl2
Ph
strained cyclic allene intermediate2 that normally evolves
to aromatic products by cyclohexatriene isomerization.1b,3
We have recently reported that the intramolecular dehy-
dro Diels–Alder (IDDA) reaction of alkynes and diaryl-
acetylenes provides a new route to the tetracyclic nucleus
of the benzo[b]fluorene antibiotics (Scheme 1).4 In that
study and related work5 the main characteristic of the
starting substrates has been a three-atom tether linking the
two reacting fragments.
3 (100%)
Scheme 2
some of them had 1H NMR signals suggesting that the cy-
clization reaction had occurred).
In order to improve the above results we introduced a ni-
trogen atom in the connecting tether; phenylpropiol-
amides had behaved well in IDDA reactions,5b so we
decided to try the cyclization reaction of a series of anil-
ides (Scheme 3). Diarylacetylenic anilides 6 and 7 and cy-
clohexenyl anilides 10 and 11 were easily prepared by
Sonogashira coupling of the corresponding alkynes with
o-iodoaniline (4) followed by reaction of the intermediate
anilines 5 and 9 with the appropriate propiolic acid.
Gratifyingly, when a toluene solution of the amide 6 was
heated at 160 °C, a 1.5:1 mixture of benzo[j]phenanthrid-
inones 8a8 and 8b resulting from the two possible cy-
cloadditions of the phenylacetylene moieties was
obtained in 64% yield as a rather insoluble white solid.9
By contrast, amide 7 was not sufficiently activated for the
cyclization4 and only starting material was recovered after
heating.
O
O
Toluene, 150 °C
sealed tube
74%
Scheme 1
To explore the scope of the IDDA reactions of diarylacet-
ylenes, we have now studied the thermolysis of substrates
that have a four-carbon tether between the reactive units.6
First, we prepared the propargylic alcohol 2 by addition of
cerium phenylacetylide to the known aldehyde 1,7 and the
ethynyl ketone 3 by oxidation of 2 with activated MnO2
(Scheme 2). Alcohol 2 was very reluctant to undergo cy-
clization when a toluene solution of 2 was heated at 160
°C for 12 h, the starting material was recovered unaltered.
Ketone 3 proved to be more reactive,5a but even so, heat-
ing at 160 °C afforded only relatively low yields of a mix-
ture of products that could not be identified (although
As expected, the reactions of cyclohexenyl anilides 10
and 11, which involve no loss of aromaticity, proceeded
more readily than those of the diarylacetylenic anilides 6
and 7, affording the tetrahydrobenzo[j]phenanthridinones
12 and 13 as single reaction products in 64% and 41%
yields, respectively.
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1524,1526,ftx,en;G09503ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Intramolecular Dehydro Diels–Alder Reactions of Diarylacetylenes
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H
N
O
Ph(H)
(Ph)H
H
N
R'
NH2
I
NH2
i)
ii)
8a + 8b (1.5:1, 63%)
O
H
R
R
N
O
4
5, R = Ph
9, R =
(96%)
6, R = Ph, R' = Ph (40%)
7, R = Ph, R' = H (53%)
R'
(88%)
10, R = 1-cyclohexenyl,
11, R = 1-cyclohexenyl,
R' = Ph (45%)
R' = H (37%)
12 R' = Ph (64%)
13 R' = H (41%)
Scheme 3 Reagents and conditions: i) R–≡ 1.1 equiv, PdCl2(PPh3)2 3%, CuI 5%, THF, Et3N, r.t.; ii) R¢–≡–CO2H 1 equiv, DCC 1.2 equiv,
DMAP cat, CH2Cl2, 0 °C → r.t.; iii) toluene, 160 °C (0.03–0.05) M.
Interesting results were also achieved using oxygen-te-
thered substrates (Scheme 4). Unexpectedly, we were un-
able to prepare the oxygen analog of the previous
substrates, the diarylacetylenic propiolate 14, in spite of
trying a variety of conditions.10 This led us to place an
electron-withdrawing group at the terminal end of the
alkyne by lithiation acetylenic ether 1511,12 and trapping of
the corresponding acetylide with acetic anhydride or ethyl
chloroformate to obtain high yields of substituted acety-
lenes 16 and 17, respectively. The other electron-poor
substrate examined, arylacetylene 18, was prepared by
Sonogashira coupling of 15 and p-iodonitrobenzene in
91% yield. To our delight, 16, 17 and 18 cyclized smooth-
ly when heated in toluene, giving the pharmacologically
interesting naphtho[2,3-c]chromenes 19, 20 and 21 in
71%, 54% and 72% yield, respectively.13,14
Acknowledgement
We thank the Ministerio de Ciencia y Tecnología (Spain) and the
European Regional Development Fund for financial support under
Project BQU2002-02135. D. Rodríguez and F. Martínez-Esperón
thank USC (Spain) for postdoctoral and predoctoral grants, respec-
tively. F. Martínez-Esperón also thanks Caixa Galicia for a student
grant.
References
(1) (a) Michael, A.; Bucher, J. E. Chem. Ber. 1895, 28, 2511.
(b) Danheiser, R. L.; Gould, A.; Fernández de la Pradilla, R.;
Helgason, A. L. J. Org. Chem. 1994, 59, 5514. (c) Burrell,
R. C.; Daoust, K. J.; Bradley, A. Z.; DiRico, K. J.; Johnson,
R. P. J. Am. Chem. Soc. 1996, 118, 4218. (d) Schmittel, M.;
Strittmatter, M.; Schemk, W. A.; Hagel, M. Z. Naturforsch.,
B: Chem. Sci. 1998, 53, 1015.
(2) For a review of the reactivities and structures of cyclic
allenes, see: Johnson, R. P. Chem. Rev. 1989, 89, 1111.
(3) Rodríguez, D.; Navarro-Vázquez, A.; Castedo, L.;
Domínguez, D.; Saá, C. J. Org. Chem. 2003, 68, 1938.
(4) Rodríguez, D.; Castedo, L.; Domínguez, D.; Saá, C.
Tetrahedron Lett. 1999, 40, 7701.
In conclusion, we have shown that IDDA reactions be-
tween arylacetylenes (or enynes) and electron–deficient
alkynes are useful for the synthesis of the benzo[j]phenan-
thridinone and naphtho[2,3-c]chromene skeletons. The
method developed is atom economic and involves com-
mercial available catalysts. Further exploration of IDDA
reactions is in progress in our laboratories.
O
R
O
O
Toluene
160 °C
R
1. n–BuLi
X
15
2. Ac2O or ClCO2Et
14, X = O
15, X = H2
19, R = COMe (71%)
20, R = CO2Et (54%)
21, R = p-NO2C6H4 (72%)
16, R = COMe (89%)
17, R = CO2Et (92%)
18, R = p-NO2C6H4 (91%)
Scheme 4
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D. Rodríguez et al.
LETTER
(13) (a) Naphtho[2,3-c]chromene antibiotics: Hauser, F. M.;
(5) (a) Rodríguez, D.; Navarro, A.; Castedo, L.; Domínguez, D.;
Saá, C. Org. Lett. 2000, 2, 1497. (b) Rodríguez, D.;
Navarro-Vázquez, A.; Castedo, L.; Domínguez, D.; Saá, C.
J. Am. Chem. Soc. 2001, 123, 9178. (c) Rodríguez, D.;
Navarro-Vázquez, A.; Castedo, L.; Domínguez, D.; Saá, C.
Tetrahedron Lett. 2002, 43, 2717.
(6) To our knowledge, there is only one precedent for this kind
of tether in IDDA reactions of arylacetylenes: White, E. H.;
Sieber, A. A. F. Tetrahedron Lett. 1967, 8, 2713; for related
cyclizations, see ref.1b.
(7) Zhang, S.-W.; Sugioka, T.; Takahashi, S. J. Mol. Cat. A:
Chem. 1999, 143, 211.
(8) Patra, P. K.; Suresh, J. R.; Ila, H.; Junjappa, H. Tetrahedron
1998, 54, 10167.
(9) All new compounds gave satisfactory analytical and
spectroscopic data.
(10) All unsuccessful attempts were esterifications of 2-(2-
phenyl-1-ethynyl)phenol under different conditions: a)
propiolic acid, DCC, DMAP; b) propiolic acid, SOCl2; c)
methyl propiolate, p-TsOH, 90 °C.
Combs, D. W. J. Org. Chem. 1980, 45, 4073.
(b) Naphtho[2,3-c]chromenes as intermediates in the
synthesis of pradimicine antibiotics: Kitamura, M.; Ohmori,
K.; Kawase, T.; Suzuki, K. Angew. Chem. Int. Ed. 1999, 38,
1229. (c) Naphthopyrans as photochromic materials:
Tanaka, K.; Aoki, H.; Hosomi, H.; Ohba, S. Org. Lett. 2000,
2, 2133.
(14) Typical experimental procedure: A solution of 16 (70 mg,
0.26 mmol) in toluene (10 mL) was heated in a sealed tube
at 160 °C for 10 h. After removal of the solvent, the crude
residue was purified by column chromatography on silica
gel using a mixture of hexanes/EtOAc (7:1) as eluent, giving
50 mg (71%) of 19 as a pale yellow oil. 1H NMR (250 MHz,
CD3Cl) d: 8.16 (s, 1 H, ArH), 7.94–7.87 (m, 2 H, ArH),
7.72–7.64 (m, 1 H, ArH), 7.55–7.46 (m, 2 H, ArH), 7.31 (td,
J = 7.2 Hz, 1.6 Hz, 1 H, ArH), 7.13 (td, J = 8.5 Hz, 1.3 Hz,
1 H, ArH), 7.05 (dd, J = 7.9 Hz, 1.3 Hz, 1 H, ArH), 5.15 (s,
2 H, CH2), 2.71 (s, 3 H, CH3). 13C NMR + DEPT (62.83
MHz, CD3Cl) d: 206.1 (CO), 155.0 (C), 136.1 (C), 133.2
(C), 129.9 (CH), 128.8 (CH), 128.2 (C), 128.0 (C), 127.0
(CH), 126.6 (CH), 126.2 (C), 124.3 (CH), 123.8 (CH), 122.5
(CH), 122.4 (C), 122.1 (CH), 117.6 (CH), 66.1 (CH2), 33.1
(CH3). EM m/z (%): 274 (M+, 100), 273 (45), 231 (61), 202
(53). HRMS C19H14O2: calcd 274.09938, found 274.09940.
(11) Cacchi, S.; Fabrizi, G.; Moro, L. Tetrahedron Lett. 1998, 39,
5101.
(12) Thermolysis of a mesitylene solution of 15 for 20 h at 215 °C
gave a 15% yield of naphtho[2,3-c]chromene.
Synlett 2003, No. 10, 1524–1526 © Thieme Stuttgart · New York