Synthesis of carbazoles from ynamides by intramolecular dehydro Diels-Alder reactions

Article abstract of DOI:10.1021/ol050609a

(Chemical Equation Presented) A new approach to carbazoles and benzannulated carbazoles by means of intramolecular dehydro Diels-Alder reactions of ynamides is reported. By using this approach, carbazoles and benzo[b]-, tetrahydrobenzo[b]-, naphtho[1,2-b]

Full text of DOI:10.1021/ol050609a

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2213-2216
Synthesis of Carbazoles from Ynamides
by Intramolecular Dehydro Diels
−Alder
Reactions†
Mar´ıa Fernanda Mart´ınez-Espero´n, David Rodr´ıguez, Luis Castedo, and
Carlos Saa´*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC,
Facultad de Qu´ımica, UniVersidad de Santiago de Compostela,
15782 Santiago de Compostela, Spain
qocsaa@usc.es
Received March 21, 2005 (Revised Manuscript Received April 23, 2005)
ABSTRACT
A new approach to carbazoles and benzannulated carbazoles by means of intramolecular dehydro Diels
−Alder reactions of ynamides is
reported. By using this approach, carbazoles and benzo[b]-, tetrahydrobenzo[b]-, naphtho[1,2-b]-, naphtho[2,1-b]-, and dibenzo[a,c]carbazoles
have been prepared in moderate-to-good yields.
Carbazoles constitute an important and growing class of
alkaloids displaying a wide variety of biological activities.1
Carbazole derivatives are also widely used as building blocks
for potential organic semiconductors,2 organic light-emitting
diodes,3 electroluminiscent materials,4 and polymers with
other useful electrical properties.5 Accordingly, syntheses of
carbazoles and modified carbazoles have been extensively
studied.6,7 We recently described the preparation of substi-
tuted benzo[b]- and benzo[c]fluorenes, the carboanalogues
of benzannulated carbazoles, by means of intramolecular
dehydro Diels-Alder (IDDA) reactions of substituted di-
arylacetylene systems (arenynes).8 We now report a new
adaptation of this strategy using substituted ynamides 19-11
(5) (a) Kawamura, Y.; Yanagida, S.; Forrest, S. R. J. Appl. Phys. 2002,
92, 87. (b) Das, R. R.; Lee, C.-L.; Noh, Y.-Y.; Kim, J.-J. Opt. Mater.
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14, 581. (d) Lamansky, S.; Kwong, R. C.; Nugent, M.; Djurovich, P. I.;
Thompson, M. E. Org. Electron. 2001, 2, 53. (e) Lee, C. L.; Lee, K. B.;
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Polymer 1982, 23, 1713.
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Kirsch, G. H. Curr. Org. Chem. 2001, 5, 507. (c) Hagelin, H.; Oslob, J.
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1989, 89, 1681.
† Dedicated with best wishes to Prof. Rafael Suau on the occasion of
his 60th birthday.
(1) (a) Chakraborty, D. P. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 1993; Vol. 44, p 257. (b) Gallagher, P. T. Science of
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Y.; Iwai, Y.; Takeshima, H. J. Antibiot. 1995, 48, 535. (d) Kno¨lker, H. J.
In AdVances in Nitrogen Heterocycles; Moody, C. J., Ed.; JAI: Greenwich,
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Soc. 2001, 123, 9404.
10.1021/ol050609a CCC: $30.25
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to synthesize carbazoles and benzannulated carbazoles 212
(Scheme 1).
Initially, IDDA reactions were carried out by simply
heating ynamides 1 in toluene at 150 °C (Table 1, conditions
A).8 Not unexpectedly, in most cases, much better results
were obtained at the same temperature in a mixture of toluene
and Et3N (Table 1, conditions B).8b,d For example, for
ynamide 1a, the change of medium raised the yield of
2-methylcarbazole 2a from a poor 16% yield to an acceptable
40% (Table 1, entries 1 and 2). Remarkably, however, access
to the interesting tetrahydro-5H-benzo[b]carbazole nucleus
2b was achieved in 55% yield using toluene alone (entry
3),14 and yields that were almost as good were obtained when
the nitrogen was protected as a carbamate (entries 4 and 5).
To our delight, our metal-free IDDA approach to carbazoles
nicely complements the efficient intermolecular Rh(I)-
catalyzed [2 + 2 + 2] cycloaddition of ynamides with
alkynes.7a
Scheme 1. Strategy for Synthesis of Carbazoles and
Benzannulated Carbazoles by Intramolecular Dehydro
Diels-Alder Reaction of Ynamides
Benzannulated carbazole ring systems are found only
rarely in nature but are of considerable interest because of
their potential antitumoral15 and other pharmacological
properties,16 and as building blocks for organic materials.2-5
Several synthetic approaches to benzo[b]carbazoles (2-
deazaellipticines) have been developed over the past half-
century,6 including benzannulation of indoles,17 Fischer
indolization of phenylhydrazones,18 Diels-Alder reactions
of pyrano[3,4-b]indol-3-ones,19 4H-furo[3,4-b]indoles20 and
2,4-dihydropyrrolo[3,4-b]indoles,21 and cycloaromatization
of N-[2-(1-alkynyl)phenyl]keteneimines;12b yields have varied
between 22% and 98%. The main failing of these methods
is their lack of flexibility, since they allow almost exclusively
the synthesis of the parent benzo[b]carbazole nucleus but
not that of benz[b]annulated analogues. In this work, we first
approached the parent benzo[b]carbazole 2c by heating 1c
in toluene (conditions A), which gave 2c in a moderate 30%
Ynamides 1 were prepared in three steps starting from
commercially available o-iodoaniline (3). Sonogashira reac-
tions between 3 and terminal alkynes 4, followed by
N-tosylation, gave alkynes 5 (which were also obtained by
Sonogashira reactions of tosylated 3 with 4) and N-
ethynylation of alkynes 5 with (trimethylsilyl)ethynyliodo-
nium salt 6, then gave the desired ynamides 1 in good overall
yields (Scheme 2, Table 1).13 Using Cs2CO3 as the base in
Scheme 2
(12) (a) For reviews on carbazoles and benzannulated carbazoles, see
ref 6a,e. (b) For syntheses of benzo[b]carbazoles via related cycloaroma-
tizations of arenyne ketenimines, see Shi, C.; Wang, K. K. J. Org. Chem.
1998, 63, 3517 and Schmittel, M.; Rodr´ıguez, D.; Steffen, J.-P. Angew.
Chem., Int. Ed. 2000, 39, 2152. (c) For a recent synthesis of benzo[a]-
carbazoles, see ref 7e.
(13) See Supporting Information.
(14) For an extraordinarily slow Diels-Alder approach to 5,6-dimeth-
yltetrahydro-5H-benzo[b]carbazole, see Van Broeck, P. I.; Van Doren, P.
E.; Toppet, S. M.; Hoornaert, G. J. J. Chem. Soc., Perkin Trans. 1 1992,
415.
the last step afforded desilylated 1 (R ) H); using KHMDS
retained the TMS group.7a,13
(15) (a) Gribble, G. W.; Saulnier, M. J. Chem. Soc., Chem Commun.
1984, 168. (b) Pindur, U.; Haber, M.; Sattler, K. J. Chem. Educ. 1993, 70,
263. (c) Kuckla¨nder, U.; Pitzler, H.; Kuna, K. Arch. Pharm. (Weinheim,
Ger.) 1994, 327, 137. (d) Segall, A.; Pappa, R.; Causabon, R.; Martin, G.;
Bergoc, R.; Pizzorno, M. T. Eur. J. Med. Chem. 1995, 30, 165.
(16) (a) Bergman, J. In StereoselectiVe Synthesis (Part A), Studies in
Natural Product Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam,
1988; Vol 1, p 3. (b) Gribble, G. W. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1990; Vol 39, p 239.
(17) (a) Kano, S.; Sugino, E.; Shibuya, S.; Hibino, S. J. Org. Chem.
1981, 46, 2979. (b) Bergman, J.; Pelcman, B. Tetrahedron 1988, 44, 5215.
(c) Boogaard, A. T.; Pandit, U. K.; Koomen, G.-J. Tetrahedron 1994, 50,
4811. (d) Syam Kumar, U. K.; Patra, P. K.; Ila, H.; Junjappa, H. Tetrahedron
Lett. 1998, 39, 2029. (e) Fraser, H. L.; Gribble, G. W. Can. J. Chem. 2001,
79, 1515.
(8) (a) Rodr´ıguez, D.; Navarro, A.; Castedo, L.; Dom´ınguez, D.; Saa´,
C. Org. Lett. 2000, 2, 1497. (b) Rodr´ıguez, D.; Navarro-Va´zquez, A.;
Castedo, L.; Dom´ınguez, D.; Saa´, C. Tetrahedron Lett. 2002, 43, 2717. (c)
Rodr´ıguez, D.; Navarro-Va´zquez, A.; Castedo, L.; Dom´ınguez, D.; Saa´, C.
J. Org. Chem. 2003, 68, 1938. (d) Rodr´ıguez, D.; Mart´ınez-Espero´n, M.
F.; Navarro-Va´zquez, A.; Castedo, L.; Dom´ınguez, D.; Saa´, C. J. Org. Chem.
2004, 69, 3842.
(9) (a) For the first use of ynamides in intramolecular Diels-Alder
reactions, see Witulski, B.; Lumtscher, J.; Bergstra¨sser, U. Synlett 2003,
708. (b) For an intermolecular Diels-Alder reaction of ynamines, see
Himbert, G.; Brum, W. Liebigs Ann. Chem. 1986, 1067.
(10) For useful syntheses of ynamides, see (a) Witulski, B.; Stengel, T.
Angew. Chem., Int. Ed. Engl. 1998, 37, 489. (b) Bru¨ckner, D. Synlett 2000,
1402. (c) Wie, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas,
C. J.; Hsung, R. P. Tetrahedron 2001, 57, 459. (d) Frederick, M. O.; Mulder,
J. A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.;
Douglas, C. J. J. Am. Chem. Soc. 2003, 125, 2368. (e) Dunetz, J.; Danheiser,
R. L. Org. Lett. 2003, 5, 4011. (f) Zhang, Y.; Hsung, R. P.; Tracey, M. R.;
Kurtz, K. C. M.; Vera, E. L. Org. Lett. 2004, 6, 1151.
(18) Martarello, L.; Joseph, D.; Kirsch, G. Heterocycles 1996, 43, 367.
(19) Moody, C. J. J. Chem. Soc., Perkin Trans. 1 1985, 2505.
(20) Gribble, G. W.; Keavy, D. J.; Davis, D. A.; Saulnier, M. G.;
Pelcman, B.; Barden, T. C.; Sibi, M. P.; Olson, E. R.; BelBruno, J. J. J.
Org. Chem. 1992, 57, 5878 and references therein.
(11) For a related synthesis of indoles and indolines via [4 + 2]
cycloaddition of ynamides and conjugated enynes, see Dunetz, J. R.;
Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776.
(21) (a) Sha, C.-K.; Chuang, K.-S.; Young; Wey, S.-J. J. Chem. Soc.,
Perkin Trans. 1 1987, 977. (b) Kreher, R. P.; Dyker, G. Z. Naturforsch.
1987, 42b, 473.
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Org. Lett., Vol. 7, No. 11, 2005

Table 1. Results of Intramolecular Dehydro Diels-Alder Reactions of Ynamides 1
a Experimental conditions. A: 1 (0.01M), toluene (typically, 6 mL), 150 °C, sealed tube. B: conditions A plus 0.5 mL of Et3N. C: conditions A plus 0.5
mL of MeOH or iPrOH. D: conditions A plus 1 eq of AcOH. b Reagents and conditions: 1b (1 eq), PhI (1.1 eq), 5% Pd(PPh3)4, 2% CuI, 2:1 Et3N/toluene,
60 °C. c Refluxing 2d with TBAF gave detosylated 2d* in 95% yield.13
Org. Lett., Vol. 7, No. 11, 2005
2215

yield (entry 6). Surprisingly, lower yields (12-15%) were
obtained in basic or protic media (conditions B and C,
respectively; entries 7 and 8),8 and when a mixture of toluene
and AcOH was used, hydrolysis of the ynamide group
occurred giving 7c in 68% yield (Figure 1).13 However,
starting ynamide 1 (R ) Ar). Substrates in which the extra
ring was electron-deficient (1h and 1i)25 gave the 6-aryl-
benzo[b]carbazoles 2h and 2i regioselectively, though in
rather poor yields (entries 23 and 24), indicating that the
cycloaddition occurred selectively on the more electron-rich
phenyl.26 Interestingly, when the cyclohexenylynamide 1b
was subjected to Sonogashira conditions in the presence of
iodobenzene, two carbazoles were isolated, 11-cyclohex-
enylbenzo[b]carbazole 2c* in 8% yield and 6-phenyltetrahy-
drobenzo[b]carbazole 2b* in 18% yield,13 suggesting that
after initial phenylation of 1b25 the two possible cycloaddi-
tions had occurred in roughly a 1:2 ratio (entry 25).
Finally, we investigated whether benzo[c]carbazoles might
be prepared through rearrangement of the cyclic allene
intermediate that would be formed in the course of the IDDA
reaction of phenylsilylynamide 1j.27 Unfortunately, all at-
tempts at IDDA reaction of 1j led to its decomposition (entry
26), even when we tried to trap the putative initial cyclic
allene in the presence of MeOH (entry 27). By contrast,
cyclohexenylsilylynamide 1k smoothly cyclized in very good
yields to the 6-(trimethylsilyl)tetrahydrobenzo[b]carbazole
2k (entries 28 and 29).
Figure 1.
protecting the nitrogen as a carbamate gave more satisfactory
yields (42% and 50%; entries 9 and 10). More importantly,
unlike the methods mentioned above, the ynamide IDDA
approach allowed the uneventful preparation of benz[b]-
annulated carbazoles with additional benzene rings: heating
ynamides 1d-f in conditions B gave the known naphtho-
[1,2-b]carbazole17d 2d (90% yield, entry 12), and the hitherto
unknowns naphtho[2,1-b]carbazole 2e (30% yield, entry 14)
and dibenzo[a,c]carbazole 2f (58% yield, entry 16). The
parent 12H-naphtho[1,2-b]carbazole 2d* was obtained from
2d in 95% yield by refluxing with TBAF in THF to remove
the protecting group.7a
Our next goal was the synthesis of isomers of the skeleton
of the interesting antitumoral agent ellipticine (Figure 1),6
but all attempts to prepare pyrido[4,3-b]benzo[f]indole,
pyrido[3,2-b]carbazoles, or indolo[2,3-b]quinolines met with
failure. Heating 822 or 1g in toluene at 150 °C led to their
decomposition, giving at best traces of the desired cyclized
products (entries 17 and 18), heating 1g in the presence of
AcOH gave exclusively the hydrolysis product 7g (Figure
1), albeit in very good yield (entry 19), and heating
cyanamide 923 had no effect (entries 20-22), a result that
contrasts with the exceptionally easy photocyclizations of
the related aryldiimides.24
In conclusion, we have shown that IDDA reactions of
ynamides allow the synthesis of both carbazoles and benz-
annulated carbazoles in relatively good yields. These results
open new perspectives for the application of ynamides in
the field of polycyclic aromatic chemistry.
Acknowledgment. We thank the Ministerio de Ciencia
y Tecnolog´ıa (Spain), the European Regional Development
Fund and the Xunta de Galicia (XUGA) for financial support
under projects BQU2002-02135 and PGIDT03PXIC20909PN.
M. F. Mart´ınez-Espero´n and D. Rodr´ıguez also thank XUGA
and the Universidad de Santiago de Compostela (Spain) for
predoctoral and postdoctoral grants, respectively.
Supporting Information Available: Experimental pro-
cedures and spectral data for 1a,c,e,f,h,k, 2a,c,e,f,h,k, 2b*,
1
2c*, 7c, and 8; and H and 13C/DEPT spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL050609A
(25) Prepared by Sonogashira cross-coupling reactions of 1 (R′ ) H)
with the corresponding aryl iodides. Tracey, M. R.; Zhang, Y.; Frederick,
M. O.; Mulder, J. A.; Hsung, R. P. Org. Lett. 2004, 6, 2209.
(26) In fact, electron-rich substrates, gave complex mixtures showing
that, most likely, the cycloaddition is not regioselective.
(27) TMS-substituted cyclic allenes of the benzo[b]- series could
isomerize to the more stable benzo[c]- form, see (a) Rodr´ıguez, D.; Navarro-
Va´zquez, A.; Castedo, L.; Dom´ınguez, D.; Saa´, C. J. Am. Chem. Soc. 2001,
123, 9178. (b) Rodr´ıguez, D.; Castedo, L.; Dom´ınguez, D.; Saa´, C. Synthesis
2004, 761.
We next examined the regioselectivity of the dehydro
Diels-Alder reaction by installing a second aryl ring in the
(22) Obtained following the same procedure as for 1 (Scheme 2) but
starting with 4-amino-3-bromopyridine.
(23) Prepared in 51% yield by treatment of 5c with BrCN in the presence
of KH.
(24) Schmittel, M.; Rodr´ıguez, D.; Steffen, J.-P. Angew. Chem., Int. Ed.
2000, 39, 2152.
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