Sequential Diels - Alder reaction of in situ generated 2,3-dimethylenepyrrole and carbodienophiles: Rapid synthesis of 2,3,6,7-tetrasubstituted carbazoles

Article abstract of DOI:10.1021/ol991220o

(formula presented) 2,3,6,7-Tetrasubstituted-1,2,3,4,5,6,7,8-octahydrocarbazoles 2 were synthesized in 46-90% yields by sequential Diels-Alder reactions from N-benzyl-2,5-dimethyl-3,4-bisacetoxymethylpyrrole (1) and dienophiles such as maleic anhydride, maleimides, ethyl maleate, fumaronitrile, and ethyl acrylate. The 2,3,6,7-tetrasubstituted carbazoles 3 were then synthesized in 32-87% yields from 2 by oxidation with DDQ.

Full text of DOI:10.1021/ol991220o

ORGANIC
LETTERS
2000
Vol. 2, No. 1
73-76
Sequential Diels−Alder Reaction of in
Situ Generated 2,3-Dimethylenepyrrole
and Carbodienophiles: Rapid Synthesis
of 2,3,6,7-Tetrasubstituted Carbazoles
Jeffrey T. Vessels, Slawomir Z. Janicki, and Peter A. Petillo*
Department of Chemistry, UniVersity of Illinois at Urbana-Champaign,
600 South Mathews AVenue, Urbana, Illinois 61801
alchmist@alchmist.scs.uiuc.edu
Received November 4, 1999
ABSTRACT
2,3,6,7-Tetrasubstituted-1,2,3,4,5,6,7,8-octahydrocarbazoles 2 were synthesized in 46−90% yields by sequential Diels−Alder reactions from
N-benzyl-2,5-dimethyl-3,4-bisacetoxymethylpyrrole (1) and dienophiles such as maleic anhydride, maleimides, ethyl maleate, fumaronitrile, and
ethyl acrylate. The 2,3,6,7-tetrasubstituted carbazoles 3 were then synthesized in 32−87% yields from 2 by oxidation with DDQ.
The carbazole ring system and its hydrogenated analogues
form the core of a wide range of alkaloids, and several
strategies exist for their construction.1 Carbazoles are also
important building blocks for the construction of polymers
with thermal,2 electrical,3 and photoelectrical properties4 and
as polymer-blend additives for the fabrication of photore-
fractive materials.5 Despite the importance of carbazoles in
natural products and materials applications, methodology for
the rapid, selective synthesis of 2,3,6,7-tetrasubstituted
carbazoles has not been developed. To date, only a limited
number of reports describe the efficient construction of highly
substituted symmetric skeletons6-8 and no general methodol-
ogy exists for the synthesis of functionalized 2,3,6,7-
tetrasubstituted-1,2,3,4,5,6,7,8-octahydrocarbazoles 2 and
2,3,6,7-tetrasubstituted carbazoles 3.9 Such methodology may
prove important for the generation of new carbazole polymers
with more refined material properties.
(1) (a) Pindur, V. U.; Pfeuffer, L. Chem.-Zeit. 1986, 95-100. (b) Pindur,
U. Chimia 1990, 44, 406-412. (c) Bergman, J.; Pelcman, B. Pure Appl.
Chem. 1990, 62, 1967-1976. (d) Gribble, G. W. Synlett 1991, 289-300.
(e) Kno¨lker, H. Synlett 1991, 371-387. (f) Moody, C. J. Synlett 1994, 681-
688. (g) Joule, J. A. In AdVances in Heterocyclic Chemistry; Katritzky, A.
R., Ed.; Vol. 35; Academic Press: Orlando, 1984; pp 83-198. (h) Sundberg,
R. J. In ComprehensiVe Heterocyclic Chemistry: The Structure, Reactions,
Synthesis, and Uses of Heterocyclic Compounds; Katritzky, A. R., Rees,
C. W., Bird, C. W., Cheeseman, G. W. H., Eds.; Pergamon Press: New
York, 1984; Vol. 4, Chapter 6. (i) Sundberg, R. J. In ComprehensiVe
Heterocyclic Chemistry II: A ReView of the Literature 1982-1995: The
Structure, Reactions, Synthesis, and Uses of Heterocyclic Compounds;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Bird, C. W., Eds.; Pergamon
Press: New York, 1996; Vol. 2, Chapter 3.
(5) Zhang, Y.; Wada, T.; Sasabe, H. J. Mater. Chem. 1998, 6, 809-
828.
(6) (a) Plant, S. G. P.; Rogers, K. M.; Williams, S. B. C. J. Chem. Soc.
1935, 741-744. (b) Mitchell, B. R.; Plat, S. G. P. J. Chem. Soc. 1936,
1295-1298. (c) Nagai, Y.; Huang, C. Bull. Chem. Soc. Jpn. 1965, 38, 951-
953. (d) Nagai, Y.; Huang, C. Bull. Chem. Soc. Jpn. 1965, 38, 1136-1141.
(7) (a) Reymond, G.; Vasilevskis, J.; Toome, V. Heterocycles 1982, 19,
2345-2347. (b) Zelent, B.; Durocher, G. Can. J. Chem. 1985, 63, 1654-
1665. (c) Manchand, P. S.; Coffen, D. L.; Belica, P. S.; Wong, F.; Wong,
H. S.; Berger, L. Heterocycles 1994, 39, 833-845. (d) Harfenist, M.; Joyner,
C. T.; Mize, P. D.; White, H. L. J. Med. Chem. 1994, 37, 2085-2089. (e)
Bonesi, S. M.; Erra-Balsells, R. J. Heterocycl. Chem. 1997, 34, 877-889.
(8) (a) Smith, P. A. S.; Brown, B. B. J. Am. Chem. Soc. 1951, 73, 2435-
2437. (b) Simpson, J. E.; Baub, G. H.; Hayes, F. N. J. Org. Chem. 1973,
38, 4428-4431.
(2) (a) Biswas, M.; Mishra, G. C. Makromol. Chem. 1981, 182, 261. (b)
Biswas, M.; Das, S. K. Eur. Polym. J. 1981, 17, 1245.
(3) Biswas, M.; Das, S. K. Polymer 1982, 23, 1713-1725.
(4) Strohriegl, P.; Grazulevicius, J. V. In Handbook of Organic Conduc-
tiVe Molecules and Polymers: Charge-Transfer Salts, Fullerenes and
Photoconductors; Nalwa, H. S., Ed.; John Wiley & Sons: New York, 1997;
Vol. 1, pp 553-620.
(9) There is a report of 9-acetylcarbazole-2,3,6,7-tetracarboxylic acid
2,3;6,7-dianhydride. However, the preparation and characterization of this
compound was not reported. Kampar, V. E.; Mazere, I. V.; Meirovits, I.
A.; Neiland, O. Y. Chem. Heterocycl. Compd. 1979, 15, 153-155.
10.1021/ol991220o CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/17/1999

Table 1. Products of the Diels-Alder Reaction and Oxidation
We now report a novel tandem Diels-Alder reaction that
assembles 210,11 in one step from pyrrole 1 and 2 equiv of
carbodienophile (Table 1).12,13 The corresponding carbazole
3 is subsequently generated by the action of DDQ (Table
1). This methodology provides for the rapid construction of
a variety of highly substituted carbazoles, including substitu-
74
Org. Lett., Vol. 2, No. 1, 2000

tion patterns that are difficult to achieve by existing methods.
Furthermore, this new methodology can be readily adapted
to the formation of polymers by employing bis- or polydi-
enophiles instead of the simple carbodienophiles described
herein.
Reduction of pyrrole ethyl ester 4 followed by acetylation
under standard conditions readily provides 1 on scales as
large as 0.1 mol (Scheme 1). The heating of a solution of 1
Diels-Alder reactions are sequential. Compound 8a could
potentially allow access to unsymmetrically substituted
octahydrocarbazoles simply by utilizing a different dienophile
after isolation of monoadduct 8a.
The corresponding carbazoles 3a-j, with the exception
of 3b,15 were generated in 29-87% yield by oxidation of
the octahydrocarbazoles 2a-j with DDQ (Table 1).16 Struc-
tural confirmation was provided by an X-ray crystal structure
of 3d (Figure 1). The oxidation of 2f-h afforded three
Scheme 1. Synthesis of Pyrrole 1
and any acid stronger than acetic acid (e.g., TsOH, maleic
acid, or HCl) results in the rapid decomposition of 1 and
the formation of an intractable black solid. We believe this
is due to the rapid formation of diene 6 or 7, which undergoes
stereorandom [4 + 2] cycloadditions between dienes (vide
infra).
The formation of 2d was systematically examined, reveal-
ing that the transformation is sensitive to the concentration
of 1, and acid impurities (e.g., maleic acid), but is insensitive
to light and small amounts of O2. The formation of
octahydrocarbazoles 2a-j employed a variety of dienophiles
with yields ranging from 46 to 90%.14 When fumaronitrile
was employed and the reaction prematurely halted, a mixture
of 2i and 8a was isolated. When 8a was reintroduced to the
reaction conditions, 2i was obtained, suggesting that the two
Figure 1. Crystal structure of 3d.
structural isomers, 3f (18%), 3g (29%), and 3h (19%), that
were assigned by HMBC and HMQC NMR spectroscopy
experiments. There does not appear to be electronic regio-
chemical control for the formation of the octahydrocarbazoles
with unsymmetrical dienophiles.
The mechanism for the formation of 2 appears to be two
sequential [4 + 2] cycloadditions between the exocyclic
diene portion of 6 and 9 and a dienophile (Scheme 2).17 The
2,3-dimethylenepyrrole required for the Diels-Alder reaction
can be generated by the thermal elimination of acetic acid
to form 6 (Scheme 2), which is observed by mass spectros-
copy.18 There are two possible pathways by which 6 can
(10) 2a: 1H NMR (399.95 MHz, DMSO-d6) 2.65 (dd, J ) 15.3, 7.49
Hz; 2H), 2.70 (dd, J ) 15.82, 7.86 Hz; 2H), 2.82 (dd, J ) 15.3, 2.18 Hz;
2H), 2.95 (dd, J ) 15.82, 1.91 Hz; 2H), 3.66 (ddABq, J ) 9.86, 7.49, 2.18
Hz; 2H), 3.73 (ddABq, J ) 9.86, 7.86, 1.91 Hz; 2H), 4.95 (ABq, J ) 16.77
Hz, 1H), 5.08 (ABq, J ) 16.77 Hz, 1H), 6.88-6.93 (m, 2H), 7.20-7.32
(m, 3H); 13C NMR (100.58 MHz, DMSO-d6) 20.47, 20.68, 40.20, 40.39,
45.82, 111.79, 124.25, 126.28, 127.20, 128.60, 138.29, 175.39, 175.57; MS
(EI, 70 eV) exact mass calcd for C23H19NO6 405.1204, found 405.1212.
(11) The relative stereochemistry of 2a, 2b, 2c, and 2d was assigned on
the basis of the splitting pattern of the benzylic protons. The trans
arrangement of the anhydrides or imides makes the protons on the benzylic
carbon diastereotopic, thus giving rise to an ABq in the 1H NMR. If the
anhydrides or imides were oriented cis, the benzylic protons would be
1
homotopic, giving rise to a singlet in the H NMR.
(15) Carbazole 3b was not observed in attempts to oxidize a mixture of
2b and 2c with DDQ.
(12) Diels-Alder reactions with in situ generated 2,3-dimethylenepyrroles
and dienophiles for the generation of 4,5-carbodisubstituted-2,3,4,5-
tetrahydroindoles. Chou, T.; Chang, R. J. Chem. Soc., Chem. Commun. 1992,
549-551.
(16) Representative Oxidation. Synthesis of 3a: A solution of 2a (50
mg, 0.151 mmol) and DDQ (112 mg, 0.49 mmol) in 1,4 dioxane (8.5 mL,
distilled from Na°) was stirred at room temperature under Ar in a dry round-
bottom flask for 23 h. The precipitated 4,5-dichloro-3,6-dihydroxyphtha-
lonitrile was filtered, and the dioxane was removed in vacuo to afford a
brown solid, which was purified by flash chromatography (SiO2, THF:CH2-
Cl2, 1:1) to afford 42.6 mg (0.11 mmol, 87%) of 3a as a yellow solid: mp
>310 °C; 1H NMR (499.70 MHz, DMSO-d6) 6.04 (s, 1H), 7.18-7.20 (m,
2H), 7.25-7.30 (m, 3H), 8.55 (s, 2H), 9.26 (s, 2H); 13C NMR (125.7 MHz,
DMSO-d6) 46.65, 108.67, 120.98, 122.71, 126.80, 127.27, 127.92, 128.88,
130.44, 136.16, 145.53, 163.31, 163.45; MS (EI, 70 eV) exact mass calcd
for C23H11NO6 397.0586, found 397.0581.
(17) The formation of 2a, 2b, 2c, and 2d are stereospecific and arise
from two sequential [4 + 2] cycloaddition reactions. When fumaronitrile
is used as a dienophile, two diastereomers of 2i are observed that were not
separated, and thus, the relative configurations of the nitriles were not
determined. The transformation with ethyl maleate affords six diastereomers
of 2e. We hypothesize that the 2e mixture arises from isomerization of the
dienophile and/or epimerization of each cycloadduct.
(13) Diels-Alder reactions have been reported with in situ generated
indole-2,3-quinodimethanes for the generation of 2,3-carbodisubstituted-
1,2,3,4-tetrahydrocarbazoles. (a) Gallagher, T.; Magnus, P. Tetrahedron 1981
37, 3889-3897. (b) Marinelli, E. R. Tetrahedron Lett. 1982, 23, 2745-
2748. (c) Saulnier, M. G.; Gribble, G. W. Tetrahedron Lett. 1983, 24, 5435-
5438. (d) Saroja, B.; Srinivaan, P. C. Tetrahedron Lett. 1984, 25, 5429-
5430. (e) Vice, S. F.; Carvalho, H. N.; Taylor, N. G.; Dmitrienko, G. I.
Tetrahedron Lett. 1989, 30, 7289-7292. (f) Pindur, U.; Haber, M.
Tetrahedron 1991, 47, 1925-1936. (g) Pindur, U.; Haber, M. Heterocycles
1991, 32, 1463-1470. (h) Fray, E. B.; Moody, C. J.; Shah, P. Tetrahedron
1993, 49, 439-450.
(14) General experimental for 2a-j: A solution of 1 (50 mg, 0.151
mmol) and dienophile (0.81 mmol, free of acid) in mesitylene (4 mL,
distilled from Na°) was refluxed in a dry round-bottom flask fitted with an
air-cooled reflux condenser under Ar until all of 1 was consumed. The
solution was cooled, and the solvent was removed in vacuo.
Org. Lett., Vol. 2, No. 1, 2000
75

undergoes a second elimination of acetic acid to form 9
(observed in MS of 8a).22 This is followed by a second
Diels-Alder reaction to form 2. Attempts to improve the
yield of 2 by accelerating the elimination of acetic acid by
acid or base catalysis failed.23
Scheme 2. Mechanism of Formation of Octahydrocarbazole 2
The yields for the formation of 2a, 2e, 2f-h, and 2i appear
to be related to the relative reactivity of the dienophiles
toward cyclopentadiene in a Diels-Alder reaction.24 The
reactivity of maleic anhydride and N-methylmaleimide,
which show the best yields, are approximately 2 orders of
magnitude greater than the dienophiles in entries 3-6. The
reduced yields in entries 3-6 may be due to the reduced
reactivity of the dienophiles, allowing the diene concentration
to increase. Therefore, nonproductive [4 + 2] cycloadditions
between dienes to form dimers and polymer would be more
likely to occur.25,26 This is consistent with the observation
that a reduction in the concentration of 1 results in an increase
in the yield of 2.
In conclusion, this study demonstrates the effective
synthesis of 2,3,6,7-tetrasubstituted-1,2,3,4,5,6,7,8-octahy-
drocarbazoles 2 and 2,3,6,7-tetrasubstituted carbazoles 3. The
generation of 2 proceeds through the sequential generation
of 6 and 9, each of which undergoes a [4 + 2] cycloaddition
reaction.
Acknowledgment. This work has been supported by the
UIUC Research Board and a Procter and Gamble Fellowship
in Synthetic Organic Chemistry. NMR spectra were obtained
in the Varian Oxford Instrument Center for Excellence in
NMR Laboratory.
proceed to 2. The first is the elimination of a second molecule
of acetic acid from 6 to form 5-benzyl-aza[5]radialene (7),
which is also observed by mass spectroscopy.19,20 Radialene
7 can subsequently undergo the tandem Diels-Alder reac-
tions with 2 equiv of dienophile to generate 2. In the second
pathway, 6 reacts with a dienophile to form 8,21 which
Supporting Information Available: X-ray structure
tables for 3d. Full experimental details and characterization
data for compounds 1, 2a-j, 3a-j, and 8a. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL991220O
(22) Triene 9 (R ) CN) was observed in the mass spectrum: MS (EI,
70 eV) mass calcd for C19H17N3 287, found 287.
(23) Use of pyridine in the formation of 2d resulted in a reduction of
the yield from 89% to 70%. Use of DBU and KHMDS resulted in the rapid
decomposition of 1. The use of acids such as TsOH, maleic acid, or HCl
resulted in the decomposition of 1.
(24) Sauer, J.; Wuest, H.; Mielert, A. Chem. Ber. 1964, 97, 3183-3207.
(25) In an analogous reaction, dimers were isolated for indole-2,3-
quinodimethanes12 and furanoradialene.20
(18) Triene 6 was observed in the high-resolution mass spectrum of 1:
MS (EI, 70 eV) exact mass calcd for C17H19NO2 269.1415, found 296.1416.
(19) Radialene 7 was observed in the high-resolution mass spectrum of
1: MS (EI, 70 eV) exact mass calcd for C15H15N 209.1205, found 209.1210.
(20) In an analogous reaction, Trahanovsky and Cassady isolated
furanoradialene at -60 °C via the flash vacuum pyrolysis of 3,4-bis-
(acetoxymethyl)-2,5-dimethylfuran. Trahanovsky, W. S.; Cassady, T. J. J.
Am. Chem. Soc. 1984, 106, 8197-8201.
(21) The monoadduct 8a was isolated when the reaction was not allowed
to go to completion.
(26) The yield of the dimers of indole-2,3-quinodimethanes increased
as with the less reactive dienophiles.12g
76
Org. Lett., Vol. 2, No. 1, 2000