A highly efficient and flexible synthesis of substituted carbazoles by rhodium-catalyzed inter- and intramolecular alkyne cyclotrimerizations

Article abstract of DOI:10.1002/1521-3773(20020902)41:17<3281::AID-ANIE3281>3.0.CO;2-G

An A→ABC or A→ABCD ring-formation strategy proves extremely efficient for generating substituted carbazoles ([Eq. (1)]; Ts = tosyl). Inter- and intramolecular alkyne cyclotrimerizations mediated by Wilkinson's catalyst provide substituted carbazoles of re

Full text of DOI:10.1002/1521-3773(20020902)41:17<3281::AID-ANIE3281>3.0.CO;2-G

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Kato, H. Kaneko, A. Nishida, M. Nakagawa, J. Chem. Soc. Perkin
Trans. 1 2000, 1873 1876; for insightful discussion see: e) A. F¸rstner,
K. Radkowski, C. Wirtz, R. Goddard, C. W. Lehmann, R. Mynott, J.
Am. Chem. Soc. 2002, 124, 7061 7069.
[9] a) P. Schwab, M. B. France, J. W. Ziller, R. H. Grubbs, Angew. Chem.
1995, 107, 2179 2181; Angew. Chem. Int. Ed. Engl. 1995, 34, 2039
2041; b) P. Schwab, R. H. Grubbs, J. W. Ziller, J. Am. Chem. Soc. 1996,
118, 100 110.
[10] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1, 953
956.
Scheme 1. A!ABC or A!ABCD ring-formation approach to substituted
carbazoles by rhodium-catalyzed alkyne cyclotrimerization.
[11] CCDC-187042 and CCDC-187043 contain the supplementary crys-
tallographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (þ 44)1223-336-033; or deposit@ccdc.ca-
m.ac.uk).
[12] For insightful discussion into the effects of entropy in the olefin
metathesis reaction and examples see: a) A. F¸rstner, K. Langemann,
J. Org. Chem. 1996, 61, 3942 3943; b) A. F¸rstner, K. Langemann,
Synthesis 1997, 792 803; c) A. F¸rstner, G. Seidel, N. Kindler,
Tetrahedron 1999, 55, 8215 8230; d) C. Galli, L. Mandolini, Eur. J.
Org. Chem. 2000, 3117 3125.
The diynes 2 were prepared in three steps starting from
readily available 2-iodoanilines 1. Sonogashira reactions
between 1 and terminal alkynes 5 followed by N-tosylation
of the aniline functionality gave alkynes 6, which thereafter
underwent N-ethynylation with alkynyliodonium salts 7 to
give the diynes 2 in good overall yields (Scheme 2, path A).
[13] It should be noted that no flash column chromatography was required
in the last two steps because compounds 22a, 22b, 1, and 2 were
isolated after a standard base/acid workup as spectroscopically pure
compounds.
R1
+ Ph
I
-
c) R2
R1
(R1 = H)
R
OTf
a) H
b)
5
7
R2: SiMe3, Ph, H
NHTs
Path A
Path B
6
2
1
(R1 = H)
R1
R
H
d)
A Highly Efficient and Flexible Synthesis of
Substituted Carbazoles by Rhodium-Catalyzed
Inter- and Intramolecular Alkyne
Cyclotrimerizations**
I
R2
b)
c)
5
+
I
R2: SiMe3
Ph
-
N
Me3Si
OTf
Ts
7a
8
Scheme 2. a) 5 (1.3 equiv), 5 mol% [PdCl2(PPh3)2], 10 mol% CuI, NEt3,
DMF, room temperature, 60 98%; b) TsCl, pyridine, THF, 70 92%;
c) potassium hexamethyldisilazane (KHMDS), toluene, 08C, then addition
of 7 (1.4 equiv), room temperature, 52 93% for 6!2, 87 98% for 8; d) 5
(1.4 equiv), 5 mol% [PdCl2(PPh3)2], 10 mol% CuI, 10 mol% PPh3, NEt3,
DMF, 808C, 54 68%.
Bernhard Witulski* and Carole Alayrac
Syntheses of substituted carbazoles have attracted consid-
erable attention because carbazole alkaloids are a growing
class of natural products that exhibit a variety of biological
activities.[1,2] Moreover, annelated carbazoles structurally
related to the natural indolocarbazole staurosporine have
gained significance because of their protein kinase C (PKC)
and topoisomerase inhibitory activity.[3]
Although several syntheses of substituted carbazoles as
well as chemical modifications of the carbazole nucleus are
established,[1,4] the major challenge in carbazole chemistry
arises from the question of how to functionalize regioselec-
tively up to eight aromatic ring positions. We have designed a
strategy for the assembly of the carbazole nucleus by an
A!ABC or A!ABCD ring-formation approach that is
based on the reliability of the Sonogashira reaction,[5] our
previously reported synthesis of functionalized ynamides,[6]
and the efficiency of transition-metal-catalyzed alkyne cyclo-
trimerizations (Scheme 1).[7]
Alternatively, N-ethynylation reactions with 7a were carried
out with tosylated 1 to give the ynamides 8, which were then
converted to 2 through Sonogashira reactions (Scheme 2,
path B). While the conversion of 1 to 6 proceeded readily at
room temperature, cross-coupling reactions with 8 to give 2
required heating to 808C, probably because of an increase of
steric hindrance. Notably, the use of trimethylsilylacetylene in
the Sonogashira reaction, or the use of 7a for the N-
ethynylation reaction following either path A or B in
Scheme 2 allowed further manipulations of the diynes 2
through protective group strategies.
Crossed alkyne cyclotrimerizations between diynes 2 and
monoalkynes 3 promoted by Wilkinson©s catalyst[6b,8] pro-
ceeded under very mild conditions (3 5 mol% [RhCl(PPh3)3],
5 6 equivalents of 3, toluene as solvent) to give the carbazoles
4 in high yields (Scheme 1, Table 1). Notably, the additional
triple bond in 2e did not interfere with the formation of
carbazole 4e (80% yield, Table 1, entry 5). The outstanding
efficiency of the carbazole formation by crossed alkyne
cyclotrimerizations is presumably a consequence of confor-
mational restrictions present in the diynes 2. A conformation
in which both alkyne moieties are close to each other appears
likely and therefore favors the overall catalytic process.
[*] Priv.-Doz. Dr. B. Witulski, Dr. C. Alayrac
Fachbereich Chemie der Universit‰t Kaiserslautern
Erwin-Schrˆdinger-Strasse, 67663 Kaiserslautern (Germany)
Fax : (þ 49)631-205-3921
E-mail: witulski@rhrk.uni-kl.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. C.A. is grateful to the
Alexander von Humboldt Foundation for a Research Fellowship.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
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Table 1. Functionalized carbazoles 4 through rhodium-catalyzed crossed alkyne cyclotrimerizations (3 5 mol% [RhCl(PPh3)3], 5 6 equivalents of
monoalkyne 3, toluene, room temperature, 1 12 h).
Entry
Diyne 2
Monoalkyne 3
Carbazole 4
Isomer ratio
Yield [%]
1
2
3
4[b]
2a: R1 ¼ H; R2 ¼ H
3a
3a
3a
3a
4a: R1 ¼ H; R2 ¼ H
90
95
98
90
2b: R1 ¼ CH2OTHP;[a] R2 ¼ H
2c: R1 ¼ H; R2 ¼ Ph
4b: R1 ¼ CH2OTHP; R2 ¼ H
4c: R1 ¼ H; R2 ¼ Ph
2d: R1 ¼ CH2OTHP; R2 ¼ SiMe3
4d: R1 ¼ CH2OTHP; R2 ¼ SiMe3
5[c]
2
2
2
e
c
f
3b
3c
3c
4e
80
95
6
4 f (5:1)
7
4gtoluene: (3.5:1)
89
71
ethanol: (1.4:1)
8
9
2
2
g
a
3c
3d
4htoluene: (1.5:1)
ethanol: (5.8:1)
97
68
4i (4:1)
72
10
11
12
2
2
2
h
c
c
3d
3e
3 f
4j (3.8:1)
4k(6:1)
4l (1:1)
78
91
98
[a] THP ¼ tetrahydropyran. [b] T¼ 808C, 17 h. [c] T¼ 408C, 19 h.
Cyclotrimerizations of diynes 2 with the terminal mono-
alkyne 3c afforded one major regioisomer of 4 (Table 1,
entries 6 8).[9] In agreement with previously reported crossed
alkyne cyclotrimerizations utilizing Wilkinson©s catalyst,[8e,g]
regioselectivities observed in the carbazole series were based
on a complex interplay between steric factors and on solvent
effects. In the case of 4g, for which the ortho isomer was
favored, the regioselectivity was best in toluene (Table 1,
entry 7), whereas in the case of 4h, for which the meta isomer
was favored, the selectivity could be significantly improved by
using ethanol as solvent (Table 1, entry 8). Furthermore,
regioselectivity was influenced by electronic parameters.
Although electron-deficient monoalkynes are poor cyclo-
trimerization partners, the reaction of propiolic ester 3d with
the diynes 2a and 2h afforded the carbazoles 4i (72% yield,
ratio of isomers 4:1) and 4j (78% yield, ratio of isomers
3.8:1), respectively, as major isomers. Using the electron-
deficient disubstituted monoalkyne 3e a high selectivity was
achieved in the preparation of carbazole 4k (Table 1, en-
try 11). The latter result was again driven by electronic effects
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as revealed by the lack of regioselectivity observed with the
electron-neutral disubstituted monoalkyne 3 f (Table 1, en-
try 12).
carbazole 4m was obtained with excellent chemo- and
regioselectivity by utilizing the electron-rich monoalkyne 3g
and Wilkinson©s catalyst (89% yield, isomer ratio ¼ 30:1,
toluene, 208C). Isomerically pure hyellazole was thereafter
obtained through deprotection of the tosyl group (Ts) with
TBAF in refluxing THF followed by crystallization. With only
six steps starting from commercially available 2-iodoaniline
and an overall yield of 39%, this synthesis of hyellazole
becomes the most efficient one in terms of conciseness and
overall yield.[13]
Finally, the intramolecular version of this new carbazole
synthesis offered a straightforward access to annelated
carbazoles (Scheme 4). Although intramolecular alkyne cy-
clotrimerizations are completely regioselective due to an
additional tether, the synthesis of the corresponding triynes is
normally much more demanding. However, in the carbazole
series this could be easily solved by using the Sonogashira
reaction for the assembly of the triynes 13, and 15a and 15b.
They were obtained in 80, 71, and 66% overall yield,
respectively, starting from 11. Intramolecular cyclotrimeriza-
tions in the presence of 2 5 mol% Wilkinson©s catalyst
afforded then the annelated carbazoles 4n, 4o, and 4p (77
99% yield). Notably, the intramolecular version not only
allowed the use of two ynamide moieties, it also offered the
possibility for a six-membered-ring annelation that cannot be
achieved easily in the corresponding crossed version of this
reaction.
To illustrate the applicability of our method in natural
product synthesis, the target-oriented syntheses of two
naturally occurring carbazole alkaloids–clausine C and hy-
ellazole–were investigated. Clausine C,[10] which was recent-
ly isolated from the stem bark of Clausena excavata, a wild
shrub that has been claimed to be a useful folk medicine in the
treatment of snake bites, was readily accessible after depro-
tection of carbazole 4j (Table 1, entry 10) with tetrabutylam-
monium fluoride (TBAF) in refluxing THF (98% yield).[11]
Clausine C was thus obtained in six steps from 2-iodo-5-
methoxyaniline with an overall yield of 40%.
Further potential of our methodology was demonstrated
through the straightforward synthesis of hyellazole, a marine
carbazole alkaloid isolated from the blue-green algae Hyella
caespitosa.[12] The key step of our synthesis resides in the
regioselective alkyne cyclotrimerization of diyne 2c with 1-
methoxy-propyne 3g (Scheme 3). Based on previous results
with electron-deficient monoalkynes, we expected that the
use of an electron-rich monoalkyne as cyclotrimerization
partner would invert the regioselective outcome of the
reaction as observed with 3e (Table 1, entry 11). Indeed,
H
H
+
I
Ph
–
d) Ph
OTf
a) – c)
7b
1
In conclusion, we have developed a novel synthesis of
substituted carbazoles based on inter- and intramolecular
alkyne cyclotrimerizations. The flexibility of this approach
and the diversity of the carbazole substitution pattern that can
be reached now permits application of this methodology in
the synthesis of natural products and drug-related targets.
NHTs
N
Ts
9
2c
OCH3
OCH3
CH3
H3C
OCH3
CH3
f)
3g
e)
Received: May 31, 2002 [Z19409]
N
N
Ts
H
[1] a) P. T. Gallagher, Science of Synthesis, Vol. 10, Thieme, Stuttgart,
2000, pp. 693 744; b) H.-J. Knˆlker in Advances in Nitrogen Hetero-
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Brunner, C. Jutz, Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952 ,
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Academic Press, New York, 1993, p. 257; b) D. P. Chakraborty, S.
Roy, Prog. Chem. Org. Nat. Prod. 1991, 57, 71.
Hyellazole
4m (30:1)
Scheme 3. Synthesis of hyellazole: a) trimethylsilylacetylene (1.3 equiv),
5 mol% [PdCl2(PPh3)2], 10 mol% CuI, Et3N, DMF room temperature,
quant.; b) TsCl, pyridine, THF, 89%; c) TBAF, THF, 08C, 90%;
d) KHMDS, toluene, 08C, then addition of 7b (1.4 equiv), 56%; e) 3g
(10 equiv), 10 mol% [RhCl(PPh3)3], toluene, room temperature, 89%;
f) TBAF, THF, reflux, 98%.
Ts
N
N
Ts
a)
b)
N
H
CH3
CH3
Ts
c)
12
CH3
N
N
Ts
Ts
I
SiMe3
4n
13
N
Ts
11
NTs
Ts
NTs
N
Ts
(CH2)n
N
a)
SiMe3
H
d)
(CH2)n
or
14a: n = 1; 14b: n = 2
H
N
N
Ts
Ts
b)
N
Ts
15a: n = 1; 15b: n = 2
4o
4p
Scheme 4. Annelated carbazoles by intramolecular alkyne cyclotrimerization. a) terminal alkyne 12 or 14a or 14b (1.3 equiv), 5 mol% [PdCl2(PPh3)2],
10 mol% CuI, 10 mol% PPh3, Et3N, DMF, 808C, 2 h, 13 (89%), 15a or 15b, (79 84%); b) TBAF, THF, 08C, 10 min., 85 90%; c) 2 mol% [RhCl(PPh3)2],
toluene, room temperature, 12 h, 99%; d) 5 mol% [RhCl(PPh3)2], CH2Cl2, 408C, 15 h, 4o (95%), 4p (77%).
Angew. Chem. Int. Ed. 2002, 41, No. 17
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Transannular Radical Cascade as an Approach
to the Diastereoselective Synthesis of Linear
Triquinane**
Anne-Lise Dhimane, Christophe AÔssa, and
Max Malacria*
Diastereoselective constructions of polycyclic structures
such as triquinanes by 5-exo-radical-cyclization cascade
reactions that start from a templating ring are well-known;[1]
from acyclic systems only a few such reactions involve
[2]
diastereoselective processes. However, transannular cycli-
zations, which are nowadays frequently used as a key step in
the synthesis of polycyclic frameworks,[3] have been poorly
described as an efficient means of reaching linear triquinane
systems diastereoselectively. There is only one specific
example reported by Winkler in which linear triquinanes
were obtained as a mixture of diastereomers, from suitably
substituted cycloocta-1,5-dienes, by a unique transannular
process.[4]
[5] K. Sonogashira in Metal-catalyzed Cross-Coupling Reactions (Eds.: F.
Diederich, P. J. Stang), Wiley-VCH, Weinheim, 1998.
[6] a) B. Witulski, T. Stengel, Angew. Chem. 1998, 110, 495; Angew.
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1999, 111, 2521; Angew. Chem. Int. Ed. 1999, 38, 2426; c) B. Witulski,
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Buschmann, U. Bergstr‰˚er, Tetrahedron 2000, 56, 8473; e) B.
Witulski, M. Gˆ˚mann, Synlett 2000, 1793; for other contributions
to the chemistry of ynamides, see: f) D. Br¸ckner, Synlett 2000, 1402;
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Rainier, J. E. Imbriglio, J. Org. Chem. 2000, 65, 7272; i) J. A. Mulder,
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[9] Isomers of 4 were separated by either chromatography on silica gel
(4 f g, 4k, and 4l), crystallization (4i), or after detosylation with
tetrabutylammonium fluoride (TBAF) (4h and 4j).
[10] T.-S. Wu, S.-C. Huang, P.-L. Wu, Phytochemistry 1996, 43, 1427.
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During the last decade, we have been interested in the
development of highly chemo-, regio-, and stereoselective
cascade processes which rely on radical transannular reac-
tions.[5] The diastereoselective total synthesis of the proto-
illudane epi-illudol, which has an angularly fused 4,6,5-
tricyclic framework, was achieved by a cascade of radical
transannular cyclizations from a (bromomethyl)dimethylsilyl
(BMDMS) ether of a cycloundeca-4,8-dien-1-yne (Sche-
me 1).[5b] By following the same type of cascade, we believed
that switching the BMDMS-ether tether from the C-1 atom to
the C-4 atom should now lead to a triquinane skeleton of
type 1. We anticipated that the disubstituted double-bond
geometry would be crucial for the behavior of the trans-
annular cascade. In fact, when the Z,E precursor 2 was
submitted to radical cyclization conditions, the generated
vinyl radical cyclized regioselectively in a 6-endo mode,
leading to the 6,7-bicyclic compound 4(Scheme 1).[5c] In con-
trast, we report herein the stereoselective construction of a
linear triquinane through an unprecedented cascade of
diastereoselective transannular cyclizations from an E,E pre-
cursor.
Access to precursor 3 was envisaged by following a similar
strategy to that developed for the eleven-membered ring 2, by
using Nozaki-Hiyama-Kishi-Takai (NHKT) macrocyclization
as the key step. Thus, E-heptenal 6 (as a common precursor),[6]
was subjected to the mild Horner-Wadsworth-Emmons olefi-
nation conditions described by Masamune and Roush[7] to
furnish, after tetrabutylammonium fluoride (TBAF) medi-
ated cleavage of the resulting silylated ether, the E-a,b-
unsaturated ester 7. Dess-Martin oxidation[8] of the homoal-
[*] Prof. M. Malacria, Dr. A.-L. Dhimane, Dr. C. AÔssa
Laboratoire de Chimie Organique de Synthõse
UMR 7611, CNRS- Universitÿ Pierre et Marie Curie
4, place Jussieu, Tour 44-54, Case 229, 75252 Paris Cedex 05 (France)
Fax : (þ 33)1-44-27-73-60
E-mail: malacria@ccr.jussieu.fr
[**] C.A. acknowledges the M.R.E.S. for financial support.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
3284
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0044-8249/02/4117-3284 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 17