Aryl hydrazide beyond as surrogate of aryl hydrazine in the Fischer indolization: The synthesis of N-Cbz-indoles, N-Cbz-carbazoles, and N,N-Bis-Cbz-pyrrolo[2,3-f]indoles

Article abstract of DOI:10.1021/ol902250x

"Chemical Equation Presented" Aryl hydrazides underwent the Fischer indolizatlon reactions, while the N-carbamate group(s) remained intact to directly provide N-Cbz-indoles. This new method allowed the synthesis of various N-Cbz-carbazoles and N,N-bis-Cbz

Full text of DOI:10.1021/ol902250x

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5454-5456
Aryl Hydrazide beyond as Surrogate of
Aryl Hydrazine in the Fischer
Indolization: The Synthesis of
N-Cbz-indoles, N-Cbz-carbazoles, and
N,N′-Bis-Cbz-pyrrolo[2,3-f]indoles
In-Keol Park, Sung-Eun Suh, Byeong-Yun Lim, and Cheon-Gyu Cho*
Department of Chemistry, Hanyang UniVersity, Seoul 133-791, Korea
ccho@hanyang.ac.kr
Received September 29, 2009
ABSTRACT
Aryl hydrazides underwent the Fischer indolization reactions, while the N-carbamate group(s) remained intact to directly provide N-Cbz-
indoles. This new method allowed the synthesis of various N-Cbz-carbazoles and N,N′-bis-Cbz-pyrrolo[2,3-f]indoles.
The indole nucleus is arguably the most privileged molecular
scaffold in nature.1 A wide variety of important biological
activities featured by a plethora of indole-based natural
products have driven them to be highly attractive targets for
synthesis over the years.2 A number of elegant synthetic
methods and strategies, most notably those based on the Pd-
catalyzed C-N bonding formation, have been developed and
successfully applied for the synthesis of indoles and related
products.3 The Fischer indole synthesis,4 reported over 100
years ago, still remains of considerable value, although
somewhat compromised by the poor availability of the
starting aryl hydrazines. In our previous report,5 we have
demonstrated that aryl hydrazides 1 are effective surrogates
of aryl hydrazines in the Fischer indolization reaction. The
use of more readily accessed aryl hydrazides 16 (than aryl
hydrazines) would thus complement the above limitation in
the conventional Fischer method (Scheme 1).7
Scheme 1. Fischer Indolization of Aryl Hydrazide 1
(1) Saxton, J. E. The Chemistry of Heterocyclic Compounds; Wiley: New
York, 1983; Vol. 25, Part IV.
(2) (a) Rahman, A. Indole Alkaloids; Harwood Academic Publisher:
Amsterdam, 1998. (b) Raffauf, R. F. A Handbook of Alkaloids and Alkaloid-
containing Plants; Wiley-Interscience: New York, 1970. (c) Manske,
R. H. F.; Holmes, H. L. The Alkaloids: The Ergot Alkaloids; Academic
Press: New York, 1965; Vol. 8, p 725.
As a part of our ongoing study exploring the synthetic
utility of aryl hydrazides,8 we have elaborated the double
Fischer indolization9 of 1,4-phenylene-bishydrazide 4 toward
the synthesis of the indolo[3,2-b]carbazole system (Scheme
2). The requisite 1,4-phenylene-bishydrazide 4 was prepared
from the Cu(I)-catalyzed coupling reaction of BocNHNH2
with 1,4-diiodobenzene.6d A subsequent reaction with cy-
clohexanone gave bishydrazone 5 in 82% isolated yields.
(3) For reviews, see: (a) Humphrey, G. R.; Kuethe, J. T. Chem. ReV.
2006, 106, 2875. (b) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873.
(c) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285. (d) Nakamura, I.;
Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (e) Gribble, G. W. J. Chem.
Soc., Perkin Trans. I 2000, 1045. (f) Hegedus, L. S. Angew. Chem., Int.
Ed. 1988, 27, 1113.
(4) For reviews, see: (a) Robinson, B. The Fischer Indole Synthesis;
John Wiley and Sons: Chichester, 1982. (b) Hughes, D. L. Org. Prep.
Proceed. Int. 1993, 25, 609.
10.1021/ol902250x CCC: $40.75
Published on Web 11/03/2009
 2009 American Chemical Society

Further extension to the synthesis of N-Cbz-carbazoles was
elaborated by first preparing tetrahydro-N-Cbz-carbazoles
12a-12l from the reactions of aryl hydrazides 10a-10l with
cyclohexanone (Table 2). The substrates with a meta-
Scheme 2. Fischer Reaction of Bishydrazide 4
Table 2. Syntheses of N-Cbz-carbazoles
When heated with catalytic amount of HCl(aq) in EtOH, it
afforded octahydroindolo[3,2-b]carbazole 6 and octahydroin-
dolo[2,3-c]carbazole 8 in 14% and 43% yield, respectively,
together with various other byproducts including, to our
surprise, the carbazoles 7 and 9 bearing Boc groups attached,
albeit in low yields.10
entry
arylhydrazide
10a (R1 ) H)
time 12 (yield) time 13 (yield)
1
2
3
4
5
6
7
2 h 12a (86%) 1 h 13a (87%)
2 h 12b (98%) 1 h 13b (85%)
2 h 12c (98%) 1 h 13c (80%)
10b (R1 ) p-OMe)
10c (R1 ) p-Me)
10d (R1 ) p-CO2Me) 5 h 12d (70%) 3 ha 13d (49%)
10e (R1 ) p-t-Bu)
10f (R1 ) p-Ph)
10j (R ) m-OMe)
6 h 12e (85%) 1 h 13e (86%)
6 h 12f (86%) 1 h 13f (86%)
6 h 12j (53%)b 1 h 13j (80%)
12j′ (32%)b 1 h 13j′ (88%)
These unprecedented results11 prompted us to reinvestigate
our previous study (Scheme 1) and screen the conditions that
may tolerate the presence of an N-Boc group. A series of control
experiments were then conducted on the Fischer reaction of
phenyl hydrazide 1a (R1 ) H) with 2-butanone, as a model,
which involved variation of reaction temperature, solvent, and
acid catalyst. Running the reaction in MeOH at 50 °C with 2
equiv of conc. H2SO4 turned out to be the best, which furnished
2,3-dimethyl-N-Boc-indole, but only up to 20% yield.
With no further improvement availed, aryl hydrazide 10a
bearing a less acid labile N-Cbz group was prepared from
the Cu(I)-catalyzed coupling reaction of CBzNHNH2 with
phenyl iodide (Supporting Information for details). To our
delight, its reaction with ketone 2a in boiling MeOH provided
N-Cbz-indole 11a in 95% yield (entry 1, Table 1). The
reactions with various other aryl hydrazides 10b-10j also
proceeded smoothly to afford N-Cbz indoles 11b-11l in fair
to excellent isolated yields.
8
9
10k (R ) m-Me)
10l (R1 ) p-hexyl)
3 h 12k (87%)c 1 h 13k (67%)c
6 h 12l (87%)
1 h 13l (77%)
a At 50 °C. b Two regioisomers 12j (R ) 6-OMe) and 12j′ (R ) 4-OMe)
were separated and subjected to aromatization. c For a mixture of two
regioisomers.
substituent provided a mixture of two regioisomers (entries
7 and 8). Subsequent oxidative aromatization with DDQ in
benzene afforded the corresponding N-Cbz-carbazoles
13a-13l mostly in good yields, except the one with the
methyl ester group (12d, entry 4).12 In entry 7, the isomeric
products 12j and 12j′ were separated by column chroma-
tography and subjected individually to the aromatization
reaction to give 13j and 13j′.
Table 1. Double Fischer Indolization of 10
entry
10
2
time
N-CBz-indole
1
2
3
4
5
6
7
8
9
10a (R1 ) H)
2a (R2 ) Me)
2a (R2 ) Me)
2a (R2 ) Me)
2a (R2 ) Me)
2b (R2 ) nBu)
2c (R2 ) CH2CO2Me)
2a (R2 ) Me)
2a (R2 ) Me)
2a (R2 ) Me)
2a (R2 ) Me)
2a (R2 ) Me)
2a (R2 ) Me)
2 h
2 h
2 h
72 h
4 h
24 h
4 h
11a (95%)
11b (91%)
11c (84%)
11d (50%)
11e (71%)
11f (73%)
11g (77%)
11h (93%)
11i (75%)
11j (77%)
11k (40%)
11l (91%)a
10b (R1 ) p-OMe)
10c (R1 ) p-Me)
10d (R1 ) p-CO2Me)
10a (R1 ) H)
10b (R1 ) p-OMe)
10e (R1 ) p-tBu)
10f (R1 ) p-Ph)
10g (R1 ) p-Br)
10h (R1 ) p-NH2)
10i (R1 ) o-Me)
10j (R1 ) m-OMe)
8 h
12 h
12 h
2 h
10
11
12
12 h
a 6:4 mixture of two regioisomers.
Org. Lett., Vol. 11, No. 23, 2009
5455

For the synthesis of the pyrrolo[2,3-f]indole system, we
prepared 1,4-phenylene bishydrazide 14 from 1,4-diiodo-
benzene via the Cu(I)-catalyzed coupling reaction with
benzyl carbazate (75% yield). The double Fischer reactions
of bishydrazide 14 with ketones 2 afforded a mixture of
pyrrolo[2,3-f]indoles 15 and pyrrolo[3,2-e]indoles 16 in good
to fair total yields (Table 3). Although inseparable on column
value as there are no other general methods available in the
literature for the synthesis of pyrrolo[2,3-f]indoles.14
In summary, aryl hydrazides underwent the Fischer
indolization reactions while the N-carbamate group(s) re-
mained intact, to provide N-Cbz-indoles, N-Cbz-carbazoles,
and N,N′-bis-Cbz-pyrrolo[2,3-f]indoles.
Acknowledgment. This work was supported by the grant
from the Korea Science and Engineering Foundation through
Center for Bioactive Molecular Hybrids (CBMH), Yonsei
University. PIK thanks the BK21 Fellowship.
Table 3. Syntheses of N,N′-Bis-Cbz-pyrrolo[2,3-f]indoles
Supporting Information Available: Details of experi-
mental procedures and compound characterizations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL902250X
entry
ketone
R1 ) R2 ) Me
time
yield (ratio)a
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2
12 h 95% (15a:16a ) 3:2)
12 h 90% (15b:16b ) 1:2)
R1 ) Me, R2 ) nBu
3
4
5
6
R1 ) Me, R2 ) CH2CO2Me 72 h 55% (15c:16c ) 5:1)
R1 ) Me, R2 ) CH2Ph
R1 ) Ph, R2 ) Me
12 h 76% (15d:16d ) 1:2)
12 h 57% (15e:16e ) 1:1)
12 h 50% (15f:16f ) 1:1)
24 h 47% (15g:16g ) 2:3)
1
R1 ) Ph(2-F), R2 ) Me
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