TiCl4/t-BuNH2 as the sole catalyst for a hydroamination-based Fischer indole synthesis

Article abstract of DOI:10.1016/j.tetlet.2004.10.160

A system comprising TiCl₄ and t-BuNH₂ converts alkynes and hydrazines directly to the corresponding indoles in a highly regioselective manner and generates substituted pyrroles from a 1,3-diyne and aniline derivatives. A system comprising TiCl₄ and t-BuNH₂ acts as a catalyst for highly regioselective hydroamination reactions of alkynes using hydrazines and at the same time a Lewis acid in the transformation of the generated hydrazones into indole derivatives, while a 1,3-diyne is converted to pyrroles using the same precatalyst.

Full text of DOI:10.1016/j.tetlet.2004.10.160

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9541–9544
TiCl /t-BuNH as the sole catalyst for a hydroamination-based
4
2
Fischer indole synthesis
*
Lutz Ackermann and Robert Born
Department of Chemistry, Ludwig-Maximilians-Universit a¨ t M u¨ nchen, D-81377 M u¨ nchen, Germany
Received 27 September 2004; revised 28 October 2004; accepted 29 October 2004
Available online 13 November 2004
Abstract—A system comprising TiCl and t-BuNH acts as a catalyst for highly regioselective hydroamination reactions of alkynes
2
4
using hydrazines and at the same time a Lewis acid in the transformation of the generated hydrazones into indole derivatives, while a
,3-diyne is converted to pyrroles using the same precatalyst.
2004 Elsevier Ltd. All rights reserved.
1
ꢀ
1. Introduction
comprising commercially available TiCl and t-BuNH
4 2
for the transformation of hydrazines and unsymmetri-
cally substituted alkynes into indoles in a highly regiose-
The occurrence of the indole subunit in biologically ac-
tive compounds has stimulated continued strong interest
1
0
lective fashion. Furthermore, the scope of a pyrrole
synthesis based on a TiCl -catalyzed hydroamination
of 1,3-diynes is evaluated.
1
in practical syntheses of the indole scaffold. Despite re-
cently developed methodologies, such as palladium-cat-
4
2
alyzed transformations, the classical Fischer-indole
3
cyclization remains one of the most important ap-
proaches. Traditionally, the required hydrazones are
generated via condensation of the corresponding carbo-
nylcompound with a hydrazine derivative. Recen tyl ,
Odom and co-workers presented an elegant, atom-eco-
nomicalapproach to the indoel framework based on
2. Results and discussion
The system generated through the addition of t-BuNH2
to a solution of TiCl in toluene catalyzed the addition
4
of 1,1-disubstituted hydrazines onto aryl- and alkyl-sub-
11
4
intermolecular titanium amide-catalyzed hydroamina-
1
stituted alkynes efficiently (Scheme 1, Table 1). For
most examples the corresponding hydrazone was not
observed according to GC/MS-analysis, but was directly
d,5
tion reactions
hydrazines, followed by a cyclization employing 3–
of alkynes with 1,1-disubstituted
6
5equiv ZnCl . Based on this methodology, Beller and
2
co-workers described a one-pot tryptamine synthesis
via hydroamination of terminal chloroalkylalkynes.
7
R3
For the majority of substrate combinations, in particu-
lar internal alkynes, a subsequent addition of 3–5equiv
ZnCl is necessary to convert the generated hydrazone
R
3
R2
TiCl
, t-BuNH
2
4
+
NH2
2
PhMe, N , 105 °C, 24 - 48h
N
2
6
,7b
N
R1
into the corresponding indole.
procedures for the intermolecular hydroamination of
alkynes and norbornene, using the inexpensive
Lewis-acid TiCl as the precatalyst. Consequently, we
Recently, we reported
N
R1
R
2
8
9
4
-NH3
R3
wondered if the addition of the Lewis-acid ZnCl could
2
be circumvented through the use of our TiCl -based
4
methodology. Herein, we present a user-friendly system
R2
N
Keywords: Hydroamination; Indoles; Titanium.
*
R1
Corresponding author. Tel.: +49 89 2180 77675; fax: +49 89 2180
7425; e-mail: lutz.ackermann@cup.uni-muenchen.de
7
4 2
Scheme 1. TiCl /t-BuNH -catalyzed regioselective indole synthesis.
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.160

9
542
L. Ackermann, R. Born / Tetrahedron Letters 45 (2004) 9541–9544
4
-catalyzed indole synthesis
Table 1. TiCl
1
R
2
R
3
R
a
Isolated yield (%)
Entry
Product
Ph
1
2
3
A
B
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
55
N
N
N
Ph
Ph
b
71
H
Ph
Ph
c
63
A
Et
Et
Ph
CF
3
4
5
6
B
B
B
Ph
Ph
Ph
n-Hex
n-Hex
n-Bu
4-(CF
3
)C
6
H
4
76
70
62
n-Hex
N
Ph
OMe
6 4
4-MeOC H
n-Hex
N
Ph
Cl
4-ClC
6
H
4
n-Bu
N
N
Ph
Ph
7
A
Me
Et
Ph
Et
73
Me
CF3
8
C
Me
n-Hex
3-(CF
3
)C
6
H
4
71
n-Hex
N
Me
Cl
9
C
Me
n-Bu
4-ClC
6
H
4
57
n-Bu
N
Me

L. Ackermann, R. Born / Tetrahedron Letters 45 (2004) 9541–9544
9543
Table 1 (continued)
1
R
2
R
3
R
a
Isolated yield (%)
Entry
Product
Br
10
C
Me
n-Hex
6
4-BrC H
4
66
n-Hex
N
Me
Ph
Cl
11
C
Me
(CH
2
)
4
ClPh
52
4
N
Me
a
b
c
Reaction conditions: 1.0mmola kl yne, 1.0–3.0mmolhydrazine, 2mL PhMe, 24–48h; A: 30mo l% TiCl
4
4 4
, B: 40–50mol% TiCl , C: 1.00equiv TiCl .
At 75ꢁC.
Using Ph NNH Cl.
2 3
converted to the indole derivative. While catalytic quan-
tities of TiCl were sufficient for quantitative conversion
tions (Scheme 2). With the in situ generated catalyst,
1
3
the diyne was quantitatively converted at 105ꢁC.
4
of alkynes using 1,1-diphenylhydrazine (entries 1–6),
stoichiometric amounts proved beneficialfor the synthe-
sis of N-methylsubstituted indo le s (entries 8–11). Termi-
nal ak lynes were more reactive substrates, providing
quantitative conversion of the alkyne even at 75ꢁC
Along with products stemming from hydroamination
of both triple bonds, the corresponding pyrroles were
formed as the major product and obtained in 30% iso-
1
4
lated yield.
1
2
(
entry 2). Also a hydrazine hydrochloride gave the cor-
responding indole with good isolated yield through the
use of an excess of t-BuNH (entry 3).
Acknowledgements
2
Generous support by the Ludwig-Maximilians-Univer-
sit a¨ t, and Professor P. Knochel is gratefully acknowl-
edged. We thank the DFG for financialsupport
(Emmy Noether-Programm).
The hydroamination of unsymmetrically substituted
alkynes proceeded with excellent regioselectivity, giving
rise to a single regioisomer as judged by GC/MS-analy-
sis of the crude reaction mixture (entries 2–11). A variety
of different functionalgroups, such as CF - (entries 4
3
and 8), MeO- (entry 5), Cl- (entries 6 and 9) and Br-sub-
stituents (entry 10) were tolerated, which enables further
elaboration of the products. Interestingly, a chloro-
alkylalkyne proved compatible with our reaction condi-
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2004.10.160.
tions, without any evidence of nucleophilic substitution
7
(
entry 11). Although dodeca-5,7-diyne was quantita-
tively converted under analogous reaction conditions,
the corresponding N-phenyl-substituted indole was only
isolated in a yield of 16%. We considered pyrrole forma-
tion via a sequence consisting of hydroamination and
subsequent 5-endo cyclization as a potential reason for
the low yield in the indole synthesis.
References and notes
1. (a) Gilchrist, T. L. Heterocycl. Chem.; Longman Limited:
Singapore, 1997; (b) Joule, J. A.; Mills, K.; Smith, G. F.
Heterocycl. Chem.; Stanley Thornes Ltd.: Cheltenham,
1
2
998; (c) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1
001, 20, 2491; (d) Alonso, F.; Beletskaya, I. P.; Yus, M.
Chem. Rev. 2004, 104, 3079.
We probed our hypothesis by subjecting different aniline
derivatives and dodeca-5,7-diyne to the reaction condi-
2
3
4
. (a) Hegedus, L. S. Angew. Chem., Int. Ed. 1988, 27, 1113;
(
b) Larock, R. C. J. Organomet. Chem. 1999, 576, 111.
. Robinson, B. The Fischer Indole Synthesis; Wiley & Sons:
Chichester, 1982.
R
n-Bu
R
. (a) Haak, E.; Bytschkov, I.; Doye, S. Angew. Chem., Int.
Ed. 1999, 38, 3389; (b) Heutling, A.; Pohlki, F.; Doye, S.
Chem. Eur. J. 2004, 10, 3059; (c) Johnson, J. S.; Bergman,
R. G. J. Am. Chem. Soc. 2001, 123, 2923; (d) Shi, Y.;
Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20,
2
4 2
0 mol% TiCl , t-BuNH
+
PhMe, N , 105 °C, 18h
2
N
quant. conversion
n-Bu
n-Bu
NH2
n-Bu
3
967; (e) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.;
Odom, A. L. Chem. Commun. 2003, 586; (f) Tillack, A.;
Garcia Castro, I.; Hartung, C. G.; Beller, M. Angew.
Chem., Int. Ed. 2002, 41, 2541; (g) Tillack, A.; Jiao, H.;
Castro, I. G.; Hartung, C. G.; Beller, M. Chem. Eur. J.
R = H, Cl 30%
4 2
Scheme 2. TiCl /t-BuNH -catalyzed pyrrole synthesis using a 1,3-
diyne.

9544
L. Ackermann, R. Born / Tetrahedron Letters 45 (2004) 9541–9544
2
004, 10, 2409; (h) Ong, T.-G.; Yap, G. P. A.; Richeson,
(50mL) and aq HCl(2N, 50mL) were added to the codl
suspension. The separated aq phase was washed with
CH Cl (2 · 50mL). The combined organic phases were
D. S. Organometallics 2002, 21, 2839; (i) Zhang, Z.;
Schafer, L. Chem. Commun. 2003, 2462; (j) Lorber, C.;
Choukroun, R.; Vendier, L. Organometallics 2004, 23,
1649; (k) for a review, see: Bytschkov, I.; Doye, S. Eur. J.
Org. Chem. 2003, 935.
. (a) M u¨ ller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675; (b)
Brunet, J. J.; Neibecker, D. In Catalytic Heterofunctional-
ization; Togni, A., Gr u¨ tzmacher, H., Eds.; Wiley-VCH:
Weinheim, 2001; p 91.
2
2
washed with sat. aq. NaHCO
Drying with MgSO
tography (silica gel, n-pentane/Et
2-ethyl-N-methyl-3-phenylindole as a yellow solid (172mg,
3
(30mL) and brine (30mL).
and purification by column chroma-
O 50/1 ! 30/1) yielded
4
2
5
1
73%).
H
NMR (300MHz, CDCl ): 7.57 (md,
3
d
J = 7.9Hz, 1H), 7.44–7.36 (m, 4H), 7.28–7.21 (m, 2H),
7.18–7.12 (m, 1H), 7.04 (ddd, J = 8.0Hz, 7.1, 1.1Hz, 1H),
3.70 (s, 3H), 2.81 (q, J = 7.5Hz, 2H), 1.23 (t, J = 7.5Hz,
6
. (a) Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853;
(
1
3
b) Li, Y.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2004,
26, 1794.
3H). C NMR (75MHz, CDCl
135.8 (C ), 129.7 (CH), 128.4 (CH), 127.2 (C
(CH), 121.2 (CH), 119.6 (CH), 118.9 (CH), 113.7 (Cq),
108.8 (CH), 29.6 (CH ), 18.1 (CH ), 14.9 (CH ). IR (KBr,
3
): d 139.0 (C
q
), 136.7 (C
q
),
1
q
q
), 125.8
7
. (a) Khedkar, V.; Tillack, A.; Michalik, M.; Beller, M.
Tetrahedron Lett. 2004, 45, 3123; (b) Tillack, A.; Jiao, H.;
Garcia Castro, I.; Hartung, C. G.; Beller, M. Chem. Eur.
J. 2004, 10, 2409.
. Ackermann, L. Organometallics 2003, 22, 4367.
. Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Org. Lett.
3
2
3
ꢀ
1
cm ): 3054 (m), 2978 (m), 2933 (m), 1601 (m), 1470 (vs),
1371 (s), 775 (s), 744 (vs), 704 (vs). MS (EI) m/z (relative
+
intensity) 235 ([M ] 100), 220 (70), 204 (17), 179 (6). HR-
MS (EI) m/z calcd for C17H17N 235.1361, found 235.1355.
8
9
2
004, 6, 2515.
12. Terminal alkynes can react with titanium imido complexes
via formation of anilido-acetylide complexes: Polse, J. L.;
Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1998,
120, 13405.
13. Note that CuClcat ay lzes the hydroamination of 1,3-
diynes to yield pyrroles efficiently, albeit at significantly
higher temperatures of 140–170ꢁC: Schulte, K. E.; Reisch,
J.; Walker, H. Chem. Ber. 1965, 98, 98.
14. Odom presented recently a pyrrole synthesis based on
hydroamination reactions of 1,4- and 1,5-diynes: Rama-
nathan, B.; Keith, A. J.; Armstrong, D.; Odom, A. L. Org.
Lett. 2004, 6, 2957.
1
1
0. For sequences consisting of a titanium-catalyzed hydro-
amination reaction and a subsequent palladium-catalyzed
transformation, see Ref. 8 and: Bytschkov, I.; Siebenrei-
cher, H.; Doye, S. Eur. J. Org. Chem. 2003, 2888.
1. A representative procedure is given for 2-ethyl-N-methyl-
2
3-phenylindole (entry 7, Table 1): Under N , N-methyl-N-
phenylhydrazine (390mg, 3.18mmol) was added in three
portions to a solution of 1-phenyl-1-butyne (130mg,
1.00mmol), TiCl (0.022mL, 0.20mmol, 20mol%) and t-
BuNH
4
2
(0.130mL, 1.20 mmol) in toluene (2mL). The
Cl
resulting mixture was stirred for 40h at 105ꢁC. CH
2
2