A novel access to tetrahydro-β-carbolines via one-pot hydroformylation/fischer indole synthesis: Rearrangement of 3,3- spiroindoleninium cations

Article abstract of DOI:10.1021/ol801071y

(Chemical Equation Presented) The two component one-pot hydroformylation/Fischer indole synthesis sequence of 2,5 dihydropyrroles and phenyl hydrazines allows a facile and convenient access to tetrahydro-β- carbolines in moderate to good yields.

Full text of DOI:10.1021/ol801071y

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3433-3436
A Novel Access to
Tetrahydro-ꢀ-Carbolines via One-Pot
Hydroformylation/Fischer Indole
Synthesis: Rearrangement of
3,3-Spiroindoleninium Cations
Bojan P. Bondzic´ and Peter Eilbracht*
Fachbereich Chemie, Organische Chemie I, TechnischeUniVersita¨t Dortmund,
Otto-Hahn-Strasse 6, 44227 Dortmund, Germany
peter.eilbracht@udo.edu
Received May 9, 2008
ABSTRACT
The two component one-pot hydroformylation/Fischer indole synthesis sequence of 2,5 dihydropyrroles and phenyl hydrazines allows a facile
and convenient access to tetrahydro-ꢀ-carbolines in moderate to good yields.
The tetrahydro-ꢀ-carboline (THBC) ring system is present
in many synthetic and naturally occurring indole alkaloids,
possessing a wide diversity of structural types and displaying
a variety of important biological activities.1 Traditional
strategies for the synthesis of functionalized variants of this
“privileged” moiety have relied largely upon cycloconden-
sation of appropriately substituted tryptophan or tryptamine
derivatives with carbonyl compounds under aprotic or acidic
conditions, known as the Pictet-Spengler (PS) reaction.2
However, despite the wide scope of the PS condensation and
its continuous development, it turns out to be less applicable
when 3- or 4-substituted THBC systems are targeted. In these
cases syntheses of appropriate R or ꢀ substituted tryptamine
precursors are required, which can be a very laborious and
time-demanding process especially when enantiomerically
pure molecules are targeted. Most of the known 3-substituted
THBCs are tryptophan derivatives and are synthesized
starting from this essential amino acid. As a part of our
research interest adressed toward the investigation of new
tandem reactions involving regio-, and/or stereocontrolled
Rh catalyzed hydroformylation,3 we have recently reported
on the use of carbo- and heterocyclic olefins in tandem
hydroformylation/Fischer indole synthesis sequence yielding
carbazoles, sila-carbazoles and ꢀ-carboline.4 We envisaged
using this strategy for the synthesis of substituted carboline
derivatives starting from enantiopure 2-substituted 2,5-
dihydropyrroles. These substrates possess two available
(1) (a) Greeberger, L. M. Cancer Res. 1998, 58, 5850. (b) Introduction
to Alkaloids: A Biosynthetic Approach; Cordell, G. A., Ed.; Wiley: New
York, 1981. (c) Ulven, T.; Kostenis, E. J. Med. Chem. 2005, 48, 898. (d)
Schott, Y.; Decker, M.; Rommelspacher, H.; Lehmann, J. Bioorg. Med.
Chem. Lett. 2006, 16, 5840–5843. (e) Bentley, K. W. Nat. Prod. Rep 2001,
18, 148.
(2) (a) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030.
(b) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797–1842, and references
cited therein. (c) Czerwinski, K. M.; Cook, J. M. In AdVances in Heterocyclic
Natural Products Synthesis; Pearson, W., Ed.; JAI Press: Greenwich, CT,
1996; Vol. III, pp 217-277. (d) Royer, J.; Bonin, M.; Micouin, L. Chem.
ReV. 2004, 104, 2311–235.
(3) (a) Ba¨rfacker, L.; Buss, C.; Hollmann, C.; Kitsos-Rzychon, B. E.;
Kranemann, C. L.; Rische, T.; Roggenbuck, R.; Schmidt, A.; Eilbracht, P
Chem. ReV. 1999, 99, 3329. (b) Schmidt, A. M., Eilbracht, P. In Transition
Metals for Organic Synthesis: Building Blocks and Fine Chemicals, 2nd
ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004; pp 57-
111.
(4) Linnepe (nee Ko¨hling), P.; Schmidt, A. M.; Eilbracht, P. Org. Biomol.
Chem. 2006, 4, 302–13.
10.1021/ol801071y CCC: $40.75
Published on Web 07/19/2008
2008 American Chemical Society

positions for the hydroformylation and, in the presence of
phenyl hydrazines the aldehydes formed, can yield in two
diastereomeric pairs of regioisomeric phenyl hydrazones.
After acidic indolization 3,3-spiroindolenine intermediates
are undergoing rearrangement to form the THBC products.4
If the rearrangement selectively occurs with retention of the
precursor configuration both diastereomers of each pair
should give the same configuration in the final regioisomeric
product independently from the second stereogenic center
formed during hydroformylation (Scheme 1). Since under
Scheme 2
. Synthesis of 2-Substituted 2,5-Dihydropyrroles via Ir
Catalyzed Allylic Amination/Ring Closing Metathesis Sequencea
Scheme 1. Envisaged Reaction Pathway Hydrazones Formed
after Hydroformylation Are Depicted to Undergo Acid Promoted
Indolization and Rearrangement
aSee Supporting Information for details.
wt % H2SO4 has been applied for the test reaction with
substrate 4a. Unmodified Rh catalyst yielded in two products
5a and 6a, in good yield of 87% and ratio of 1/1.3 in favor
of 6a (Table 1, entry 1). Tetrahydro-ꢀ-carbolines were
Table 1. Testing of Ligands in Sequential Hydroformylation/
Tetrahydro-ꢀ-carboline Synthesis
hydroformylation conditions primary and secondary amines
undergo hydroaminomethylation reaction,3 use of N-protected
starting materials was required. For the synthesis of the
enantiopure 2-substituted 2,5-dihydropyrroles Ir catalyzed
allylic amination/ring closing metathesis (RCM) strategy was
applied.6c Ir catalyzed intramolecular allylic substitution, as
well as combination of intermolecular version of the latter
with RCM have recently allowed asymmetric syntheses of
various carbo-5 and heterocycles.6 For our synthesis, we used
phosphoramidite type ligand L1. Good yields and excelent
enantioselectivities were obtained in all cases (Scheme 2).7
Next, we focused on optimization of reaction conditions
and investigation of the product distribution in the hydro-
formylation/indolization sequence. A stepwise procedure4
involving tandem hydroformylation/ hydrazone formation
using 1 mol % Rh(acac)(CO)2 under 50/10 bar CO/H2 in
THF at 100 °C for 3 days with subsequent indolization in 4
yield, %b ratioc
ee, %d
olefin
entry
ligand
convn %a 5a + 6a 5a/6a 5a 6a
1
2
3
4
5
6
7
8
/
full
full
0
30
0
full
full
full
87
85
/
1:1.3
1:2.7
/
0
0
/
97
96
/
PPh3
DPPF
DPPB
BINAP
XANTPHOS
P(OPh)3
BIPHEPHOS
22
/
37
72
81
1:1.3
/
nde nde
/
/
1: 5.2 nde nde
1:1.6
1:1.4
0
0
96
96
a Determined by 1H-NMR of crude reaction mixture. b Isolated yield
after column chromatography. c Based on isolated product. d Determined
by HPLC on chiral column. e Not determined.
(5) (a) Streiff, S.; Welter, C.; Schelweis, M.; Lipowsky, G.; Miller, N.;
Helmchen, G. Chem. Commun. 2005, 2957–9. (b) Schelwies, M.; Dubon,
P.; Helmchen, G. Angew. Chem., Int. Ed. 2006, 45, 2466–9.
(6) (a) Shu, C.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 4794.
(b) Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.; Dubon, P.; Helmchen,
G. Org. Lett. 2005, 7, 1239. (c) Welter, C.; Moreno, R. M; Streiff, S.;
Helmchen, G. Org. Biomol. Chem. 2005, 3, 3266-8. (d) Weihofen, R.;
Tverskoy, O.; Helmchen, G Angew. Chem., Int. Ed. 2006, 45, 5546. 3,
3266-8. (e) Dahnz, A.; Dubon, P.; Schelwies, M.; Weihofen, R.; Helmchen,
G. Chem. Commun 2007, 67, 5–91.
obtained exclusively, no rearrangement toward γ-carboline
was observed, in contrast to carbocyclic and cyclic silyl
olefins which are known to give γ-carboline analogues.4 To
selectively obtain the desired 3-substituted THBCs, regiose-
lective hydroformylation step is required (Scheme 1).
Modifications of the rhodium catalyst with phosphine and
phosphite ligands are well-known to influence regioselectivity
of the hydroformylation.8 Reaction with PPh3 modified
catalyst (Table 1, entry 1), gave 1/2.7 ratio of 5a/6a in 85%
yield. Rh catalyst modified with diphosphine ligands such
as DPPF, BINAP, and DPPB gave no aldehyde at all or gave
(7) For selected examples on application of phosphoramidite ligands in
Ir catalyzed allylic aminations, see: (a) Ohmura, T.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 15164. (b) Lopez, F.; Ohmura, T.; Hartwig, J. F.
J. Am. Chem. Soc. 2003, 125, 3426. (c) Shu, C.; Leitner, A.; Hartwig, J. F.
Angew. Chem., Int. Ed. 2004, 43, 4797. Lipowsky, G; Miller, N; Helmchen,
G. Angew. Chem., Int. Ed. 2004, 43, 4595. (e) Alexakis, A.; Polet, D.; El
Hajjaji, S.; Rathgeb, G. Org. Lett. 2007, 9, 3393–5.
(8) See for instance: (a) Rhodium Catalyzed Hydroformylation; van
Leeuwen, P. W. N. M., Claver, C., Eds.; Kluwer Academic Publishers:
Dordrecht, 2000.
3434
Org. Lett., Vol. 10, No. 16, 2008

low conversions of substrate (Table 1, entries 3-5). Bulky
diphosphine ligand XANTPHOS usually used for n-selective
hydroformylations of terminal olefins yielded in 1/5.2 ratio
of 5a/6a but in poor yield of 37%. Phosphite ligand P(OPh)3
and bulky diphosphite BIPHEPHOS gave good yields but
had low influence on regioselectivity of the reaction (Table
1, entries 7 and 8). Because PPh3 appeared to be the best
compromise between yield and selectivity of hydroformy-
lation step, this ligand was chosen for further investigations.
Surprisingly, in all cases, 1-substituted carboline 5a was
isolated as racemate while 3-substituted 6a retained enan-
tiopurity of substrate. Racemization of the 1-substituted
carbolines was also observed by Danishevsky et al. during
their investigation on this type of rearrangement. The authors
proposed two possible rearrangement pathways of the
intermediate enantiopure 3,3-spiroindoleninium cations 7
(Scheme 3).9f Wagner-Meerwein like 1,2 shift proceeds in
and occurs presumably via C1-Nb bond scission.2b To test
whether racemization in our case is promoted by the acid
used in indolization step, stepwise procedure involving
thermally induced indolization9c was attempted starting from
4a, but no products were obtained. Lewis acid catalyzed
indolization with the same substrate gave the desired products
5a and 6a but again 1-substituted THBC was isolated as a
racemate. Stereochemical outcome is also determined by the
rearrangement pathway. To resolve whether retro Mannich
reaction or 1,2 shift are occurring, a crossover experiment
with a mixture of the acyclic, symmetric allylic amines was
performed.12 This experiment indicates that the rearrange-
ment occurs in an intramolecular fashion. This is in ac-
cordance with previous studies, which also showed that the
rearrangement of the 3,3-spiroindoleninium cations is an
intramolecular proces.9a This observation therefore excludes
the retro Mannich pathway and indicates that racemization
is most probably a post rearrangment event, in this case
caused by the acid used for indolization. The stereocenter
of 3-substituted carboline product is not influenced by any
of the possible reaction pathways; therefore, it stays intact.
We next turned our attention to the scope of the reaction
(Table 2). Several substrates with various alkyl or aromatic
Scheme 3. Possible Rearrangement Pathways
Table 2. Syntheses of THBCs from Substrates 4a-g, a′
olefin
yield
5 + 6c
85 (a)
ee, %e
entry
R
PG
Ts
R1
Ha
5: 6d
5
6
a suprafacial fashion,10 and leads to preservation of the
stereochemical information. A second mechanistic pathway
involves retro Mannich reaction of 7 to give the achiral, ring
opened intermediate 8, followed by subsequent cyclization
directly yielding 9rac. However, attack of the iminium ion
8 can also occur at position 311 of indole core, giving back
7. This implies that an equilibrium between 7 and 8 might
exist, leading to racemization of the spiroindoleninium cation
7 as a consequence. In addition, another factor that has to
be taken into consideration is the acid-promoted racemization
of 1-substituted THBCs. This is a well-documented process
1
2
3
4
5
6
7
8
9
Ph
Ph
1:2.7
0
0
0
0
0
0
0
0
/
97
98
96
95
ndg
ndg
94
93
95
95
Eoc Ha
63 (a′) 1:2.1
p-MeO-Ph Ts
Ha
Ha
Ha
Ha
Ha
Ha
76 (b)
71 (c)
74 (d)
58 (e)
65 (f)
69 (g)
1:5.5
1:5.2
1:2.4
1:1.4
1:3.3
1:3.6
o-MeO-Ph
p-Cl-Ph
p-CF3-Ph
Et
Ts
Ts
Ts
Ts
Ts
Ts
Ts
nPr
Ph
Ph
o-Meb 45 (h)
/
f
10
p-Clb
41 (i)
1:4.4
0
a Conditions: 1 equiv 4, 1 equiv phenyl hydrazine, 1 mol % Rh(acac)-
(CO)2, 5 mol % PPh3, 50/10 bar CO/H2, THF, 100 °C, 3 d then 4 w %
H2SO4, THF, 80 °C. b Tandem reaction run with 1 equiv of PTSA and 1
equiv of benzhydrylidene protected phenyl hydrazine. c Isolated yield after
column chromatography. d Determined by isolation. e Determined by HPLC
on chiral column. f Only 3-substituted product isolated. g Not determined.
(9) For some previous work considering this type of rearrangement, see:
(a) Jackson, A. H.; Smith, A. E. Tetrahedron 1968, 24, 403. (b) Jackson,
A. H.; Smith, P. Tetrahedron 1968, 24, 222. (c) Benito, Y.; Temporano,
F.; Rodriguez, J. G. J. Heterocyclic Chem, 1985, 22, 1207. (d) Benito, Y.;
Canoira, L.; Martinez-Lopez, N.; Temporano, F.; Rodriguez, J. G. J. Het-
erocyclic Chem, 1987, 24, 623. (e) Lynch, P. P.; Jackson, A. H. J. Chem.
Soc., Perkin Trans. 1 1987, 1215. (f) Li, C.; Chan, K.; Heimamm, A. C.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 1444–7. (g) Liu, K. G.;
Robichaud, A. J.; Lo, J. R.; Mattes, J. F.; Cai, Y. Org. Lett. 2006, 8, 5769–
71.
groups at the pyrrole ring were tested using the optimized
conditions in the presence of unsubstituted phenyl hydrazines
(10) Starling, S. M.; Vonwiller, S. C.; Reek, J. N. H. J. Org. Chem.
1998, 63, 2262.
(12) See Supporting Information for details on crossover experiment.
(13) (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 6621–6622. (b) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1998, 121, 10251–10263.
(11) (a) van Maarseveen, J. H.; Scheeren, H. W.; Kruse, C. G.
Tetrahedron 1993, 49, 2325. (b) He, F.; Bo, Y.; Altom, J. D.; Corey, E. J.
J. Am. Chem. Soc. 1999, 121, 6771. (c) Amat, M.; Santos, M. M. M.;
Gomez, A. M.; Jokic, D.; Molins, E.; Bosch, J. Org. Lett. 2007, 9, 2907–
10.
(14) (a) Schmidt, A. M.; Eilbracht, P. Org. Biomol. Chem. 2005, 3, 124–
134. (b) Schmidt, A. M.; Eilbracht, P. J. Org. Chem. 2005, 70, 5528–5535.
Org. Lett., Vol. 10, No. 16, 2008
3435

(Table 2, entries 1-8). Ts-protected 4a gave better yields
in this sequence than Eoc-protected 4a′ (Table 2, entries 1,
2); hence, Ts-protected substrates were preferably investi-
gated. In all cases, 3-substituted THBCs were obtained as
the major products. Pyrroles containing both electron-
donating and electron-withdrawing aromatic substituents
were included. Regioselectivities of products ranged from
1/2.7 to 1/5.5 in favor of 6. Electron donating substituents
on the substrate shifted the regioselectivity toward 3-sub-
stituted product (Table 2, Entries 3 and 4) in contrast to
electron withdrawing ones (Table 2, entries 5 and 6). Pyrroles
possessing alkyl substituents (Table 2, entries 7 and 8) gave
THBCs in good overall yields of 65 and 69%, respectively,
and in moderate selectivities. 3-Substituted products retained
the enantiopurity of starting material in all cases whereas
1-substituted products were obtained as racemates. To
introduce substituents in the indole part of the molecule,
substituted hydrazines were used. For this purpose, benzhy-
drylidene-protected aryl hydrazones have been synthesized
via Buchwald’s method.13 These substrates are known to
undergo high-yielding Fischer indolization in the presence
of olefins under hydroformylation conditions.14 Because the
benzhydrylidene group is stable under hydroformylation
conditions, reactions were conducted in the presence of 1
equiv of PTSA.14 In general, lower yields than with
unprotected hydrazines were observed. Tandem reaction of
4a with o-Me substituted benzhydrylidene hydrazone yielded
exclusively the 3-substituted product although in moderate
yield of 45% (Table 2, Entry 9), whereas p-Cl substituted
hydrazone gave only 41% yield of products in 1/4.4 ratio
(Table 2, entry 10).
To simultaneously introduce two substituents in the final
carboline molecule, it was necessary to synthesize 2,5-
disubstituted pyrroles. This was achieved by a modified
procedure of Helmchen (Scheme 4).6d Enantiopure (R)-10
was thus obtained in 98% ee. This was tosylated to give 11,
which was converted to Li anion and submitted to an Ir
catalyzed amination reaction with cinnamyl carbonate in the
presence of ligand L1. Product 12 was obtained in 45% yield
as a 90/10 mixture of diastereoisomers. After ring-closing
metathesis, 13 was obtained in 89% yield. Pyrrole 13 was
submitted to standard reaction conditions in a stepwise
manner in the presence of phenylhydrazine to yield 14 as
single diastereoisomer in 71% yield. Disubstituted pyrroles
Scheme 4
.
Synthesis of Enantiopure 1,3-Disubstituted
Tetrahydro-ꢀ-carboline 14
such as 13 thus allow fast access to enantiopure 1,3-
disubstituted tetrahydro-ꢀ-carbolines. Substrates of this type
are particularly promising due to the fact that they are not
suffering from problems with regioselectivity of hydroformy-
lation.
In summary, this convergent, one-pot strategy offers a
convenient approach toward 1- and 3-substituted tetrahydro-
ꢀ-carbolines independent from the usual indole precursors
such as tryptophane and tryptamines. Highly functionalized
building blocks are assembled to simultaneously form the
indole and carboline core in the final synthetic step. This
allows flexible determination of the substitution pattern in
the products. The outcome of the reaction sequence depends
on two factors, the regioselective hydroformylation to yield
desired aldehyde and the selective migration of one of the
two available positions. For both factors clear tendencies are
observed.
Acknowledgment. We thank Prof. Dr. Bernd Plietker
(Stuttgart) for support in the HPLC separations.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL801071Y
3436
Org. Lett., Vol. 10, No. 16, 2008