Palladium-catalyzed intramolecular trapping of the blaise reaction intermediate for tandem one-pot synthesis of indole derivatives

Article abstract of DOI:10.1021/ol200045q

Palladium-catalyzed intramolecular N-arylative and N-alkylative/N-arylative trappings of the Blaise reaction intermediates could be a new route to construct the indole moiety in a tandem one-pot manner from nitriles.

Full text of DOI:10.1021/ol200045q

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1350–1353
Palladium-Catalyzed Intramolecular
Trapping of the Blaise Reaction
Intermediate for Tandem One-Pot
Synthesis of Indole Derivatives
Ju Hyun Kim and Sang-gi Lee*
Department of Chemistry and Nano Science (BK21), Ewha Womans University, Seoul
120-750, Korea
sanggi@ewha.ac.kr
Received January 7, 2011
ABSTRACT
Palladium-catalyzed intramolecular N-arylative and N-alkylative/N-arylative trappings of the Blaise reaction intermediates could be a new route to
construct the indole moiety in a tandem one-pot manner from nitriles.
Indole is a structural component in a vast number of
natural products and biologically relevant compounds.1
To date, numerous elegant approaches have been con-
tinuously developed to generate this unique heterocyclic
ring moiety.2 Most of these approaches rely on anilines
or amines as nitrogen sources, and therefore the develop-
ment of new methods for the synthesis of indoles
from simple and readily available nonamino compounds
is still a subject of interest. Moreover, methods for
metal-catalyzed one-pot construction of N-fused indole
moieties are quite limited.3 We herein report a concep-
tually distinctive tandem one-pot approach for the
construction of indoles and N-fused indole moieties
from nitriles, which is based upon Pd-catalyzed intramo-
lecular N-arylative or N-alkylative/N-arylative trappings
of the Blaise reaction intermediates (Scheme 1). To
the best of our knowledge, this represents the first example
of the metal-catalyzed trapping of the Blaise re-
action intermediate, a transformation of great synthetic
potential.
(1) (a) Somi, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73. (b)
Kawasaki, T; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761. (c) Van Znadt,
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Kim, J. W. J. Am. Chem. Soc. 2010, 132, 1792. (h) Kramer, S.;
Because of their undeniable benefits such as atom
economy and one-pot operation with maximization of
molecular complexicity, the device and implementation
€
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S. G.; Lautens, M. J. Am. Chem. Soc. 2010, 132, 11416. (k) Barluenga, J.;
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r
10.1021/ol200045q
Published on Web 02/18/2011
2011 American Chemical Society

carbon-nitrogen bond forming reactions via electrophi-
lic trapping.7 In the present work, by taking advantage
of the well-developed Pd-catalyzed C-N bond forming
process,8 we became interested in studying the Pd-
catalyzed intramolecular trapping of Blaise reaction
intermediate 3 to construct the indole moiety 4
(Scheme 1a). In addition, if chemoselective intramo-
lecular N-alkylation proceeded with the intermediate 6
having chloroalkyl appendages, the intramolecular N-al-
kylative/Pd-catalyzed N-arylative trapping cascade
might be possible and provide a new one-pot route to
N-fused indoles 7 (Scheme 1b).9
Scheme 1. Pd-Catalyzed Intramolecular Trapping Strategies for
Tandem One-Pot Synthesis of (a) Indole and (b) N-Fused Indole
Derivatives
Table 1. Optimization Study for the Pd-Catalyzed N-Arylative
Trapping of the Blaise Intermediate 3aa
of tandem reactions is a challenging facet and has become
increasingly important in organic synthesis.4 Due to the
functional group tolerance, the electrophilic trapping of
the zinc enolate intermediates is one of the most fre-
quently employed strategies for tandem carbon-carbon
bond formation reactions.5 For example, Krische et al.
reported the intramolecular electrophilic trapping of
the zinc enolates, generated by Cu-catalyzed conjugate
addition of organozinc to enones.5d Quite recently,
Johnson et al. elegantly developed the double Re-
formatsky reaction and the tandem Reformatsky/
quaternary Claisen condensation, through the elec-
trophilic trapping of zinc enolate intermediates gener-
ated by the reaction of Reformatsky reagents with
silylglyoxalates.5e,f Along these lines, we recently envi-
sioned that the Blaise reaction intermediate, generated
by the addition of a Reformatsky reagent to nitriles,6
could be considered as a reactive aza-isostere of the zinc
enolate of β-ketoesters for tandem carbon-carbon and
temp time yield
entry
Pd/base
solvent (°C)
(h)
(%)b
1c
2
Pd(dba)2þSPhos/-
Pd(PPh3)4/-
THF
THF
DMF
65
65
48
48
24
48
48
15
24
24
24
15
-
-
>10
47
3
Pd(PPh3)4/-
120
4d
5e
6
Pd(dba)2þSPhos/NaHMDS toluene 110
Pd(dba)2þXPhos/NaHMDS toluene 110
38
Pd(dba)2þSPhos/tBuLi
Pd(PPh3)4 /NaHMDS
Pd(PPh3)4 /NaHMDS
Pd(PPh3)4 /NaHMDS
Pd(PPh3)4 /tBuOK
toluene 110
74
7
DMF
120
120
31
8
DMSO
60
9
toluene 110
DMF 120
30
10
84
a Conditions: Ethyl (o-bromophenyl)-R-bromoacetate (1.3 equiv)
was added over 1 h to a solution of 1a (2.29 mmol) and Zn (2.0 equiv)
in THF (0.9 mL) at reflux. After 1.5 h of reflux, the palladium catalyst
[Pd(PPh3)4 (7.4 mol %) or Pd(dba)2 (5 mol %)/ligand (10 mol %)],
solvent (THF/solvent = 1/10, v/v), and base (1.3 equiv) were added at
room temperature. b Isolated yield by column chromatography. c SPhos:
2-Dicyclohexylphosphino-20,60-dimethoxybiphenyl. d NaHMDS: So-
dium bis(trimethylsilyl)amide. e XPhos: 2-Dicyclohexylphosphino-
20,40.60-triisopropylbiphenyl.
(4) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(b) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006. (c) Nicolaou, K. C.; Edmonds,
€
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (d) Furstner, A.
Angew. Chem., Int. Ed. 2009, 48, 1364. (e) Parsons, P. J.; Penkett, C. S.;
Shell, A. J. Chem. Rev. 1999, 96, 195.
To investigate the reactivity of the Blaise reaction inter-
mediate under Pd-catalyzed intramolecular coupling con-
ditions, we chose the intermediate 3a, prepared by the
reactions of benzonitrile (1a) with a Reformatsky reagent
generated in situ from ethyl (o-bromophenyl)-R-bromoa-
cetate 2 (Table 1).
(5) (a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de
Vries, A. H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620. (b)
Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J. Am. Chem. Soc. 2001,
123, 4358. (c) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am.
Chem. Soc. 2002, 124, 779. (d) Agapiou, K.; Cauble, D. F.; Krische, M. J.
J. Am. Chem. Soc. 2004, 126, 4528. (e) Greszler, S. N.; Johnson, J. S.
Angew. Chem., Int. Ed. 2009, 48, 3689. (f) Greszler, S. N.; Malinowski,
J. T.; Johnson, J. S. J. Am. Chem. Soc. 2010, 132, 17393.
(6) (a) Blaise, E. E. C.R. Hebd. Seances Acad. Sci. 1901, 132, 478. (b)
Blaise, E. E. C.R. Hebd. Seances Acad. Sci. 1901, 132, 987. (c) Rathke,
M. W.; Weipert, P. In Zinc Enolates:The Reformatsky and Blaise
Reaction in Comprehensive Organic Reactions; Trost, B. M., Ed.; Perga-
mon: Oxford, 1991; Vol. 2, pp 277-299. (d) Rao, H. S. P.; Rafi, S.;
Padmavathy, K. Tetrahedron 2008, 64, 8037.
(7) (a) Chun, Y. S.; Lee, K. K.; Ko, Y. O.; Shin, H.; Lee, S.-g. Chem.
Commun. 2008, 5098. (b) Ko, Y. O.; Chun, Y. S.; Park, C.-L.; Kim, Y.;
Shin, H.; Ahn, S.; Hong, J.; Lee, S.-g. Org. Biomol. Chem. 2009, 7, 1132.
(c) Chun, Y. S.; Ko., Y. O.; Shin, H.; Lee, S.-g. Org. Lett. 2009, 11, 3414.
(d) Chun, Y. S.; Ryu, K. Y.; Ko, Y. O.; Hong, J. Y.; Hong, J.; Shin, H.;
Lee, S.-g. J. Org. Chem. 2009, 74, 7556. (e) Ko, Y. O.; Chun, Y. S.; Kim,
Y.; Kim, S. J.; Shin, H.; Lee, S.-g. Tetrahedron Lett. 2010, 51, 6893.
Considering the recently disclosed Pd-catalyzed cross-
couplings of the Reformatsky reagents with aryl halides
(8) (a) Jiang, L.; Buchwald, S. L. Metal-Catalyzed Cross Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004; Vol. 2, pp 699-760. (b)
Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (c)
Hartwig, J. F. In Handbook of Organopalladium Chemistry of Organic
Synthesis; Wiley-Interscience: New York, 2002; Vol. 1, pp 1051-1069. (d)
Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599. (e)
Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127.
(9) Alkylative trapping of the Blaise reaction intermediate, see:
Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833.
Org. Lett., Vol. 13, No. 6, 2011
1351

catalyst (entries 1 and 2, Table 1). When the reaction
temperature was increased to 120 °C by heating in THF/
DMF (1/10, v/v), the intramolecular N-arylation of 3a
proceeded but afforded 4a in less than 10% yield (entry 3,
Table 1). These results suggest that the nucleophilicity of
the Blaise reaction intermediate 3a may not be sufficient
for the intramolecular transmetalation of the Pd2þ species,
formed by oxidative addition of the o-bromide with Pd(0).
Although the reaction efficiencies were substantially in-
creased by addition of base and alteration of either the Pd
source or the solvent, the yields were not sufficiently high
(entries 4-9, Table 1). Gratifyingly, it was found that the
N-arylative trapping of 3a was effective in the presence of
Pd(PPhh3)4 (7.4 mol %) and tBuOK (1.3 equiv) in THF/
DMF (1/10, v/v) and afforded the corresponding indole 4a
in 84% yield (entry 10, Table 1).
Table 2. Tandem One-Pot Synthesis of Indole Derivatives 4a
Under the optimized conditions, various aromatic ni-
triles 1a-1h with electron-donating and -withdrawing
substitutents (entries 1-8, Table 2), heteroaromatic ni-
triles 1i and 1j (entries 9 and 10, Table 2), and aliphatic
nitriles 1k and 1l (entries 11 and 12, Table 2) can be
converted into the corresponding indoles 4a-4l in a one-
pot manner. Although 4-fluorobenzonitrile and propioni-
trile were converted to the corresponding indoles 4e and
4k in slightly diminished yields, the electronic nature of the
substituents on the aromatic nitriles did not significantly
influence the reactivity. The p-ethyl ester substituted
benzonitrile 1g afforded the mixture of indoles 4g (71%)
t
and 4g0 (ca. 6%) formed by ester exchange with BuOK
(entry 7, Table 2). One of the nitriles of terephthalonitrile
1h can be transformed into the indole ring to afford 4g in
62% yield (entry 8, Table 2).
To our delight, these reaction conditions could be
applied to the N-alkylative/N-arylative trapping reactions.
Thus, under the same reaction conditions, the tandem
reaction of the Blaise reaction intermediate 6a, formed
from 4-chlorobutyronitrile 5a, afforded the N-fused indole
7a in 62% yield (Scheme 2). When the tandem reaction of
6a was carried out at a lower temperature (80 °C), only the
N-alkylated product 9 was isolated in 71% yield. These
a Conditions: Ethyl (o-bromophenyl)-R-bromoacetate (1.3 equiv)
was added over 1 h to a solution of nitrile 1 (2.29 mmol) and Zn (2.0
equiv) in THF (0.9 mL) at reflux. After 1.5 h of reflux, Pd(PPh3)4 (7.4
mol %), DMF (9.0 mL), and BuOK (1.3 equiv) were added at room
temperature, and the reaction mixture was heated to 120 °C for 15 h.
Scheme 2. Pd-Catalyzed N-Alkylative/N-Arylative Trapping of
the Blaise Reaction Intermdiate 6a
t
under base-free conditions,10 we initially anticipated that
the nucleophilic nature of the intermediate 3a would make
it possible to conduct the Pd-catalyzed intramolecular
N-arylation in the absence of base. However, the tandem
reactions did not proceed at all at THF reflux temperature
in the presence of Pd(dba)2/Sphos or Pd(PPh3)4 as the
(10) (a) Hama, T.; Liu, X. X.; Culkin, D. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 11176. (b) Cossy, J.; de Filippis, A.; Pardo, D. G.
Org. Lett. 2003, 5, 3037. (c) de Filippis, A.; Pardo, D. G.; Cossy, J.
Synthesis 2004, 2930. (d) de Filippis, A.; Pardo, D. G.; Cossy, J.
Tetrahedron 2004, 60, 9757. (e) Hama, T.; Culkin, D. A.; Hartwig,
J. F. J. Am. Chem. Soc. 2006, 128, 4976.
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Org. Lett., Vol. 13, No. 6, 2011

results suggested that the intramolecular N-alkylative
trapping reaction of 6a proceeded prior to the N-arylation
with high chemoselectivity to generate 8a, which has
enough nucleophilicity for the intramolecular transmeta-
lation of the oxidative addition adduct, Ar-Pd(II)-Br
complex, to afford 7a.
Scheme 4. Possible Reaction Pathways for Indole 4 and
N-Fused Indole 7
Scheme 3. Tandem One-Pot Synthesis of N-Fused Indoles 7
Addition of one more equivalent of base increased the
yield of 7a to 70% (Scheme 3). Through the N-alkylative/
N-arylative trapping reactions, the 6- and 7-membered
N-fused indoles 7b (74%) and 7c (60%) could also be
synthesized efficiently starting from the corresponding
5-chloropentanenitrile 5b (n = 2) and 6-chlorohexaneni-
trile 5c (n = 3). By using the Reformatsky reagent,
generated from ethyl (1-bromonaphthalene-2-yl)-R-bro-
moacetate, the tetrahydrobenzopyrridoindole 7d was
synthesized from 5b in 52% yield .
The possible reaction pathways for the formation of
indoles 4 and N-fused indoles 7 are depicted in Scheme 4.
Deprotonation of the acidic N-H of 3 could generate the
iminoenolate 10, which could oxidatively add to Pd(0)
affording the arylpalladium(II) bromide complex 11. In-
tramolecular transmetalation, followed by reductive elim-
ination of the resulting Aryl-Pd(II)-N complex 12, could
regenerate Pd(0) for the next catalytic cycle, as well as the
zinc bromide complex of indole 4-ZnBr, which can then be
converted to indole 4 after workup (Scheme 4a). For the
formation of N-fused indoles 7, the intramolecular N-al-
kylation of the Blaise reaction intermediate 6 may proceed
first in the presence of base to form 8 having enough
nucleophilicity for the intramolecular transmetalation of
13 to form 14. Reductive elimination afforded the N-fused
indole 7 (Scheme 4b).
In summary, we have developed a novel tandem one-pot
method for the synthesis of indoles and N-fused indoles
from readily available nitriles and Reformatsky reagents
through the Pd-catalyzed intramolecular N-arylative and
N-alkylative/N-arylative trappings of the Blaise reaction
intermediates. This result has provided a platform for
future studies probing applications of the Blaise reaction
intermediate as a functionalized organozinc nucleophile
for metal-catalyzed bond forming reactions.
Acknowledgment. This work was supported by the
Korea Research Foundation (KRF-20090070898) and
the Center for Intelligent Nano-Bio Materials at Ewha
Womans University (KRF-20090063004). We thank Pro-
fessor J. Hong at Kyung Hee University for his HRMS
analysis.
Supporting Information Available. Experimental de-
tails and spectral data of 4a-4l, 7a-7d, 8a and their 1H
and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 6, 2011
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