Rapid access to amino-substituted quinoline, (Di)benzofuran, and carbazole heterocycles through an aminobenzannulation reaction

Article abstract of DOI:10.1021/jo800249f

(Chemical Equation Presented) The use of a powerful aminobenzannulation reaction has been applied for the synthesis of amino-substituted quinolines, dibenzofurans, and carbazoles. The precursors are heterocycles bearing a methyl ketone group ortho to an i

Full text of DOI:10.1021/jo800249f

Rapid Access to Amino-Substituted Quinoline, (Di)Benzofuran, and
Carbazole Heterocycles through an Aminobenzannulation Reaction
Martin Tiano and Philippe Belmont*
Institut de Chimie et Biochimie Mole´culaires et Supramole´culaires (ICBMS), Laboratoire de Synthe`se et
Me´thodologie Organiques (LSMO), UniVersite´ de Lyon, UniVersite´ Claude Bernard, Lyon I, UMR CNRS
5246, Baˆtiment CPE, 43 bouleVard du 11 NoVembre 1918, 69622 Villeurbanne cedex, France
philippe.belmont@uniV-lyon1.fr
ReceiVed January 30, 2008
The use of a powerful aminobenzannulation reaction has been applied for the synthesis of amino-substituted
quinolines, dibenzofurans, and carbazoles. The precursors are heterocycles bearing a methyl ketone group
ortho to an internal alkyne. They are commercially available or can be obtained in three to four classical
and efficient reactions: Vilsmeier-Haack, Sonogashira (diversity point), Grignard, and Ley’s oxidation.
Upon aminobenzannulation reaction—classical conditions being pyrrolidine neat or in a solvent and 4 Å
MS—an interesting range of disubstituted quinolines, dibenzofurans, and carbazoles are obtained along
with enamine formation in some cases. The reaction is useful since meta-substituted heterocycles are
produced and also differs from classical heterocyclic methods which go through closure at the heteroatom-
containing ring instead of benzene ring formation.
Introduction
has been illustrated.6a The palladium-catalyzed [4 + 2] or [2 +
2 + 2] benzannulation has been well studied2a,7 along with other
transition or Lewis acidic metals.3a,8 Recently, we developed a
method for acridine derivatives using a rhodium catalysis9
Since the pioneering work of Berthelot,1 protocols for the de
novo construction of functionalized benzenoid rings (benzan-
nulations) have emerged.2 Metal-mediated benzannulations are
very useful reactions.3 The chromium-templated [3 + 2 + 1]
cycloaddition, based on the reactivity of chromium Fisher
carbenes,4 was first reported by Do¨tz in 1975.5 Cobalt-mediated
[2 + 2 + 2] cyclotrimerization of alkynes led to many
developments,6 also chemo- and regioselective benzannulation
(4) (a) Do¨tz, K. H.; Tomuschat, P. Chem. Soc. ReV. 1999, 28, 187. (b) Do¨tz,
K. H.; Wenzel, B.; Jahr, H. C. Top. Curr. Chem. 2004, 248, 63. (c) Davies,
M. W.; Johnson, C. N.; Harrity, J. P. A. J. Org. Chem. 2001, 66, 3525. (d)
Minatti, A.; Do¨tz, K. H. Tetrahedron: Asymmetry 2005, 16, 3256. (e) Lian, Y.;
Wulff, W. D. J. Am. Chem. Soc. 2005, 127, 17162. (f) Pulley, S. R.; Czako, B.
Tetrahedron Lett. 2004, 45, 5511. (g) Pulley, S. R.; Czako, B.; Brown, G. D.
Tetrahedron Lett. 2005, 46, 9039. (h) Gupta, A.; Sen, S.; Harmata, M.; Pulley,
S. R. J. Org. Chem. 2005, 70, 7422.
To whom correspondence should be addressed. Phone: 00-33-4-72-44-58-
68. Fax: 00-33-4-72-43-29-63.
(5) Do¨tz, K. H. Angew. Chem., Int. Ed. Engl. 1975, 14, 644.
(6) (a) Chouraqui, G.; Petit, M.; Aubert, C.; Malacria, M. Org. Lett. 2004,
6, 1519. (b) Bonaga, L. V. R.; Zhang, H.-C.; Moretto, A. F.; Ye, H.; Gauthier,
D. A.; Li, J.; Leo, G. C.; Maryanoff, B. E. J. Am. Chem. Soc. 2005, 127, 3473.
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Chem. Soc. 2006, 128, 8509. (d) Vollhardt, K. P. C. Acc. Chem. Res. 1977, 10,
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(b) Katritzky, A. R.; Li, J.; Xie, L. Tetrahedron 1999, 55, 8263. (c) Belmont, P.
Modern Approaches to the Synthesis of O- and N-Heterocycles; Research
Signpost: Kerala, India, 2007, Vol. 2, Chapter 9.
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M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (c) Ojima, I.; Tzamarioudaki,
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10.1021/jo800249f CCC: $40.75
Published on Web 05/07/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4101–4109 4101

Tiano and Belmont
SCHEME 1. Previous Work21
SCHEME 2. Starting Materials
SCHEME 3. Precursor Synthesis in the Indole Series
inspired from a naphthalene synthesis reported previously.8q,10
an aminobenzannulation method based on the deprotonation of
2-(1-alkynyl)benzaldimines through a multistep rearrangement
cascade. This method was also used to construct decahy-
dronaphthalen-1-ylamines, 7-aminobenzofurans, and more re-
cently polysubstituted aminobenzannulated heterocycles.19 Hern-
don’s group20 reported in 2001 a powerful method allowing
access to aminonaphthalenes taking advantage of the dual role
of a palladium catalyst. Inspired from Herndon’s results, we
built up a metal-free pyrrolidine-triggered aminobenzannulation
reaction21 where the enamine formation and the aminobenzan-
12
Also, a metal-free iodocyclization using ICl11 or I(py)2BF4
led to functionalized benzene and heterocyclic nuclei. Upon
irradiation (Hanovia mercury lamp, Pyrex filter)13 or thermal
conditions,14 the synthesis of highly substituted benzenoid
derivatives has been nicely achieved. Benzannulation can be
also completed with acid (camphorsulfonic acid)15 or various
basic conditions.16
Aminobenzannulation arose some years ago as a benzannu-
lation method with the participation of an external nitrogen unit.
Thus Merlic’s group17 developed an aminobenzannulation
method with chromium dienylcarbene complex (Do¨tz reaction),
and the use of simple isonitriles as the nitrogen unit, to generate
o-alkoxy aromatic amine derivatives upon thermal activation.
This group reported also a photoinduced cyclization of tert-
butoxycarbonyl-coordinated tetracarbonyl complexes yielding
o-amino aromatic alcohols.17c Wu¨rthwein’s group18 designed
(9) Belmont, P.; Andrez, J.-C.; Allan, C. S. M. Tetrahedron Lett. 2004, 45,
2783.
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4102 J. Org. Chem. Vol. 73, No. 11, 2008

Rapid Access to Amino-Substituted Compounds
SCHEME 4. Precursor Synthesis in the Benzofuran Series
SCHEME 5. Precursor Synthesis in the Quinoline Series
nulation step took place subsequently. The scope of this method
was limited to the construction of 1-aminoacridine derivatives
(Scheme 1).
We thus became interested in widening the field of application
of our method and also extend the nature of the substitution
pattern on the newly formed heterocycles. Therefore, starting
from commercially available pyridine or easily accessible indole
and benzofuran, we wish to report in this paper a new and
efficient access to amino-substituted quinoline, carbazole, and
dibenzofuran rings. Also, these heterocycles are of interest for
their broad biological or physical properties. Indeed, quinoline
nucleus is incorporated in numerous alkaloids and displays many
biological activities.22 Dibenzofuran rings display interesting
physical and biological properties.23 Finally, carbazole units are
found in many bioactive molecules, particularly in antitumor
derivatives.24
conditions (TPAP/NMO),29 the desired methyl ketone deriva-
tives 15-19 were produced in good yields (71-96%).
Using the same reaction sequence (Sonogashira, Grignard,
Ley’s oxidation), the benzofuran derivative 4 was transformed
at first in coupling compounds 20-22 (Scheme 4), respectively,
with a phenyl (86%), butyl (72%), or 2-pyridine (50%)
substituent on the alkynyl group.30 Further Grignard reaction
on 20-22 afforded secondary alcohols 23-25 in high yields
(96% quant.) and, upon oxidation, the needed methyl ketones
26-28 in fair to high yield (57-96%).
For the quinoline series, we began with commercially
available 1-(2-bromopyridin-3-yl)ethanone31 that underwent
several efficient Sonogashira reactions to obtain directly the
desired methyl ketone derivatives (Scheme 5) bearing on the
alkynyl group either a 2-pyridine 29 (78%), a phenyl 30 (82%),
a trimethylsilyl 31 (91%), a butyl 32 (92%), or a tetrahydro-
pyranyl moiety 33 (73%).
Results and Discussion
For the synthesis of the starting materials, we followed a
classical Vilsmeier-Haack bromoformylation reaction25 to get
efficiently 2-bromo-1H-indole-3-carbaldehyde 1 (98%) from
commercial oxindole (Scheme 2). The nitrogen of indole 1 was
then protected either by methylation or by benzylation to get,
respectively, in high to fair yield, compound 2 (95%) or 3 (52%).
In the carbazole series, 2-chlorobenzofuran-3-carbaldehyde 4
(Scheme 2) was obtained from commercial coumaranone as
previously reported (57%).26
The first diversity point was introduced thanks to a Sono-
gashira reaction27 on the halogen derivatives 2, 3, and 4.
Therefore, from methylindole 2 (Scheme 3), following Toyota-
Ihara’s conditions,28 we obtained efficiently four different
alkynyl compounds bearing a 2-pyridyl unit 5 (96%), a phenyl
unit 6 (96%), a butyl unit 7 (70%), or a tetrahydropyranyl unit
8 (95%). Also, benzyl-protected indole 3 (Scheme 3) was
coupled with phenylethynyl reagent to produce compound 9
(96%). The coupling products 5-9 were then submitted to a
Grignard reaction with methyl magnesium bromide, yielding,
respectively, secondary alcohol derivatives 10-14 in high yields
(91% quant.). Upon oxidation of alcohols 10-14 with Ley’s
Having in hand the requisite heteroaryl substrates 15-19 and
26-33, bearing a methyl ketone group and ortho-functionalized
with an alkynyl group, we could then test their reactivity toward
our pyrrolidine-triggered aminobenzannulation (Tables 1–3).
Using pyridine 29 in simple reaction conditions (3 equiv of
pyrrolidine, 6 weight equiv powdered 4 Å molecular sieves in
CH2Cl2), quinoline 34 was obtained in very good yield (87%)
at room temperature (Method A, Table 1). With the other
pyridine derivatives 30-33, following Method A conditions,
only starting material was recovered. Heating the reaction
mixture (Method B, in Cl(CH2)2Cl) led only to the formation
of traces of the desired products. Finally, performing the reaction
in the amine as the solvent and at reflux (Method C) gave
successfully quinoline 35 (91%), 36 (85%), 37 (45%), and 38
(53%). It is worth noting that having an alkyl substituent (37
and 38) diminishes the efficiency of the 6-endo-dig cyclization/
aromatization reaction. Activation of the triple bond seems to
play an important role since smooth conditions are needed to
build quinoline 34, bearing an electron-deficient pyridine ring,
whereas heating in pyrrolidine neat is required to get phenyl-
substituted quinoline 36. Interestingly, trimethylsilyl quinoline
intermediate 31 cyclized nicely to give quinoline 35 with
concomitant loss of the TMS group.32
(21) Belmont, P.; Belhadj, T. Org. Lett. 2005, 7, 1793.
(22) (a) Michael, J. P. Nat. Prod. Rep. 2007, 24, 223. (b) Michael, J. P. Nat.
Prod. Rep. 2005, 22, 627. (c) Michael, J. P. Nat. Prod. Rep 2004, 21, 650. (d)
Michael, J. P. Nat. Prod. Rep 2003, 20, 476. (e) Michael, J. P. Nat. Prod. Rep
2002, 19, 742.
(23) (a) Kaniwa, K.; Ohtsuki, T.; Yamamoto, Y.; Ishibashi, M. Tetrahedron
Lett. 2006, 47, 1505. (b) D’Silva, K.; Fernandes, A.; Rose, M. Crit. ReV. EnViron.
Sci. Technol. 2004, 34, 141.
(24) Asche, C.; Demeunynck, M. Anti-Cancer Agents Med. Chem. 2007, 7,
247.
(29) Ley, S. V.; Normant, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
(25) For a recent review, see: (a) Brahma, S.; Ray, J. K. Tetrahedron 2008,
64, 2883. (b) Kirsch, G.; Deprets, S. Z. Naturforsch. 2006, 61b, 427. (c) Somei,
M.; Sayama, S.; Naka, K.; Yamada, F. Heterocycles 1988, 27, 1585.
(26) Coppola, G. M. J. Heterocycl. Chem. 1981, 18, 845.
(27) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16,
4467.
(30) In this case, dimethylacetamide (DMA) was used instead of DMF to
avoid partial reduction of the triple bond.
(31) Otherwise, this compound can be easily made from commercially
available 2-bromopyridine-3-carbaldehyde by standard procedure (Grignard and
oxidation).
(32) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 7048.
(28) Toyota, M; Komori, C.; Ihara, M. J. Org. Chem. 2000, 65, 7110.
J. Org. Chem. Vol. 73, No. 11, 2008 4103

Tiano and Belmont
TABLE 1. Aminobenzannulation Products: Quinolines from
Pyridines
derivatives, whereas the aminobenzannulation products are
obtained through a 6-endo-dig cyclization driven by the aro-
matization (see more details in ref 35). For the same reasons as
earlier, reaction of alkyl-substituted benzofuran such as 27 is
less effective and only 17% of the desired dibenzofuran 42 is
isolated. The compound of direct addition 43 is also observed
but was hard to characterize due to the instability of the butyl
enamino group compared to the aromatic enamino group present
in 40 and 41.
In the indole series, activation of the triple bond for compound
15 (Table 3), due to the indole and pyridine moieties, led as
before only to direct addition of pyrrolidine onto the alkynyl
bond (44, quant.), even at room temperature (Method A). For
the other indole precursors 16-18, an efficient synthesis of
disubstituted carbazoles was made possible with a phenyl (45,
96%), a butyl (46, 65%), or a tetrahydropyranyl (47, 65%)
substitution (Method B). Changing the nitrogen protecting group
for a benzyl group, as seen in phenylindole 19, had no impact
on cyclization since we observed, in the same reaction condition
(Method B), an efficient aminobenzannulation yielding carbazole
48 (80%). We used this last transformation as a test reaction in
order to show that no remaining palladium traces from previous
Sonogashira reaction could participate in the aminobenzannu-
lation step. Indeed, based on recent studies36 applied in our case,
palladium traces do not appear to be involved, and thus we are
confident in our metal-free aminobenzannulation reaction.
a Method A: 1 mmol starting material in dry dichloromethane (5 mL)
under argon, 4 Å molecular sieves (6 weight equiv) and amine (3
equiv), at room temperature. Method C: 1 mmol starting material in
pyrrolidine (5 mL), with 4 Å molecular sieves (6 weight equiv), at
reflux.
Also, the amine moiety can be changed for benzylamine or
diethylamine producing, respectively, carbazoles 49 (73%) or
50 (70%) from indole 16, showing that cyclic secondary amine
was not compulsory. Indeed, carbazole 49 is interesting since
it opens the way to further substitution or deprotection reactions.
On the other hand, reactions performed with benzofuran
derivatives 26-28 led surprisingly to undesired compounds or
even mixtures (Table 2). In the case of phenylbenzofuran 26,
following Method B (heating in Cl(CH2)2Cl) was necessary to
run the reaction, and the desired dibenzofuran derivative 39
(55%) was accompanied by another compound 40 (45%) formed
through direct attack on the alkynyl function.
(35) The C-2/C-3 double bond in benzo[b]furans is known to behave like a
localized double bond. See: The Chemistry of Heterocycles, 2nd ed.; Eicher, T.,
Hauptmann, S., Eds.; Wiley-VCH: Weinheim, Germany, 2003; Chapter 5.
Therefore, compared to reactions operated with quinoline and indole moieties,
the alkynyl bond in benzofuran systems is more prone to a pseudo 1,6-addition
competing with the 6-endo-dig cyclization leading to aminobenzannulation
reaction, as shown in the following scheme
The structure of this enamino-benzofuran derivative 40 (45%),
along with its stereo- and regiochemistry, has been confirmed
by NMR data and X-ray analysis.33 It is interesting to see that
in the case of pyridine benzofuran 28 (Table 2) the same reaction
led only to the formation of enamino-benzofuran 41 (quant.).
The reactivity pattern between these two benzofurans recalls
what was observed earlier in the case of quinoline synthesis,
attesting the higher reactivity of the triple bond when linked to
a pyridine instead of a phenyl moiety.34 Hence, the benzofuran
nucleus is obviously more electrophilic than the quinoline one
since direct pyrrolidine addition onto the alkynyl function is
preferred toward the aminobenzannulation reaction.35 We can
thus propose a pseudo 1,6-addition leading to the enamine
(33) Crystallographic information concerning compound 40 can be found in
the Supporting Information.
(34) Indeed, in the quinoline series, synthesis of compound 34 from the
pyridyl-substituted derivative 29 was performed at room temperature and does
not require heating as for other substituent (e.g., phenyl-substituted derivative
30). Pyridine is known as a π-deficient nitrogen heterocycle, and position-2 which
bears here the alkynyl group is electronically deficient which may explain the
higher reactivity of the alkyne group in the 2-pyridine-substituted compounds
compared with that of the phenyl group. Therefore, this could explain the different
reactivity pattern of 26 versus 28 leading to exclusive formation of compound
41 in the case of pyridine substitution. More data on pyridine properties can be
viewed in the following: The Chemistry of Heterocycles, 2nd ed.; Eicher, T.,
Hauptmann, S., Eds.; Wiley-VCH: Weinheim, Germany, 2003; Chapter 6.
(36) This point was further investigated following one reviewer’s useful
comment. For a review, see: (a) Garret, C. E.; Prasad, K. AdV. Synth. Catal
2004, 346, 889. (b) Urawa, Y.; Miyazawa, M.; Ozeki, N.; Ogura, K. Org. Process
Res. DeV 2003, 7, 191. (c) Following ref 36b, compound 19, previously
recrystallized, was treated with a polymer-bound tris(2-aminoethyl)amine in order
to complex the remaining traces of Pd(0) and Pd(II) and then subjected to the
aminobenzannulation reaction. After purification, we obtained carbazole 48bis
in 84% yield; therefore, the reaction is reproducible and in the same range of
yield and time than without treatment, which strengthens our belief that no
palladium residue is involved (see Supporting Information for more details on
the procedure and copy of the 1H NMR for carbazole 48bis).
4104 J. Org. Chem. Vol. 73, No. 11, 2008

Rapid Access to Amino-Substituted Compounds
TABLE 2. Dibenzofurans and Enamino-benzofuran Synthesis
a Method B: 1 mmol starting material in dry dichloroethane (5 mL) under argon, 4 Å molecular sieves (6 weight equiv) and pyrrolidine (3-6 equiv),
at reflux.
Overall, the development of an aminobenzannulation reaction
onto pyridine, benzofuran, and indole heterocycles is powerful
since it leads to the synthesis of attractive amino-substituted
quinoline, dibenzofuran, and carbazole structures with moderate
to excellent yield. Our methodology allows all the substituents
to be in the meta position in the newly formed ring. Also, an
interesting reactivity is observed with benzofuran nuclei where
a competition occurs between aminobenzannulation reaction
versus regio- and stereoselective enamine formation. Finally,
the most important point is to note that this methodology brings
some novelty in these heterocycle’s synthesis since the key step
is the benzene ring formation instead of the usual heteroatom-
containing ring formation. Improvements are still sought after
in term of nitrogen source for the aminobenzannulation reaction
and will be published in due course.
TABLE 3. Aminobenzannulation Products: Carbazoles from
Indoles
Experimental Section
General Information: Unless otherwise noted, all commercial
materials were used without further purification. TLC analysis of
reaction mixtures was performed on silica gel F254 TLC plates.
Flash chromatography was carried out on silica gel (32-63 µm).
1H and 13C NMR spectra were recorded with 300 MHz spectrom-
eters and referenced to CDCl3 unless otherwise noted. High-
resolution mass spectra (m/z) and crystallographic data were
obtained thanks to the facilities operated by the Universite´ Claude
Bernard, Lyon 1. For all the general methods, see Supporting
Information.
2-Bromo-1H-indole-3-carbaldehyde (1). To a solution of
dimethylformamide (3.6 mL, 46 mmol) in dichloromethane (12 mL)
was added dropwise a solution of phosphorus oxybromide (11.1g,
36.6 mmol) in dichloromethane (20 mL) at 0 °C. The white thick
mixture was refluxed during 15 min, and then oxindole (2.053 g,
15.42 mmol) was added portionwise. The mixture was stirred at
reflux during 1 h. The reaction was quenched by addition of crushed
ice to the media. The mixture was stirred for 20 min, then the two
layers were separated. The aqueous layer was neutralized with solid
potassium carbonate. The pale yellow precipitate which appeared
was washed with cold water and cold dichloromethane then was
triturated with acetone. After evaporation of solvent, pure 2-bromo-
1H-indole-3-carbaldehyde was obtained as 3.44 g (15.35 mmol)
a Method A: 1 mmol starting material in dry dichloromethane (5 mL)
under argon, 4 Å molecular sieves (6 weight equiv) and pyrrolidine (3
equiv), at room temperature. Method B: 1 mmol starting material in dry
dichloroethane (5 mL) under argon, 4 Å molecular sieves (6 weight
equiv) and the appropriate amine (3-6 equiv), at reflux.
37
1
of pale yellow solid (98%): mp 186 °C (lit. 196-198 °C ); H
NMR (300 MHz, CDCl3, δ) 13.05 (br s, 1H), 9.98 (s, 1H), 8.49
(dd, J ) 8.6, 1.9 Hz, 1H), 7.43 (dd, J ) 8.6, 1.9 Hz, 1H), 7.30-7.20
(m, 2H).
J. Org. Chem. Vol. 73, No. 11, 2008 4105

Tiano and Belmont
2-Bromo-1-methyl-1H-indole-3-carbaldehyde (2). To a solu-
tion of 2-bromo-1H-indole-3-carbaldehyde (4.52 g, 20 mmol) in
dry THF was added at 0 °C sodium hydride (60% weight in mineral
oil, 994 mg, 24 mmol). The mixture was stirred for 15 min, then
MeI (1.5 mL, 24 mmol) was added dropwise. The mixture was
stirred 20 min at 0 °C, then water was added. Extraction with
dichloromethane and evaporation of solvents afforded 4.52 g (19
mmol, 95%) of the pure desired product: mp 106-107 °C (lit.
110-111 °C38); 1H NMR (300 MHz, CDCl3, δ) 9.97 (s, 1H), 8.19
(d, J ) 7.0 Hz, 1H), 7.51 (d, J ) 7.6 Hz, 1H), 7.34-7.23 (m, 2H),
3.86 (s, 3H).
1-Methyl-2-[3-(tetrahydropyran-2-yloxy)prop-1-ynyl]-1H-
indole-3-carbaldehyde (8): Orange thick oil, 95%; IR (neat) 3055,
2944, 2852, 2360, 1728, 1651; H NMR (300 MHz, CDCl3, δ)
1
10.03 (s, 1H), 8.18 (d, J ) 7.2 Hz, 1H), 7.24-7.13 (m, 3H),
4.83-4.80 (m, 1H), 4.53 (s, 2H), 3.84-3.77 (m, 1H), 3.66 (s, 3H),
3.53-3.47 (m, 1H), 1.77-1.49 (m, 6H); 13C NMR (75 MHz,
CDCl3, δ) 185.1, 137.2, 131.2, 125.0, 124.1, 123.5, 122.0, 120.1,
109.8, 97.8, 97.4, 74.0, 62.2, 54.6, 31.1, 30.2, 25.3, 19.0; HRMS-
EI (m/z) for [C18H19NO3]+• calcd 297.1365, found 297.1367.
1-Benzyl-2-phenylethynyl-1H-indole-3-carbaldehyde (9): Pale
brown solid, 96%; mp 110-112 °C (lit.32119-120 °C); 1H NMR
(300 MHz, CDCl3, δ) 10.42 (s, 1H), 8.48-8.46 (m, 1H), 7.62-7.60
(m, 2H), 7.45-7.28 (m, 11H), 5.52 (s, 2H); HRMS-CI (m/z) for
[C24H17NO+H]+ calcd 336.1388, found 336.1385.
1-(1-Methyl-2-pyridin-2-ylethynyl-1H-indol-3-yl)ethanol
(10): Pale brown solid, quant.; 1H NMR (300 MHz, CDCl3, δ) 8.61
(d, J ) 4.8 Hz, 1H), 7.89 (d, J ) 8.1 Hz, 1H), 7.69 (ddd, J ) 7.7,
7.7, 1.7 Hz, 1H), 7.54 (d, J ) 7.7 Hz, 1H), 7.32-7.22 (m, 3H),
7.15-7.10 (m, 1H), 5.47 (q, J ) 6.6 Hz, 1H), 3.84 (s, 3H), 2.32
(br s, 1H), 1.74 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3,
δ) 150.1, 142.9, 137.8, 136.3, 127.1, 126.2, 124.8, 123.9, 123.0,
121.0, 120.0, 118.1, 109.7, 97.8, 80.1, 64.8, 30.7, 24.0; HRMS-
ESI (m/z) for [C18H16N2O + H - H2O]+ calcd 259.1235, found
259.1238.
1-Benzyl-2-bromo-1H-indole-3-carbaldehyde (3). To a solution
of 2-bromo-1H-indole-3-carbaldehyde (440 mg, 1.96 mmol) in dry
THF was added at 0 °C sodium hydride (60% weight in mineral
oil, 100 mg, 2.5 mmol). The mixture was stirred for 15 min, then
benzyl bromide (0.3 mL, 2.5 mmol) was added dropwise. The
mixture was stirred 8 h, then water was added. Extraction with
dichloromethane and evaporation of solvents and purification by
flash chromatography on silica gel using ethyl acetate/cyclohexane
(1:1) as eluent afforded 317 mg of a white solid (52%): mp
39
1
122-125 °C (lit. 125 °C ); H NMR (300 MHz, CDCl3, δ) 9.89
(s, 1H), 8.17 (d, J ) 7.1 Hz, 1H), 7.13-7.08 (m, 6H), 6.95-6.92
(m, 2H), 5.27 (s, 2H).
2-Chlorobenzofuran-3-carbaldehyde (4). To a solution of
dimethylformamide (2 g) in chloroform (10 mL) was added
dropwise phosphorus oxychloride (3.1 g) at 0 °C. After stirring at
0-5 °C for 5 min, a solution of coumaranone (1.1 g, 8.12 mmol)
in chloroform (7.5 mL) was added dropwise under ice cooling and
then refluxed for 18 h. The chloroform was removed under reduced
pressure, and water was added to the residue. Potasssium acetate
was added until pH 5 then 2 N sodium hydroxide was added until
pH 7 was reached. The mixture was extracted with dichloromethane,
dried over sodium sulfate, and the solvent was removed under
reduced pressure. The residue was chromatographed on a column
of silica gel using chloroform as eluent, and 643 mg of pale yellow
solid was obtained (4.68 mmol, 57%): mp 87 °C (lit.26 83-86 °C);
1H NMR (300 MHz, CDCl3, δ) 10.13 (s, 1H), 8.19-8.12 (m, 1H),
7.47-7.42 (m, 1H), 7.37-7.33 (m, 2H).
1-(1-Methyl-2-phenylethynyl-1H-indol-3-yl)ethanol (11): Or-
ange oil, 99%; H NMR (300 MHz, CDCl3, δ) 7.91 (d, J ) 8.0
1
Hz, 1H), 7.61-7.57 (m, 2H), 7.42-7.37 (m, 3H), 7.31-7.26 (m,
2H), 7.16 (ddd, J ) 8.0 Hz, J ) 5.8 Hz, J ) 2.2 Hz, 1H), 5.47 (q,
J ) 6.6 Hz, 1H), 3.82 (s, 3H), 2.27 (br s, 1H), 1.78 (d, J ) 6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3, δ) 137.5, 131.4 (2C), 128.8, 128.6
(2C), 124.8, 124.3, 123.4, 122.6, 120.7, 119.9, 119.1, 109.5, 98.7,
79.8, 65.0, 30.5, 23.8; HRMS-EI (m/z) for [C19H17NO]+• calcd
275.1310, found 275.1309.
1-(2-Hex-1-ynyl-1-methyl-1H-indol-3-yl)ethanol (12): Red oil,
1
95%; H NMR (300 MHz, CDCl3, δ) 7.85 (d, J ) 8.0 Hz, 1H),
7.27-7.23 (m, 2H), 7.15-7.10 (m, 1H), 5.36 (q, J ) 5.6 Hz, 1H),
3.73 (s, 3H), 2.57 (t, J ) 6.9 Hz, 2H), 2.26 (br s, 1H), 1.74-1.64
(m, 5H), 1.62-1.50 (m, 2H), 1.02 (t, J ) 7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3, δ) 137.0, 124.8, 122.9, 122.8, 120.3, 119.9, 119.6,
109.3, 100.1, 71.1, 65.0, 30.7, 30.3, 23.7, 22.1, 19.5, 13.6; HRMS-
EI (m/z) for [C17H21NO]+• calcd 255.1623, found 255.1624.
1-{1-Methyl-2-[3-(tetrahydropyran-2-yloxy)prop-1-ynyl]-
1H-indol-3-yl}ethanol (13): Brown oil, 91%; 1H NMR (300 MHz,
CDCl3, δ) 7.88 (d, J ) 8.0 Hz, 1H), 7.28-7.20 (m, 2H), 7.15-7.10
(m, 1H), 5.37 (q, J ) 6.6 Hz, 1H), 4.94-4.92 (m, 1H), 4.61 (s,
2H), 3.96-3.88 (m, 1H), 3.76 (s, 3H), 3.63-3.58 (m, 1H), 2.58
(br s, 1H), 1.91-1.56 (m, 6H), 1.71 (d, J ) 6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3, δ) 137.3, 124.8, 124.6, 123.4, 120.7, 119.8, 118.4,
109.5, 97.1, 94.8, 76.4, 64.8, 62.1, 54.9, 30.5, 30.3, 25.3, 23.8, 19.0;
HRMS-ESI (m/z) for [C19H23NO3 + Na]+ calcd 336.1576, found
336.1578.
1-Methyl-2-pyridin-2-ylethynyl-1H-indole-3-carbaldehyde
(5): Pale yellow solid, 96%; mp 144-145 °C; IR (neat) 3048, 2781,
1
2737, 2208, 1656; H NMR (300 MHz, CDCl3, δ) 10.32 (s, 1H),
8.70 (ddd, J ) 4.8, 1.5, 0.9 Hz, 1H), 8.34 (ddd, J ) 7.4, 1.2, 1.2
Hz, 1H), 7.79 (ddd, J ) 7.7, 7.7, 1.7 Hz, 1H), 7.68-7.64 (m, 1H),
7.42-7.32 (m, 4H), 3.98 (s, 3H); 13C NMR (75 MHz, CDCl3, δ)
185.0, 150.4, 141.7, 137.7, 136.6, 130.6, 127.9, 125.4, 124.4, 124.0,
123.7, 122.3, 120.7, 109.9, 99.7, 76.9, 31.4; HRMS-EI (m/z) for
[C17H12N2O]+• calcd 260.0950, found 260.0954.
1-Methyl-2-phenylethynyl-1H-indole-3-carbaldehyde (6): Yel-
40
1
low solid, 96%; mp 113-114 °C (lit. 120-121 °C ); H NMR
(300 MHz, CDCl3, δ) 10.33 (s, 1H), 8.40 (d, J ) 7.2 Hz, 1H),
7.71-7.68 (m, 2H), 7.53-7.34 (m, 6H), 3.91 (s, 3H).
1-(1-Benzyl-2-phenylethynyl-1H-indol-3-yl)ethanol (14): Yel-
low oil, 95%; 1H NMR (300 MHz, CDCl3, δ) 7.94 (d, J ) 7.9 Hz,
1H), 7.52-7.48 (m, 2H), 7.37-7.33 (m, 3H), 7.29-7.20 (m, 7H),
7.17-7.12 (m, 1H), 5.51 (q, J ) 6.6 Hz, 1H), 5.45 (s, 2H), 2.34
(br s, 1H), 1.81 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3,
δ) 137.6, 137.1, 131.3, 128.8, 128.7, 128.5, 127.5, 126.9, 125.1,
124.7, 123.5, 122.4, 120.8, 120.1, 118.8, 110.1, 98.8, 79.9, 65.1,
47.9, 23.8; HRMS-ESI (m/z) for [C25H21NO + Na]+ calcd
374.1521, found 374.1521.
2-Hex-1-ynyl-1-methyl-1H-indole-3-carbaldehyde (7): Yellow
1
thick oil, 70%; IR (neat) 3057, 2953, 2936, 2871, 1703, 1641; H
NMR (300 MHz, CDCl3, δ) 10.08 (s, 1H), 8.28-8.25 (m, 1H),
7.27-7.24 (m, 2H), 7.15-7.12 (m, 1H), 3.62 (s, 3H), 2.55 (t, J )
6.9 Hz, 2H), 1.71-1.61 (m, 2H), 1.57-1.45 (m, 2H), 0.98 (t, J )
7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3, δ) 185.0, 136.8, 133.1,
124.4, 124.1, 123.0, 121.6, 119.1, 109.5, 103.5, 69.0, 30.7, 30.2,
22.0, 19.4, 13.5; HRMS-EI (m/z) for [C16H17NO]+• calcd 239.1310,
found 239.1310.
1-(1-Methyl-2-pyridin-2-ylethynyl-1H-indol-3-yl)ethanone
(15): Pale brown solid, 71%; mp 116-118 °C; IR (neat) 3053,
1
2925, 2851, 2210, 1726, 1641; H NMR (300 MHz, CDCl3, δ)
(37) Gilchrist, T. L.; Kemmitt, P. D.; Germain, A. L. Tetrahedron 1997, 53,
4447.
8.60 (br s, 1H), 8.38-8-35 (m, 1H), 7.66 (ddd, J ) 7.7, 7.7, 1.5
Hz, 1H), 7.52 (d, J ) 7.6 Hz, 1H), 7.29-7.19 (m, 4H), 3.83 (s,
3H), 2.74 (s, 3H); 13C NMR (75 MHz, CDCl3, δ) 193.7, 150.5,
142.1, 137.3, 136.6, 127.5, 125.9, 125.6, 125.0, 123.9, 123.3, 123.3,
120.6, 109.6, 100.7, 80.1, 31.4, 30.1; HRMS-ESI (m/z) for
[C18H14N2O + H]+ calcd 275.1184, found 275.1186.
(38) Schowalter, H. D. H.; Sercel, A. D.; Leja, B. M.; Wolfangel, C. D.;
Ambroso, L. A.; Linda, A. J. Med. Chem. 1997, 40, 413.
(39) Erba, E.; Pocar, D.; Valle, M. J. Chem. Soc., Perkin Trans. 1 1999,
421.
(40) Prikhod’ko, T. A.; Vasilevskii, S. F.; Shvartsberg, M. S. Bull. Acad.
Sci. USSR, DiV. Chem. Sci. 1984, 33, 2383.
4106 J. Org. Chem. Vol. 73, No. 11, 2008

Rapid Access to Amino-Substituted Compounds
1-(1-Methyl-2-phenylethynyl-1H-indol-3-yl)ethanone (16):
Pale yellow solid, 96%; mp 113-115 °C; IR (neat) 3053, 2927,
J ) 6.6 Hz, 1H), 2.52 (t, J ) 7.1 Hz, 2H), 2.18 (br s, 1H),
1.67-1.59 (m, 5H), 1.56-1.44 (m, 2H), 0.97 (t, J ) 6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3, δ) 154.5, 135.3, 126.9, 126.1, 125.4,
123.0, 121.0, 111.3, 100.4, 70.2, 63.9, 30.4, 23.1, 22.1, 19.5, 13.7;
HRMS-EI (m/z) for [C16H18O2]+• calcd 242.1307, found 242.1307.
1-(2-Pyridin-2-ylethynylbenzofuran-3-yl)ethanol (25): Brown
1
2861, 1679; H NMR (300 MHz, CDCl3, δ) 8.38 (d, J ) 6.8 Hz,
1H), 7.53-7.50 (m, 2H), 7.35-7.32 (m, 3H), 7.26-7.16 (m, 3H),
3.78 (s, 3H), 2.72 (s, 3H); 13C NMR (75 MHz, CDCl3, δ) 193.8,
137.2, 131.5, 129.8, 128.8, 126.9, 126.1, 124.7, 123.2, 123.2, 121.8,
119.8, 109.5, 102.2, 80.8, 31.3, 30.0; HRMS-CI (m/z) for
[C19H15NO + H]+ calcd 274.1232, found 274.1235.
1
oil, quant.; H NMR (300 MHz, CDCl3, δ) 8.52 (d, J ) 4.8 Hz,
1H), 7.85 (d, J ) 7.8 Hz, 1H), 7.67 (ddd, J ) 7.8, 7.8, 1.8 Hz,
1H), 7.52 (d, J ) 7.8 Hz, 1H), 7.42 (d, J ) 8.2 Hz, 1H), 7.35
(ddd, J ) 7.0, 7.0, 1.3 Hz, 1H), 7.27-7.20 (m, 2H), 5.42 (q, J )
6.6 Hz, 4H), 1.72 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3,
δ) 155.5, 150.4, 142.5, 136.8, 134.1, 131.2, 127.6, 126.6, 126.3,
123.8, 123.5, 122.0, 111.8, 97.2, 79.0, 63.8, 23.7; HRMS-EI (m/z)
for [C17H13NO2]+• calcd 263.0946, found 263.0941.
1-(2-Hex-1-ynyl-1-methyl-1H-indol-3-yl)ethanone (17): Pale
green oil, 84%; IR (neat): 3053, 2958, 2932, 2230, 1713, 1643; 1H
NMR (300 MHz, CDCl3, δ) 8.44-8.41 (m, 1H), 7.30-7.16 (m,
3H), 3.73 (s, 3H), 2.69 (s, 3H), 2.59 (t, J ) 6.9 Hz, 2H), 1.72-1.63
(m, 2H), 1.58-1.46 (m, 2H), 0.97 (t, J ) 7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3, δ) 191.8, 134.6, 125.9, 123.8, 122.1, 120.9, 120.8,
116.8, 107.3, 102.8, 70.4, 28.9, 28.3, 27.7, 20.2, 17.6, 11.6; HRMS-
EI (m/z) for [C17H19NO]+• calcd 253.1466, found 253.1464.
1-{1-Methyl-2-[3-(tetrahydropyran-2-yloxy)prop-1-ynyl]-
1H-indol-3-yl}ethanone (18): Brown oil, 77%; IR (neat) 2942,
1-(2-Phenylethynylbenzofuran-3-yl)ethanone (26): Yellow solid,
1
82%; mp 89-92 °C; IR (neat) 3055, 2987, 2214, 1665; H NMR
(300 MHz, CDCl3, δ) 8.30-8.27 (m, 1H), 7.63-7.60 (m, 2H),
7.48-7.33 (m, 6H), 2.82 (s, 3H); 13C NMR (75 MHz, CDCl3, δ)
194.0, 154.8, 143.2, 132.2, 130.7, 129.2, 127.1, 125.6, 125.3, 124.2,
123.9, 121.3, 111.3, 102.2, 80.3, 30.4; HRMS-EI (m/z) for
[C18H12O2]+• calcd 260.0837, found 260.0838.
1
1728, 1640; H NMR (300 MHz, CDCl3, δ) 8.46-8.43 (m, 1H),
7.37-7.25 (m, 3H), 4.95 (m, 1H), 4.67 (s, 2H), 3.94-3.88 (m,
1H), 3.82 (s, 3H), 3.63-3.56 (m, 1H), 2.73 (s, 3H), 1.89-1.57
(m, 6H); 13C NMR (75 MHz, CDCl3, δ) 193.8, 136.9, 126.1, 125.8,
124.6, 123.2, 123.2, 120.0, 109.5, 99.0, 97.4, 77.1, 62.3, 54.8, 31.2,
30.3, 29.9, 25.4, 19.1; HRMS-ESI (m/z) for [C19H21NO3 + Na]+
calcd 334.1419, found 334.1417.
1-(2-Hex-1-ynylbenzofuran-3-yl)ethanone (27): Yellow oil,
96%; IR (neat) 2959, 2933, 2873, 2226, 1664; 1H NMR (300 MHz,
CDCl3, δ) 8.26-8.22 (m, 1H), 7.44-7.30 (m, 3H), 2.72 (s, 3H),
2.60 (t, J ) 7.0 Hz, 2H), 1.74-1.46 (m, 2H), 1.58-1.46 (m, 2H),
0.98 (t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3, δ) 194.0,
154.0, 143.5, 126.4, 125.3, 124.8, 123.4, 123.0, 110.9, 104.9, 71.9,
30.0, 29.9, 22.2, 19.7, 13.7 HRMS-EI (m/z) for [C16H16O2]+• calcd
240.1150, found 240.1149.
1-(1-Benzyl-2-phenylethynyl-1H-indol-3-yl)ethanone (19):
White solid, 78%; mp 138-139 °C; IR (neat) 3063, 3028, 2916,
1
2208, 1632; H NMR (300 MHz, CDCl3, δ) 8.56-8.53 (m, 1H),
7.56-7.53 (m, 2H), 7.44-7.41 (m, 2H), 7.34-7.22 (9H), 5.59 (s,
2H), 2.89 (s, 3H); 13C NMR (75 MHz, CDCl3, δ) 194.0, 136.8,
136.5, 131.6, 129.8, 129.0 (2C), 128.8 (2C), 128.0, 126.9, 126.7,
126.4, 124.9, 123.4, 123.4, 121.7, 120.3, 110.1, 102.3, 81.0, 48.6,
30.1; HRMS-ESI (m/z) for [C25H19NO + H]+ calcd 350.1545, found
350.1546.
1-(2-Pyridin-2-ylethynylbenzofuran-3-yl)ethanone
(28):
Brown solid, 57%; mp 129-130 °C; IR (neat) 3053, 2921, 2850,
1656; 1H NMR (300 MHz, CDCl3, δ) 8.67 (ddd, J ) 4.9, 1.4, 0.8
Hz, 1H), 8.28-8.24 (m, 1H), 7.73 (ddd, J ) 7.8, 7.8, 1.8 Hz, 1H),
7.61 (ddd, J ) 7.8, 1.1, 1.1 Hz, 1H), 7.48-7.31 (m, 4H), 2.84 (s,
3H); 13C NMR (75 MHz, CDCl3, δ) 193.6, 154.7, 150.7, 141.8,
141.5, 136.4, 127.8, 127.1, 125.1, 125.0, 125.0, 124.3, 123.6, 114.6,
111.1, 100.1, 78.7, 30.2; HRMS-CI (m/z) for [C17H11NO2 + H]+
calcd 262.0868, found 262.0869.
2-Phenylethynylbenzofuran-3-carbaldehyde (20): Yellow solid,
86%; mp 86 °C; IR (neat) 3060, 2209, 1673; 1H NMR (300 MHz,
CDCl3, δ) 10.36 (s, 1H), 8.21-8.18 (m, 1H), 7.67-7.63 (m, 2H),
7.53-7.36 (m, 6H); 13C NMR (75 MHz, CDCl3, δ) 185.5, 154.7,
148.0, 132.2 (2C), 130.4, 128.8 (2C), 127.2, 125.3, 123.9, 123.4,
122.5, 120.5, 111.3, 101.0, 77.2; HRMS-EI (m/z) for [C17H10O2]+•
calcd 246.0681, found 246.0678.
1-(2-Pyridin-2-ylethynylpyridin-3-yl)ethanone (29): Orange
solid, 78%; mp 86-89 °C; IR (neat) 3058, 2994, 2925, 2851, 1724,
1
1666; H NMR (300 MHz, CDCl3, δ) 8.66 (dd, J ) 4.7, 1.6 Hz,
2-Hex-1-ynylbenzofuran-3-carbaldehyde (21): Orange oil,
72%; IR (neat) 2972, 2958, 2932, 2230,1672, 1721; 1H NMR (300
MHz, CDCl3, δ) 10.22 (s, 1H), 8.15-8.13 (m, 1H), 7.47-7.32 (m,
3H), 2.59 (t, J ) 6.9 Hz, 2H), 1.73-1.63 (m, 2H), 1.58-1.46 (m,
2H), 0.98 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3, δ) 185.8,
154.3, 148.8, 126.8, 125.1, 123.4, 123.3, 122.3, 111.2, 103.9, 69.3,
30.0, 22.1, 19.6, 13.6; HRMS-EI (m/z) for [C15H14O2]+• calcd
226.0994, found 226.0994.
1H), 8.57 (d, J ) 4.6 Hz, 1H), 8.01 (dd, J ) 8.0, 1.6 Hz, 1H),
7.67-7.54 (m, 2H), 7.32 (dd, J ) 8.0, 4.8 Hz, 1H), 7.22 (ddd, J )
7.3, 6.0, 1.2 Hz, 1H), 2.80 (s, 3H); 13C NMR (75 MHz, CDCl3, δ)
198.7, 152.2, 150.3, 142.2, 140.1, 137.1, 136.5, 136.2, 127.7, 123.7,
123.3, 96.2, 86.8, 30.1 ; HRMS-EI (m/z) for [C14H10N2O]+• calcd
222.0793, found 222.0791.
1-(2-Phenylethynylpyridin-3-yl)ethanone (30): Colorless oil,
82%; IR (neat) 3059, 2924, 2851, 2220, 1682; 1H NMR (300 MHz,
CDCl3, δ) 8.72 (d, J ) 3.3 Hz, 1H), 8.05 (dd, J ) 8.0, 1.7 Hz,
1H), 7.62-7.59 (m, 2H), 7.40-7.31 (m, 4H), 2.84 (s, 3H); 13C
NMR (75 MHz, CDCl3, δ) 199.1, 152.3, 141.0, 136.8, 136.6, 132.0
(2C), 129.7, 128.6 (2C), 122.8, 121.8, 95.0, 88.1, 30.1; HRMS-EI
(m/z) for [C15H11NO]+• calcd 221.0841, found 221.0842.
1-(2-Trimethylsilanylethynylpyridin-3-yl)ethanone (31): Col-
2-Pyridin-2-ylethynylbenzofuran-3-carbaldehyde (22): Brown
1
solid, 50%; mp 89-92 °C; IR (neat) 3055, 2216, 1681; H NMR
(300 MHz, CDCl3, δ) 10.37 (s, 1H), 8.67 (d, J ) 4.8 Hz, 1H),
8.17 (d, J ) 7.1 Hz, 1H), 7.74 (ddd, J ) 7.7, 7.7, 1.8 Hz, 1H),
7.64 (d, J ) 7.7 Hz, 1H), 7.49 (d, J ) 7.7 Hz, 1H), 7.43 (ddd, J )
7.1, 7.1, 1.5 Hz, 1H), 7.40-7.31 (m, 2H); 13C NMR (75 MHz,
CDCl3, δ) 185.3, 154.9, 150.6, 146.8, 141.1, 136.5, 128.1, 127.5,
125.3, 125.0, 124.4, 123.2, 122.6, 111.4, 99.1, 76.2; HRMS-EI (m/
z) for [C16H9NO2]+• calcd 247.0633, found 247.0632.
1
orless oil, 91%; IR (neat) 2961, 2896, 2168, 1686; H NMR (300
MHz, CDCl3, δ) 8.67 (dd, J ) 1.7, 4.7 Hz, 1H), 8.00 (dd, J ) 8.0,
4.7 Hz, 1H), 7.33 (dd, J ) 8.0, 4.7 Hz, 1H), 2.80 (s, 3H), 0.28 (s,
9H); 13C NMR (75 MHz, CDCl3, δ) 199.5, 152.2, 140.5, 137.4,
136.6, 123.2, 102.8, 102.2, 30.3, -0.5; HRMS-EI (m/z) for
[C12H15NOSi + H]+ calcd 218.1001, found 218.1003.
1-(2-Hex-1-ynylpyridin-3-yl)ethanone (32): Colorless oil, 90%;
IR (neat) 2959, 2932, 2872, 1694, 1715; 1H NMR (300 MHz,
CDCl3, δ) 8.59 (dd, J ) 4.7, 1.7 Hz, 1H), 7.91 (dd, J ) 7.9, 1.7
Hz, 1H), 7.23 (dd, J ) 7.9, 4.7 Hz, 1H), 2.72 (s, 3H), 2.46 (t, J )
7.2 Hz, 2H), 1.64-1.54 (m, 2H), 1.50-1.37 (m, 2H), 0.89 (t, J )
7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3, δ) 199.6, 152.0, 141.3,
136.7, 136.3, 122.3, 97.7, 79.9, 30.1 (2C), 22.1, 19.3, 13.6; HRMS-
EI (m/z) for [C13H15NO]+• calcd 201.1154, found 201.1155.
1-(2-Phenylethynylbenzofuran-3-yl)ethanol (23): Yellow oil,
1
96%; H NMR (300 MHz, CDCl3, δ) 7.78 (d, J ) 7.6 Hz, 1H),
7.56-7.53 (m, 2H), 7.42 (d, J ) 8.2 Hz, 1H), 7.36-7.29 (m, 4H),
7.22 (ddd, J ) 7.0, 7.0, 1.0 Hz, 1H), 5.31 (q, J ) 6.6 Hz, 1H),
2.37 (br s, 1H), 1.69 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3, δ) 154.9, 134.6, 131.6, 129.3, 128.6, 128.4, 126.0, 125.9,
123.1, 121.8, 121.3, 111.4, 98.3, 78.6, 63.9, 23.1; HRMS-EI (m/z)
for [C18H14O2]+• calcd 262.0994, found 262.0992.
1-(2-Hex-1-ynylbenzofuran-3-yl)ethanol (24): Yellow oil, 99%;
1H NMR (300 MHz, CDCl3, δ) 7.76 (d, J ) 7.6 Hz, 1H), 7.40 (d,
J ) 8.1 Hz, 1H), 7.33-7.27 (m, 1H), 7.25-7.19 (m, 1H), 5.23 (q,
J. Org. Chem. Vol. 73, No. 11, 2008 4107

Tiano and Belmont
1-{2-[3-(Tetrahydropyran-2-yloxy)prop-1-ynyl]pyridin-3-
δ) 7.59 (d, J ) 7.7 Hz, 1H), 7.43-7.40 (m, 3H), 7.31-7.26 (m,
2H), 7.10 (dd, J ) 7.6, 7.7 Hz, 1H), 6.95 (dd, J ) 7.7, 7.7 Hz,
1H), 6.63 (d, J ) 7.8 Hz, 1H), 6.49 (s, 1H), 3.31 (br s, 4H), 2.61
(s, 3H), 1.9 (br s, 4H); 13C NMR (75 MHz, CDCl3, δ) 193.2, 164.5,
162.4 (2C), 157.1, 152.4, 138.3, 128.3, 128.3 (2C), 127.3, 123.1,
122.2, 119.6, 109.9, 109.7, 87.5 (2C), 49.6, 31.6 (2C), 25.5; HRMS-
ESI (m/z) for [C22H21NO2 + Na]+ calcd 354.1470, found 354.1469.
1-[2-(2-Pyridin-2-yl-2-pyrrolidin-1-ylvinyl)benzofuran-3-yl]-
ethanone (41): Yellow/brown solid, Method B: quant.; mp
yl}ethanone (33): Brown oil, 73%; IR (neat) 2941, 2861, 1726,
1
1686; H NMR (300 MHz, CDCl3, δ) 8.60 (d, J ) 4.8 Hz, 1H),
7.94 (d, J ) 7.7 Hz, 1H), 7.28 (dd, J ) 7.7, 4.8 Hz, 1H), 4.84 (br
s, 1H), 4.49 (s, 2H), 3.82-3.75 (m, 1H), 3.51-3-45 (m, 1H), 2.70
(s, 3H), 1.77-1.47 (m, 6H); 13C NMR (75 MHz, CDCl3, δ) 198.9,
152.0, 140.2, 136.8, 136.3, 122.9, 97.0, 91.5, 84.2, 61.9, 54.4, 30.1,
29.9, 25.2, 18.9; HRMS-EI (m/z) for [C15H17NO3]+• calcd 259.1208,
found 259.1207.
1
7-Pyridin-2-yl-5-pyrrolidin-1-ylquinoline (34): Brown oil,
Method A: 87%; IR (neat) 2964, 1870, 1607, 1586, 1560; 1H NMR
(300 MHz, CDCl3, δ) 8.88 (dd, J ) 4.1, 1.4 Hz, 1H), 8.75 (d, J )
4.8 Hz, 1H), 8.55 (d, J ) 8.6 Hz, 1H), 8.15 (s, 1H), 7.94 (d, J )
8.0 Hz, 1H), 7.83-7.77 (m, 2H), 7.34-7.26 (m, 2H), 3.54-3.50
(m, 4H), 2.07-2.03 (m, 4H); 13C NMR (75 MHz, CDCl3, δ) 157.5,
150.2, 150.0, 149.7, 148.4, 140.4, 136.9, 133.4, 123.0, 122.5, 121.4,
119.8, 119.2, 109.8, 53.0 (2C), 25.3 (2C); HRMS-ESI (m/z) for
[C18H17N3 + H]+ calcd 276.1501, found 276.1502.
5-Pyrrolidin-1-ylquinoline (35): Pale yellow oil, Method A: 0%,
Method B: traces, Method C: 91%; IR (neat) 2865, 2871, 2825,
1585, 1571; 1H NMR (300 MHz, CDCl3, δ) 8.83 (dd, J ) 4.1, 1.6
Hz, 1H), 8.53 (d, J ) 8.6 Hz, 1H), 7.65 (d, J ) 8.3 Hz, 1H),7.56
(m, 1H), 7.29 (dd, J ) 8.6 Hz, 4.2 Hz, 1H), 6.92 (d, J ) 7.6 Hz,
1H), 3.41-3.37 (m, 4H), 2.04-1.99 (m, 4H); 13C NMR (75 MHz,
CDCl3, δ) 149.8 (2C), 147.9, 133.4, 129.5, 122.8, 121.6, 118.8,
110.9, 52.9 (2C), 25.2 (2C); HRMS-CI (m/z) for [C13H14N2 + H]+
calcd 199.1235, found 199.1235.
145-148 °C; IR (neat) 3052, 2976, 2871, 1640; H NMR (300
MHz, CDCl3, δ) 8.71 (s, 1H), 7.75-7.70 (m, 1H), 7.59 (d, J ) 8.0
Hz, 1H), 7.37-7.33 (m, 2H), 7.08 (dd, J ) 7.7, 7.7 Hz, 1H), 6.93
(dd, J ) 7.7, 7.7 Hz, 1H), 6.58 (d, J ) 8.3 Hz, 1H), 6.45 (s, 1H),
3.35 (br s, 4H), 2.58 (s, 3H), 1.94 (br s, 4H); 13C NMR (75 MHz,
CDCl3, δ) 193.1, 163.7, 156.6, 154.4, 152.3, 149.4, 136.4, 127.1,
124.1, 123.1 (2C), 122.2, 119.7, 110.0, 109.7, 87.6, 49.1 (2C), 31.5,
25.3 (2C); HRMS-EI (m/z) for [C21H20N2O2]+• calcd 332.1525,
found 332.1525.
1-(3-Butyldibenzofuran-1-yl)pyrrolidine (42): Brown oil, Method
1
B: 17%; IR (neat) 2955, 2928, 2857, 2810, 1628, 1599, 1579; H
NMR (300 MHz, CDCl3, δ) 7.88-7.85 (m, 1H), 7.56-7.53 (m,
1H), 7.42-7.31 (m, 2H), 7.03 (s, 1H), 6.71 (s, 1H), 3.36 (br s,
4H), 2.79-2.73 (m, 2H), 2.09-2.05 (m, 4H), 1.76-1.66 (m, 2H),
1.49-1.37 (m, 2H), 0.98 (t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3, δ) 158.1, 155.8, 146.0, 143.6, 125.3, 124.2, 122.7, 122.5,
113.9, 111.0, 110.4, 104.2, 51.1 (2C), 36.5, 34.0, 24.4 (2C), 22.6,
14.1; HRMS-EI (m/z) for [C20H23NO]+• calcd 293.1780, found
293.1781.
7-Phenyl-5-pyrrolidin-1-ylquinoline (36): Pale brown oil,
Method C: 85%; IR (neat) 2970, 2870, 2830, 1683, 1595, 1579,
1-[2-(2-Pyrrolidin-1-ylhex-1-enyl)benzofuran-3-yl]ethanone
(43): Yellow slurry solid, Method B; HRMS-ESI (m/z) for
[C20H25NO2 + H]+ calcd 312.1964, found 312.1963.
1
1557; H NMR (300 MHz, CDCl3, δ) 8.74 (dd, J ) 4.1, 1.6 Hz,
1H), 8.41 (d, J ) 8.4 Hz, 1H), 7.71 (br s, 1H), 7.66-7.63 (m, 2H),
7.40-7.35 (m, 2H), 7.31-7.25 (m, 1H), 7.16 (dd, J ) 8.4, 4.1 Hz,
1H), 7.04 (d, 1.5 Hz, 1H), 3.37-3.33 (m, 4H), 1.94-1.89 (m, 4H);
13C NMR (75 MHz, CDCl3, δ) 150.2, 150.1, 148.1, 142.3, 141.3,
133.4, 129.0, 127.7, 127.5, 121.7, 119.4, 118.6, 110.4, 52.9, 25.2;
HRMS-ESI (m/z) for [C19H18N2 + H]+ calcd 275.1548, found
275.1546.
1-[1-Methyl-2-(2-pyridin-2-yl-2-pyrrolidin-1-ylvinyl)-1H-
indol-3-yl]ethanone (44): Yellow solid, Method A: quant.; mp 200
1
°C; IR (neat) 3048, 2966, 2873, 1623, 1584, 1563; H NMR (300
MHz, CDCl3, δ) 8.61 (d, J ) 4.3 Hz, 1H), 8.19 (d, J ) 7.9 Hz,
1H), 7.35-7.32 (m, 1H), 7.18 (dd, J ) 7.4, 7.4 Hz, 1H), 7.14-7.08
(m, 2H), 7.01 (d, J ) 8.0 Hz, 1H), 6.88 (d, J ) 7.9 Hz, 1H), 5.59
(s, 1H), 3.33-3.30 (m, 4H), 3.18 (s, 3H), 2.70 (s, 3H), 2.01-1.99
(m, 4H); 13C NMR (75 MHz, CDCl3, δ) 194.1, 155.6, 151.5, 149.5,
146.7, 137.0, 136.6, 127.3, 125.1, 123.2, 122.1, 122.0, 121.5, 114.8,
109.3, 89.0, 49.3 (2C), 31.2, 31.0, 25.4 (2C); HRMS-CI (m/z) for
[C22H23N3O + H]+ calcd 346.1919, found 346.1917.
9-Methyl-2-phenyl-4-pyrrolidin-1-yl-9H-carbazole (45): White
solid, Method A: 0%, Method B: 96%; mp 126-127 °C; IR (neat)
3050, 2924, 2853, 2804, 1593, 1563; 1H NMR (300 MHz, CDCl3,
δ) 8.07 (d, J ) 7.8 Hz, 1H), 7.76-7.73 (m, 2H), 7.52-7.35 (m,
5H), 7.31-7.26 (m, 2H), 7.10 (s, 1H), 3.89 (s, 3H), 3.43-3.39
(m, 4H), 2.14-2.09 (m, 4H); 13C NMR (75 MHz, CDCl3, δ) 146.6,
143.2, 142.7, 141.2, 140.0, 128.8 (2C), 127.8 (2C), 127.1, 124.6,
123.1, 122.2, 119.1, 114.8, 108.0, 107.1, 101.5, 51.3 (2C), 29.3,
24.1 (2C); HRMS-ESI (m/z) for [C23H22N2 + H]+ calcd 327.1861,
found 327.1864.
5-Pyrrolidin-1-yl-7-(tetrahydropyran-2-yloxymethyl)quino-
line (37): Brown oil, Method C: 45%; IR (neat) 2942, 2870, 1614,
1589, 1569; 1H NMR (300 MHz, CDCl3, δ) 8.81 (dd, J ) 4.2, 1.5
Hz, 1H), 8.52 (d, J ) 8.6 Hz, 1H), 7.65 (s, 1H), 7.27 (dd, J ) 8.4,
4.1 Hz, 1H), 6.91 (s, 1H), 4.92 (d, J ) 12.6 Hz, 1H), 4.77 (t, J )
3.85 Hz, 1H) 4.66 (d, J ) 12.6 Hz, 1H), 4.00-3.92 (m, 1H),
3.60-3.53 (m, 1H), 3.44-3.40 (m, 4H), 2.04-2.00 (m, 4H),
1.81-1.52 (m, 6H); 13C NMR (75 MHz, CDCl3, δ) 149.5, 149.3,
148.0, 140.5, 134.0, 122.1, 119.2, 118.6, 110.4, 98.1, 69.0, 62.4,
52.9 (2C), 30.7, 25.6, 25.3 (2C), 19.5; HRMS-ESI (m/z) for
[C19H24N2O2 + H]+ calcd 313.1916, found 313.1917.
7-Butyl-5-pyrrolidin-1-ylquinoline (38): Brown oil, Method C:
53%; IR (neat) 2955, 2924, 2854, 1737, 1612, 1589, 1567; 1H NMR
(300 MHz, CDCl3, δ) 8.79 (d, J ) 3.6 Hz, 1H), 8.59 (d, J ) 8.5
Hz, 1H), 7.53 (s, 1H), 7.30-7.26 (m, 1H), 6.77 (s, 1H), 3.46-3.41
(m, 4H), 2.76 (t, J ) 7.7 Hz, 2H), 2.06-2.02 (m, 4H), 1.75-1.65
(m, 2H), 1.47-1.37 (m, 2H), 0.95 (t, J ) 7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3, δ) 147.9, 147.7, 147.5, 147.4, 136.4, 121.5, 117.6
(2C), 112.9, 53.3 (2C), 36.9, 33.6, 25.7 (2C), 22.9, 14.4; HRMS-
ESI (m/z) for [C17H22N2 + H]+ calcd 255.1861, found 255.1863.
1-(3-Phenyldibenzofuran-1-yl)pyrrolidine (39): Brown oil,
Method B: 55%; IR (neat) 2923, 2853, 1627, 1598, 1572; 1H MNR
(300 MHz, CDCl3, δ) 7.79 (d, J ) 7.2 Hz, 1H), 7.59-7.57 (m,
2H), 7.47-7.45 (m, 1H), 7.39-7.34 (m, 2H), 7.31-7.23 (m, 4H)
6.97 (s, 1H), 3.30 (br s, 4H), 1.96 (br s, 4H); 13C NMR (75 MHz,
CDCl3, δ) 158.3, 156.2, 146.4, 141.8, 141.5, 128.9 (2C), 127.6 (2C),
127.5, 125.8, 124.0, 123.0, 122.7, 115.2, 111.2, 109.3, 103.2, 51.2
(2C), 24.5 (2C); HRMS-ESI (m/z) for [C22H19NO + H]+ calcd
314.1545, found 314.1544.
2-Butyl-9-methyl-4-pyrrolidin-1-yl-9H-carbazole (46): Brown
oil, Method B: 65%; mp ) 59-61 °C; IR (neat) 2955, 2926, 2855,
1
1598, 1570; H NMR (300 MHz, CDCl3, δ) 8.01 (d, J ) 7.6 Hz,
1H), 7.44-7.33 (m, 2H), 7.24 (dd, J ) 7.6, 7.6 Hz, 1H), 6.89 (s,
1H), 6.72 (s, 1H), 3.79 (s, 3H), 3.33 (br s, 4H), 2.80 (t, J ) 7.7
Hz, 2H), 2.08 (br s, 4H), 1.78-1.67 (m, 2H), 1.50-1.38 (m, 2H),
0.98 (t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3, δ) 142.9
(2C), 141.9 (2C), 140.7 (2C), 124.0, 122.7 (3C), 118.8, 107.8, 51.2
(2C), 36.8, 34.3, 29.2, 24.0 (2C), 22.7, 14.2; HRMS-ESI (m/z) for
[C21H26N2 + H]+ calcd 307.2174, found 307.2175.
9-Methyl-4-pyrrolidin-1-yl-2-(tetrahydropyran-2-yloxymethyl)-
9H-carbazole (47): Brown oil, Method B: 65%; IR (neat) 2970,
2870, 2831, 1683, 1595, 1579, 1557; 1H NMR (300 MHz, CDCl3,
δ) 8.02 (d, J ) 7.9 Hz, 1H), 7.45-7.36 (m, 2H), 7.27-7.21 (m,
1H), 7.09 (s, 1H), 6.84 (s, 1H), 4.96 (d, J ) 12.0 Hz, 1H),
4.78-4.75 (m, 1H), 4.68 (d, J ) 12.0 Hz, 1H), 4.03-3.95 (m,
1H), 3.83 (s, 3H), 3.61-3.54 (m, 1H), 3.33-3.30 (m, 4H),
1-[2-(2-Phenyl-2-pyrrolidin-1-ylvinyl)benzofuran-3-yl]eth-
anone (40): Yellow/brown solid, Method B: 45%; mp 140-142
°C; IR (neat) 3041, 2964, 2860, 1634; 1H NMR (300 MHz, CDCl3,
4108 J. Org. Chem. Vol. 73, No. 11, 2008

Rapid Access to Amino-Substituted Compounds
2.08-2.04 (m, 4H), 1.77-1.52 (m, 6H); 13C NMR (75 MHz,
CDCl3, δ) 142.8, 140.9, 136.7, 124.5, 123.0, 122.1, 119.0, 114.9,
108.0, 107.5, 102.5, 97.8, 97.0, 69.8, 62.5, 51.3, 30.8, 30.3, 29.3,
27.0, 25.6, 24.0, 19.7; HRMS-CI (m/z) for [C23H28N2O3 + H]+
calcd 365.2229, found 365.2226.
9-Benzyl-2-phenyl-4-pyrrolidin-1-yl-9H-carbazole (48): Pale
brown solid, Method B: 80%; mp 130-131 °C; IR (neat) 3048,
3028, 2965, 2922, 2810, 1596, 1563; 1H NMR (300 MHz, CDCl3,
δ) 8.10 (d, J ) 7.6 Hz, 1H), 7.67-7.65 (m, 2H), 7.45-7.11 (m,
13H), 5.50 (s, 2H), 3.40 (br s, 4H), 2.09 (br s, 4H); 13C NMR (75
MHz, CDCl3, δ) 146.7, 142.9, 142.6, 140.8, 140.1, 137.3, 128.8
(2C), 128.8 (2C), 127.7 (2C), 127.4, 127.1, 126.5 (2C), 124.8, 123.2,
122.5, 119.5, 115.0, 108.5, 107.4, 101.8, 51.3 (2C), 46.6, 24.1 (2C);
HRMS-ESI (m/z) for [C29H26N2 + H]+ calcd 403.2174, found
403.2175.
Benzyl-(9-methyl-2-phenyl-9H-carbazol-4-yl)amine (49): Pale
brown solid, Method B: 73%; mp 142-145 °C; IR (neat) 3049,
3023, 2924, 2854, 1732, 1585, 1567; 1H NMR (300 MHz, CDCl3,
δ) 7.89 (d, J ) 7.8 Hz, 1H), 7.65 (d, J ) 7.3 Hz, 2H), 7.50 (d, J
) 7.2 Hz, 2H), 7.44-7.30 (m, 8H), 7.21-7.17 (m, 1H), 7.02 (s,
1H), 4.91 (br s, 1H), 4.64 (s, 2H), 3.83 (s, 3H); 13C NMR (75 MHz,
CDCl3, δ) 149.9, 144.7, 143.0, 142.8, 140.8, 139.5, 128.9 (2C),
128.7 (2C), 127.8 (4C), 127.5, 127.1, 124.2, 122.3, 120.4, 119.1,
108.6, 108.3, 101.0, 97.8, 48.6, 29.3; HRMS-ESI (m/z) for
[C26H22N2 + H]+ calcd 363.1861, found 363.1862.
Diethyl-(9-methyl-2-phenyl-9H-carbazol-4-yl)amine
(50):
White solid, Method B: 70%; mp 146-150 °C; IR (neat) 3053,
1
2967, 2925, 2852, 1596, 1562; H NMR (300 MHz, CDCl3, δ)
8.30 (d, J ) 7.8 Hz, 1H), 7.72-7.69 (m, 2H), 7.49-7.41 (m, 3H),
7.39-7.31 (m, 2H), 7.26-7.21 (m, 2H), 7.10 (d, J ) 1.1 Hz, 1H),
3.84 (s, 3H), 3.40 (q, J ) 7.1 Hz, 4H), 1.10 (t, J ) 7.1 Hz, 6H);
13C NMR (75 MHz, CDCl3, δ) 147.4, 143.2, 142.8, 141.2, 139.4,
128.8 (2C), 127.8 (2C), 127.1, 124.9, 123.4, 122.3, 119.1, 116.9,
111.6, 107.9, 102.0, 45.9 (2C), 29.3, 11.9 (2C); HRMS-ESI (m/z)
for [C23H24N2 + H]+ calcd 329.2018, found 329.2016.
Acknowledgment. We thank the Centre National de la
Recherche Scientifique (CNRS), the Ministe`re de l’Education
Nationale et de la Recherche (Fellowship for M.T.), and the
Association pour la Recherche sur le Cancer (A.R.C.) for
financial support. We also thank Ms. M.-A. De Wispelaere, Mr.
C. Duchamp, and Dr. D. Bouchu and for the mass spectrometry
data. Dr. E. Jeanneau and the “Centre de Diffractome´trie Henri
Longchambon” are thanked for the crystallization data.
Supporting Information Available: General synthetic meth-
ods and copies of 1H NMR and 13C NMR spectra for compounds
5, 7, 8, 10-42, and 44-50. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO800249F
J. Org. Chem. Vol. 73, No. 11, 2008 4109