Titanocene-based method for indole synthesis

Article abstract of DOI:10.1021/ja972281p

A new approach for the construction of indoles employing the air- and moisture-stable reagent Cp₂TiCl₂ is described. The key steps involved are (1) the intermolecular insertion reactions of an olefin and a titanocene- stabilized benzyne complex and (2) the Pd-catalyzed aryl amination reaction. The simplicity and availability of the requisite starting materials give the method a broad scope for the preparation of polysubstituted indoles.

Full text of DOI:10.1021/ja972281p

3068
J. Am. Chem. Soc. 1998, 120, 3068-3073
Titanocene-Based Method for Indole Synthesis
Kazumasa Aoki, Andrew J. Peat, and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed July 9, 1997
Abstract: A new approach for the construction of indoles employing the air- and moisture-stable reagent
Cp2TiCl2 is described. The key steps involved are (1) the intermolecular insertion reactions of an olefin and
a titanocene-stabilized benzyne complex and (2) the Pd-catalyzed aryl amination reaction. The simplicity and
availability of the requisite starting materials give the method a broad scope for the preparation of polysubstituted
indoles.
Introduction
Scheme 1
The synthesis of functionalized indoles has been of interest
to organic chemists for many years due to the large number of
natural products that contain this structural element.1 More
importantly, indole-containing compounds have pronounced
effects in many physiological processes.2 For these reasons,
numerous methods exist to construct the indole skeleton.3
Recently, we reported a synthesis of substituted indolines which
involves the intramolecular olefin insertion reactions of a
zirconocene-stabilized benzyne complex.4 This allows for the
one-pot synthesis of regiochemically pure 3,4-diiodoindolines,
which served as convenient precursors to the analogous indole
derivatives including intermediates in the total or formal
syntheses of several natural products, such as makaluvamine
C, damirones A and B, dehydrobufotenine, the pharmacophore
of CC-1065, and the clavicipitic acids.5 Although the method
is regioselective and is compatible with a variety of functional
groups, we recognized the major drawback to its use was the
need to employ the air- and moisture-sensitive complex
Cp2Zr(Me)Cl. In addition, the synthesis of the other starting
material, an N-allyl-o-bromoaniline, can be difficult, depending
upon the nature of the substitution of the aromatic ring.
Additionally, the method is limited to the formation of indoles
bearing substituents at both the 3- and 4-positions. In an effort
to ameliorate these problems, we decided to investigate an
alternative route. Herein, we describe a novel approach for the
synthesis of indoles involving the intermolecular insertion
reaction of an olefin with a titanocene-benzyne complex. The
required starting materials, an aryl Grignard reagent, an olefin,
a primary amine, and the air-stable reagent, Cp2TiCl2, are
commercially available or readily prepared. This imparts this
method with a wide generality for the synthesis of polysubsti-
tuted indoles.
Results and Discussion
The retrosynthetic analysis for our indole synthesis is shown
in Scheme 1. The indole system A is constructed from the
indoline adduct B, which is formed from 2-bromophenethyl-
amine C via a palladium-catalyzed ring closure of the five-
membered ring.6 The amine C is formed from dibromide D,
which in turn is prepared from the appropriate metallocene-
benzyne complex E.7
(1) (a) The Alkaloids; Specialist Periodical Reports; The Chemical
Society: London, 1971. (b) Saxton, J. E. Nat. Prod. Rep 1989, 6, 1. (c)
Hesse, M. Alkaloid Chemistry; Wiley: New York, 1978. (d) Cordell, G.
A. Introduction to Alkaloids: A Biogenetic Approach; Wiley: New York,
1981. (e) Gilchrist, T. L. Heterocyclic Chemistry; Pitman: London, 1981.
(f) Pindur, A. R. J. Heterocycl. Chem. 1988, 25, 1.
(2) (a) Hugel, H. M.; Kennaway, D. J. Org. Prep. Proc. Int. 1995, 27,
1. (b) Glennon, R. A. J. Med. Chem. 1987, 30, 1.
(3) (a) Sundberg, R. J. Indoles; Academic Press: San Diego, CA, 1996
and refernces therein. (b) Gribble, G. W. Contemp. Org. Synth. 1994, 1,
145. (c) Robinson, B. The Fischer Indole Sythesis; Wiley-Interscience: New
York, 1982. (d) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27,
1113.
Research from our laboratories provides a means for the ready
access to the requisite dihalide D via intermolecular insertion
(6) For recent examples of this methodology, see: (a) Wolfe, J. P.;
Buchwald, S. L. J. Org. Chem. 1997, 62, 1264. (b) Wolfe, J. P.; Buchwald,
S. L. J. Org. Chem. 1996, 61, 1133. (c) Wolfe, J. P.; Wagaw, S.; Buchwald,
S. L. J. Am. Chem. Soc. 1996, 118, 7215. (d) Wolfe, J. P.; Rennels, R. A.;
Buchwald, S. L. Tetrahedron 1996, 52, 7525. (e) Guram, A. S.; Rennels,
R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1995, 34, 1348. (f)
Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217. (g) Kosugi,
M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927.
(4) Tidwell, J. H.; Senn, D. R.; Buchwald, S. L. J. Am. Chem. Soc. 1991,
113, 4685.
(5) (a) Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 1028.
(b) Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11797
and references therein. (c) Tidwell, J. H.; Peat, A. J.; Buchwald, S. L. J.
Org. Chem. 1994, 59, 7164. (d) Tidwell, J. H.; Buchwald, S. L. J. Org.
Chem. 1992, 57, 6380. (e) see also Tietze, L. F.; Buhr, W. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1366.
(7) (a) Buchwald, S. L.; Watson, B. T.; Lum, R. T.; Nugent, W. A. J.
Am. Chem. Soc. 1987, 109, 7137. For recent reviews of Zr-benzyne
chemistry, see: (b) Broene, R. D.; Buchwald, S. L. Science 1993, 261,
1696. (c) Buchwald, S. L.; Broene, R. D. In ComprehensiVe Organometallic
Chemistry, 2nd ed.; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon Press, Oxford, U.K., 1995; Vol. 12, Chapter 7.4, pp 771-784.
S0002-7863(97)02281-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/18/1998

Titanocene-Based Method for Indole Synthesis
J. Am. Chem. Soc., Vol. 120, No. 13, 1998 3069
Scheme 2
Scheme 3
Table 1
of an olefin into the Zr-C bond of a zirconocene-benzyne
complex, followed by treatment of the intermediate zirconacycle
with iodine.7 In our previous method, E (M ) Zr) was
generated by the addition of an aryllithium reagent to Cp2Zr-
(Me)Cl. In an effort to simplify the experimental procedure
for the preparation of E, we modified the previous method by
using titanocene dichloride in lieu of zirconocene methyl
chloride. This substitution has two advantages: (1) titanocene
dichloride is air- and moisture-stable and (2) the titanium
complex should exhibit greater functional group tolerance than
the corresponding highly oxophilic, zirconium reagent.8 Treat-
ment of titanocene dichloride with an o-substituted aryl Grignard
reagent (1.1 equiv) in toluene at 25 °C cleanly affords
arylchlorotitanocene I (Scheme 2). It should be noted that the
analogous aryllithium reagents do not give I, but instead reduce
the metal complex to a Ti(III) species.9 An olefin (2.0 equiv)
and MeMgBr (1.0 equiv) are added to the reaction mixture to
produce arylmethyltitanocene II, which upon heating generates
the titanocene-stabilized benzyne complex III. The olefin
coordinates to the metal opposite from the o-aryl substituent,7
with the olefin R′-substituent situated away from the cyclopen-
tadienyl ligands as depicted in intermediate III.7 Insertion of
the olefin into the carbon-titanium bond of the benzyne
complex yields metallacyclopentane IV.10 The toluene was
removed in vacuo, CH2Cl2 was added, and the solution was
cooled to -78 °C. Addition at -78 °C of a solution of bromine
in CH2Cl2 produces the desired dibromide D in moderate yield
with excellent regiochemical purity. The overall process
increases the level of substitution of the aromatic ring by one,
thereby producing a contiguously trisubstituted benzene deriva-
tive. It should be noted that the formation of the dibromide is
the yield-limiting step in all of the following procedures.
With a method to prepare dibromides D in hand, we turned
our attention to their conversion to indolines. Our original idea
was to convert D to the corresponding amine C, and then close
the five-membered ring via the Pd-catalyzed intramolecular aryl
amination reaction.6 After much experimentation, we found that
it was not necessary to isolate the amine. Instead, the dibromide
could be converted directly to the indoline derivative (Scheme
3). Treatment of D with benzylamine, Pd2(dba)3, P(o-tolyl)3,
and NaO-t-Bu in toluene affords the indoline B in good overall
yield. At this stage it was necessary to remove the P(o-tolyl)3
by flash chromatography since it hinders the subsequent reaction.
Deprotection and oxidation of indoline B with Pd/C and
ammonium formate gives the desired indole A.11
A variety of substituted indoles were prepared using this
three-step procedure (Table 1). Initially, we used the com-
mercially available o-tolylmagnesium bromide to test the
feasibility of our approach. Insertion of olefins containing TIPS-
protected alcohols (entries 1 and 2) gave good overall yields of
(8) Cardin, D. J.; Lappert, M. F.; Raston, C. L. Chemistry of Organo-
zirconium and -hafnium Compounds; Wiley: New York, 1986.
(9) (a) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994,
116, 11703. (b) Martin, H. A.; Jellinek, F. J. Organomet. Chem. 1968, 12,
149.
(11) Kiguchi, T.; Kuninobu, N.; Takahashi, Y.; Yoshida, Y.; Naito, T.;
(10) Ca´mpora, J.; Buchwald, S. L. Organometallics 1993, 12, 4182.
Ninmiya, I. Synthesis 1989, 778.

3070 J. Am. Chem. Soc., Vol. 120, No. 13, 1998
Aoki et al.
Scheme 4
Scheme 5
the indole derivatives. It should be noted that no racemization
was detected when an enantiomerically enriched TIPS-protected
alcohol12 was used (entry 2). Also, 1-hexene was inserted to
give 3-butyl-7-methylindole in 54% yield (entry 3). In addition
to o-tolylmagnesium bromide, the use of disubstituted aryl
Grignard reagents allowed for the construction of trisubstituted
indole derivatives (entries 4-6). For example, 1-naphthylmag-
nesium bromide and 1-hexene produced the 3-butyl-naph-
thylindole in 34% yield.
The use of 1,5-hexadiene produced the interesting bis-indole
3 (Scheme 4). Addition of o-tolylmagnesium bromide, MeMg-
Br, and 1,5-hexadiene to a solution of titanocene dichloride in
toluene afforded the bis-metallacyclopentane V, which was
treated with bromine to form 1 as a mixture of diastereomers.
The Pd-catalyzed aryl amination reaction proceeded smoothly
using excess benzylamine to produce the bis-indoline adduct
2. Finally, the benzyl groups were cleaved and the indoline
rings were oxidized to afford bis-indole 3 in 15% overall yield
from Cp2TiCl2.
ethylene as the olefin component in our method (Scheme 5). A
solution of titanocene dichloride in toluene in a Fischer-Porter
bottle was treated with o-tolylmagnesium bromide at room
temperature (RT) to generate the arylchlorotitanocene. The
solution was cooled to 0 °C, and MeMgBr was added. After
the mixture was stirred for 0.5 h, the Fischer-Porter bottle was
charged with 30 psig of high-purity ethylene13 and the vessel
was heated to 65 °C for 16 h. The solution was cooled to 25
°C, the pressure was carefully vented, and the solvent was
removed. Methylene chloride was added, the reaction vessel
was cooled to -78 °C, and a solution of bromine in CH2Cl2
was added at this temperature. It should be noted that the
success of the reaction is highly dependent upon the purity of
the ethylene.14 The conversion of the dibromide to the indoline
system via the previously described protocol gave only trace
amounts of the desired indoline adduct 5. Instead, the major
product was the styrene derivative 7; formation of the indoline
compound (pathway a) is slow compared to dehydrohalogena-
(13) The ethylene used was of Grade 5 quality (99.99% pure) and was
purchased from Middlesex Gases & Technology Inc.
In an effort to make the procedure as general as possible, we
wished to determine whether we could synthesize indoles that
were not functionalized at the 3-position. Such compounds are
important precursors in the syntheses of more elaborate indole
compounds.1 With this in mind, we investigated the use of
(14) We obtained only trace amounts of the desired product when using
the 95% ethylene purchased from Aldrich Chemical Co.
(15) (a) Prudent Practices in the Laboratory; National Academy Press:
Washington, DC, 1995. (b) Mohring, J. R.; Hammond, J. R.; Morrill, T.
C.; Neckers, D. C. Experimental Organic Chemistry; Freeman: New York,
1998.
(12) Roush, W. R.; Hoong, L. K. J. Am. Chem. Soc. 1985, 107, 8186.
(16) Commercially available from Aldrich Chemical Co.

Titanocene-Based Method for Indole Synthesis
J. Am. Chem. Soc., Vol. 120, No. 13, 1998 3071
Scheme 6
Table 2
to procedures B and C (entries 3 and 4). When an ester-
containing olefinic substrate was examined, a ca. 4:1 ratio of
the metallacycle to the product in which insertion of the carbonyl
group into the Ti-C bond took place. Instead of using the bulky
tert-butyl ester, for the analogous substrate containing a methyl
ester, carbonyl insertion was the predominant course of the
reaction.
The use of 2-methoxy-5-tolylmagnesium bromide gave access
to 4,7-differentially disubstituted indole derivatives (Table 1,
entry 6; Table 2, entry 2). Insertion of the olefin into the Ti-C
bond of the unsymmetrical benzyne complex 8a,b proceeded
with a high degree of regioselectivity, especially when ethylene
was used (Scheme 6). We believe that this selectivity is a result
of the difference in size between the two substituents (Me versus
OMe).7 The olefin preferentially coordinates to the metal
opposite from the larger methyl substituent, thereby favoring
the formation of metallacycle 9a. Treatment of metallacycles
9a,b with bromine produces the two isomeric dihalide deriva-
tives. We found that it was not necessary to separate these
compounds. Instead, the crude mixture was used in the
subsequent reactions and the major indole isomer, obtained in
the final step of the reaction sequence, was easily purified by
flash chromatography.
In summary, a novel procedure for the regioselective synthesis
of substituted indoles has been developed. The key steps in
this method are (1) the intermolecular reaction of an olefin with
a titanocene-stabilized benzyne complex and (2) the Pd-
catalyzed amination of an aryl bromide. We believe that this
approach will allow for the facile construction of a variety of
highly substituted indoles since the required starting materials
are widely available. In addition, the use of titanocene
dichloride removes the need to prepare air- and moisture-
sensitive organometallic intermediates necessitated in our previ-
ous procedures. Further investigations on this and related
methodologies are currently underway in our laboratories.
tion (pathway b). We believe that elimination of HBr induced
by NaO-t-Bu produces 2-bromo-3-methylstyrene (6), which then
undergoes a cross-coupling reaction with benzylamine to give
the aniline 7. We reasoned that dehydrohalogenation could be
circumvented by using an alternative protocol. This involved
first displacing the alkyl bromide with benzylamine and isolating
intermediate C (Table 2, Procedures B and C), followed by Pd-
catalyzed formation of the five-membered ring. Treatment of
dibromide D with excess benzylamine, NaI, and K2CO3 gave
the desired amine C with little formation of the styrene
byproduct. Closure of the five-membered ring by way of Pd
catalysis proceeded smoothly to form indoline B. Indole A was
formed using the procedure which employed 10 mol % Pd/C
as described above. In addition to the dibromides derived from
ethylene, several others gave only minor amounts of the desired
indole products when the first procedure was used. However,
we obtained much better yields of these compounds by switching
Experimental Section
All reactions involving organometallic reagents were conducted
under an atmosphere of purified argon using standard Schlenk
techniques or under nitrogen in a Vacuum Atmospheres Co. drybox.
Other reactions were performed under an atmosphere of argon or
nitrogen. NMR spectra were recorded on a Varian XL-300 or VXR-
500 or a Bruker AC250 FT spectrometer. IR spectra were recorded
on a Perkin-Elmer Series 1600 FT spectrometer. Gas chromatography
analyses were performed on a Hewlett-Packard model 5890 GC with
a 3392A integrator and FID detector using a 25-m capillary column
with cross-linked SE-30 as a stationary phase. Electron impact mass
spectra and high-resolution mass determinations (HRMS) were recorded
on a Finnegan MAT System 8200. Tetrahydrofuran, benzene, diethyl

3072 J. Am. Chem. Soc., Vol. 120, No. 13, 1998
Aoki et al.
ether, and hexane were dried and deoxygenated by continuous refluxing
over sodium/benzophenone ketyl under nitrogen or argon followed by
distillation. Methylene chloride was dried by refluxing over CaH2 under
nitrogen followed by distillation. Anhydrous N,N-dimethylformamide
(DMF) was purchased from Aldrich Chemical Co. and was used without
further purification. Cp2TiCl2 was a gift from Boulder Scientific Inc.
(Mead, CO). All other reagents either were prepared according to
published procedures or were available from commercial sources and
used without further purification. Unless otherwise stated, preparative
flash chromatography was performed on E. M. Science Kieselgel 60
(230-400 mesh). Yields refer to isolated yields of compounds
estimated to be g95% pure (unless otherwise noted) as determined by
1H NMR and either capillary GC or combustion analysis. All reported
yields are representative. Elemental analyses were performed by E &
R Microanalytical Laboratory, Inc. (Corona, NY).
General Procedure A. A solution of arylmagnesium bromide (1.1
equiv) in THF was added dropwise to a solution of Cp2TiCl2 (1.0 equiv,
typically 2-4 mmol) in toluene (∼0.08 M) at RT under argon in a
resealable Schlenk flask. After 1 h, the olefin (2.0 equiv) and a solution
of MeMgBr (1.0 equiv) in Et2O was added, then the flask was sealed
and heated to 50 °C for 4 h. The solution was cooled to RT, and the
solvent was removed in vacuo. Upon the addition of CH2Cl2 (12 mL/
mmol of Cp2TiCl2), the solution was cooled to -78 °C and a solution
of Br2 (2.05 equiv) in CH2Cl2 (6 mL/mmol of Cp2TiCl2) at -78 °C
was added dropwise. The solution was warmed slowly to RT, then
the solvent was removed in vacuo. Caution: care should be used to
ensure that excess bromine has been destroyed. Hexane (30 mL/mmol
of Cp2TiCl2) was added, then the mixture was filtered through Celite,
and the solvent was removed using a rotary evaporator. The dibromide
product was partially purified by flash chromatography, and a portion
of the material (typically ca. 25-50%) was used directly in the next
step.
The dibromide (1.0 equiv) was treated with Pd2(dba)3 (4 mol %),
P(o-tolyl)3 (16 mol %), NaO-t-Bu (4.0 equiv), and benzylamine (2.0
equiv) in toluene. The flask was sealed then heated to 80 °C for 16 h.
Upon cooling to RT, the mixture was poured into a separatory funnel
containing Et2O and H2O. The organic layer was washed with brine,
dried over MgSO4, and filtered, and the solvent was removed using a
rotary evaporator. The indoline product was partially purified by flash
chromatography, and a portion of the material (typically ca. 50%) was
used directly in the next step.
The indoline derivative (1.0 equiv) was treated with 10 mol % (by
weight) Pd/C (10 mol %) and ammonium formate (10.0 equiv) in
MeOH. The solution was heated to reflux for 1.5 h, then allowed to
cool to RT and filtered through Celite. The solvent was removed using
a rotary evaporator, and the residue was dissolved in CH2Cl2. The
organic layer was washed with H2O and brine, dried over Na2SO4, and
filtered, and the solvent was removed using a rotary evaporator. The
product was purified by flash chromatography.
was washed with H2O and brine, dried over MgSO4, and filtered, and
the solvent was removed using a rotary evaporator. The excess
benzylamine was removed by Kugelrohr distillation. The desired
product was partially purified by flash chromatography and used directly
in the next step.
A mixture of Pd2(dba)3 (2 mol %), P(o-tolyl)3 (8 mol %), and NaO-
t-Bu (1.4 equiv) was added to a solution of the amine (1.0 equiv) in
toluene, and the flask was heated to 80 °C for 16 h. Upon cooling to
RT, the solution was poured into a separatory funnel containing H2O
and Et2O. The organic layer was washed with brine, dried over MgSO4,
and filtered, and the solvents were removed in vacuo. The indoline
product was partially purified by flash chromatography and used directly
in the next step.
The indoline derivative (1.0 equiv) was treated with 10 mol % (by
weight) Pd/C (10 mol %) and ammonium formate (10.0 equiv) in
MeOH. After heating to reflux for 24 h, the solution was cooled to
RT and filtered through Celite. The solvent was removed using a rotary
evaporator, and the residue was dissolved in CH2Cl2. The organic layer
was washed with H2O and brine, dried over Na2SO4, and filtered, and
the solvent was removed using a rotary evaporator. The product was
purified by flash chromatography.
General Procedure C. A solution of arylmagnesium bromide (1.1
equiv) in THF was added dropwise to a solution of Cp2TiCl2 (1.0 equiv,
typically 4 mmol) in toluene (∼0.08 M) at RT under argon in a
resealable Schlenk flask. After 1 h, the olefin (2.0 equiv) and a solution
of MeMgBr (1.0 equiv) in Et2O was added, then the flask was sealed
and heated to 50 °C for 4 h. The solution was cooled to RT, and the
solvent was removed in vacuo. To the flask was added CH2Cl2 (12
mL/mmol of Cp2TiCl2), and the solution was cooled to -78 °C. At
this point a solution of Br2 (2.05 equiv) in CH2Cl2 (6 mL/mmol of
Cp2TiCl2) at -78 °C was added dropwise. The solution was warmed
slowly to RT, then the solvent was removed in vacuo. Caution: care
should be used to ensure that excess bromine has been destroyed.15
Hexane (30 mL/mmol of Cp2TiCl2) was added, then the mixture was
filtered through Celite, and the solvent was removed using a rotary
evaporator. The dibromide product was partially purified by flash
chromatography, and a portion of the material (typically ca. 30%) was
used directly in the next step.
The dibromide (1.0 equiv) was treated with benzylamine (4.0 equiv),
K2CO3 (4.0 equiv), and KI (2.0 equiv) in DMF, then the mixture was
heated to 100 °C for 4 h. After cooling to RT, the mixture was poured
into a separatory funnel containing Et2O and H2O. The organic layer
was washed with H2O and brine, dried over MgSO4, and filtered, and
the solvent was removed using a rotary evaporator. The amine product
was partially purified by flash chromatography, and a portion of the
material (typically ca. 75%) was used directly in the next step.
A mixture of Pd(PPh3)4 (4 mol %), K2CO3 (1.7 equiv), and NaO-
t-Bu (1.7 equiv) was added to a solution of the amine (1.0 equiv) in
toluene, and the flask was heated to 100 °C for 16 h. After cooling to
RT, the solution was poured into a separatory funnel containing H2O
and Et2O. The organic layer was washed with brine, dried over MgSO4,
and filtered, and the solvents were removed in vacuo. The indoline
product was partially purified by flash chromatography, and a portion
of the material (typically ca. 75%) was used directly in the next step.
The indoline derivative (1.0 equiv) was treated with 10 mol % (by
weight) Pd/C (10 mol %) and ammonium formate (10.0 equiv) in
MeOH. After heating to reflux for 2 h, the solution was cooled to RT
and filtered through Celite. The solvent was removed using a rotary
evaporator, and the residue was dissolved in CH2Cl2. The organic layer
was washed with H2O and brine, dried over Na2SO4, and filtered, and
the solvent was removed using a rotary evaporator. The product was
purified by flash chromatography.
General Procedure B. A solution of arylmagnesium bromide (1.1
equiv) in THF was added dropwise to a solution of Cp2TiCl2 (1.0 mmol)
in toluene at RT under argon in a Fischer-Porter bottle. After 1 h,
the solution was cooled to 0 °C and a solution of MeMgBr (1.0 equiv)
was added dropwise. After 0.5 h, the bottle was charged with 30 psig
of ethylene and the solution was heated to 50 °C for 8 h. Caution:
reactions at elevated pressure should be run behind a safety shield.
The solution was cooled to RT, the pressure was carefully vented, and
the solvent was removed in vacuo. Upon the addition of CH2Cl2 (6
mL/mmol of Cp2TiCl2), the solution was cooled to -78 °C. At this
point, a solution of Br2 (2.05 equiv) in CH2Cl2 (12 mL/mmol of
Cp2TiCl2) at -78 °C was added dropwise. The solution was warmed
slowly to RT, then the solvent was removed in vacuo. Caution: care
should be used to ensure that excess bromine has been destroyed.
Hexane (30 mL/mmol of Cp2TiCl2) was added, then the mixture was
filtered through Celite, and the solvent was removed using a rotary
evaporator. The dibromide product was partially purified by flash
chromatography and used directly in the next step.
Table 1, Entry 1: 3-[4-[(Triisopropylsilyl)oxy]butyl]-7-methyl-
indole. The title compound (80 mg, 45% from Cp2TiCl2) was prepared
as a colorless oil using general procedure A and was purified by flash
chromatography (4:1 then 2:1 hexane/CH2Cl2): 1H NMR (300 MHz,
CDCl3) δ 7.80 (br s, 1 H), 7.46 (d, J ) 7.5 Hz, 1 H), 7.07-6.95 (m,
3 H), 3.72 (t, J ) 6.3 Hz, 2 H), 2.77 (t, J ) 7.5 Hz, 2 H), 2.47 (s, 3
H), 1.86-1.72 (m, 2 H), 1.71-1.59 (m, 2 H), 1.20-1.04 (m, 21 H);
13C NMR (75 MHz, CDCl3) δ 136.0, 127.2, 122.4, 120.7, 120.1, 119.3,
117.6, 116.8, 63.3, 33.0, 26.4, 25.1, 18.1, 16.5, 12.1; IR (neat) 3422,
The dibromide (1.0 equiv) was treated with benzylamine (6.0 equiv),
K2CO3 (6.0 equiv), and NaI (6.0 equiv) in THF, then the mixture was
heated to 65 °C for 12 h. Upon cooling to RT, the mixture was poured
into a separatory funnel containing Et2O and H2O. The organic layer

Titanocene-Based Method for Indole Synthesis
J. Am. Chem. Soc., Vol. 120, No. 13, 1998 3073
2941, 2865, 1459, 1106, 882 cm-1. Anal. Calcd for C22H37NOSi: C,
73.48; H, 10.37. Found: C, 73.74; H, 10.59.
IR (KBr) 3406, 2880, 2838, 2536, 1492, 1458, 1436, 1064 cm-1. Anal.
Calcd for C20H20N2: C, 83.30; H, 6.99. Found: C, 83.55; H, 7.28.
Table 1, Entry 2: 7-Methyl-3-[2-phenyl-2-[(triisopropylsilyl)oxy]-
ethyl]indole. The title compound (0.10 g, 40% from Cp2TiCl2) was
prepared as a colorless oil using general procedure A and was purified
2-Methyl-6-vinyl-N-benzylaniline (7). A mixture of Pd2(dba)3 (41
mg, 2 mol %), P(o-tolyl)3 (84 mg, 6 mol %), and NaO-t-Bu (0.30 g,
3.16 mmol) was added to a solution of the dibromide 4 (0.63 g, 2.26
mmol) in toluene, and the flask was heated to 80 °C for 16 h. Upon
cooling to RT, the solution was poured into a separatory funnel
containing H2O and Et2O. The organic layer was washed with brine,
dried over MgSO4, and filtered, and the solvents were removed in vacuo.
The product was purified by flash chromatography (20:1 hexane/ethyl
acetate) to give 0.19 g (38%) of a yellow oil: 1H NMR (250 MHz,
CDCl3) δ 7.62-7.56 (m, 6 H), 7.36-7.30 (m, 2 H), 7.19 (t, J ) 7.5
Hz, 1 H), 5.93 (dd, J ) 1.6, 19.2 Hz, 1 H), 5.54 (dd, J ) 1.6, 10.8 Hz,
1 H), 4.43 (s, 2 H), 3.63 (br s, 1 H), 2.45 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 145.0, 140.4, 134.6, 130.8, 130.1, 129.4, 128.5, 127.8, 127.3,
125.2, 122.2, 114.4, 54.0, 18.0; IR (neat) 3367, 3028, 2928, 1591, 1464,
by flash chromatography (2:1 hexane/Et2O):[R]25 ) +23.9 (c 1.09,
D
CHCl3); HPLC Chiralcel OD 25 cm × 0.46 cm column (Daicel
Chemical Ind., Ltd.), eluent 99:1 hexane/isopropyl alcohol, flow rate
0.5 mL/min, detection UV 254 nm, retention time for (S)-enantiomer
23.6 min, retention time for (R)-enantiomer 25.5 min, optical purity
67% ee; 1H NMR (300 MHz, CDCl3) δ 7.7 (br s, 1H), 7.35-6.90 (m,
8H), 6.56 (m, 1H), 5.01 (dd, J ) 5.4, 8.0 Hz, 1 H), 3.31 (dd, J ) 5.4,
14.0 Hz, 1 H), 3.05 (dd, J ) 8.0, 14.0 Hz, 1 H), 2.43 (s, 3 H), 1.10-
0.85 (m, 21 H); 13C NMR (75 MHz, CDCl3) δ 145.5, 135.6, 127.6,
126.8, 126.5, 122.8, 122.2, 119.9, 119.3, 116.6, 112.8, 75.7, 37.5, 18.0,
17.9, 16.5, 12.4; IR (neat) 3425, 2942, 2865, 1460, 1090, 1065, 882
cm-1. Anal. Calcd for C26H37NOSi: C, 76.60; H, 9.15. Found: C,
76.79; H, 8.96.
700 cm-1
.
Table 2, Entry 1: 7-Methylindole.16 Cp2TiCl2 (2.61 g, 10.48 mmol)
in toluene (70 mL) was employed according to general procedure B.
The indole product was purified by flash chromatography (10:1 hexane/
ethyl acetate) to yield 0.56 g of a white solid (40% from Cp2TiCl2):
mp 80-82 °C; H NMR (300 MHz, CDCl3) δ 8.02 (br s, 1 H), 7.56
(d, J ) 7.5 Hz, 1 H), 7.20 (m, 1 H), 7.10 (t, J ) 7.3 Hz, 1 H), 7.04 (d,
J ) 7.3 Hz, 1 H), 6.60 (s, 1 H), 2.52 (s, 3 H).
Table 2, Entry 2: 4-Methoxy-7-methylindole. Cp2TiCl2 (0.93 g,
3.75 mmol) in toluene (25 mL) was employed according to general
procedure B. The indole product was purified by flash chromatography
(10:1 hexane/ethyl acetate) to yield 0.21 g of a colorless oil (34% from
Cp2TiCl2): 1H NMR (300 MHz, CDCl3) δ 8.06 (br s, 1 H), 7.11 (s, 1
H), 6.94 (d, J ) 7.7 Hz, 1 H), 6.72 (s, 1 H), 6.50 (d, J ) 7.7 Hz, 1 H),
3.98 (s, 3 H), 2.45 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 151.8, 136.6,
122.6, 122.5, 118.0, 113.3, 100.3, 99.6, 55.4, 16.0; IR (KBr) 3394,
3105, 2962, 1524, 1500, 1262 cm-1. Anal. Calcd for C10H11NO: C,
74.51; H, 6.88. Found: C, 74.59; H, 7.22.
Table 1, Entry 3: 3-Butyl-7-methylindole. The title compound
(47 mg, 54% from Cp2TiCl2) was prepared as colorless needles using
general procedure A and was purified by flash chromatography (3:1
1
hexane/CH2Cl2): mp 39.5-40.0 °C; H NMR (300 MHz, CDCl3) δ
1
7.80 (br s, 1 H), 7.47 (d, J ) 7.5 Hz, 1 H), 7.10-6.95 (m, 3 H), 2.75
(t, J ) 7.0 Hz, 2 H), 2.48 (s, 3 H), 1.75-1.60 (m, 2 H), 1.42 (sextet,
J ) 7.0 Hz, 2 H), 0.95 (t, J ) 7.0 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 135.9, 127.2, 122.3, 120.7, 120.1, 119.3, 117.7, 116.8, 32.4,
25.0, 22.7, 16.6, 14.0; IR (KBr) 3433, 2960, 2920, 2855, 1464, 1430,
1100, 1066, 788, 745 cm-1. Anal. Calcd for C13H17N: C, 83.37; H,
9.15. Found: C, 83.40; H, 9.33.
Table 1, Entry 4: 3-Butyl-4,7-dimethylindole. The title compound
(88 mg, 37% from Cp2TiCl2) was prepared as colorless needles using
general procedure A and was purified by flash chromatography (3:1
hexane/CH2Cl2): mp 73.5-74 °C; 1H NMR (300 MHz, CDCl3) δ 7.77
(br s, 1 H), 6.94 (s, 1 H), 6.85 (d, J ) 7.1 Hz, 1 H), 6.75 (d, J ) 7.1
Hz, 1 H), 2.90 (t, J ) 7.4 Hz, 2 H), 2.68 (s, 3 H), 2.42 (s, 3 H), 1.67
(m, 2 H), 1.47 (sextet, J ) 7.3 Hz, 2 H), 0.97 (t, J ) 7.3 Hz, 3 H); 13
C
NMR (75 MHz, CDCl3) δ 136.3, 128.6, 125.5, 122.2, 120.9, 118.8,
Table 2, Entry 3: 3-Butyl-7-methoxyindole. The title compound
(65 mg, 43% from Cp2TiCl2) was prepared as a colorless oil using
general procedure C and was purified by flash chromatography (4:1
hexane/CH2Cl2): 1H NMR (250 MHz, CDCl3) δ 8.10 (br s, 1H), 7.22
(d, J ) 7.8 Hz, 1 H), 7.02 (t, J ) 7.8 Hz, 1 H), 6.9 (m, 1 H), 6.62 (d,
J ) 7.8 Hz, 1 H), 3.93 (s, 3 H), 2.73 (t, J ) 7.3 Hz, 2 H), 1.75-1.55
117.7, 33.7, 26.9, 22.6, 20.0, 16.2, 14.0; IR (KBr) 3425, 2953, 2856,
1511, 803 cm-1
. Anal. Calcd for C14H19N: C, 83.53; H, 9.51.
Found: C, 83.76; H, 9.79.
Table 1, Entry 5: 3-Butylnaphthoindole. The title compound (43
mg, 35% from Cp2TiCl2) was prepared as colorless needles using
general procedure A and was purified by flash chromatography (4:1
hexane/CH2Cl2): mp 132-133 °C; 1H NMR (300 MHz, CDCl3) δ 8.6
(br s, 1H), 7.98 (d, J ) 8.4 Hz, 1 H), 7.92 (d, J ) 8.4 Hz, 1 H), 7.71
(d, J ) 9.3 Hz, 1 H), 7.55-7.38 (m, 3 H), 7.06 (m, 1H), 2.83 (t, J )
7 Hz, 2 H), 1.80-1.64 (m, 2 H), 1.45 (sextet, J ) 7.2 Hz, 2 H), 0.97
(t, J ) 7.2 Hz, 3 H); 13C NMR (62.5 MHz, CDCl3) δ 130.8, 130.4,
128.8, 125.3, 123.7, 123.4, 121.8, 119.9, 119.3, 119.2, 119.0, 32.7,
24.9, 22.6, 14.0; IR (KBr) 3411, 2957, 2915, 2855, 1524, 1452, 1392,
811 cm-1. Anal. Calcd for C16H17N: C, 86.05; H, 7.67. Found: C,
86.34; H, 7.83.
(m, 2 H), 1.40 (sextet, J ) 7.2 Hz, 2 H), 0.94 (t, J ) 7.2 Hz, 3 H); 13
C
NMR (75 MHz, CDCl3) δ 146.1, 129.0, 126.8, 120.6, 119.4, 117.5,
111.8, 101.7, 55.3, 32.4, 25.0, 22.6, 14.0; IR (neat) 3416, 2952, 2927,
2854, 1577, 1498, 1446, 1373, 1258, 1077, 1040 cm-1. Anal. Calcd
for C13H17NO: C, 76.81; H, 8.43. Found: C, 77.08; H, 8.56.
Table 2, Entry 4: 3-[8-(tert-Butoxycarbonyl)octyl]-7-methylindole.
The title compound (86 mg, 33% from Cp2TiCl2) was prepared as
colorless needles using general procedure C and was purified by flash
chromatography (3:1 hexane/Et2O): mp 57-58 °C; 1H NMR (300
MHz, CDCl3) δ 7.8 (br s, 1H), 7.46 (d, J ) 7.8 Hz, 1 H), 7.08-6.95
(m, 3 H), 2.73 (t, J ) 7.2 Hz, 2 H), 2.48 (s, 3 H), 2.19 (t, J ) 6.9 Hz,
2 H), 1.76-1.50 (m, 4 H), 1.44 (s, 9 H), 1.42-1.20 (m, 8 H); 13C
NMR (75 MHz, CDCl3) δ 173.4, 135.9, 127.1 122.3, 120.7, 120.1,
119.2, 117.6, 116.7, 79.9, 35.6, 30.2, 29.5, 29.3, 29.1, 28.1, 25.3, 25.1,
16.6; IR (KBr) 3356, 2917, 2849, 1718, 1466, 1160 cm-1. Anal. Calcd
for C22H33NO2: C, 76.92; H, 9.68. Found: C, 77.15; H, 9.95.
Table 1, Entry 6: 3-Butyl-4-methoxy-7-methylindole. The title
compound (0.12 g, 18% from Cp2TiCl2) was prepared as a colorless
oil using general procedure A and was purified by flash chromatography
(10:1 hexane/ethyl acetate): 1H NMR (300 MHz, CDCl3) δ 7.76 (br s,
1 H), 6.86 (m, 2 H), 6.40 (d, J ) 7.9 Hz, 1 H), 3.89 (s, 3 H), 2.87 (t,
J ) 7.4 Hz, 2 H), 2.39 (s, 3 H), 1.66 (m, 2 H), 1.42 (sextet, J ) 7.3
Hz, 2 H), 0.95 (t, J ) 7.3 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ
146.8, 137.4, 122.4, 119.5, 118.5, 113.0, 99.3, 97.3, 55.2, 42.0, 33.4,
26.5, 22.6, 14.1; IR (neat) 3470, 2958, 2861, 1604, 1515, 1264 cm-1
.
Acknowledgment. We thank the National Institutes of
Health for support of this work. We thank Boulder Scientific
for a generous gift of titanocene dichloride. We thank Prof.
Richard R. Schrock and Prof. Christopher C. Cummins for the
donation of high-purity ethylene. Dr. Kazumasa Aoki gratefully
acknowledges support from the Uehara Memorial Foundation.
We also thank Dr. Bryant Yang for considerable help in the
preparation of the manuscript.
Anal. Calcd for C14H19NO: C, 77.38; H, 8.81. Found: C, 77.44; H,
9.04.
7-Methyl-3-[2-(7-methyl-3-indolyl)ethyl]indole (3). The title com-
pound (26 mg, 16% from 1,5-hexadiene) was prepared as colorless
needles from Cp2TiCl2 (2 mol equiv) and 1,5-hexadiene (1 mol equiv)
using general procedure A and was purified by flash chromatography
(2:1 hexane/acetone): mp 225-226 °C; 1H NMR (250 MHz, acetone-
d6) δ 9.90 (br s, 2 H), 7.49 (d, J ) 7.1 Hz, 2 H), 7.15 (m, 2 H), 7.05-
6.85 (m, 4 H), 3.15 (s, 4 H), 2.49 (s, 6 H); 13C NMR (75 MHz, acetone-
d6) δ 137.2, 128.5, 122.7, 122.6, 122.4, 121.3, 119.7, 117.3, 27.4, 17.0;
JA972281P