A novel palladium-catalyzed synthesis of β-carbolines: Application in total synthesis of naturally occurring alkaloids

Article abstract of DOI:10.1016/S0040-4020(03)00824-X

Two naturally occurring β-carbolines, 6-methoxy-2-methyl-1,2,3,4-tetrahydro-β-carboline and bauerine A, have been prepared using a Stille-type coupling, followed by a palladium-phosphine catalyzed N-heteroannulation as the key steps.

Full text of DOI:10.1016/S0040-4020(03)00824-X

Tetrahedron 59 (2003) 5507–5514
A novel palladium-catalyzed synthesis of b-carbolines:
application in total synthesis of naturally occurring alkaloids
*
¨ ¨
Shubhada W. Dantale and Bjorn C. G. Soderberg
Department of Chemistry, West Virginia University, P.O. Box 6045, Morgantown, WV 26506-6045, USA
Received 8 April 2003; revised 27 May 2003; accepted 27 May 2003
Abstract—Two naturally occurring b-carbolines, 6-methoxy-2-methyl-1,2,3,4-tetrahydro-b-carboline and bauerine A, have been prepared
using a Stille-type coupling, followed by a palladium-phosphine catalyzed N-heteroannulation as the key steps. q 2003 Elsevier Science Ltd.
All rights reserved.
We have recently developed a relatively mild palladium-
phosphine catalyzed reductive N-heteroannulation of
2-nitrostyrenes forming indoles1–6 and 1,2-dihydro-4(3H)-
carbazolones7 in good to excellent yields. A variety of
2-nitrostyrenes having electron-donating or electron-with-
drawing substituents on the aromatic ring furnished indoles
in good to excellent yield. Using this methodology as the
key step, we have reported short syntheses of some naturally
occurring indole alkaloids.8 As a continuation of our interest
in the synthesis of biologically active molecules utilizing
this methodology, we envisioned a short synthesis of
b-carbolines. Herein is reported the synthesis of two
naturally occurring b-carbolines, 6-methoxy-2-methyl-
1,2,3,4-tetrahydro-b-carboline (1) and bauerine A (Fig. 1).
The synthesis of 1 also constitutes a formal total synthesis of
the oxindole alkaloid, horsfiline.9
line 1 has been isolated from a variety of plant sources, for
example, Phalaris tuberosa10 and Horsfieldia superba.9
Bauerine A was isolated by Moore et al. from the blue–
green alga Dichotrix baueriana.11 Two additional chlorine
containing b-carbolines, bauerines B–C, were also isolated
from the same source. The bauerine alkaloids show activity
against herpes simplex virus type 2. A short synthesis of
bauerine B was reported by Queguiner and co-workers a few
years ago.12 However, the methodology used for bauerine B
is not suitable for the synthesis of bauerine A due to
potential formation of isomeric products in one of the key
steps.
Synthesis of 6-methoxy-1,2,3,4-tetrahydro-b-carboline (1)
was initially examined to evaluate the feasibility of the
proposed route to b-carboline alkaloids. Tri-n-butyl-(5-
methyl-2-nitro-phenyl)stannane (4) was prepared from
commercially available 4-nitroanisole in three steps
(Scheme 1). Amination of 4-nitroanisole with O-methyl-
hydroxylamine according to a literature procedure gave
5-methoxy-2-nitro-aniline (2).13 Transformation of 2, via
reaction of the corresponding diazonium salt with potassium
iodide, gave 2-iodo-4-methoxy-1-nitro-benzene (3) in 71%
1. Results and discussion
Two naturally occurring b-carboline alkaloids, 6-methoxy-
2-methyl-1,2,3,4-tetrahydro-b-carboline (1) and bauerine
A, were selected as our synthetic targets (Fig. 1). b-Carbo-
Figure 1.
Keywords: palladium; catalysis; alkaloids; carboline.
*
Corresponding author. Tel.: þ1-304-293-3435; fax: þ1-304-293-4904; e-mail: bjorn.soderberg@mail.wvu.edu
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00824-X

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S. W. Dantale, B. C. G. Soderberg / Tetrahedron 59 (2003) 5507–5514
5508
Scheme 1.
yield. Palladium-catalyzed reaction of 3 with hexa-n-
butylditin in toluene at 808C for 4 days furnished
arylstannane 4 in 69% yield.14 Stille coupling of 4
with vinyl triflate 5, using bis(dibenzylideneacetone)-
palladium(0) (5 mol%), triphenylarsine (20 mol%), and
copper iodide (10 mol%) in N-methylpyrrolidine (NMP)
gave the expected coupling product 6 in good yield.
Synthesis of 5 from N-methyl-4-piperidone and related
Stille cross-coupling reactions have been reported.15
(6 atm) in dimethylformamide (DMF, 808C, 12 h), gave
the expected 6-methoxy-2-methyl-1,2,3,4-tetrahydro-b-car-
boline (1) in 80% yield. It should be noted that the described
route cannot compete with previously published syntheses
of 1.17,18 However, it demonstrates the feasibility of the key
steps for the preparation of b-carboline type alkaloids.
Based on the successful completion of the synthesis of 1, we
decided to pursue a synthesis of bauerine A using a related
synthetic relay. Formation of a diazonium salt from
4-chloro-2-nitroaniline (7) followed by reaction with
potassium iodide, using a modification of a published
procedure,19 gave 4-chloro-1-iodo-2-nitrobenzene (8) in
90% yield. Reaction of 8 with hexa-n-butylditin catalyzed
by palladium as described above furnished tri-n-butyl-(4-
chloro-2-nitro-phenyl)stannane (9) in 70% yield (Scheme 2).
Three different N-protected vinyl triflates were prepared
from 4-piperidone. In addition to the known N-benzyl-20,21
and N-BOC-protected22 vinyl triflates 10 and 11, the
N-tosyl-protected vinyl triflate 12 was prepared from the
corresponding N-protected piperidones23 using N-phenyltri-
fluoromethansulfonamide and lithium hexamethyldisilazide
(LiHMDS) (Scheme 3). A fourth compound, 4-iodo-N-
benzyl-1,2,5,6-tetrahydropyridine (13) was prepared in 70%
Palladium-catalyzed N-heteroannulation of 6 under con-
ditions previously employed to prepare indoles (conditions
A),2 palladium diacetate (6 mol%), triphenylphosphine
(24 mol%), and carbon monoxide (4 atm) in acetonitrile at
708C (60 h), gave a 7:3 mixture of 6 and the expected
product 1. Palladium–phenanthroline complexes have been
shown to be particularly active catalysts for the reductive
carbonylation of nitrobenzenes to give isocyanates.16 We
have previously successfully employed this type of catalyst
system for the preparation of 1,2-dihydro-4(3H)-carbazo-
lones.7 Application of the modified conditions (conditions
B), bis(dibenzylideneacetone)palladium(0) (Pd(dba)2,
6 mol%), 1,3-bis(diphenylphosphino)propane (dppp,
12 mol%), 1,10-phenanthroline (12 mol%), and CO
Scheme 2.

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S. W. Dantale, B. C. G. Soderberg / Tetrahedron 59 (2003) 5507–5514
5509
were readily purified by column chromatography on silica
gel to give pure products in 50 and 62% yield, respectively.
Palladium catalyzed N-heteroannulation of 14, formed from
coupling of 13 with 9, under standard reaction conditions
(conditions A) gave the tetrahydro-b-carboline 17 in 61%
yield (from 13, Scheme 4). For the N-tosyl and N-BOC
protected Stille coupling products 15 and 16, the modified
reaction conditions B were required for complete trans-
formation to afford the tetrahydro-b-carbolines 18 and 19.
Considering the substantially lower yield of 19 compared to
17 and 18, the former, N-tosylated compound, was not
further pursued for the synthesis of bauerine A.
Scheme 3.
yield in a three-step reaction sequence from commercially
available 3-butyne-1-ol according to a literature pro-
cedure.24
Removal of the benzyl group from 17 was readily achieved
using a number of reagents. Unfortunately, attempted
debenzylation using Pd/C on Ba(OH)2 and ammonium
formate25 in refluxing methanol, Pd/C and formic acid (aq.,
4.4%) in methanol,26 or Pd(OH)2/C and ammonium formate
gave the dechlorinated product 20 in 85–91% yield, as the
formate salt (Scheme 5). Methylation of the pyrrole
nitrogen, using sodium hydride and methyl iodide in THF
at 08C, gave 22 in 81% yield. The benzyl protecting was
removed in quantitative yield, again accompanied with the
facile and complete dechlorination, to give 23.
Stille cross-coupling of 10 with arylstannane 9 using
Pd(dba)2 (5 mol%), triphenylarsine (20 mol%), and copper
iodide (10 mol%) in NMP at 508C gave the expected
product 14 (Scheme 4). However, the coupling product
could not be completely separated from a substantial
amount of tin-containing impurities even after extensive
purification. The impurity co-elutes upon chromatography
and was only partially removed by bulb-to-bulb distillation.
To a much lesser extent, the problem of co-eluting, tin-
containing, impurities was also encountered upon
palladium-catalyzed reaction of vinyl iodide 13 with
arylstannane 9. To improve the purity of the Stille coupling
product, 11 and 12 were used, and the cross-coupling
products 15 and 16 were obtained. The latter compounds
Aromatization of 1,2,3,4-tetrahydro-b-carbolines, without
substituents on the six-membered nitrogen ring is not a
Scheme 4.
Scheme 5.

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S. W. Dantale, B. C. G. Soderberg / Tetrahedron 59 (2003) 5507–5514
5510
Scheme 6.
trivial transformation.27 Using 20 as a model substrate,
commonly used oxidizing reagents, such as manganese
dioxide,28 selenium dioxide,29 palladium on carbon,30
iodosobenzene,31 or palladium on barium carbonate in
butanol32 gave unsatisfactory results. The starting material
was usually recovered together with minor amounts of the
expected aromatized product 21 (,20%).
been footnoted the first time used; all other reagents were
obtained from commercial sources and used as received. All
reactions were performed in oven-dried glassware under an
argon atmosphere unless otherwise stated. Solvents were
removed from crude reaction mixtures and products on a
rotary evaporator at water aspirator pressure. Melting points
were determined on a MelTemp and are uncorrected.
Elemental analyses were performed by Alantic Microlab
Inc. (Norcross, GA). High-resolution mass-spectra analyses
were performed at University of California Riverside Mass
Spectrometry Facility (Riverside, CA).
Next, we turned our focus to the N-BOC protected
annulation product 18. Tetrahydro-b-carboline 18 was
N-methylated in 82% yield (Scheme 6). The BOC
protecting group was removed by treatment with 3N HCl
in ethyl acetate at ambient temperature affording tetrahydro-
b-carboline 25 in almost quantitative yield. The deprotected
carboline was difficult to purify and was therefore used in
the next step without prior purification. Oxidation of 25 was
achieved employing MnO2 in refluxing toluene to give
bauerine A in 70% yield. Thus, the first total synthesis of
bauerine A was completed in 7 linear steps, in 18% overall
yield, from commercially available starting materials.
2.1.1. 2-Iodo-4-methoxy-1-nitro-benzene (3).33 5-Methoxy-
2-nitroaniline (2)13 (400 mg, 2.38 mmol) was dissolved in
H2SO4 (conc., 5 mL) and cooled to 08C in an ice-bath. To
this solution was added dropwise a solution of NaNO2
(197 mg, 2.85 mmol) in H2SO4 (conc., 5 mL). The resulting
diazonium salt solution was stirred at 08C for 30 min, and
then slowly allowed to warm to room temperature over 2 h.
The diazonium salt solution was added dropwise (15 min) to
an ice–water solution of KI (592 mg, 3.56 mmol) at 08C,
and the resulting mixture was stirred for an additional 2 h.
The solution was made basic with NaOH (aq., 10%) and
extracted with CH2Cl2 (3£25 mL). The combined organic
extracts were dried (MgSO4), filtered, and the solvent was
removed at reduced pressure to give 3 (470 mg, 1.68 mmol,
71%) as a yellow solid. No further purification was required.
Mp 658C; 1H NMR d 7.96 (d, J¼9 Hz, 1H), 7.52 (d,
J¼2.5 Hz, 1H), 6.97 (dd, J¼9, 2.5 Hz), 3.85 (s, 3H); 13C
NMR d 162.3 (þ), 144.8 (þ), 127.2 (2), 126.9 (2), 113.9
(2), 88.0 (þ), 56.0 (2).
In conclusion, we have achieved the synthesis of two
naturally occurring b-carbolines employing two successive
palladium catalyzed reactions, namely, a Stille coupling
followed by a reductive N-heteroannulation. Further
application for the total synthesis of some chiral b-carbo-
lines is currently underway in our laboratories.
2. Experimental
2.1. General procedures
2.1.2. Tri-n-butyl (5-methoxy-2-nitro-phenyl)stannane
(4). To a mixture of 2-iodo-4-methoxy-1-nitrobenzene (3)
(450 mg, 1.61 mmol) in dry toluene (15 mL) under argon
was added, hexa-n-butylditin (890 mL, 1.76 mmol),
followed by PdCl2(PPh3)2 (11 mg, 0.015 mmol), and
triphenylphosphine (8.4 mg, 0.032 mmol). The reaction
mixture was stirred at 808C for 5 days. Upon completion
of the reaction, the solvent was removed under reduced
pressure. The residue was dissolved in CH2Cl2 (200 mL)
and washed with ammonium hydroxide solution (aq.,
3£10 mL). The organic phase was dried (MgSO4), filtered,
and the solvent was removed at reduced pressure. The crude
product was purified by chromatography (hexanes) to give 4
(487 mg, 1.10 mmol, 69%) as a pale yellow oil. 1H NMR d
8.31 (d, J¼9.0 Hz, 1H), 7.1 (d, J¼2.7 Hz, 1H), 6.92 (dd,
J¼9.0, 2.7 Hz, 1H), 3.90 (s, 3H), 1.47 (m, 6H), 1.39 (m,
All NMR spectra were determined in CDCl3 at 270 MHz
(1H NMR) and 67.5 MHz (13C NMR) unless otherwise
stated. The chemical shifts are expressed in d values relative
to Me4Si (0.0, 1H and 13C), CDCl3 (77.0, 13C), or DMSO-d6
1
(39.5, 13C) internal standards. H–1H spin–spin coupling
constants are reported as calculated from spectra; thus, a
slight difference between Jab and Jba is usually obtained.
Results of APT (attached proton test) 13C NMR experiments
are shown in parentheses where, relative to CDCl3, (2)
denotes CH3 or CH and (þ) denotes CH2 or
C. Tetrahydrofuran (THF) and diethyl ether were distilled
from sodium benzophenone ketyl prior to use. Toluene,
hexanes, dimethylformamide (DMF), triethylamine, metha-
nol, and ethyl acetate were distilled from calcium hydride.
Chemicals prepared according to literature procedures have

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S. W. Dantale, B. C. G. Soderberg / Tetrahedron 59 (2003) 5507–5514
5511
6H), 1.12 (m, 6H), 0.86 (t, J¼7.1 Hz, 9H); 13C NMR d 163.2
(þ), 146.5 (þ), 143.3 (þ), 126.4 (2), 122.1 (2), 113.3 (2),
55.6 (2), 28.8 (þ), 27.2 (þ), 13.5 (2), 11.0 (þ); IR (neat)
2955, 1571, 1500, 1463, 1331, 1230 cm21. HRMS (DCI)
calcd for C19H37N2O3Sn (MþNH4þ) 461.1826, found
461.1827.
literature yield 54%) as a yellow solid. Mp 598C; 1H NMR d
8.00 (d, J¼5.9 Hz, 1H), 7.86 (d, J¼2.3 Hz, 1H), 7.28 (dd,
J¼6.9, 2.3 Hz, 1H); 13C NMR d 142.6 (2), 135.2 (þ), 133.5
(2), 125.6 (2), 83.5 (þ).
2.1.6. Tri-n-butyl-(4-chloro-2-nitro-phenyl)stannane (9).
To a mixture of 4-chloro-1-iodo-2-nitro-benzene (8)
(1.00 g, 3.52 mmol) in dry toluene (25 mL), under argon,
was added, hexa-n-butylditin (1.94 mL, 3.85 mmol),
followed by PdCl2(PPh3)2 (24.5 mg, 0.035 mmol), and
triphenylphosphine (18 mg, 0.068 mmol). The resulting
reaction mixture was stirred at 808C for 4 days. The solvent
was removed under reduced pressure. The residue was
dissolved in CH2Cl2 (200 mL) and washed with ammonium
hydroxide solution (aq., 3£10 mL). The organic phase was
dried (MgSO4), filtered, and the solvent was removed under
reduced pressure. The crude product was purified by
chromatography (hexanes) to give 9 (1.11 g, 2.48 mmol,
2.1.3. 4-(5-Methoxy-2-nitro-phenyl)-1-methyl-1,2,3,6-
tetrahydro-pyridine (6). To a solution of 4 (360 mg,
8.15 mmol) in N-methylpyrrolidinone (1.5 mL), under
argon, was added 1-methyl-4-[(trifluoromethanesulfonyl)-
oxy]-1,2,3,6-tetrahydropyridine (5)15 (200 mg, 8.15 mmol),
Pd(dba)2 (23.4 mg, 0.40 mmol), triphenylarsine (49.9 mg,
0.16 mmol), and copper iodide (15.5 mg, 0.081 mmol). The
reaction mixture was stirred at 508C for 10 h. The reaction
mixture was allowed to cool to ambient temperature and
was diluted with CH2Cl2 (100 mL). The organic phase was
washed with ammonium hydroxide (aq., 3£10 mL). The
organic phase was dried (MgSO4), filtered, and the solvent
was removed under reduced pressure. The residual NMP
together with unknown tin impurities were removed by
bulb–bulb distillation. The residue was purified by
chromatography (hexanes–EtOAc, 2:8) to give 6 (166 mg,
1
70%) as a pale yellow oil. H NMR d 8.29 (d, J¼1.2 Hz,
1H), 7.58 (m, 2H), 1.48 (m, 6H), 1.33(m, 6H), 1.14 (m, 6H),
0.85 (t, J¼7.3 Hz, 9H); 13C NMR d 154.1 (þ), 138.5 (2),
135.2 (þ), 133.3 (2), 124.1 (2), 28.8 (þ), 27.2 (þ), 13.7
(2), 11.0 (þ); IR (neat) 2955, 1525, 1456, 1343 cm21
.
1
0.66 mmol, 82%) as a faint yellow oil. H NMR d 8.05 (d,
Anal. calcd for C18H30ClNO2Sn: C, 48.41; H, 6.77. Found:
C, 48.78; H, 6.60.
J¼9 Hz, 1H), 6.86 (dd, J¼9.0, 2.7 Hz, 1H), 6.75 (d,
J¼2.7 Hz, 1H), 3.86 (s, 3H), 3.10 (q, J¼3.3 Hz, 2H), 2.7
(t, J¼5.5 Hz, 2H), 2.42 (s, 3H), 2.39 (m, 2H); 13C NMR d
163.0 (þ), 141.3 (þ), 135.4 (þ), 127.1 (2), 123.1 (2),
115.8 (2), 113.1 (2), 55.9 (2), 54.5 (þ), 52.0 (þ), 45.8
(2), 3.3 (þ); IR (neat) 1575, 1513 cm21. HRMS (DCI)
calcd for C13H16N2O3 248.1161 (Mþ), found 248.1158.
2.1.7. N-(4-Methylphenylsulfonyl)-4-[(trifluoromethane-
sulfonyl)oxy]-1,2,3,6-tetrahydropyridine (12). To
a
freshly prepared solution of LDA in THF (10 mL), from
diisopropylamine (243 mL, 1.73 mmol) and n-BuLi (2 M in
hexane, 0.86 mL, 1.73 mmol) at 2788C, was added a
solution
of
N-(4-methylphenylsulfonyl)-4-piperidone
2.1.4. 6-Methoxy-2-methyl-1,2,3,4-tetrahydro-b-carbo-
line (1).14 To an oven dried, threaded ACE glass pressure
tube was added 6 (160 mg, 0.64 mmol), Pd(dba)2 (22 mg,
0.038 mmol), 1,3-bis(diphenylphosphino)propane (15.9 mg,
0.038 mmol), 1,10-phenanthroline (15.3 mg, 0.077 mmol),
and DMF (5 mL). The tube was fitted with a pressure head,
and the solution was saturated with carbon monoxide (four
cycles of 6 atm of CO). The reaction mixture was heated at
908C (oil bath temperature) under CO (6 atm) until all
starting material was consumed (12 h), as judged by TLC.
The reaction mixture was filtered through a Celite pad, and
the pad was washed with CH2Cl2 (10 mL). The solvent was
removed under reduced pressure, and crude product was
purified by chromatography (CH2Cl2–MeOH, 8:2) to give 1
(111 mg, 0.51 mmol, 80%) as a pale yellow solid.
(400 mg, 1.58 mmol) in THF (5 mL). The resulting mixture
was stirred at 2788C for 30 min where after a solution of
N-phenyltrifluoromethanesulfonimide (400 mg, 1.58 mmol)
in THF (8 mL) was added dropwise. After stirring for an
additional 1 h, the solution was allowed to slowly warm to
ambient temperature. The solvent was removed, and the
residue was purified by chromatography (hexanes–EtOAc,
19:1) to give 12 (485 mg, 1.25 mmol, 80%) as a colorless oil
that solidified in the freezer. Mp 698C; 1H NMR d 7.68 (d,
J¼8.3 Hz, 2H), 7.35 (d, J¼8.1 Hz, 2H), 5.73 (m, 1H), 3.79
(q, J¼3.0 Hz, 2H), 3.37 (q, J¼8.5 Hz, 2H), 2.48 (m, 2H),
2.44 (s, 3H); 13C NMR d 146.3 (þ), 144.2 (þ), 133.1 (2),
129.9 (2), 127.4 (2), 114.3 (2), 43.3 (þ), 42.7 (þ), 27.8
(þ), 21.4 (2); IR (neat)1352, 1166 cm21; HRMS (CI) calcd
for C13H14F3NO5S2 385.0265 (Mþ), found 385.0258.
2.1.5. 4-Chloro-1-iodo-2-nitro-benzene (8).19 The pro-
cedure by Liedholm was followed with a few modifications.
2.1.8. 1-Benzyl-4-(4-chloro-2-nitro-phenyl)-1,2,3,6-tetra-
hydropyridine (14). To a solution of 9 (830 mg,
A
solution of 4-chloro-2-nitroaniline (7) (2.60 g,
1.86 mmol) in NMP (5 mL), under argon, was added 10
(597 mg, 1.86 mmol), Pd(dba)2 (53 mg, 0.093 mmol),
triphenylarsine (113 mg, 0.37 mmol), and copper iodide
(35 mg, 0.18 mmol). The resulting mixture was stirred at
508C (oil-bath temperature) for 10 h. After cooling to
ambient temperature, the mixture was diluted with CH2Cl2
(200 mL), washed with ammonium hydroxide (aq.,
3£10 mL), and brine (10 mL). The organic phase was
dried (MgSO4), filtered, and the solvents were evaporated
under reduced pressure. The remaining NMP was removed
by bulb-to-bulb distillation under vacuum, followed by
purification of the residue by chromatography (hexanes–
EtOAc, 9:1) to give 415 mg of a pale yellow oil. The oil was
15.0 mmol) in H2SO4 (conc., 25 mL) was cooled to 08C in
an ice-bath. To the solution was added dropwise a solution
of NaNO2 (1.24 g, 18.0 mmol) in H2SO4 (conc., 15 mL).
The resulting diazonium salt solution was stirred at 08C for
30 min and then slowly allowed to warm to room
temperature over 2 h. The diazonium salt solution was
added dropwise (15 min) to an ice–water solution of KI
(3.73 g, 22.5 mmol) at 08C and stirred for another 2 h at 8C.
The reaction mixture was made basic with NaOH (aq., 10%)
and extracted with CH2Cl2. The combined organic extracts
were dried (MgSO4), filtered, and the solvent was removed
at reduced pressure to give 10 (3.90 g, 13.8 mmol, 90%,

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5512
1
a mixture of 14 (by H NMR) and an unidentified tin-
containing impurity. All attempts to further purify 14 were
unsuccessful.
temperature) under CO (4 atm) until all starting material
was consumed (15 h), as judged by TLC. The solvent was
evaporated under reduced pressure, and the crude product
was purified by chromatography (hexanes–EtOAc, 8:2) to
give 17 (380 mg, 1.28 mmol) as a white solid. The yield
Similar reaction of 9 (939 mg, 2.10 mmol) with 13 (600 mg,
2.11 mmol), in the presence of PdCl2(PPh3)2 (74 mg,
0.10 mmol), triphenylphosphine (55 mg, 0.21 mmol), and
copper iodide (40 mg, 0.21 mmol) in NMP (4 mL), as
described above, gave after purification by chromatography
(hexanes–EtOAc, 9:1) 14 (469 mg) as a pale yellow oil.
The product was contaminated with a small amount of an
unknown tin-containing impurity. Spectral data from the
mixture: 1H NMR d 7.85 (d, J¼1.9 Hz, 1H), 7.49 (dd,
J¼8.2, 2.1 Hz, 1H), 7.36 (m, 6H), 5.61 (m, 1H), 3.65 (s,
2H), 3.12 (m, 2H), 2.71 (t, J¼5.7 Hz, 2H), 2.33 (m, 2H); 13C
NMR d 148.2 (þ), 137.7 (þ), 136.0 (þ), 132.9 (þ), 132.4
(2), 131.7 (2), 128.8 (2), 128 (2), 126.8 (2), 124.9 (2),
123.8 (2), 62.1 (þ), 52.4 (þ), 49.1 (þ), 29.5 (þ); IR (neat)
1531, 1351 cm21; HRMS (DEI) calcd for C18H17ClN2O2
328.0978 (Mþ), found 328.0978.
1
in two steps starting from 13 was 61%. Mp 1648C; H
NMR d 7.65 (br s, NH, 1H), 7.38 (m, 7H), 7.05 (dd, J¼8.2,
1.7 Hz, 1H), 3.76 (s, 2H), 3.61 (s, 2H), 2.89 (t, J¼5.5 Hz,
2H), 2.78 (t, J¼5.3 Hz, 2H); 13C NMR d 138.1 (þ), 136.3
(þ), 132.6 (þ), 129.1 (2), 128.4 (2), 127.2 (2), 119.9 (2),
118.6 (2), 110.7 (2), 108.4 (þ), 62.0 (þ), 50.7 (þ). 49.9
(þ), 21.1 (þ); IR (CCl4) 3450, 2359, 1616, 1435 cm21
.
HRMS (DEI) calcd for C18H17ClN2 328.0978 (Mþ), found
328.0978.
2.1.12. 1,2,3,4-Tetrahydro-b-carboline (20).33 To a stirred
suspension of 17 (200 mg, 0.67 mmol) and Pd(OH)2/C
(200 mg, ca. 20% palladium) in dry methanol (20 mL) was
added ammonium formate (210 mg, 3.33 mmol) under an
argon atmosphere. The mixture was stirred at reflux until
disappearance of starting material (TLC, 3.5 h). After
cooling to ambient temperature, the suspension was filtered
through a Celite pad, and the pad was washed with methanol
(10 mL). The solvent was evaporated at reduced pressure to
give 20 (106 mg, 0.62 mmol, 91%).
2.1.9. 4-(4-Chloro-2-nitro-phenyl)-3,6-dihydro-2H-pyri-
dine-1-carboxylic acid tert-butyl ester (15). Reaction of 9
(950 mg, 2.12 mmol) with 11 (710 mg, 2.12 mmol) in the
presence of Pd(dba)2 (61.5 mg, 0.10 mmol), triphenylarsine
(131 mg, 0.42 mmol), copper iodide (40 mg, 0.21 mmol) in
NMP, as described above, gave after chromatography
(hexanes EtOAc, 9:1) 15 (450 mg, 1.32 mmol, 62%) as an
2.1.13. 7-Chloro-1,3,4,9-tetrahydro-b-carboline-2-car-
boxylic acid tert-butyl ester (18). Reaction of 15
(215 mg, 0.63 mmol) with CO in the presence of Pd(dba)2
(21.9 mg, 0.038 mmol), 1.3-bis(diphenylphosphino)pro-
pane (15.7 mg, 0.038 mmol), 1,10-phenanthroline (15 mg,
0.075 mmol), in DMF (3 mL), as described for 1, gave after
chromatography (hexanes–EtOAc, 9:1) 18 (157 mg,
1
oil. H NMR d 7.91 (d, J¼1.9 Hz, 1H), 7.55 (dd, J¼8.1,
2.1 Hz, 1H), 7.26 (d, J¼1.6 Hz, 1H), 5.6 (s, 1H), 4.03 (br s,
2H), 3.63 (t, J¼5.4 Hz, 2H), 2.30 (br s, 2H), 1.49 (s, 9H);
13C NMR d 154.5 (þ), 148.1 (þ), 135.9 (þ), 133.6 (þ),
133.4 (þ), 132.8 (2), 131.8 (2), 124.4 (2), 79.6 (þ), 29.0
(þ), 28.2 (2); IR (neat) 2930, 1693, 1537, 1415, 1365,
1
0.80 mmol, 81%) as a white solid. Mp 1888C; H NMR d
1238, 1169, 1112 cm21
.
HRMS (CI) calcd for
8.70 (br s, NH, 1H), 7.37 (d, J¼8.3 Hz, 1H), 7.28 (d,
J¼1.7 Hz, 1H), 7.07 (dd, J¼8.5, 1.6 Hz, 1H), 4.6 (s, 2H),
3.77 (t, J¼5.7 Hz, 2H), 2.78 (t, J¼5.7 Hz, 2H), 1.52 (s, 9H);
C16H23ClN3O4 356.1377 (MþNH4þ), found 356.1362.
2.1.10. 4-(4-Chloro-2-nitro-phenyl)-2-(4-methylphenyl-
sulfonyloxy)-1,2,3,6-tetrahydropyridine (16). To
13C NMR (DMSO-d6) d IR (CCl4) 3278, 1674 cm21
.
a
HRMS (DCI) calcd for C16H2OClN2O2 306.1135 (MHþ),
found 306.1130.
solution of 9 (540 mg, 1.21 mmol) in NMP (2 mL) was
added vinyl triflate 12 (467 mg, 1.21 mmol) under argon,
followed by Pd(dba)2 (34.7 mg, 0.060 mmol), triphenyl-
arsine (74.1 mg, 0.24 mmol), and copper iodide (23 mg,
0.12 mmol). The reaction mixture was worked up as
described above to give after purification by chromato-
graphy (hexanes–EtOAc, 9:1) 16 (239 mg, 0.60 mmol,
50%) as a pale yellow solid. Mp 1118C; 1H NMR d 7.91 (d,
J¼2.1 Hz, 1H), 7.71 (d, J¼8.2 Hz, 2H), 7.5 (dd, J¼8.3,
2.1 Hz, 1H), 7.37 (d, J¼7.9 Hz, 1H), 7.2 (d, J¼8.1 Hz, 2H),
5.55 (m, 1H), 3.71 (m, 2H), 3.34 (t, J¼5.5 Hz, 2H), 2.45 (s,
3H), 2.39 (m, 2H); 13C NMR d 143.7 (þ), 133.8 (þ), 133.1
(þ), 131.9 (2), 129.7 (2), 129.6 (2), 127.5 (2), 124.3 (2),
121.6 (2), 44.8 (þ), 42.7 (þ), 29.5 (þ), 21.4 (2); IR (CCl4)
1595, 1337, 1163, 980 cm21. Anal. calcd for C18H17ClN2-
O4S: C, 55.03; H, 4.36. Found: C, 54.75; H, 4.37.
2.1.14. 7-Chloro-2-(4-methylphenylsulfonyloxy)-1,2,3,4-
tetrahydro-1H-b-carboline (19). Reaction of 16 (230 mg,
0.58 mmol) with carbon monoxide in the presence of
Pd(dba)2 (20 mg, 0.034 mmol), 1.3-bis(diphenylphos-
phino)propane (14.4 mg, 0.035 mmol), 1,10-phenanthroline
(13.9 mg, 0.07 mmol), in DMF (5 mL), as described above
for 1, gave after chromatography (hexanes–EtOAc, 7:3) 19
(105 mg, 0.29 mmol, 50%) as a pale yellow solid. Mp
1
.2508C; H NMR (DMSO-d6) d 6.78 (d, J¼8.3 Hz, 2H),
6.48 (m, 4H), 6.05 (d, J¼7.2 Hz, 1H), 3.36 (br s, 2H), 1.58
(br s, 2H), 1.45 (brs, 4H); 13C NMR (DMSO-d6) d 143.6
(þ), 136.3 (þ), 133.6 (þ), 130.5 (þ), 129.9 (2), 127.2 (2),
125.6 (þ), 125.0 (þ), 118.9 (2), 118.8 (2), 110.8 (2),
106.5 (þ), 43.8 (þ), 43.2 (þ), 20.9 (2), 20.7 (þ); IR (CCl4)
3384, 2361 cm21. HRMS (DCI) calcd for C18H18ClN2O2S
361.0778, found 361.0766.
2.1.11. 2-Benzyl-7-chloro-1,2,3,4-tetrahydro-1H-b-car-
boline (17). To an oven dried, threaded ACE glass pressure
tube was added 14 (469 mg, 1.43 mmol), Pd(OAc)2
(19.2 mg, 0.085 mmol), PPh3 (90 mg, 0.34 mmol), and
MeCN (5 mL). The tube was fitted with a pressure head,
and the solution was saturated with CO (four cycles of 4 atm
of CO). The reaction mixture was heated at 708C (oil-bath
2.1.15. 2-Benzyl-7-chloro-9-methyl-2,3,4,9-tetrahydro-
solution of 17 (420 mg,
1H-b-carboline (22).
A
1.41 mmol) in THF (5 mL) was added dropwise, under
argon, to a 08C cold suspension of NaH (71 mg, 2.95 mmol)
in THF (5 mL). After stirring for 45 min, iodomethane

¨
S. W. Dantale, B. C. G. Soderberg / Tetrahedron 59 (2003) 5507–5514
5513
(92 mL, 1.47 mmol) was added, and the reaction mixture
Acknowledgements
was stirred at 08C for 4 h. Upon completion of the reaction
(monitored by TLC), the solvent was evaporated under
reduced pressure. The crude residue was purified by
chromatography (hexanes–EtOAc, 85:15) to give 22
(355 mg, 1.14 mmol, 81%) as a yellow solid. Mp 1388C;
1H NMR d 7.38 (m, 7H), 7.05 (dd, J¼8.2, 1.7 Hz, 1H), 3.8
(s, 2H), 3.65 (s, 2H), 3.5 (s, 3H), 2.86 (m, 2H), 2.81 (m, 2H);
13C NMR d 138.2 (þ), 137.3 (þ), 134.2 (þ), 128.9 (2),
128.3 (2), 127.1 (2), 126.4 (þ), 125.2 (þ), 119.2 (2),
118.6 (2), 108.6 (2), 107.4 (þ), 62.2 (þ), 50.4 (þ), 49.2
(þ), 29.0 (2), 21.2 (þ); IR (CCl4) 2359, 1680 cm21. HRMS
(DEI) calcd for C19H19ClN2 310.1237 (Mþ), found
310.1230.
This work was supported by a research grant from the
National Institutes of Health (R01 GM57416). Copy editing
by Diana G. Duran is gratefully acknowledged.
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