4-Trifloxy-9-SEM-β-carboline: Preparation and synthetic utility

Full text of DOI:10.1021/jo990316t

4564
J . Org. Chem. 1999, 64, 4564-4568
Sch em e 1
4-Tr ifloxy-9-SEM-â-Ca r bolin e: P r ep a r a tion
a n d Syn th etic Utility
Carl A. Busacca*, Magnus C. Eriksson, Yong Dong,
Anthony S. Prokopowicz, Annette M. Salvagno, and
Matt A. Tschantz
Departments of Chemical Development and Medicinal
Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900
Ridgebury Road, Ridgefield, Connecticut 06877-0368
Received February 19, 1999
Numerous compounds with a â-carboline nucleus have
been shown to possess CNS (central nervous system)
activity, particularly at brain benzodiazepine receptors.1
We were especially interested in preparing a variety of
4-substituted â-carbolines for biological evaluation since
betacarbolines with 4-substitution and lacking substitu-
tion at the 3-position are not well represented in the
literature. Syntheses typically involve introduction of the
latent 4-substituent in the first synthetic step, Michael
addition2 of indole to a â-substituted nitroolefin. Reduc-
tion to a tryptamine3, ring closure (either Pictet-Spen-
gler4 or Bischler-Napieralski5), and aromatization6 have
generally been used to complete the synthesis. For the
purposes of rapid SAR (structure activity relationship)
development, however, this linear approach was imprac-
tical, and we required instead a common advanced
intermediate suitable for facile derivitization to generate
a diverse group of 4-substituted â-carbolines.
An obvious target to fulfill these requirements would
then be the 4-halo or 4-trifloxy-â-carbolines which would
be readily derivatized through well-established palladium
and nickel catalyzed cross coupling reactions. None of the
four 4-halo or the 4-trifloxy derivatives lacking additional
ring substitution have ever been reported. The synthesis
and derivatization of the first such 4-trifloxy-â-carboline
is the subject of this note.
4-Alkoxy derivatives are described, yet no synthesis,
characterization data, or reference to the presumed
4-hydroxy precursor is given. In 1982, however, Cook8
described fully the synthesis of 1-ethyl-4-hydroxy-â-
carboline 5 from the tetrahydro-â-carboline two as shown
in Scheme 1. The key step was installation of the 4-keto
functionality via oxidation with DDQ9 in aqueous THF.
Saponification of the benzamide to furnish aminoketone
(4) and sulfur promoted aromatization completed the
synthesis. Two practical limitations of this methodology
precluded its use for our purposes, however. The saponi-
fication was performed under high dilution (0.004M) in
6 N NaOH due to the low solubility of ketoamide (3). In
addition, the excellent water solubility of aminoketone
(4) necessitated 48 h of continuous liquid/liquid extraction
with methylene chloride to furnish the product in 65%
isolated yield. We reasoned that use of an appropriate
cosolvent might circumvent the use of high dilution, while
introduction of a protecting group on the indole nitrogen
should dramatically increase the organic solubility of an
intermediate aminoketone, thereby allowing for standard
extractive workup. A successful protecting group would
also have to survive all subsequent synthetic steps (basic
hydrolysis, oxidation, triflation, and coupling) and be
easily removed following coupling. The SEM10 group has
been found to fulfill all of these requirements.
The first report of a 4-hydroxy-â-carboline of which we
are aware comes from the French patent literature.7
Our synthesis thus commences with preparation of
ketoamide (7) in two steps from tetrahydro-â-carboline
(53% overall) using the Cook9e protocol as shown in
Scheme 2. Alkylation with SEM-Cl then provided 8 as a
stable crystalline solid in 80% yield. When 8 was heated
for 1 h at 100 °C in 1:1 6N NaOH:MeOH (0.13M),
consumption of starting material was observed with
formation of two new products by TLC. These species
proved to be the anticipated product, aminoketone (9),
and 4-hydroxy-â-carboline11 derivative (10). By simply
stirring the reaction mixture at ambient temperature in
an open flask, air oxidation to 10 was realized in 84%
(1) (a) Cook, J . M.; Cox, E. D.; Diaz-Arauzo, H.; Huang, Q.; Reddy,
M. S.; Ma, C.; Harris, B.; McKernan, R.; Skolnick, P. J . Med. Chem.
1998, 41, 1 (14), 2537. (b) Dodd, R. H.; Batch, A. J . Org. Chem. 1998,
63, 3 (3), 872. (c) Cook, J . M.; Skolnick, P.; Shannon, H. E. Heterocycles
1986, 24 (10), 2845. (d) Cook, J . M.; Cain, M.; Weber, R. W.; Guzman,
F.; Barker, S. A.; Rice, K. C.; Crawley, J . N.; Paul, S. M.; Skolnick, P.
J . Med. Chem. 1982, 25 (9), 1081. (e) Lippke, K. P.; Schunack, W. G.;
Wenning, W.; Muller, W. E. J . Med. Chem. 1983, 26 (4), 499.
(2) (a) Kozikowski, A. P.; Chen, Y.-Y. J . Org. Chem. 1981, 46 (25),
5248. (b) Hartman, P. J .; Noland, W. E. J . Am. Chem. Soc. 1954, 76,
3227. (c) Noland, W. E.; Christensen, G. M., Sauer, G. L.; Dutton, G.
G. S. J . Am. Chem. Soc. 1955, 77, 456. (d) Lehmann, J .; J iang, N.;
Behncke, A. Arch. Pharm. (Weinheim, Ger.) 1993, 326, 6 (10), 813. (e)
Cook, J . M.; Skolnick, P.; McKernan, R.; Cox, E. D.; Diaz-Arauzo, H.;
Huang, Q.; Reddy, M. S.; Ma, C.; Harris, B. J . Med. Chem. 1998, 41
(14), 2537.
(3) For recent examples, see: (a) Rodriguez, R.; Diez, A.; Rubiralta,
M.; Giralt, E. Heterocycles 1996, 43 (3), 513. (b) Dubois, L.; Dorey, G.;
Potier, P.; Dodd, R. Tetrahedron: Asymmetry 1995, 6 (2), 455.
(4) (a) Pandit, U.K.; Hiemstra, H. C.; Bieraugel, H.; Wijnberg, M.
Tetrahedron 1983, 39 (23), 3981. (b) Cook, J . M.; Soerens, D.; Sandrin,
J .; Ungemach, F.; Mokry, P.; Wu, G. S.; Yamanaka, E.; Hutchins, L.;
DiPierro, M. J . Org. Chem. 1979, 44 (4), 535.
(5) (a) Kuehne, M. E.; Muth, R. S. J . Org. Chem. 1991, 56 (8), 2701.
(b) Martin, S. F.; Benage, B.; Hunter, J . E. J . Am. Chem. Soc. 1988,
110 (17), 5925.
(6) (a) Cook, J . M.; Campos, O.; DiPierro, M.; Cain, M.; Mantei, R.;
Gawish, A. Heterocycles 1980, 14 (7), 975.
(7) Corbiere, J . 19 Nov. 1981, D’Invention 81 21650. No. de publica-
tion 2, 516, 512.
(8) Cook, J . M.; Cain, M.; Mantei, R. J . Org. Chem. 1982, 47 (25),
4933.
(9) (a) Bergman, J .; Carlsson, R.; Misztal, S. Acta Chem. Scand. B
1976, 30, 853. (b) Yonemitsu, O.; Oikawa, Y. J . Org. Chem. 1977, 42,
1213. (c) Yonemitsu, O.; Oikawa, Y.; Yoshioka, T.; Mohri, K. Hetero-
cycles 1979, 12 (11), 1457. (d) Yonemitsu, O.; Oikawa, Y.; Yoshioka,
T.; Mohri, K. J . Chem. Res. Synth. 1981, 194. (e) Cook, J . M.; Hagen,
T. J .; Narayanan, K.; Names, J . J . Org. Chem. 1989, 54 (9), 2170.
(10) SEM ) Trimethysilylethoxymethyl.
(11) For a seven step synthesis of 4-hydroxy-9-benzyl â-carboline
by an entirely different route, see: Murakami, Y.; Suzuki, H.; Iwata,
C.; Sakurai, K.; Tokumoto, K.; Takahashi, H.; Hanada, M.; Yokoyama,
Y. Tetrahedron 1997, 53 (5), 1593.
10.1021/jo990316t CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/26/1999

Notes
J . Org. Chem., Vol. 64, No. 12, 1999 4565
Ta ble 1. Su zu k i Cou p lin gsa of Tr ifla te 1 a n d Ar yl
Bor on ic Acid s
Sch em e 2
coupling
product (%)
deprotected
product (%)
entry
aryl group
solvent
1
2
3
4
5
4-OMePh
Ph
3-MePh
2-naphthyl
4-ClPh
dioxane
THF
dioxane
THF
11 (86)
12 (61)
13 (67)b
14 (55)c
15 (53)
16 (79)
17 (65)
18 (84)
19 (85)
20 (82)
dioxane
a
Isolated yields after flash chromatography. PdCl2dppf/K3PO4
was used in all cases except entry 1 where Pd(PPh3)4/K3PO4 was
b
used. 57% yield in DME. c No reaction in DME.
Ta ble 2. Ra tio of Cou p lin g P r od u ct 21 to Red u ced
P r od u ct 35a
isolated yield. The need for a separate oxidation step,
typically performed with sulfur or palladium at high
temperature,1d,6 was thus conveniently eliminated. The
reasons for this facile oxidation of 9 (vs 4) were not
investigated, yet the 9-SEM group might act to stabilize
the presumed benzylic radical, thereby facilitating oxida-
tion with ambient oxygen. Alcohol 10 was then triflated
in quantitative yield with Tf2O/DMAP at low temperature
to generate title compound 1 as a stable crystalline solid.
Triflations using tertiary amine bases invariably gave
lower yields with formation of colored impurities. The
synthesis of 1 was thus completed in five steps from
commercial starting material.
With multigram quantities of triflate 1 in hand, we
turned our attention to its reactivity under palladium
catalysis. The results obtained for Suzuki coupling12 of
triflate 1 are shown in Table 1. Suzuki coupling of
p-methoxyphenylboronic acid with triflate 1 under the
original conditions12 (Pd(PPh3)4, K3PO4, p-dioxane) pro-
vided adduct 11 in 86% yield (Table 1). When these
conditions were applied to phenyl-, m-tolyl- and 2-naph-
thylboronic acids, however, only trace amounts of cou-
pling products were observed. Use of PdCl2dppf with
K3PO4 proved to be more general, although the choice of
solvent proved critical. Phenyl adduct 12 was obtained
in 61% yield using THF. The m-tolyl product 13 was
obtained in 67% yield in p-dioxane, yet use of DME led
to a lower yield. No product was obtained using DME as
solvent for 2-naphthylboronic acid, yet in THF, naphthyl
product 14 was obtained in 55% yield. Use of p-chlo-
rophenyl boronic acid in p-dioxane gave the adduct 15
in 53% yield. In addition to the desired coupling products,
small amounts of reduced â-carboline (35) and the
product of triflate hydrolysis, 4-hydroxy species 10, were
generally formed. We next moved our attention to the
Kumada13 coupling for further preparation of 4-substi-
tuted â-carbolines.
entry
catalyst
coupling 21:reduced 35
1
2
3
4
5
6
7
8
9
NiCl2(Ph3P)2
PdCl2(Ph3P)2
Ni(acac)2
NiCl2dppf
PdCl2dppf
NiCl2dchxpe
NiCl2dppb
NiCl2dppp
NiCl2dppe
PdCl2dppe
15:85c
20:80f
29:71b
35:65d
92:8f
45:55b
55:45b
55:45c
96:4e
10
70:30f
a
All reactions were run using 1.5 equiv PrMgCl, 10 mol %
catalyst at 0.05 M in toluene, and ratios were measured by HPLC.
Ratio measured after 1 h at room temperature. c Ratio measured
b
d
after 18 h at room temperature. 3.0 equiv PrMgCl, 20 mol %
catalyst. Ratio measured after 20 h at room temperature and 5 h
at 55 °C. e Ratio measured after 30 min at room temperature.
f Ratio measured after 1 h at 55 °C.
the reaction were found to be ligand choice and rate of
Grignard addition. A set of 10 catalyst/ligand combina-
tions were examined in the coupling of triflate 1 with
n-PrMgCl as detailed in Table 2. Mixtures of desired
product 21 and reduced species 35 were formed. The best
results were obtained using PdCl2dppf (entry 5) and
NiCl2dppe (entry 9), with the nickel species proving to
be slightly superior. The use of large bite angle ligands
with palladium and small bite angle ligands with nickel
gave the highest selectivities.
It is interesting to note that Ni(acac)2 (Table 3, entry
3), which performs admirably in the coupling of aryl
Grignard’s,14 is a very poor ligand for the coupling of
n-propylmagnesium chloride. We found that rapid addi-
tion of the Grignard reagent often had a deleterious effect
on the reaction leading to low yields and incomplete
conversions.18 We thus developed a protocol where only
Cross coupling of triflate 1 with both aryl and alkyl
Grignard reagents was found to be a general method for
construction of 4-substituted â-carbolines as shown in
Tables 2 and 3. Two key parameters to the success of
(12) Oh-e, T.; Miyaura, N.; Suzuki, A. J . Org. Chem. 1993, 58, 2201.
(13) (a) Kumada, M.; Tamao, K.; Sumitani, K. J . Am. Chem. Soc.
1972, 94, 4374. (b) Kumada, M.; Tamao, K.; Sumitani, K.; Kiso, Y.;
Zembayashi, M.; Fujioka, A.; Kodama, S-i.; Nakajima, I.; Minato, A.
Bull. Chem. Soc. J pn. 1976, 49, 1958. (c) Corriu, R. J . P.; Masse, J . P.
J . Chem. Soc., Chem. Commun. 1972, 144.
(14) Snieckus, V.; Sengupta, S.; Leite, M., Raslan, D. S.; Quesnelle,
C. A. J . Org. Chem. 1992, 57, 4066.

4566 J . Org. Chem., Vol. 64, No. 12, 1999
Notes
Ta ble 3. Ku m a d a Cou p lin gs of Tr ifla te 1 w ith Gr ign a r d
Rea gen tsa
Sch em e 4
coupling
conditions
coupling
product (%)
deprotected
product (%)
entry
R group
1
2
3
4
5
6
7
propyl
cyclohexyl
benzyl
4-MePh
3-OMePh
4-t-BuPh
4-CF3Ph
NiCl2dppe
NiCl2dppe
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
21 (89)
22 (57)
23 (55)
24 (53)
25 (54)
26 (76)
27 (93)
28 (86)b
29 (66)b
30 (98)b
31 (60)c
32 (74)c
33 (68)c
34 (80)c
when applied to p-tert-butylphenyl adduct 26, p-trifluo-
romethylphenyl adduct 27, and ester 36. Use of TBAF
trihydrate in THF or DMF together with EDA17 was
found to be a completely general method and was applied
successfully in all cases. Deprotection yields were gener-
ally high and are shown in Tables 1 and 3. Surprisingly,
small amounts of ethoxymethyl species 40 were formed
also when TBAF/DMF/EDA was used. We have investi-
gated the mechanism of their formation through deute-
rium labeling studies. When propyl adduct 21 was
hydrolyzed in aqueous HCl/C2D5OD, analysis of minor
component 40 by 1H NMR showed > 95% d5 incorporation
(Scheme 4). Compound 40 was thus shown to be formed
exclusively by attack of the solvent ethanol on the
intermediate methyleneiminium ion. When 21 was treated
with four equivalents of TBAF trihydrate in the presence
of 3 equiv added D2O, 1H NMR analysis of minor product
40 showed ca. 20% deuterium incorporation in the
terminal methyl group. The curious situation thus exists
in which no protiodesilylation occurs under acidic condi-
tions, yet under the basic conditions (excess EDA) of the
TBAF deprotection, byproduct formation occurs only via
protiodesilylation, with residual water on the TBAF
reagent being the proton source.
a
Isolated yields after flash chromatography. All reactions in
toluene. Aqueous HCl deprotection. c TBAF deprotection.
b
Sch em e 3
enough Grignard was added to reduce nickel(II) to nickel-
(0),13 with the remainder being added via syringe pump
over a period of 4-6 h. Use of cyclohexylmagnesium
chloride (Table 3, entry 2) and benzylmagnesium chloride
(entry 3) furnished product under similar conditions. A
series of commercially available aryl Grignard reagents
(entries 4-7) were coupled analogously in good yield
using exclusively Ni(acac)2 as catalyst.
The reactivity of triflate 1 under carbonylative condi-
tions was also examined as shown in Scheme 3. When
treated under 100 psi CO at 100 °C using a Pd(OAc)2/
dppp combination,15 the acylated adducts 36 and 37 were
obtained in high yield.
In summary, a series of novel 4-substituted â-carbo-
lines have been prepared from 4-trifloxy-9-SEM-â-car-
boline. Use of palladium and nickel catalyzed cross
coupling and carbonylation reactions have allowed for the
facile preparation of 4-aryl, -alkyl, and -acyl â-carboline
derivatives from a common advanced intermediate.
The syntheses of the 4-substituted â-carbolines were
completed by removal of the SEM protecting group. Two
different protocols were employed: aqueous HCl/EtOH
and tetrabutylammonium fluoride (TBAF)/DMF/1,2-eth-
ylenediamine (EDA). Our initial attempts using aqueous
HCl/EtOH16 gave the deprotected material along with ca.
15% of a side product which turned out to be the
(nondeuterated) species corresponding to 40. Better
results, without formation of this side product, were
obtained with THF in place of EtOH. While the aqueous
HCl/THF protocol was suitable for several species, it gave
mixtures of desired product and hydrolysis byproducts
Exp er im en ta l Section
Gen er a l. All melting points are uncorrected. 1H and 13C NMR
spectra were generally obtained at 400 and 100 MHz, respec-
tively. Elemental analysis were performed by QTI Analyses, NJ .
All chemicals were obtained from commercial sources and used
as received unless otherwise noted. Anhydrous solvents from
Aldrich were generally used directly. NiCl2dppb was prepared
following the method of Frauenrath et al.19 and NiCl2dppf using
the method of Rudie et al.20 p-Trifluoro-methylphenylmagnesium
bromide was prepared in a standard fashion in diethyl ether
from p-bromobenzotrifluoride and magnesium powder (Aldrich).
See Supporting Information for all compounds not discussed
here.
(15) Colquhoun, H. M.; Thompson, D. J .; Twigg, M. V. Carbonyla-
tion: Direct Synthesis of Carbonyl Compounds; Plenum Press: New
York, 1991.
(16) Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett. 1995, 36 (15),
2615.
9-SEM-k etoa m id e (8). To a solution of 12.0 g of ketoamide
7 (41.4 mmol, 1 equiv) in 90 mL of DMF at ambient temperature
under N2 was cautiously added 1.04 g of NaH (43.4 mmol, 1.05
(17) (a) Muchowski, J . M.; Solas, D. R. J . Org. Chem. 1984, 49, 203-
205. (b) Labadie, S. S.; Teng, E. J . Org. Chem. 1994, 59, 4250.
(18) J ohnstone, R. A. W.; Neil McLean, W. Tetrahedron Lett. 1988,
29, 5553.
(19) Frauenrath, H.; Wille, A.; Tomm, S. Synthesis 1998, 305.
(20) Rudie, A. W.; Lichtenberg, D. W.; Katcher, M. L.; Davison, A.
Inorg. Chem. 1978, 17, 2859-2863.

Notes
J . Org. Chem., Vol. 64, No. 12, 1999 4567
equiv) in portions over 15 min. After 30 min, a solution of 7.69
mL of SEM-Cl (43.4 mmol, 1.05 equiv) in 20 mL of DMF was
added dropwise over 30 min. After 1 h at ambient temperature,
200 mL of half-saturated NaCl was added, and the mixture was
extracted with EtOAc (4 × 200 mL). The combined EtOAc layers
were washed with saturated NaCl (2x), dried (MgSO4), and the
solvents were removed in vacuo to give 25 g of oil which was
then chromatographed on Si gel eluting with 2:1 Hex:EtOAc to
give 13.4 g of 8 (77%) as a colorless crystalline solid, mp ) 97-
2.2 mL of 1 M TBAF/THF (2.2 mmol, 5.6 equiv) and 79 µL of
ethylenediamine (1.19 mmol, 3 equiv). The mixture was heated
at 50 °C for 48 h. The volatiles were removed in vacuo, and the
residue was chromatographed on silica eluting with EtOAc to
1
give 85 mg of 16 (79%) as a pale yellow solid, mp > 250 °C. H
NMR (DMSO-d6) δ: 11.80 (s, 1H), 8.90 (s, 1H), 8.18 (s, 1H), 7.61
(m, 4H), 7.50 (t, J ) 7.7 Hz, 1H), 7.17 (d, J ) 8.6 Hz, 2H), 7.07
(t, J ) 7.7 Hz, 1H), 3.88 (s, 3H). 13C NMR (DMSO-d6) δ: 159.2
(s), 140.8 (s), 138.3 (d), 135.9 (s), 132.8 (d), 130.8 (s), 130.2 (d),
129.7 (s), 127.9 (d), 124.7 (s), 122.6 (d), 120.2 (s), 119.0 (d), 114.2
(d), 112.1 (d), 55.2 (q). EIMS M+ 274. Anal. Calcd for
C18H14N2O: C, 78.81; H, 5.14; N, 10.21. Found: C, 78.70; H,
5.29; N, 10.20.
1
98 °C. H NMR (C6D6) δ: 8.73 (d, J ) 7.5 Hz, 1H), 7.43 (d, J )
6.2 Hz, 2H), 7.34-7.27 (m, 5H), 7.14 (m, 1H), 4.98 (br s, 2H),
4.87 (br s, 2H), 4.10 (br s, 2H), 0.86 (br s, 2H), 0.00 (s, 9H). 13C
NMR (C6D6) δ: 186.55 (s), 170.49 (s), 137.61 (s), 135.25 (s), 130.17
(d), 128.64 (d), 127.71 (d), 125.00 (s), 124.14 (d), 123.65 (d), 122.16
(d), 112.65 (s), 110.30 (d), 72.76 (t), 66.49 (t), 55.59 (br t), 39.54
(br t), 17.73 (t), -1.48 (q). Anal. Calcd for C24H28N2O3Si: C,
68.54; H, 6.71; N, 6.66. Found: C, 68.38; H, 6.68; N, 6.48.
9-SEM-4-h yd r oxy-â-ca r bolin e (10). To a solution of 13.0 g
of 8 (30.9 mmol, 1 equiv) in 120 mL MeOH at ambient
temperature under N2 was added 120 mL 6M NaOH, and the
mixture was refluxed for 1.5 h. The mixture was then allowed
to cool to 23 °C, opened to the air, and stirred vigorously for 36
h. The MeOH was then removed in vacuo and the residual liquid
extracted with EtOAc (3 × 250 mL), the combined EtOAc layers
were washed with H2O (2 × 300 mL) and dried (MgSO4), and
the solvents were removed in vacuo to give 10.5 g of a pink solid.
Recrystallization (EtOAc) gave 7.00 g of pure 10 as pale yellow
crystals, mp ) 201-203 °C. Chromatography of the mother
liquors on Si gel (EtOAc) gave an additional 1.16 g. Total 8.16
g, 84% yield. 1H NMR (C6D6) δ: 9.08 (d, J ) 7.7 Hz, 1H), 8.91
(s, 1H), 8.67 (s, 1H), 7.51-7.43 (m, 2H), 7.40 (t, J ) 7.1 Hz, 1H),
5.24 (s, 2H), 3.40 (t, J ) 7.6 Hz, 2H), 0.81 (t, J ) 7.7 Hz, 2H),
-0.07 (s, 9H). 13C NMR (C6D6) δ: 152.64 (s), 140.98 (s), 138.82
(s), 127.45 (d), 125.65 (d), 124.98 (d), 122.03 (d), 121.97 (s), 120.93
(d), 119.22 (s), 109.47 (d), 72.41 (t), 65.83 (t), 17.34 (t), -1.75
(q). Anal. Calcd for C17H22N2O2Si: C, 64.93; H, 7.05; N, 8.91.
Found: C, 64.92; H, 6.93; N, 8.79.
Gen er a l P r oced u r e 2. Ku m a d a Cou p lin g/SEM Dep r o-
tection . 4-Ben zyl-â-ca r bolin e (30). To a suspension of 447 mg
of triflate 1 (1.0 mmol, 1.0 equiv) and 26 mg Ni(acac)2 (0.1 mmol,
0.1 equiv) in 20 mL of toluene at room temperature under Ar
was added 1.79 mL of 0.84 M benzylmagnesium chloride in Et2O
(1.5 mmol, 1.5 equiv). The resulting dark brown solution was
stirred at room temperature for 1.5 h, then another 1.79 mL
portion of Grignard was added and stirring continued. The
reaction was quenched after 5 h with 15 mL of saturated
aqueous NH4Cl. The phases were separated, and the aqueous
layer was extracted with EtOAc. The combined organic phase
was washed with water and brine and dried over MgSO4.
Evaporation of the solvent gave a yellow oil which was purified
by flash chromatography on silica using 35% EtOAc in hexanes
(Rf ) 0.42 for product) to give 211 mg of the coupling product
23, 55% yield, and 20 mg of a 55:45 mixture of coupling product
and reduced triflate 35, (Rf ) 0.31 for reduced triflate). The
coupling product 23, 211 mg, was dissolved in 10 mL of THF
and 20 mL of 3M aq HCl. The solution was refluxed for 24 h
after which THF was evaporated in vacuo. The aqueous phase
was made basic with 10% NaOH and extracted with EtOAc (3
× 30 mL). The combined organic phase was washed with water
and brine and dried over MgSO4. Evaporation of the solvent in
vacuo gave 146 mg of a yellow solid which was triturated three
times with Et2O to afford 140 mg (98%) of pure 30, mp ) 210-
213 °C. 1H NMR (CDCl3) δ: 9.37 (s, 1H), 8.94 (s, 1H), 8.29 (s,
1H), 8.06 (d, J ) 8.0 Hz, 1H), 7.48-7.58 (m, 2H), 7.22-7.34 (m,
6H), 4.66 (s, 2H). 13C NMR (CDCl3) δ: 141.11 (s), 140.35 (d),
139.31 (s), 132.32 (d), 129.09 (d), 129.00 (d), 128.50 (d), 128.31
(s), 126.85 (d), 124.35 (d), 121.81 (s), 120.61 (d), 111.99 (d), 37.65
(t). CIMS (M+H)+ 259.1. Anal. Calcd for C18H14N2‚0.3H2O: C;
81.98, H; 5.58, N; 10.62. Found: C; 81.74, H; 5.55, N; 10.32.
Gen er a l P r oced u r e 3. Ca r bon yla tion /SEM Dep r otec-
tion . 4-Dieth yla m id o-â-ca r bolin e(39). To a 20 mL vial was
added 250 mg of triflate 1 (0.56 mmol, 1.0 equiv), 13 mg Pd-
(OAc)2 (0.056 mmol, 0.1 equiv), and 24 mg dppp (0.056 mmol,
0.1 equiv). To this was added 5 mL of DMF and 2.5 mL of Et2-
NH. The vial was placed in a 60 mL of Parr bomb, and the
reaction mixture was stirred under 100 psi CO for 10 h at 100
°C. The reaction mixture was diluted with water and extracted
with EtOAc four times. The combined organic layer was washed
two times with water, once with brine, and dried over MgSO4.
Evaporation of the solvent gave a brown oil which was purified
by flash chromatography on silica using EtOAc (Rf ) 0.35) to
give 200 mg (90%) of 37 as a light yellow oil. The coupling
product 37, 200 mg (0.50 mmol, 1.0 equiv) was dissolved in 5
mL of DMF in a 25 mL flask fitted with a reflux condenser. Solid
TBAF‚3H2O, 316 mg (1.0 mmol, 2.0 equiv), was added followed
by 67 µL ethylenediamine (1.0 mmol, 2.0 equiv), and the yellow
solution was stirred under argon at 50 °C for 24 h. TLC (7.5%
MeOH/CH2Cl2) indicated incomplete conversion and another 1.0
mmol portion each of TBAF‚3H2O and ethylenediamine was
added. After a total of 48 h at 50 °C the reaction mixture was
diluted with water and extracted three times with EtOAc. The
combined organic layer was washed once with water, once with
brine and dried over MgSO4. Evaporation of the solvent gave a
yellow oil which was purified by flash chromatography on silica
using 7.5% MeOH/CH2Cl2 (Rf ) 0.25) to give 110 mg (81%) of
pure 39 as a waxy solid. 1H NMR (CDCl3) δ: 11.30 (s, 1H), 8.55
(s, 1H), 8.38 (s, 1H), 8.00 (d, J ) 8.0 Hz, 1H), 7.40 (m, 1H), 7.29
(d, J ) 8.0 Hz, 1H), 7.16 (m, 1H), 3.83 (broad s, 2H), 3.28 (q, J
) 7.0 Hz, 2H), 1.49 (t, J ) 7.0 Hz, 3H), 1.03 (t, J ) 7.0 Hz, 3H).
13C NMR (CDCl3) δ: 169.51 (s), 141.70 (s), 136.55 (s), 135.02
(d), 134.60 (d), 129.05 (d), 125.60 (s), 125.05 (s), 122.97 (d), 120.42
9-SEM-4-tr ifloxy-â-ca r bolin e (1). A 500 mL three-neck RB
flask at 23 °C under N2 was charged with 5.84 g of alcohol 10
(18.6 mmol, 1 equiv), 9.07 g of DMAP (74.3 mmol, 4 equiv), 230
mL of CH2Cl2, and 23 mL of pyridine in the order given. The
resulting solution was then cooled to -78 °C, and a solution of
3.43 mL of Tf2O (20.4 mmol, 1.1 equiv) in 30 mL of CH2Cl2 was
added dropwise over 20 min. After 1.5 h at -78 °C, a 0 °C bath
was installed, and after 30 min at this temperature, 125 mL of
saturated NaHCO3 was added and the mixture was stirred
vigorously. The phases were separated, the aqueous phase was
reextracted with CH2Cl2, the combined CH2Cl2 layers were dried
(MgSO4), and the solvents removed in vacuo azeotroping with
PhMe to give a solid. The solid was triturated with hexane and
filtered to remove unreacted DMAP, and the filtrate chromato-
graphed on Si gel eluting with 4:1 Hex:EtOAc to give 8.35 g of
1 (100 %) as a light yellow crystalline solid, mp ) 74-75 °C. 1H
NMR (C6D6) δ: 8.95 (s, 1H), 8.73 (s, 1H), 8.60 (d, J ) 8.0 Hz,
1H), 7.40 (t, J ) 7.7 Hz, 1H), 7.30 (d, J ) 8.4 Hz, 1H), 7.20 (t, J
) 7.5 Hz, 1H), 5.09 (s, 2H), 3.30 (t, J ) 7.7 Hz, 2H), 0.76 (t, J )
7.7 Hz, 2H), -0.09 (s, 9H). 13C NMR (C6D6) δ: 141.48 (s), 141.42
(s), 138.51 (s), 132.79 (d), 132.35 (d), 129.51 (d), 124.05 (d), 121.92
(d), 121.72 (s), 119.21 (q, 1J C-F ) 321 Hz), 118.80 (s), 110.45 (d),
72.65 (t), 66.45 (t), 17.57 (t), -1.58 (q). Anal. Calcd for
C
18H21F3N2O4SSi: C, 48.42; H, 4.74; N, 6.27. Found: C, 48.15;
H, 4.67; N, 6.17.
Gen er a l P r oced u r e 1. Su zu k i cou p lin g/SEM Dep r otec-
tion . 4-(4′-m eth oxyp h en yl)-â-ca r bolin e (16). A 10 mL RB
flask at 23 °C under N2 was charged with 154 mg of K3PO4 (0.725
mmol, 1.5 equiv), 200 mg of triflate 1 (0.483 mmol, 1 equiv), 81
mg of p-methoxyphenyl boronic acid (0.531 mmol, 1.1 (equiv),
28 mg Pd(PPh3)4 (0.024 mmol, 0.05 (equiv), and 2.5 mL of
p-dioxane in the order given. The flask was placed in
a
preequilibrated 90 °C oil bath and heated for 4 h. The mixture
was cooled to ambient temperature, diluted with 20 mL of H2O,
and extracted with EtOAc (2 × 20 mL). The combined EtOAc
layers were washed with saturated NaHCO3, dried (MgSO4), and
stripped in vacuo to give 250 mg of a brown oil which was
chromatographed on silica eluting with 35% EtOAc in hexanes
to give 168 mg (86%) of 11 as a yellow oil. To a solution of 160
mg of 11 (0.40 mmol, 1.0 (equiv) in 2.0 mL of THF was added

4568 J . Org. Chem., Vol. 64, No. 12, 1999
Notes
(d), 120.05 (d), 112.55 (d), 43.88 (t), 40.15 (t), 14.75 (q), 13.51
(q). ESMS (M+H)+ ) 268.3. Anal. Calcd for C16H17N3O‚0.1H2O:
C; 71.41, H; 6.44, N; 15.61. Found: C; 71.40, H; 6.21, N; 15.51.
Su p p or tin g In for m a tion Ava ila ble: Complete synthetic
details for the preparation of compounds 17-20, 28-29, 31-
34, and 38 as well as full characterization for every compound.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. We are grateful to the Analytical
Department at Boehringer Ingelheim and Mr Ed Harris
for obtaining mass spectral data on some of the final
compounds and Mr Scott Leonard and Mr Scot Camp-
bell for 500 MHz NMR spectra.
J O990316T