Synthesis of substituted β-carbolines via gold(III)-catalyzed cycloisomerization of N-propargylamides

Article abstract of DOI:10.1016/j.tet.2009.10.033

Indole-substituted N-propargylamides undergo a gold(III)-catalyzed cyclization to give oxazoles or β-carbolinones, depending on the substitution pattern at the amide nitrogen. Secondary amides furnished oxazoles via a 5-exo-dig cyclization, while tertiary

Full text of DOI:10.1016/j.tet.2009.10.033

Tetrahedron 66 (2010) 1496–1502
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of substituted b-carbolines via gold(III)-catalyzed
cycloisomerization of N-propargylamides
,
,
*
Guido Verniest a y, Dylan England b, Norbert De Kimpe a, Albert Padwa b
a Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
b Department of Organic Chemistry, Emory University, Atlanta, GA 30322, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Indole-substituted N-propargylamides undergo a gold(III)-catalyzed cyclization to give oxazoles or
Received 20 August 2009
Received in revised form 6 October 2009
Accepted 9 October 2009
Available online 5 January 2010
b
-carbolinones, depending on the substitution pattern at the amide nitrogen. Secondary amides
furnished oxazoles via a 5-exo-dig cyclization, while tertiary indole-2-carboxamides cycloisomerized to
give 2,9-dihydro- -carbolin-1-ones upon treatment with catalytic amounts of gold(III) chloride. An
optimized procedure was developed to prepare several new N-benzyl- -carbolinones as well as the
corresponding -carbolines, which are of interest as core structures found in various natural products
such as the harman, ervolanine, and lavendamycin class of alkaloids.
b
b
b
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
carried out. Herein, we describe the results obtained from an in-
vestigation of the AuCl3-catalyzed intramolecular cyclization of
indole-substituted N-propargylamides. In particular, the synthesis
Gold complexes have been extensively employed over the past
several years as homogeneous catalysts for the synthesis of a wide
range of heterocyclic compounds.1 The gold-catalyzed activation of
C–C multiple bonds and the subsequent attack by a nucleophilic
reagent on the complex has proven to be an exceptionally pow-
of a variety of substituted
b-carbolines became of interest because
the -carboline core is found in many natural compounds, which
b
show a broad spectrum of high bioactivity (e.g., carbolines 1–4)
(Fig. 1).6
erful method to construct new C–C and C–X bonds. The
p-Lewis
acidic properties of gold complexes result in a chemoselective
affinity of these catalysts for alkynes, allenes, and alkenes.2 As
a consequence, the gold-catalyzed activation of allenes,3 alkenes,
and especially alkynes1 often enables mild and efficient hydro-
amination, hydroarylation, hydroalkoxylation, and interesting
rearrangement reactions to occur. This rapidly evolving area of
research has already provided many new opportunities in the
atom-economic synthesis of heterocyclic compounds4 and has
recently been reviewed in some detail by a collection of authors.1
The synthesis of azapolycyclic heterocycles based on gold-cata-
lyzed cycloisomerization reactions involving an indole nucleus is
of particular interest because significant molecular complexity can
be obtained in one step starting from easily accessible systems.5
Because of our continuing interest in the synthesis of azahetero-
cyclic compounds and related natural products containing an
indole moiety in the molecular framework, a reactivity study of the
cycloisomerization of a series of alkynyl tethered indoles was
N
N
Br
CH3
N
N
H
N
H
MeO
1; harmine
2; eudistomine H
COOH
N
COOH
H3C
N
N
N
H
O
HO
N
H
3; dichotomine A
NH2
O
N
4; lavendamycin
R2
R1
N
H
* Corresponding author. Tel.: þ1 404 727 0283.
E-mail address: chemap@emory.edu (A. Padwa).
Postdoctoral Fellow of the Research Foundation Flanders (FWO-Vlaanderen,
5
;
R1, R2 = halogen, alkoxy
(herbicidal, fungicidal)
y
Belgium) at Emory University.
Figure 1. Selected bioactive b-carbolines.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.033

G. Verniest et al. / Tetrahedron 66 (2010) 1496–1502
1497
Harmine (1) is an antitumor agent isolated from the plants
CH3
Peganum harmala and Eurycoma longifolia.6a The alkaloid eudisto-
mine H (2) was obtained from the Caribbean Tunicate Eudistoma
olivaceum and exhibits antiviral properties.7 Dichotomine A (3) was
isolated from Stellaria dichotoma and possesses anti-allergic
properties.8 Lavendamycin (4) is an antitumor and antibiotic
compound isolated from Streptomyces lavendulae.9 Aside from
O
O
N
N
R2
5 mol% AuCl3
CH2Cl2, rt, 15 h
( )n
( )n
6a-c
N
R
2 = H
N
R
R1
these naturally occurring
derivatives show a wide variety of biological activities. For exam-
ple, halogenated and alkoxylated -carbolines of type 5 exhibit
herbicidal and antifungal properties.10 Despite the fact that the
pharmacological importance of -carbolines has already produced
a considerable array of synthetic methods, the synthesis of
b-carbolines, numerous synthetic
6a; R1 = Me, R2 = H, n = 1
6b; R1 = Ts, R2 = H, n = 1
6c; R1 = Me, R2 = H, n = 2
6d; R1 = Me, R2 = Me, n = 1
7a; R = Me, n = 1 (63%)
7b; R = Ts, n = 1 (61%)
7c; R = Me, n = 2 (70%)
b
b
6d, 5 mol% AuCl3
specifically substituted
b-carbolines still remains an attractive area
no cyclization
of research.11
8a, 5 mol% AuCl3
R = Me
CH3
2. Results and discussion
5 mol% AuCl3
O
O
O
O
CH3CN, rt, 15 h
N
CH3
CH3
N
R
Recently, the 5-exo-dig cyclization of several N-propargylamides
and related derivatives by making use of catalytic gold(III) chem-
istry was reported.12–14 We found that indolyl tethered prop-
argylamides of type 6 smoothly cyclize to give the corresponding
oxazoles 7 by reaction of the amide carbonyl group onto the gold
activated triple bond (Scheme 1). In order to evaluate the reactivity
of the corresponding tertiary N-propargylamide system, amide 6a
was methylated with NaH and MeI in DMF to give indole 6d
(R1, R2¼Me; n¼1) in 73% yield. However, the reaction of 6d with
gold(III) chloride gave no cyclized product, thereby indicating that
reaction of the amido carbonyl with the activated triple bond does
not occur when the N-atom contains an alkyl group. Even on
refluxing 6d with gold(III) chloride in dichloroethane, only starting
8b; R = H
9 (59%)
8a,b
CH3
N
5 mol% AuCl3
toluene, Δ, 15 h
O
R2 = H
N
R
O
R2
11a; R = H (75%)
N
CH (77%)
11b; R = CH2C
N
O
CH3
R1
5 mol% AuCl3
toluene, Δ, 15 h
10
R2
N
R2 = H
material was recovered. We also found that the reaction of
b-
O
N
ketoamide 8b (R¼H) with gold(III) chloride produced the cyclized
oxazole 9. However, the N-methyl derivative 8a (R¼Me) did not
undergo cyclization using the same catalytic system (Scheme 1).
These results clearly demonstrate that the intramolecular cycliza-
tion of propargylamides to give oxazoles proceeds smoothly with
secondary propargylamides, while the corresponding tertiary
amide system only gave back recovered starting material when
treated with a gold(III) catalyst. In a search for an indole-
substituted propargylamide that can cyclize by reaction of the
indole moiety with the activated triple bond, several differently
substituted indoles 10 were prepared. We thought that with these
systems, the NH-substituted propargylamides 10a,b would cyclize
to give oxazoles. On the other hand, we expected that the corre-
sponding N-methylated amides 10c–g would cyclize in a different
manner, by reaction of the indole ring with the activated triple
R1
12a; R1 = Me, R2 = Ts (85%)
12b; R1 = Me, R2 = Boc (60%)
12c; R1 = Bn, R2 = Me (87%)
12d; R1 = Bn, R2 = Ac (78%)
12e; R1 = Bn, R2 = Cbz (65%)
Scheme 1.
In this paper we report on an optimization of the procedure for
the synthesis of different -carbolines starting from indole-
substituted N-propargylamides. This conversion was undertaken
considering the range of bioactivities of -carbolines and also their
frequent occurrence as the core structure in various natural prod-
ucts, such as eudistomine H (2), dichotomine A (3), and lav-
endamycin (4). N-Tosylated propargylamines were chosen as
the preferred starting materials for the synthesis of these new
b
b
bond to afford b-carbolinones. Indeed, the reaction of indoles 10a,b
with 5 mol % AuCl3 in toluene yielded the expected oxazoles 11a
and 11b in 75 and 77% yield, respectively. However, when the
amido nitrogen of the indole-2-carboxamide 10 bears a substituent
other than hydrogen, 6-exo-dig cyclization occurred giving rise to
b-carbolines because of their easy availability in multigram quan-
tities and also the high conversion previously encountered with the
cyclization of indole-2-carboxamide 10c to carbolinone 12a.
The synthesis of 9-benzyl-1-chloro-4-methyl-b-carboline (17)
b
-carbolinones 12 by attack of the indole ring (C-3) onto the triple
bond. This synthetic pathway leads to differently substituted
-carbolinones (i.e., 12a–e) in good yield (Scheme 1). In the case of
N-Boc-1,5-dimethylcarbolin-2-one (12b), this compound was fur-
ther transformed into a -carboline by N-deprotection and sub-
started with the preparation of 1-benzylindole-2-carboxamide
(14), which was readily obtained from the reaction of N-benzyl-2-
indoloyl chloride with N-Tos-propargylamine (Scheme 2). Treat-
ment of the resulting amide 14 with a catalytic amount of AuCl3 in
b
b
dichloromethane produced N-tosyl-b-carbolinone 15 in 82% yield
sequent aromatization using POCl3.14 The reaction of indole 10d
(R2¼Boc) with AuCl3, however, did not proceed as smoothly as was
the case with the corresponding N-tosyl or N-methylamides 10c,e
and gave rise to a number of unidentified side-products. It had
been reported very recently that N-Boc-propargylamines undergo
cyclization via reaction of the Boc-group with the C–C triple bond
to furnish substituted oxazolinones.15 This could possibly be the
after purification by silica gel chromatography. Detosylation of 15
was easily accomplished using sodium naphthalenide in 1,2-
dimethoxyethane (DME)/THF, which afforded b-carbolinone 16 in
82% yield. Compound 16 was subsequently treated with neat POCl3
under reflux to give the desired 9-benzyl-1-chloro-4-methyl-
carboline 17 in 76% yield, which we intend to make use of for an
eventual synthesis of lavendamycin (4).14
reason for the lower yield of
N-Boc-amide 10d.
b
-carbolinone 12b starting from
Because of the ease and efficiency of this synthetic pathway, the
scope of the method was further evaluated in order to maximize

1498
G. Verniest et al. / Tetrahedron 66 (2010) 1496–1502
1) 1.1 equiv (COCl)2
0.1 equiv DMF,
further efforts were carried out in order to further functionalize the
-carboline skeleton. For example, an oxidation of 29 to produce
carbolinoxide 30 could easily open up an entry to the interesting 3-
hydroxymethyl-
-carboline 31 via a Boekelheide rearrangement.20
However, in complete contrast to what had been observed with
related 2-chloropyridines,21
-carboline 29 proved to be quite re-
sistant toward oxidation. While the reaction of 29 with KMnO4,
(urea)–H2O2, SeO2, oxone or dimethyldioxirane only gave recovered
starting material, the use of mCPBA (6 equiv) in CHCl3 at 70 ꢀC did
give carbolinoxide 30 (80% conversion) after 48 h, but only if the
mCPBA was added in small portions every 12 h. Although carbo-
linoxide 30 could be isolated in 57% yield after silica gel chroma-
b
b-
OH
O
N
O
Ts
benzene, rt, 3 h
b
2) 1 equiv
N
Bn
Ts
N
Bn
14 (80%)
N
H
13
b
6 equiv pyridine,
CH2Cl2, rt, 15 h
5 mol% AuCl3
CH2Cl2, rt, 15 h
CH3
N
4 equiv 1.3 M Na-
naphthalenide in DME,
THF, -78°C, 30 min
CH3
NH
O
Ts
N
tography, the desired Boekelheide rearrangement to b-carboline 31
did not occur upon treatment with acetic anhydride or trifluoro-
acetic anhydride.
O
N
Bn
15 (82%)
Bn
16 (82%)
CH3
R3
N
R3
NH
CH3
CH3
POCl3, Δ, 24 h
N
Cl
N
R2
Bn
17 (76%)
Scheme 2.
O
N
N
R1
19
R1
18
R3
R3
NHTs
the yield of variously substituted
that polysubstituted -carbolines of type 18 could be generated
from the corresponding -carbolinones 19. Starting from tosyl
b-carbolines. It was envisioned
b
Ts
N
b
21a; R3 = 2-furyl
21b; R3 = BnOCH2
21c; R3 = Me
amine 21, we intended to prepare the requisite indole-2-carbox-
amide 20 by making use of its reaction with 2-indoloyl chloride and
this would be followed by a subsequent cycloisomerization using
AuCl3 (Scheme 3). To test this possibility, the synthesis of 2-fur-
ylpropargylamine 21a was first carried out according to literature
procedures.16 However, the desired coupling of 21a with N-benzyl-
2-indoloyl chloride did not give the corresponding amide 20a
(R1¼Bn, R3¼2-furyl). Other standard coupling procedures using
DCC or isobutyl chloroformate only resulted in the recovery of the
starting propargylamine. The less sterically hindered amine 21b
was next studied and this compound was prepared by reaction of 2-
benzyloxyacetaldehyde (22) with p-tosyl amine and sodium p-
toluenesulfinate.17 The resulting imine precursor 23 was then
treated with 2.5 equiv of ethynylmagnesium bromide to give 2-
benzyloxymethylpropargylamine 24, which was subsequently
coupled with 1-benzyl-2-indoloyl chloride to produce amide 25 in
88% yield. Unfortunately, treatment of the N-propargylamide 25
O
N
R1
20
Scheme 3.
Ts
NH
1.2 equiv pTolSO2Na
2 equiv p-TsNH2
O
BnO
BnO
H
H2O/HCOOH (1:1)
rt, 36 h
SO2Tol
22
23 (71%)
2.5 equiv
MgBr
THF, 0 °C
2 h
BnO
1.2 equiv NaH
1.15 equiv 1-benzyl-
H
with AuCl3 did not give any of the desired b-carbolinone 26. Other
2-indoloyl chloride
CH2Cl2, rt, 15 h
N
Ts
N
BnO
Ts
gold and platinum catalysts (i.e., Au(I)Cl, Au(I)PPh3Cl, PtCl2) were
examined to promote this reaction, but no cycloisomerized product
could be obtained (Scheme 4). However, we did find that the re-
action of amine 21c18 with indoloyl chloride afforded amide 27 in
64% yield and further treatment of 27 with catalytic AuCl3 produced
the cyclized compound 28 (Scheme 5). For the synthesis of 9-
N
O
Bn
25 (88%)
24 (99%)
BnO
CH3
[Au]-cat.
NTs
benzyl-1-chloro-3,4-dimethyl-9H-b-carboline (29), b-carbolinone
28 was first subjected to detosylation using sodium naphthalenide
and the resulting NH-pyridone was then treated with POCl3
O
N
Bn
(Scheme 5). This reaction sequence afforded
yield, which is clearly unsatisfactory for the development of a new
synthetic method to prepare polysubstituted -carbolines. There-
fore, various reaction conditions were evaluated in order to en-
hance the yield of the cyclized -carboline 29. While the yield of the
b-carboline 29 in 22%
26
Scheme 4.
b
b
We next evaluated the reaction of 1-chloro-
b
-carboline 29 with
detosylation reaction of 28 to 29 using 2.5 or 5 equiv of sodium
naphthalenide, sodium azide19 in DMF or THF was not enhanced,
the reaction of 28 in neat POCl3 at 150 ꢀC in a pressure vessel gave
several nucleophiles and electrophiles. It was found that the
nucleophilic displacement of the chlorine atom at C-1 occurred
easily by treating 29 with a 1 M solution of sodium methoxide (or
ethoxide) in methanol (or ethanol) and DMSO (ratio methanol/
1-chloro-b-carboline 29 in 69% yield after purification via silica gel
chromatography. Use of higher temperatures only resulted in
a significant increase in the amount of tarry by-products. Having
DMSO¼1:1), which gave the 1-alkoxy-
b-carbolines 32a or 32b in
good yield. The analogous reaction of 29 with amines (isopropyl-
now established a straightforward synthesis of
b-carboline 29,
amine or morpholine) only led to a complex mixture of products,

G. Verniest et al. / Tetrahedron 66 (2010) 1496–1502
1499
CH3
Ts
3. Experimental
3.1. General
CH3
CH3
N
5 mol% AuCl3
CH2Cl2, rt, 15 h
N
N
O
Ts
N
Bn
O
Melting points are uncorrected. Mass spectra were determined
at an ionizing voltage of 70 eV. Solvents (THF, benzene, toluene)
were dried over sodium benzophenone ketyl or calcium hydride
(CH2Cl2) and distilled prior to use. Unless otherwise noted, all
reactions were performed in flame-dried glassware under dry
atmosphere (CaCl2 tube). All solids were recrystallized form ethyl
acetate/hexane for analytical data.
Bn
27
28 (58%)
(a) 1) 4 equiv Na
naphthalenide
2) POCl3, Δ, 48 h
(b) PCl3, 150°C, 48 h
CH3
CH3
CH3
CH3
N
+
-
6 equiv mCPBA
CHCl3, 70 °C, 48 h
3.2. Synthesis of 9-benzyl-1-chloro-4-methyl-9H-
O
N
b-carboline (17)
Cl
Cl
N
Bn
N
Bn
3.2.1. N-(1-Benzyl-1H-indole-2-carbonyl)-4-methyl-N-prop-2-ynyl-
benzenesulfonamide (14). To a stirred solution of 0.5 g (2.0 mmol) of
1-benzyl-1H-indole-2-carboxylic acid (13) in 8 mL of benzene con-
taining two drops of N,N-dimethylformamide was added 0.26 mL
(2.0 mmol) of oxalyl chloride. The resulting solution was stirred at rt
for 3 h, the solvent was removed under reduced pressure, and the
residue was taken up in 10 mL of CH2Cl2. To this solution was added
1 mL of pyridine and 0.41 g (2 mmol) of 4-methyl-N-prop-2-ynyl-
benzenesulfonamide, dissolved in 3 mL of CH2Cl2. The solution was
allowed to stir at rt overnight. The solution was then quenched with
water and extracted with CH2Cl2. The combined organic layer was
washed with 10% HCl and brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude residue was sub-
jected to flash silica gel chromatography to give 0.72 g (80%) of 14 as
a pale yellow oil; IR (neat) 3290, 3060, 2924, 2127, 1673, 1596, 1514,
29 (22% via a, 69% via b)
30 (57%)
see
Table 1
1) Ac2O, or TFAA
2) aq. K2CO3
CH3
N
CH3
OH
CH3
R1
N
R3
N
Cl
N
R2
Bn
31
32a; R1 = H, R2 = Bn, R3 = OMe (82%)
32b; R1 = H, R2 = Bn, R3 = OEt (74%)
32c; R1 = H, R2 = H, R3 = Cl (52%)
32d; R1 = Br, R2 = Bn, R3 = Cl (89%)
936, and 815 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
2.39 (t,1H, J¼2.4 Hz),
Scheme 5.
2.45 (s, 3H), 4.55 (d, 2H, J¼2.8 Hz), 5.49 (s, 2H), 7.01 (m, 2H), 7.22 (m,
while the use of a poor nucleophile, such as sodium azide, TBAF or
KCN in DMSO or MeOH, gave recovered starting material. In order
to evaluate the reactivity of b-carboline 29 toward electrophiles,
this compound was treated with bromine in CHCl3 at room
temperature. Under these conditions a clean reaction occurred
producing 6-bromocarboline 32d as the exclusive product in 89%
yield. Finally, in an attempt to carry out a Friedel–Crafts arylation,1-
4H), 7.34 (m, 5H), 7.74 (d,1H, J¼8.0 Hz), and 7.90 (d, 2H, J¼8.4 Hz); 13C
NMR (100 MHz, CDCl3) d 21.9, 38.5, 47.9, 73.9, 78.9, 110.7, 111.0, 121.4,
123.2, 125.9, 126.2, 127.2, 127.8, 128.9, 129.1, 129.7, 129.9, 135.7, 137.9,
139.5, 145.3, and 163.9; HRMS Calcd for [C26H22N2O3SþHþ]:
443.1424. Found: 443.1425.
3.2.2. 9-Benzyl-4-methyl-2-(toluene-4-sulfonyl)-2,9-dihydro-b-car-
chloro-
benzene in the presence of AlCl3, which led to the formation of the
debenzylated -carboline 32c in 47% yield. A control experiment
demonstrated that -carboline 29 could also be easily debenzylated
b-carboline 29 was allowed to react with 1,4-dimethoxy-
bolin-1-one (15). A 0.44 g (1 mmol) sample of indole 14 was stirred
with 15 mg of Au(III) chloride in 10 mL of CH2Cl2 at rt overnight. At
the end of this time, the mixture was filtered through a plug of silica
gel, washed with triethylamine, rinsed with ethyl acetate, and the
filtrate was concentrated under reduced pressure. The crude resi-
due was subjected to flash silica gel chromatography to give 0.36 g
(82%) of carbolinone 15 as a white solid; mp 181–182 ꢀC; IR (neat)
b
b
into 32c in 52% yield by heating it in dichloroethane in the presence
of AlCl3 (Table 1). This debenzylation is similar to some related
cases reported in the literature using substituted indoles.22
In conclusion, an optimized procedure was developed to syn-
3107, 3063, 2925, 1668, 1598, 1366, 1174, 1089, and 739 cmꢁ1
NMR (400 MHz, CDCl3)
;
1H
thesize substituted 9-benzyl-1-chloro-b-carbolines, which are of
d
2.41 (s, 3H), 2.60 (d, 3H, J¼0.8 Hz), 5.93 (s,
some interest as core structures of various natural products. The
key step consists of a gold(III) catalyzed 6-exo-dig cyclization of
indole-substituted N-propargylamides, which afforded the corre-
2H), 7.01 (m, 2H), 7.12 (m, 3H), 7.22 (m,1H), 7.34 (m, 4H), 7.72 (d,1H,
J¼1.2 Hz), 8.00 (d, 2H, J¼8.4 Hz), and 8.06 (d, 1H, J¼8.4 Hz); 13C
NMR (100 MHz, CDCl3)
d 17.6, 21.9, 48.1, 111.5, 113.4, 120.1, 121.3,
sponding
further transformed into several substituted
treatment with POCl3 or PCl3. The reaction of 1-chloro-
b
-carbolinones. The resulting
b
-carbolin-1-ones were
-carbolines by
-carbolines
122.3, 123.2, 125.8, 126.0, 127.2, 127.4, 127.5, 128.7, 129.6 129.7,
134.9, 137.9, 141.1, 145.6, and 154.7; Anal. Calcd for C26H22N2O3S: C,
70.59; H, 4.98; N, 6.33. Found: C, 70.43; H,4.82; N,6.45.
b
b
with alkoxides, bromine or AlCl3 furnished new 1-alkoxycarbolines
32a,b, 6-bromocarboline 32d, and the debenzylated 1-chloro-
carboline 32c, respectively.
3.2.3. 9-Benzyl-4-methyl-2,9-dihydro-
b
-carbolin-1-one
(16). To
a solution of 25 mg (0.06 mmol) of 9-benzyl-4-methyl-2-(toluene-
4-sulfonyl)-2,9-dihydrocarbolin-1-one (15) in 2 mL of dry THF was
added a 1.3 M solution of sodium naphthalenide (freshly prepared
from sodium metal and naphthalene) in 1,2-dimethoxyethane at
ꢁ78 ꢀC until the green color persisted for more than 2 min. The
solution was stirred for 30 min at ꢁ78 ꢀC and then quenched with
a saturated aqueous solution of NH4Cl. After the addition of 5 mL of
water, the mixture was extracted with CH2Cl2 and the extracts were
dried over MgSO4. After filtration and evaporation of the solvent,
the crude product was subjected to flash silica gel chromatography
Table 1
Functionalization of 9-benzyl-1-chloro-3,4-dimethyl-b-carboline 29 to give b-car-
bolines 32
Entry
Conditions
10 equiv 1 M NaOMe in MeOH/DMSO (1:1),
10 equiv 1 M NaOEt in EtOH/DMSO (1:1), , 15 h
2 equiv AlCl3, dichloroethane, , 15 h
1.2 equiv Br2, 1.2 equiv NaOAc, CHCl3, rt, 5 h
Product
1
2
3
4
D, 15 h
32a
32b
32c
32d
D
D

1500
G. Verniest et al. / Tetrahedron 66 (2010) 1496–1502
to give 13 mg (82%) of 9-benzyl-4-methyl-2,9-dihydro-
1-one (16) as a white solid; mp 256–258 ꢀC; IR (neat) 2965, 2939,
1644, 1622, 1456, 1435, 744, and 700 cmꢁ1 1H NMR (400 MHz,
DMSO-d6) 2.53 (s, 3H), 6.12 (s, 2H), 6.91 (s, 1H), 7.23 (m, 6H), 7.43
(t, 1H, J¼7.2 Hz), 7.62 (d, 1H, J¼8.8 Hz), 8.11 (d, 1H, J¼8.4 Hz), and
11.38 (s, 1H); 13C NMR (100 MHz, CDCl3)
17.2, 48.1, 111.2, 113.1,
b
-carbolin-
(s, 3H), 3.57 (d, 2H, J¼4.7 Hz), 4.26 (ddt, 1H, J¼2.5 Hz, J¼4.7 Hz,
J¼8.4 Hz), 4.52 (s, 2H), 5.09 (d, 1H, J¼8.4 Hz), 7.25–7.36 (m, 7H), and
;
7.76 (d, 2H, J¼8.3 Hz); 13C NMR (100 MHz, CDCl3)
d 21.6, 45.4, 71.8,
d
73.1, 73.3, 79.9, 127.5 (2ꢂ), 127.8 (2ꢂ), 127.9, 128.5 (2ꢂ), 129.5 (2ꢂ),
137.2, 137.3, and 143.6.
d
120.5, 121.9, 122.9, 123.2, 126.4, 126.6, 126.8, 127.2, 127.4, 128.8,
138.6, 140.5, and 157.0; Anal. Calcd for C19H16N2O: C, 79.17; H, 5.56;
N, 9.72. Found: C, 79.28; H, 5.46; N, 9.78.
3.3.3. N-(1-Benzyl-1H-indole-2-carbonyl)-N-(1-benzyloxymethyl-
prop-2-ynyl)-4-methylbenzenesulfonamide (25). To a suspension of
0.29 g (1.15 mmol) of N-benzylindole-2-carboxylic acid in 8 mL of
dry benzene was added one drop of DMF, followed by 0.15 mL
(1.52 mmol) of oxalyl chloride at rt. The solution was stirred at rt for
3 h, the solids were filtered and the filtrate was evaporated under
reduced pressure to give the crude 2-indoloyl chloride, which was
used as such without purification. To a suspension of 48 mg
(1.2 mmol) of a 60 wt % suspension of NaH in mineral oil in 2.5 mL
of dry CH2Cl2 was added a solution of 0.33 g (1.0 mmol) of 2-ben-
zyloxymethyl-N-tosylprop-2-ynamine 24 in 2.5 mL CH2Cl2 at 0 ꢀC.
After stirring for 30 min at 0 ꢀC a solution of the previously pre-
pared N-benzyl-2-indoloyl chloride in 5 mL of CH2Cl2 was added to
the reaction mixture and stirring was continued overnight allowing
the temperature to reach rt. After quenching with brine and addi-
tion of 5 mL of 1 M aqueous HCl, the mixture was extracted with
CH2Cl2. After drying and evaporation of the solvents, the crude
residue was subjected to flash silica gel chromatography to yield
0.5 g (0.88 mmol, 88%) of pure N-(1-benzylindole-2-carbonyl)-N-
(1-benzyloxymethylprop-2-ynyl)-4-methyl-benzenesulfonamide
25 as a sticky oil; IR 2120, 1676, 1515, 1454, 1356, 1246, 1169, and
3.2.4. 9-Benzyl-1-chloro-4-methyl-9H-
b-carboline (17). A 0.29 g
(1 mmol) sample of 9-benzyl-4-methyl-2,9-dihydro-
b-carbolin-1-
one (16) in 5 mL of POCl3 was heated at reflux for 24 h. The solution
was slowly quenched with a saturated aqueous solution of NaHCO3,
and then extracted with EtOAc. The organic phase was washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The crude residue was subjected to flash silica gel chro-
matography to give 0.23 g (76%) of carboline 17 as an off-white
solid; mp 157–159 ꢀC; IR (neat) 3033, 1616, 1562, 1496, 1444, 1060,
954, and 730 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.79 (s, 3H), 5.96
(s, 2H), 7.04 (m, 2H), 7.22 (m, 3H), 7.32 (t, 1H, J¼8.0 Hz), 7.42 (d, 1H,
J¼8.4 Hz), 7.56 (t, 1H, J¼8.4 Hz), 7.99 (s, 1H), and 8.20 (d, 1H,
J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d 17.4, 47.9, 110.6, 120.9, 121.9,
123.7, 126.2, 127.2, 127.6, 128.7, 129.0, 130.7, 131.2, 132.1, 137.9, 139.0,
and 142.3; Anal. Calcd for C19H15N2Cl: C, 74.39; H, 4.89; N, 9.14.
Found: C, 74.45; H, 4.78; N, 8.99.
3.3. Synthesis of N-(1-benzyl-1H-indole-2-carbonyl)-
N-(1-benzyloxymethylprop-2-ynyl)-4-methylbenzene-
sulfonamide (25)
1090 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.40 (s, 3H), 2.44 (d, 1H,
J¼2.2 Hz), 3.88 (dd, 1H, J¼6.0 Hz, J¼10.0 Hz), 4.01 (dd, 1H, J¼8.3 Hz,
J¼10.0 Hz), 4.48 (d, 1H, J¼11.8 Hz), 4.50 (d, 1H, J¼11.8 Hz), 5.36–
5.40 (m, 1H), 5.38 (s, 2H), 7.02–7.05 (m, 2H), 7.06 (s, 1H), 7.11–7.33
(m, 13H), 7.59 (d, 1H, J¼7.9 Hz), and 7.76 (d, 2H, J¼8.3 Hz); 13C NMR
3.3.1. N-[2-Benzyloxy-1-(toluene-4-sulfonyl)ethyl]-4-methylbenz-
enesulfonamide (23). A solution of 2.12 g (12 mmol) of sodium
p-toluenesulfinate hydrate, 3.41 g (20 mmol) of p-toluenesulfon-
amide, and 1.50 g (10 mmol) of 2-benzyloxyacetaldehyde 22 in
30 mL of formic acid and 30 mL of water was stirred for 36 h at
room temperature. The white solids formed were filtered, washed
with water (2ꢂ20 mL) and hexane (20 mL), and subsequently
dissolved in 100 mL of CH2Cl2 and dried over MgSO4. After filtration
and evaporation of 90% of the solvent, 150 mL of Et2O was added
resulting in the precipitation of (2-benzyloxy-1-toluenesulfony-
lethyl)-4-toluenesulfonamide 23 as a white solid, which was fur-
ther purified by recrystallization from EtOAc to give 3.2 g (71%) of
pure 23; mp 115–116 ꢀC; IR 3263, 1597, 1453, 1321, 1162, 1129, and
(100 MHz, CDCl3)
d 21.7, 47.9, 51.8, 70.9, 73.3, 74.1, 79.1, 111.0, 111.3,
121.1, 122.9, 125.7, 125.9, 126.9 (2ꢂ), 127.4, 127.9 (2ꢂ), 128.5 (2ꢂ),
128.6 (2ꢂ), 128.8 (2ꢂ), 129.4 (2ꢂ), 131.0, 136.3, 137.5, 139.4, 144.8,
and 164.0.
3.4. Synthesis of 3,4-dimethyl-b-carbolines 29 and 32
3.4.1. N-(1-Benzyl-1H-indole-2-carbonyl)-4-methyl-N-(1-methyl-
prop-2-ynyl)benzenesulfonamide (27). N-(1-Benzyl-1H-indole-2-
carbonyl)-4-methyl-N-(1-methylprop-2-ynyl)benzenesulfonamide
(27) was prepared analogously to the synthesis of indole 14. Puri-
fication of the crude mixture was performed via flash silica gel
chromatography (EtOAc/hexanes 1:4) yielding 64% of compound 27
as an off-white solid; mp 58–59 ꢀC; IR 1672, 1515, 1454, 1351, and
1081 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.39 (s, 3H), 2.41 (s, 3H),
3.60 (dd, 1H, J¼4.1 Hz, J¼10.8 Hz), 4.07 (dd, 1H, J¼3.2 Hz,
J¼10.8 Hz), 4.37 (d,1H, J¼11.9 Hz), 4.42 (d,1H, J¼11.9 Hz), 4.63 (ddd,
1H, J¼3.2 Hz, J¼4.1 Hz, J¼10.1 Hz), 5.60 (d, 1H, J¼10.1 Hz), 7.13–7.16
(m, 3H), 7.17 (d, 2H, J¼7.9 Hz), 7.23 (d, 2H, J¼7.9 Hz), 7.28–7.32 (m,
2H), 7.57 (d, 2H, J¼8.3 Hz), and 7.64 (d, 2H, J¼8.3 Hz); 13C NMR
1165 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.58 (d, 3H, J¼7.1 Hz), 2.35
(d, 1H, J¼2.4 Hz), 2.42 (s, 3H), 5.05 (dq, 1H, J¼7.1 Hz, J¼2.4 Hz), 5.48
(s, 2H), 7.01–7.04 (m, 2H), 7.13–7.34 (m, 9H), 7.67 (d, 1H, J¼8.3 Hz),
and 7.74 (d,1H, J¼8.3 Hz); 13C NMR (75 MHz, CDCl3)
d 21.6, 21.7, 47.6
(100 MHz, CDCl3)
d
21.8, 21.9, 66.0, 72.9, 73.7, 127.1 (2ꢂ), 128.0 (2ꢂ),
(2ꢂ), 72.6, 82.1, 110.7, 111.6, 121.1, 123.0, 125.8, 125.9, 126.9 (2ꢂ),
127.5, 128.6 (2ꢂ), 128.7 (2ꢂ), 129.4 (2ꢂ), 131.2, 136.2, 137.7, 139.6,
144.7, and 163.9; MS (ESþ) m/z (%) 457 (MþHþ, 100). Anal. Calcd for
C27H24N2O3S: C, 71.03; H, 5.30; N, 6.14. Found: C, 70.83; H, 5.18;
N,6.01.
128.1, 128.6 (2ꢂ), 129.7 (2ꢂ), 129.8 (2ꢂ), 129.9 (2ꢂ), 133.4, 136.8,
137.5, 144.0, and 145.5.
3.3.2. N-(1-Benzyloxymethylprop-2-ynyl)-4-methylbenzenesulfon-
amide (24). To a solution of 1.00 g (2.18 mmol) of hemiaminal 23 in
5 mL of dry THF was added 11.0 mL (5.5 mmol) of a 0.5 M solution
of ethynylmagnesium bromide in THF at ꢁ78 ꢀC under N2 atmo-
sphere. The solution was stirred for 1 h at ꢁ78 ꢀC, followed by 1 h at
0 ꢀC. After quenching with brine, the mixture was acidified to pH 4
using 1 M aqueous HCl. The aqueous mixture was then extracted
with EtOAc and the extracts were dried over MgSO4, filtered, and
the solvents evaporated under reduced pressure to give 0.72 g
(99%) of 2-benzyloxymethyl-N-tosylprop-2-ynamine 24 as a white
solid; mp 48–49 ꢀC; IR 3281, 2119, 1598, 1454, 1409, 1333, 1162, and
3.4.2. 9-Benzyl-3,4-dimethyl-2-(toluene-4-sulfonyl)-2,9-dihydro-b-
carbolin-1-one
nyl)-2,9-dihydro-
(28). 9-Benzyl-3,4-dimethyl-2-(toluene-4-sulfo-
b-carbolin-1-one (28) was prepared analogous to
the synthesis of carbolinone 15. Purification of the crude mixture
was performed via recrystallization from EtOAc/hexanes (1:1)
yielding 58% of compound 28 as a white solid; mp 142–143 ꢀC; IR
1661, 1586, 1456, 1348, 1163, and 818 cmꢁ1 1H NMR (300 MHz,
;
CDCl3) d 2.40 (s, 3H), 2.60 (s, 3H), 2.71 (s, 3H), 5.79 (s, 2H), 6.84–6.87
(m, 2H), 7.05–7.40 (m, 8H), 7.89 (d, 1H, J¼8.3 Hz), and 8.13 (d, 1H,
1091 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
2.11 (d, 1H, J¼2.5 Hz), 2.40
J¼8.3 Hz); 13C NMR (75 MHz, CDCl3)
d 15.4, 19.1, 21.7, 47.4, 111.0,

G. Verniest et al. / Tetrahedron 66 (2010) 1496–1502
1501
114.1, 120.9, 121.9, 123.4, 124.5, 125.2, 126.9 (4ꢂ), 128.3 (2ꢂ), 128.6
(2ꢂ), 129.1 (2ꢂ), 130.5, 137.3, 137.6, 140.7, 144.5, and 157.1; MS (ESþ)
m/z (%) 457 (MþHþ, 100). Anal. Calcd for C27H24N2O3S: C, 71.03; H,
5.30; N, 6.14. Found: C, 70.91; H, 5.13; N, 5.95.
(1.25 mmol) of AlCl3 at 0 ꢀC. The ice bath was removed and the
solution was heated to reflux for 15 h under N2 atmosphere. After
cooling, brine (5 mL) was added carefully and the mixture was
extracted with CH2Cl2 (3ꢂ5 mL). After washing with NaHCO3 and
brine, the mixture was dried over MgSO4. After filtration, the sol-
vents were evaporated and the oily residue was subjected to flash
silica gel chromatography (EtOAc/hexanes 1:5) to yield 0.07 g
3.4.3. 9-Benzyl-1-chloro-3,4-dimethyl-9H-
tion of 0.55 g (1.20 mmol) of 9-benzyl-3,4-dimethyl-2-(toluene-4-
sulfonyl)-2,9-dihydro- -carbolin-1-one (28) and 25 mL of PCl3 was
b-carboline (29). A solu-
b
(0.33 mmol, 52%) of 1-chloro-3,4-dimethyl-9H-
an orange oil; IR 1623,1555,1494,1459,1372,1327,1280,1110,1080,
and 731 cmꢁ1; 1H NMR (300 MHz, CDCl3)
2.68 (s, 3H), 2.79 (s, 3H),
b-carboline (32c) as
placed in a 50 mL-pressure vessel and sealed. The solution was
heated to 150 ꢀC for 48 h. After cooling, the excess PCl3 was evap-
orated in vacuo and the resulting brown oil was redissolved in
CH2Cl2, washed with brine and aqueous NaHCO3. After drying
(MgSO4) and evaporation of the solvent, the obtained oil was
subjected to gradient flash silica gel chromatography (EtOAc/hex-
anes 1:5–1:1) to yield 0.26 g (0.82 mmol, 69%) of 9-benzyl-1-
d
7.32 (ddd, 1H, J¼8.2 Hz, J¼5.1 Hz, J¼3.2 Hz), 7.56–7.58 (m, 2H), 8.24
(d, 1H, J¼8.2 Hz), and 8.36 (s(br), 1H); 13C NMR (75 MHz, CDCl3)
d
15.8, 21.6, 111.9, 120.7, 122.8, 123.9, 124.9, 128.4, 129.6, 130.6, 131.3,
140.6, and 145.8; MS (ESþ) m/z (%) 231/233 (MþHþ, 100).
chloro-3,4-dimethyl-9H-
156–157 ꢀC; IR 1616, 1547, 1495, 1485, 1453, 1356, 1276, 1106, and
976 cmꢁ1 1H NMR (300 MHz, CDCl3)
2.68 (s, 3H), 2.82 (s, 3H),
b
-carboline (29) as a light brown solid; mp
3.4.7. 9-Benzyl-6-bromo-1-chloro-3,4-dimethyl-9H-
(32d). To a solution of 0.10 g (0.31 mmol) of 9-benzyl-1-chloro-3,4-
dimethyl-9H- -carboline (29) in 2 mL of CHCl3 was added 31 mg
b-carboline
;
d
b
5.99 (s, 2H), 7.05–7.08 (m, 2H), 7.19–7.29 (m, 2H), 7.32 (t, 1H,
(0.37 mmol) of NaOAc and 60 mg of Br2 at rt. The mixture was
stirred for 15 h at rt, poured in aq satd NaHCO3, and extracted with
CH2Cl2. After drying (MgSO4) and evaporation of the solvents, the
crude mixture was subjected to flash silica gel chromatography
(EtOAc/hexanes 2:3) to yield 0.11 g (0.28 mmol, 89%) of 9-benzyl-6-
J¼7.8 Hz), 7.42 (d, 1H, J¼7.8 Hz), 7.54 (t, 1H, J¼7.8 Hz), and 8.29 (d,
1H, J¼7.8 Hz); 13C NMR (75 MHz, CDCl3)
d 15.7, 21.5, 47.5, 110.2,
120.4, 121.6, 123.7, 124.8, 126.0 (2ꢂ), 127.3, 128.2, 128.7 (2ꢂ), 130.9,
131.2, 137.9 (2ꢂ), 142.4, and 145.4; MS (ESþ) m/z (%) 321/323
(MþHþ, 100). Anal. Calcd for C20H17ClN2: C, 74.88; H, 5.34; N, 8.73.
Found: C, 74.42; H, 5.30; N, 8.56.
bromo-1-chloro-3,4-dimethyl-9H-
low solid; mp 157–158 ꢀC; IR 1601, 1547, 1496, 1461, 1449, 1422,
1346, 1293, 1275, and 1112 cmꢁ1; 1H NMR (300 MHz, CDCl3)
2.65
b-carboline (32d) as a light yel-
d
3.4.4. 9-Benzyl-1-methoxy-3,4-dimethyl-9H-
a solution of 0.05 g (0.16 mmol) of 9-benzyl-1-chloro-3,4-dimethyl-
9H- -carboline (29) in 0.8 mL of DMSO was added 0.8 mL
b
-carboline (32a). To
(s, 3H), 2.70 (s, 3H), 5.88 (s, 2H), 6.98–7.00 (m, 2H), 7.17–7.26
(m, 4H), 7.58 (dd,1H, J¼8.8 Hz, J¼2.2 Hz), and 8.30 (d,1H, J¼2.2 Hz);
b
13C NMR (75 MHz, CDCl3)
d 15.8, 21.5, 47.5, 111.8, 113.3, 123.3, 124.9,
(1.6 mmol) of 2 M NaOMe in MeOH and the mixture was heated to
reflux temperature for 15 h. After cooling, the reaction mixture was
poured in brine (2 mL) and extracted with ethyl acetate (5ꢂ2 mL).
The combined organic fractions were washed with brine (3ꢂ10 mL)
and dried over MgSO4. After filtration, the solvent was evaporated
and the crude residue was subjected to flash silica gel chromatog-
raphy (EtOAc/hexanes/Et3N 2:3:0.1) to yield 0.04 g (1.28 mmol,
126.0 (2ꢂ), 126.3, 127.6, 128.9 (2ꢂ), 129.1, 130.4, 131.1, 131.3, 137.4,
141.1, and 145.9; MS (ESþ) m/z (%) 398/400/402 (MþHþ, 100). Anal.
Calcd for C20H16BrN2: C, 60.10; H, 4.03; N, 7.01. Found: C, 59.65; H,
3.85; N, 6.69.
3.5. 9-Benzyl-1-chloro-3,4-dimethyl-9H-b-carboline-
82%) of 9-benzyl-1-methoxy-3,4-dimethyl-9H-
a white solid; mp 140–141 ꢀC; IR 1619, 1567, 1488, 1450, 1427, 1300,
and 1192 cmꢁ1 1H NMR (300 MHz, CDCl3)
2.57 (s, 3H), 2.70 (s,
b
-carboline (32a) as
2-oxide (30)
;
d
To a solution of 0.50 g (1.56 mmol) of 9-benzyl-1-chloro-3,4-
dimethyl-9H- -carboline (29) in 20 mL of CHCl3 was added 0.54 g
3H), 4.03 (s, 3H), 5.79 (s, 2H), 7.08–7.10 (m, 2H), 7.12–7.23 (m, 4H),
b
7.34 (d, 1H, J¼8.3 Hz), 7.40–7.45 (m, 1H), and 8.21 (d, 1H, J¼8.3 Hz);
(3.12 mmol) of mCPBA, which was purified prior to use by washing
with a phosphate buffer solution (pH 7.5) and dried over MgSO4.
After heating the solution to 70 ꢀC for 12 h, another portion of
mCPBA (0.54 g, 3.12 mmol) was added and heating was continued.
After 24 h, 0.54 g (3.12 mmol) of mCPBA was added again and the
reaction mixture was further stirred for 24 h at 70 ꢀC. After cooling,
the mixture was poured in 50 mL of aq satd NaHCO3 and extraction
was performed with CH2Cl2 (3ꢂ30 mL). After drying (MgSO4) and
evaporation of the solvents, the crude mixture was subjected to
gradient flash column chromatography (0–10% MeOH in CH2Cl2) to
yield 0.30 g (0.89 mmol, 57%) of 9-benzyl-1-chloro-3,4-dimethyl-
13C NMR (75 MHz, CDCl3)
d 15.6, 21.3, 48.5, 53.0, 110.2, 118.3, 119.4,
122.8, 123.2, 123.4, 126.6 (2ꢂ), 126.7, 127.2, 128.6 (2ꢂ), 129.7, 138.9,
141.0, 141.3, and 148.5; MS (ESþ) m/z (%) 316 (MþHþ, 100). Anal.
Calcd for C21H20N2O: C, 79.72; H, 6.37; N, 8.85. Found: C, 79.26; H,
6.74; N, 8.37.
3.4.5. 9-Benzyl-1-ethoxy-3,4-dimethyl-9H-b-carboline (32b). 9-Ben-
zyl-1-ethoxy-3,4-dimethyl-9H- -carboline (32b) was prepared
b
analogous to the synthesis of carboline 32a. Purification was per-
formed by flash silica gel chromatography (EtOAc/hexanes/Et3N
2:3:0.1) to yield 74% of 9-benzyl-1-ethoxy-3,4-dimethyl-9H-
boline (32b) as a white solid; mp 139–140 ꢀC; IR 1619, 1564, 1489,
1458, 1449, 1379, 1349, 1297, 1180, and 1125 cmꢁ1 1H NMR
(300 MHz, CDCl3)
b
-car-
9H-
IR 1597, 1504, 1496, 1465, 1451, 1278, 1259, 1248, and 1183 cmꢁ1; 1H
NMR (300 MHz, CDCl3) 2.70 (s, 3H), 2.82 (s, 3H), 5.87 (s, 2H), 6.99–
b
-carboline-2-oxide (30) as a white solid; mp 188 ꢀC (decomp.);
;
d
d
1.31 (t, 3H, J¼7.2 Hz), 2.56 (s, 3H), 2.72 (s, 3H),
7.02 (m, 2H), 7.18–7.27 (m, 2H), 7.32 (t, 1H, J¼7.8 Hz), 7.38 (d, 1H,
4.49 (q, 2H, J¼7.2 Hz), 5.84 (s, 2H), 7.08–7.11 (m, 2H), 7.13–7.24 (m,
J¼7.8 Hz), 7.50 (t, 1H, J¼7.8 Hz), and 8.19 (d, 1H, J¼7.8 Hz); 13C NMR
4H), 7.37–7.47 (m, 2H), and 8.23 (d, 1H, J¼8.4 Hz); 13C NMR
(75 MHz, CDCl3)
d 14.7, 16.9, 47.8, 110.2, 121.1, 121.3, 121.8, 123.0,
(75 MHz, CDCl3)
d
14.9, 15.6, 21.4, 48.5, 61.4, 110.1, 118.1, 119.4, 122.8,
124.0, 124.6, 125.3, 125.9 (2ꢂ), 127.6, 127.7, 128.9 (2ꢂ), 132.1, 137.3,
123.2, 123.4, 126.6 (2ꢂ), 126.7, 127.1, 128.6 (2ꢂ), 129.8, 139.0, 141.2,
141.6, and 148.4; MS (ESþ) m/z (%) 330 (MþHþ, 100). Anal. Calcd for
C22H22N2O: C, 79.97; H, 6.71; N, 8.48. Found: C, 80.31; H, 7.08; N,
8.61.
140.9, and 143.1; MS (ESþ) m/z (%) 337/339 (MþHþ, 100).
Acknowledgements
3.4.6. 1-Chloro-3,4-dimethyl-9H-
0.20 g (0.62 mmol) of 9-benzyl-1-chloro-3,4-dimethyl-9H-
boline (29) in 3 mL of 1,2-dichloroethane was added 0.17 g
b
-carboline (32c). To a solution of
A.P. appreciates the financial support provided by the National
Science Foundation (CHE-0742663) and G.V. the support from the
Research FoundationdFlanders (FWO-Vlaanderen, Belgium).
b
-car-

1502
G. Verniest et al. / Tetrahedron 66 (2010) 1496–1502
8. (a) Hagen, T. J.; Narayanan, K.; Names, J.; Cook, J. M. J. Org. Chem. 1989, 54,
References and notes
2170–2178; (b) Kuo, P.-C.; Shi, L.-S.; Damu, A. G.; Su, C.-R.; Huang, C.-H.; Ke,
C.-H.; Wu, J.-B.; Lin, A. J.; Bastow, K. F.; Lee, K.-H.; Wu, T.-S. J. Nat. Prod.
2003, 66, 1324–1327; (c) Lagoutte, D.; Nicolas, V.; Poupon, E.; Fournet, A.;
Hocquemiller, R.; Libong, D.; Chaminade, P.; Loiseau, P. M. Biomed. Phar-
macother. 2008, 62, 99–103.
9. (a) Sun, B.; Morikawa, T.; Matsuda, H.; Tewtrakul, S.; Wu, L. J.; Harima, S.;
Yoshikawa, M. J. Nat. Prod. 2004, 67, 1464–1469; (b) Omura, K.; Choshi, T.;
Watanabe, S.; Satoh, Y.; Nobuhiro, J.; Hibino, S. Chem. Pharm. Bull. 2008, 56,
237–238.
10. Barker, M. D.; Woodward, P. R.; Lewis, J. R. Brit. UK Pat. GB 2155462 A, 1985;
Chem. Abstr. 1985, 104, 207245.
11. Abbiati, G.; Beccalli, E. M.; Marchesini, A.; Rossi, E. Synthesis 2001, 2477–2483
and references cited therein.
12. Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6,
4391–4394.
13. Verniest, G.; Padwa, A. Org. Lett. 2008, 10, 4379–4382.
14. England, D. B.; Padwa, A. Org. Lett. 2008, 10, 3631–3634.
15. (a) Robles-Machin, R.; Adrio, J.; Carretero, J. C. J. Org. Chem. 2006, 71, 5023; (b)
Buzas, A.; Gagosz, F. Synlett 2006, 2727.
16. Labonne, A.; Zani, L.; Hintermann, L.; Bolm, C. J. Org. Chem. 2007, 72,
5704–5708.
17. Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc. 2006, 128,
8156–8157.
1. For general reviews on homogeneous gold catalysis, see: (a) Hashmi, A. S. K.;
Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896–7936; (b) Hashmi, A. S. K.
Chem. Rev. 2007, 107, 3180–3211; (c) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem.
Rev. 2008, 108, 3351–3378; (d) Arcadi, A. Chem. Rev. 2008, 108, 3266–3325; (e)
Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395–3442; (f) Jimenez-Nunez,
E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326–3350; (g) Zhang, L.; Sun, J.;
Kozmin, S. A. Adv. Synth. Catal. 2006, 348, 2271–2296; (h) Hashmi, A. S. K.;
Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766–1775; (i) Skouta, R.; Li, C.-J. Tetra-
hedron 2008, 64, 4917–4938.
2. (a) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395–403; (b) Fu¨rstner, A.; Davies,
P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
3. (a) Bongers, N.; Krause, N. Angew. Chem., Int. Ed. 2008, 47, 2178–2181; (b)
Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496–499; (c)
Li, H.; Widenhoefer, R. A. Org. Lett. 2009, 11, 2671–2674.
4. For selected recent examples, see: (a) Kim, S. M.; Park, J. H.; Kang, Y. K.; Chung,
Y. K. Angew. Chem., Int. Ed. 2009, 48, 4532–4535; (b) Ciu, L.; Peng, Y.; Zhang, L.
J. Am. Chem. Soc. 2009, 131, 8394–8395; (c) Toullec, P. Y.; Blarre, T.; Michelet, V.
Org. Lett. 2009, 11, 2888–2891; (d) Yeh, M.-C. P.; Pai, H.-F.; Lin, Z.-J.; Lee, B.-R.
Tetrahedron 2009, 65, 4789–4794; (e) Mauleon, P.; Zeldin, R. M.; Gonzalez, A. Z.;
Toste, F. D. J. Am. Chem. Soc. 2009, 131, 6348–6349; (f) Belting, V.; Krause, N. Org.
Biomol. Chem. 2009, 7, 1221–1225; (g) Volz, F.; Wadman, S. H.; Hoffmann-
Roeder, A.; Krause, N. Tetrahedron 2009, 65, 1902–1910.
5. (a) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem.dEur. J. 2007, 13, 1358–
1373; (b) Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804; (c) Zhang, G.; Catalano, V.
J.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 11358.
6. (a) Cao, R.; Yi, W.; Wu, Q.; Guan, X.; Feng, M.; Ma, C.; Chen, Z.; Song, H.; Peng,
W. Bioorg. Med. Chem. Lett. 2008, 18, 6558–6561 and references cited therein;
(b) Cao, R.; Peng, W.; Wang, Z.; Xy, A. Curr. Med. Chem. 2007, 14, 479–500.
7. Kobayashi, J.; Harbour, G. C.; Gilmore, J.; Rinehart, K. L., Jr. J. Am. Chem. Soc. 1984,
106, 1526–1528.
18. Aronica, L. A.; Valentini, G.; Caporusso, A. M.; Salvadori, P. Tetrahedron 2007, 63,
6843–6854.
19. Patel, S. P.; Nadkarni, D. H.; Murugesan, S.; King, J. R.; Velu, S. E. Synlett 2008,
2864–2868.
20. Fontenas, C.; Bejan, E.; Haddou, H. A.; Balavoine, G. G. A. Synth. Commun. 1995,
25, 629–633.
21. Lee, K. C.; Chi, D. Y. J. Org. Chem. 1999, 64, 8576–8581.
22. Murakami, Y.; Yokoyama, Y.; Aoki, C.; Miyagi, C.; Watanabe, T.; Ohmoto, T.
Heterocycles 1987, 26, 875–878.