Synthetic approaches to highly functional -carboline building blocks via allylic amidation

Article abstract of DOI:10.1055/s-0031-1289656

A new, straightforward synthesis of highly functional -carboline building blocks is presented that makes use of allylic amidation methodology. The products obtained carry a terminal double bond as well as an easy-to-deprotect amide, which make them perfectly suitable for further functionalization. The use of the trifluoroacetamide group is exploited in a dual fashion; it acts as a protecting group and functions as the nucleophile for the allylic amidation reaction. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1289656

PAPER
409
Synthetic Approaches to Highly Functional b-Carboline Building Blocks via
Allylic Amidation
Johannes F. Teichert, Martín Fañanás-Mastral, Ben L. Feringa*
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands
Fax +31(50)3634296; E-mail: b.l.feringa@rug.nl
Received 7 November 2011
We have recently disclosed the first asymmetric intramo-
Abstract: A new, straightforward synthesis of highly functional b-
lecular allylic amidation to give tetrahydroisoquino-
carboline building blocks is presented that makes use of allylic ami-
dation methodology. The products obtained carry a terminal double
lines,16 based on an iridium-catalyzed allylic substitution
reaction17–22 with phosphoramidite ligands.23 In this pro-
bond as well as an easy-to-deprotect amide, which make them per-
fectly suitable for further functionalization. The use of the trifluoro- tocol, the dual function of the trifluoroacetamide group is
acetamide group is exploited in a dual fashion; it acts as a protecting
crucial, as it serves both as a protecting group and as the
group and functions as the nucleophile for the allylic amidation re-
action.
actual nucleophile in the key ring-closing transformation.
We were interested in expanding this methodology to the
Key words: indoles, b-carbolines, allylic amidation, heterocycles,
synthesis of the important class of b-carbolines. This reac-
Stille reaction
tion should be independent of the electronic demands of
the indole moiety and, at the same time, deliver a terminal
double bond, which is ideal for further functionalization
such as ring annulation (Scheme 1). Together with the
b-Carboline- or tryptoline-derived alkaloids1–3 are a large
class of compounds that show a wide variety of biological
and therapeutic activities (Figure 1).4–6 The two antihy-
pertensives, reserpine and ajmalicine, are typical exam-
ples of this family of molecules.7–9 Many synthetic
strategies have been developed to arrive at substituted in-
doles and tryptamines,10–12 with Pictet–Spengler and
Mannich type condensation reactions being among the
most prominent.13–15 However, these methods are limited
by the fact that indoles carrying electron-donating groups
are required and there are restrictions to the groups that
can be introduced via the aldehyde/imine coupling part-
ner.
amide functionality, which should easily lead to the un-
protected amines, our synthetic approach was expected to
provide highly functional building blocks for the synthe-
sis of complex molecules featuring the b-carboline struc-
tural unit.
Here, we present a new route to b-carbolines that exploits
the different aspects of reactivity of the trifluoroacetamide
group. It was used as a protecting group during a palladi-
um-catalyzed Stille coupling and was also shown to act as
a nucleophile in the allylic substitution reaction.
Our synthetic approach started from commercially avail-
able tryptamines 1 (Scheme 2). After benzyl protection of
the indole nitrogen and trifluoroacetylation of the primary
amine, the protected tryptamines 3 were obtained in very
good yields. Furthermore, trifluoroacetamide 4, without a
substituent at the indole nitrogen, was also synthesized.
NH
N
N
H
N
H
β-carboline
tryptoline
We then investigated the possible iodination of 3 and 4 at
the 2-position of the indole system. The reported mercury-
mediated iodination24 proved to be feasible on a small
scale, however, in our case this proved to be difficult
when scaling up the reactions. As an alternative, we ex-
plored the use of iodine monochloride as the iodination
agent, which we had successfully applied to electron-rich
phenylethylamine derivatives.16 In the case of tryptamines
3a and 4, this did not prove to be a viable synthetic path-
way, because the corresponding chlorides 5 were isolated
(Scheme 3). The subsequent Stille reaction (see also
Scheme 4 below) with stannane 6 showed no turnover
with chlorides 5.
OMe
O
OMe
H
N
O
OMe
H
N
MeO
H
H
H
N
OMe
O
O
OMe
H
N
H
H
reserpine
antihypertensive, antipsychotic
O
OMe
ajmalicine
antihypertensive
Figure 1 Examples of b-carboline-derived compounds
The synthesis of the desired iodoindoles 7, which were
key intermediates for the envisaged palladium-catalyzed
carbon–carbon coupling reaction later on in the synthetic
route, was carried out using a lithiation/iodination proto-
col (Scheme 4). Iodo-substituted indoles 7 were obtained
SYNTHESIS 2012, 44, 409–416
Advanced online publication: 22.12.2011
DOI: 10.1055/s-0031-1289656; Art ID: T104711SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1

410
J. F. Teichert et al.
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O
O
HN
X
HN
CF3
CF3
O
N
R1
CF3
R1
R1
N
R2
N
R2
N
R2
O
LG
RNHCOCF3 group
as protecting group
RNHCOCF3 group
as nucleophile
NH
R1
N
R2
Scheme 1 Synthetic approach
CF3
NH2
HN
NH2
O
NaH (1.1 equiv)
R2X (1.1 equiv)
pyridine (1.05 equiv)
(CF3CO)2O (1.05 equiv)
R1
R1
R1
N
CH2Cl2
0 °C to r.t.
N
R2
N
R2
DMF
0 °C to 50 °C
H
yield over 2 steps
1
2a: R1 = H, R2 = Me
2b: R1 = H, R2 = Bn
3a: R1 = H, R2 = Me, 84%
3b: R1 = H, R2 = Bn, 87%
R1 = H, 5-OMe
2c: R1 = 5-OMe, R2 = Bn
3c: R1 = 5-OMe, R2 = Bn, 81%
CF3
HN
O
pyridine (4.0 equiv)
(CF3CO)2O (5.0 equiv)
CH2Cl2
0 °C to r.t.
N
H
4
98%
Scheme 2 Synthesis of trifluoroacetamide-protected indoles
in moderate yields.25 For the subsequent cross-coupling, With the starting materials 9 for the allylic amidation in
the role of the trifluoroacetamide group as a protecting hand, a method was developed for the selective ring-clos-
group was exploited. Since palladium-catalyzed coupling ing allylic amidation to give b-carbolines 10 (Scheme 5).
only rarely proceeds in the presence of primary amines, After screening the reaction conditions, it was found that
this feature could be used to our advantage. In the next cesium carbonate in dioxane at 100 °C gave the best out-
step, the allylic alcohol moiety was introduced through come for this transformation in terms of yields. When car-
Stille coupling with stannane 6.26 In the case of iodides 7, bonates 9 were heated to 100 °C in the presence of cesium
the coupling proceeded smoothly to give the desired allyl- carbonate, the corresponding tricyclic compounds 10,
ic alcohols 8 (68–71% yield), which could be transformed bearing a vinyl moiety and an easy-to-deprotect trifluoro-
into the desired methyl carbonates 9 in a straightforward acetamide, were obtained in yields of up to 82%. Among
manner (Scheme 4).
the other bases investigated, 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) and 1,4-diazabicyclo[2.2.2]octane
(DABCO) gave low conversion (10 and 50%, respective-
ly) under the reaction conditions, whereas 1,5,7-triazabi-
cyclo[4.4.0]dec-5-ene (TBD) led to decomposition of the
allylic carbonate 9. Other inorganic bases, such as K3PO4,
gave no conversion, whereas the use of sodium hydride as
a base led to deprotection of the allylic carbonate to give
the corresponding alcohols 8. The use of cesium carbon-
ate at lower reaction temperature led to considerably low-
er conversion of 9 (10% conversion at 90 °C), and no
reaction took place at 50 °C. It should be noted that the al-
CF3
CF3
O
NH
O
NH
Cl
Stille reaction
Bu3Sn
OH
ICl (1.1 equiv)
CH2Cl2, r.t.
8
N
N
R2
R2
6
5a: R2 = H, 80%
5b: R2 = Me, 78%
4: R2 = H
3a: R2 = Me
Scheme 3 Attempted Stille reaction with chlorotryptamines
Synthesis 2012, 44, 409–416
© Thieme Stuttgart · New York

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Functional b-Carboline Building Blocks
411
CF3
O
CF3
O
benzyl protecting group. To probe this hypothesis, we
have conducted variable temperature 19F NMR spectro-
scopic measurements of 10b (Figure 2). From the data
shown in Figure 2 it can be seen that two signals (peaks 1
and 3) coalesce at 80 °C, as expected for rotamers. The
fourth signal (Figure 2, peak 4) gradually disappears at
higher temperatures, a phenomenon that can be attributed
to E/Z isomers since, at higher temperatures, the thermo-
dynamically more stable species (peak 2 at d = –68.2 ppm
in Figure 2) should be prevalent in the mixture.
NH
NH
I
1.) BuLi (2.5 equiv)
Et2O, 0 °C to r.t.
2.) I2 (1.5 equiv)
Et2O, 0 °C to r.t.
R1
R1
N
R2
N
R2
7a: R1 = H, R2 = Me, 55%
7b: R1 = H, R2 = Bn, 48%
3
R1 = H, 5-OMe
R2 = Me, Bn
7c: R1 = 5-OMe, R2 = Bn, 52%
Bu3Sn
OH
6
(1.5 equiv)
Pd(PPh3)2Cl2 (5.0 mol%)
LiCl (3.0 equiv)
DMF, 75 °C
CF3
CF3
O
NH
O
NH
pyridine (1.5 equiv)
ClCOOMe (1.1 equiv)
R1
R1
N
R2
N
R2
O
CH2Cl2, 0 °C to r.t.
OH
O
OMe
9a: R1 = H, R2 = Me, 98%
9b: R1 = H, R2 = Bn, 98%
8a: R1 = H, R2 = Me, 68%
8b: R1 = H, R2 = Bn, 71%
9c: R1 = 5-OMe, R2 = Bn, 91%
8c: R1 = 5-OMe, R2 = Bn, 68%
Scheme 4 Synthesis of protected allyl carbonates
Figure 2 Variable temperature 19F NMR spectroscopic studies of
10b in DMSO-d6; temperature range from 25 °C (1) to 95 °C (15) in
increments of 5 °C
lylic amidation could also be carried out by employing
microwave heating (300 W), which led to shortening of
the reaction time (2 h compared to 16 h under standard
conditions), while retaining similar yields. All attempts to
render this transformation asymmetric by the use of
iridium16 or palladium27 catalysis have so far been fruit-
less.
In summary, we have developed a new, straightforward
synthetic pathway towards substituted b-carbolines,
which are important, multifunctional building blocks for
further syntheses of complex molecules. In our approach,
we exploit the various reactivities of the trifluoroacetic
amide moiety as a directing group, a protecting group, as
well as a nucleophile in the key allylic amidation step. The
products obtained carry a terminal olefin as well as a pro-
tected secondary amine, which open up possibilities for a
multitude of subsequent transformations, rendering these
new building blocks highly versatile.
With this allylic amidation, we have exploited the nucleo-
philic nature of the trifluoroacetic amide of 9. b-Carbo-
lines 10 are highly versatile building blocks for the
synthesis of more complex structures, allowing the gener-
ation of a variety of molecules featuring a b-carboline
core.
It is interesting to note that products 10 were isolated as
mixtures of isomers/rotamers. Whereas 10a gave rise to
two distinct resonances in the 19F NMR spectrum, which
we attribute to the E/Z isomers of the trifluoroacetamide,
10b and 10c generated a set of four signals in the 19F NMR
spectra. These additional NMR absorptions were assigned
to two rotamers resulting from hindered rotation of the
Merck silica gel type 9385, 230–400 mesh was used for chromatog-
raphy. Merck silica gel 60, 0.25 mm was used for TLC; components
were visualized by UV and cerium/molybdenum staining. Reaction
progress and conversion were determined by GC-MS (GC,
HP6890; MS HP5973) with an HP1 or HP5 column (Agilent Tech-
CF3
NH
O
O
NH
Cs2CO3 (2.0 equiv)
N
ref. 16
R1
CF3
R1
R1
dioxane, 100 °C
N
N
N
R2
O
R2
R2
O
OMe
10a: R1 = H, R2 = Me, 82%
10b: R1 = H, R2 = Bn, 76%
10c: R1 = 5-OMe, R2 = Bn, 82%
11
9
Scheme 5 Synthesis of b-carboline structures
© Thieme Stuttgart · New York
Synthesis 2012, 44, 409–416

412
J. F. Teichert et al.
PAPER
nologies, Palo Alto, CA, USA). Mass spectra were recorded with an
AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL
(ESI+). 1H, 19F, and 13C NMR spectra were recorded with a Varian
AMX400 (400 and 100.59 MHz, respectively), a Varian VXR300
(300 and 75 MHz, respectively), or a Varian Gemini 200 spectrom-
eter, using CDCl3 as solvent. Chemical shift values (d) are reported
in ppm with the solvent resonance as internal standard (CHCl3: d =
7.26 ppm for 1H, d = 77.0 ppm for 13C). Data are reported as follows:
chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, br = broad, m = multiplet), coupling constants (Hz),
and integration. All reactions were carried out under a nitrogen at-
mosphere, using oven-dried glassware and standard Schlenk tech-
niques. CH2Cl2 was dried and distilled over CaH2; THF and Et2O
were dried and distilled over Na/benzophenone. Toluene was dried
and distilled over Na. Stannane 6 was prepared according to a liter-
ature procedure.26
13C NMR (50 MHz, CDCl3): d = 137.24, 136.68, 128.77, 128.60,
127.58, 127.51, 126.66, 126.13, 122.00, 119.26, 118.59, 110.84,
109.80, 49.68, 40.04, 24.41. COCF3 peaks not observed.
19F NMR (189 MHz, CDCl3): d = –75.74.
HRMS (APCI): m/z [M + H+] calcd for C19H18F3N2O: 347.1366;
found: 347.1361.
N-[2-(1-Benzyl-5-methoxy-1H-indol-3-yl)ethyl]-2,2,2-trifluoro-
acetamide (3c)
Obtained according to general procedure A from 2c (1.00 equiv,
1.475 g, 5.26 mmol).
Yield: 1.657 g (4.40 mmol, 84%); orange solid.
1H NMR (400 MHz, CDCl3): d = 7.35–7.22 (m, 2 H), 7.18 (d,
J = 8.9 Hz, 1 H), 7.10 (d, J = 6.5 Hz, 2 H), 7.02 (s, 1 H), 6.95 (s,
1 H), 6.91–6.83 (m, 1 H), 6.41 (br s, 1 H), 5.25 (s, 2 H), 3.86 (s,
3 H), 3.68 (dd, J = 12.7, 6.4 Hz, 2 H), 3.02 (t, J = 6.6 Hz, 2 H).
13C NMR (101 MHz, CDCl3): d = 154.13, 137.31, 132.10, 128.77,
127.89, 127.69, 126.85, 126.73, 112.47, 110.83, 110.23, 100.32,
55.85, 50.14, 40.00, 24.64. COCF3 peaks not observed.
N-Benzylation or N-Methylation of Tryptamines 1 To Give 2;
General Procedure
The appropriate tryptamine 1 (1.00 equiv) was dissolved in DMF
(10 mL/mmol) at 50 °C and added to a stirred solution of NaH (1.10
equiv) in DMF (10 mL/mmol) and the mixture was stirred for 30
min. BnBr or MeI (1.10 equiv) was added dropwise. After stirring
at 50 °C for 1 h, the reaction was quenched with H2O (10 mL/
mmol) and the mixture was extracted with EtOAc (3 × 10 mL/
mmol). After drying over MgSO4 and removal of all volatiles, N-
substituted tryptamines 2 were obtained as yellow/orange solids,
which were used without further purification.
19F NMR (376 MHz, CDCl3): d = –75.97.
HRMS (ESI+): m/z [M + Na+] calcd for C20H19F3N2O2Na:
399.1291; found: 399.1277.
N-[2-(1H-Indol-3-yl)ethyl]-2,2,2-trifluoroacetamide (4)
Tryptamine (1.00 equiv, 1.00 g, 6.24 mmol) was dissolved in
CH2Cl2 (50 mL) and the solution was cooled to 0 °C. Pyridine
(0.530 mL, 6.55 mmol, 4.00 equiv) was added and, subsequently,
trifluoroacetic anhydride (0.926 mL, 6.55 mmol, 5.00 equiv) was
added dropwise. The mixture was allowed to warm to r.t. and stirred
for 16 h. After completion (reaction monitored by TLC), the mix-
ture was washed with aq 2 M HCl (3 × 10 mL) and dried over
MgSO4, filtered, and all volatiles were removed under reduced pres-
sure to give 4, which was used without further purification.
Trifluoroacetylation of 2 To Give 3; General Procedure A
N-Protected tryptamine 2 (1.00 equiv) was dissolved in CH2Cl2 (2.5
mL/mmol) and the solution was cooled to 0 °C. Pyridine (1.05
equiv) was added and, subsequently, 2,2,2-trifluoroacetic anhydride
(1.05 equiv) was added dropwise. The mixture was allowed to
warm to r.t. and stirred for 16 h. After completion, the mixture was
washed with aq 2 M HCl (3 × 2 mL/mmol) and dried over MgSO4.
After filtration and removal of all volatiles under reduced pressure,
the crude product 3 was obtained, which was used without further
purification.
Yield: 1.567 g (6.12 mmol, 98%); brown solid.
1H NMR (201 MHz, CDCl3): d = 8.46 (br s, 1 H), 7.71 (d,
J = 7.6 Hz, 1 H), 7.51–7.20 (m, 3 H), 7.17–6.97 (m, 2 H), 3.70 (q,
J = 6.6 Hz, 2 H), 3.10 (t, J = 6.9 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 157.40 (q, J = 36.9 Hz), 136.31,
126.85, 122.28, 122.02, 119.31, 118.19, 115.84 (q, J = 286.8 Hz),
111.36, 111.29, 40.17, 24.31.
2,2,2-N-[2-(1-Methyl-1H-indol-3-yl)ethyl]trifluoroacetamide
(3a)
Obtained according to general procedure A from 2a (1.00 equiv,
3.48 g, 20 mmol).
19F NMR (189 MHz, CDCl3): d = –75.89.
Yield: 4.70 g (17.40 mmol, 87%); brown solid.
HRMS (ESI+): m/z [M + H+] calcd for C12H12F3N2O: 257.0896;
found: 257.0877.
1H NMR (201 MHz, CDCl3): d = 7.59 (d, J = 7.8 Hz, 1 H), 7.42–
7.09 (m, 3 H), 6.91 (s, 1 H), 6.70–6.30 (br s, 1 H), 3.76 (s, 3 H), 3.68
(dd, J = 12.9, 6.5 Hz, 2 H), 3.15–2.97 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 137.18, 127.37, 126.91, 121.98,
119.16, 118.50, 110.14, 109.44, 40.28, 32.61, 24.56. COCF3 peaks
not observed.
19F NMR (189 MHz, CDCl3): d = –76.00.
HRMS (ESI+): m/z [M + H+] calcd for C13H14F3N2O: 271.1053;
Chlorination of 4/3a to give 5; General Procedure B
Trifluoracetamide 4 or 3a (1.00 equiv) was dissolved in CH2Cl2 (10
mL/mmol) at 21 °C, and a solution of iodine monochloride (1 N in
CH2Cl2, 1.10 equiv) was added dropwise. The reaction mixture was
stirred at this temperature until full conversion was reached (reac-
tion monitored by TLC). The mixture was washed with H2O (10
mL/mmol) and brine (10 mL/mmol), and the organic phases were
dried over MgSO4. Removal of all volatiles and purification by col-
umn chromatography gave 5.
found: 271.1035.
N-[2-(1-Benzyl-1H-indol-3-yl)ethyl]-2,2,2-trifluoroacetamide
(3b)
N-[2-(2-Chloro-1H-indol-3-yl)ethyl]-2,2,2-trifluoroacetamide
(5a)
Obtained according to general procedure B from 4 (1.00 equiv, 2.00
g, 7.81 mmol) after purification by column chromatography (SiO2;
pentane–EtOAc, 10:1).
Obtained according to general procedure A from 2b (1.00 equiv,
5.01 g, 20 mmol).
Yield: 6.44 g (18.60 mmol, 93%); brown solid.
1H NMR (201 MHz, CDCl3): d = 7.81–7.59 (m, 1 H), 7.51–7.11 (m,
8 H), 7.09–6.90 (m, 2 H), 5.31 (s, 2 H), 3.73 (dd, J = 13.1, 6.7 Hz,
2 H), 3.12 (t, J = 7.0 Hz, 2 H).
Yield: 1.807 g (6.22 mmol, 80%); light-brown solid; Rf = 0.75 (pen-
tane–EtOAc, 8:2).
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Functional b-Carboline Building Blocks
413
1H NMR (201 MHz, CDCl3): d = 8.43 (br s, 1 H), 7.56–7.43 (m,
1 H), 7.38–7.06 (m, 3 H), 6.60 (br s, 1 H), 3.64 (q, J = 6.5 Hz, 2 H),
3.03 (t, J = 6.6 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 134.49, 127.08, 122.64, 121.71,
120.46, 117.68, 110.75, 107.79, 39.77, 23.15. COCF3 resonances
not observed.
19F NMR (189 MHz, CDCl3): d = –76.06.
HRMS (APCI): m/z [M – Cl–] calcd for C12H1oF3N2O: 255.0745;
Yield: 1.309 g (2.77 mmol, 48%); white solid; Rf = 0.66 (pentane–
EtOAc, 10:1).
1H NMR (201 MHz, CDCl3): d = 7.64–7.51 (m, 1 H), 7.37–7.21 (m,
4 H), 7.20–7.09 (m, 2 H), 7.07–6.97 (m, 2 H), 6.35 (br s, 1 H), 5.44
(s, 2 H), 3.69 (q, J = 6.4 Hz, 2 H), 3.11 (t, J = 6.6 Hz, 2 H).
13C NMR (101 MHz, CDCl3): d = 157.21 (q, J = 36.4 Hz), 138.37,
136.87, 128.65, 127.78, 127.44, 126.24, 122.48, 119.99, 117.74,
117.44, 115.75 (q, J = 286.8 Hz), 110.34, 87.87, 50.60, 39.87,
26.83.
found: 255.0737.
19F NMR (376 MHz, CDCl3): d = –75.77.
N-[2-(2-Chloro-1-methyl-1H-indol-3-yl)ethyl]-2,2,2-trifluoro-
acetamide (5b)
Obtained according to general procedure B from 3a (1.00 equiv,
1.920 g, 7.10 mmol) after purification by column chromatography
(SiO2; pentane–EtOAc, 10:1).
HRMS (APCI): m/z [M + H+ – I] calcd for C19H17F3N2O: 346.1293;
found: 346.0073.
N-[2-(1-Benzyl-2-iodo-5-methoxy-1H-indol-3-yl)ethyl]-2,2,2-
trifluoroacetamide (7c)
Yield: 1.688 g (5.54 mmol, 78%); yellow solid; Rf = 0.80 (pentane–
EtOAc, 8:2).
1H NMR (201 MHz, CDCl3): d = 7.52 (d, J = 7.6 Hz, 1 H), 7.35–
7.25 (m, 2 H), 7.24–7.08 (m, 1 H), 6.48 (br s, 1 H), 3.74 (d,
J = 2.5 Hz, 3 H), 3.64 (q, J = 6.4 Hz, 2 H), 3.06 (t, J = 6.6 Hz, 2 H).
Obtained according to general procedure C from 3c (1.00 equiv,
1.657 g, 4.40 mmol) and purified by column chromatography (SiO2;
pentane–EtOAc, 10:1).
Yield: 1.150 g (2.289 mmol, 52%); white solid; Rf = 0.55 (pentane–
EtOAc, 10:1).
13C NMR (50 MHz, CDCl3): d = 135.82, 126.20, 124.50, 122.22,
120.19, 117.70, 109.30, 106.86, 39.87, 29.89, 23.58. COCF3 reso-
nances not observed.
19F NMR (189 MHz, CDCl3): d = –76.06.
HRMS (APCI): m/z [M – Cl–] calcd for C13H12F3N2O: 269.0902;
found: 269.0894.
1H NMR (201 MHz, CDCl3): d = 7.43–7.21 (m, 4 H), 7.15 (d,
J = 8.9 Hz, 1 H), 7.01 (dd, J = 9.3, 2.5 Hz, 2 H), 6.78 (dd, J = 8.9,
2.4 Hz, 1 H), 6.37 (br s, 1 H), 5.39 (s, 2 H), 3.84 (s, 3 H), 3.68 (dd,
J = 12.7, 6.4 Hz, 2 H), 3.07 (t, J = 6.6 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 154.41, 137.00, 133.78, 128.76,
128.56, 127.55, 126.98, 126.27, 116.70, 112.81, 111.30, 99.36,
55.79, 50.92, 39.88, 26.88. COCF3 resonances not observed.
Iodination of 3 To Give 7; General Procedure C
19F NMR (189 MHz, CDCl3): d = –75.88.
Trifluoroacetamide 3 (1.00 equiv) was dissolved in Et2O (5 mL/
mmol) and cooled to 0 °C. BuLi (1.6 M in hexanes, 2.50 equiv) was
added dropwise and the reaction mixture was allowed to warm to r.t.
After 2 h, the reaction mixture was cooled to 0 °C, and iodine (1.50
equiv) was added. After warming to r.t., the reaction was quenched
by addition of sat. aq Na2S2O3 (5 mL/mmol), washed with H2O
(3 × 5 mL/mmol) and extracted with Et2O (3 × 5 mL/mmol). After
drying over MgSO4, all volatiles were removed under reduced pres-
sure. Purification of the crude mixture by column chromatography
gave the desired products 7.
HRMS (ESI+): m/z [M + Na+] calcd for C20H18F3IN2O2Na:
525.0257; found: 525.0236.
Stille Reaction of 7 To Give Allylic Alcohols 8; General Proce-
dure D
Iodide 7 (1.00 equiv), (E)-3-(tributylstannyl)prop-2-en-1-ol (6; 1.50
equiv), bis(triphenylphosphine)palladium(II) chloride (5.0 mol%)
and LiCl (3.0 equiv) were dissolved in DMF (20 mL/mmol) and the
mixture was heated to 75 °C for 16 h. The reaction was quenched
by addition of H2O (20 mL/mmol), EtOAc (20 mL/mmol) was add-
ed, and the organic phases were washed with brine (20 mL/mmol).
After drying over MgSO4 and removal of all volatiles, the crude
product was purified by column chromatography to give 8.
2,2,2-Trifluoro-N-[2-(2-iodo-1-methyl-1H-indol-3-yl)eth-
yl]acetamide (7a)
Obtained according to general procedure C from 3a (1.00 equiv,
0.500 g, 1.850 mmol) and purified by column chromatography
(SiO2; pentane–EtOAc, 8:2).
(E)-2,2,2-Trifluoro-N-{2-[2-(3-hydroxyprop-1-enyl)-1-methyl-
1H-indol-3-yl]ethyl}acetamide (8a)
Yield: 0.403 g (1.018 mmol, 55%); white solid; Rf = 0.80 (pentane–
EtOAc, 8:2).
1H NMR (201 MHz, CDCl3): d = 7.60 (d, J = 7.6 Hz, 1 H), 7.32 (t,
J = 8.3 Hz, 1 H), 7.18 (dd, J = 15.9, 7.9 Hz, 2 H), 7.07 (br s, 1 H),
3.75 (s, 3 H), 3.65 (q, J = 6.7 Hz, 2 H), 3.09 (t, J = 6.9 Hz, 2 H).
Obtained according to general procedure D from 7a (1.00 equiv,
0.300 g, 0.757 mmol) and purified by column chromatography
(SiO2; pentane–EtOAc, 1:1).
Yield: 0.167 g (0.512 mmol, 68%); orange solid; Rf = 0.30 (pen-
tane–EtOAc, 1:1).
13C NMR (50 MHz, CDCl3): d = 159.29 (q, J = 36.8 Hz), 138.40,
127.36, 122.03, 119.50, 117.49, 116.63, 115.76 (q, J = 288.6 Hz),
109.69, 87.84, 39.92, 33.99, 26.61.
19F NMR (189 MHz, CDCl3): d = –75.67.
HRMS (APCI): m/z [M + H+ – I] calcd for C13H13F3N2O: 270.0980;
found: 269.9763.
1H NMR (201 MHz, CDCl3): d = 7.58 (dd, J = 7.8, 0.7 Hz, 1 H),
7.44–7.22 (m, 3 H), 7.20–7.07 (m, 1 H), 6.69 (d, J = 16.3 Hz, 1 H),
6.29 (dd, J = 13.4, 8.1 Hz, 1 H), 4.40 (d, J = 5.3 Hz, 2 H), 3.69 (s,
3 H), 3.59 (dd, J = 13.7, 6.8 Hz, 2 H), 3.14 (t, J = 7.3 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 157.44 (q, J = 37.3 Hz), 137.16,
134.46, 133.84, 127.26, 122.17, 119.43, 118.92, 118.09, 115.78 (q,
J = 287.9 Hz), 109.19, 109.09, 63.31, 40.45, 30.42, 23.92.
N-[2-(1-Benzyl-2-iodo-1H-indol-3-yl)ethyl]-2,2,2-trifluoro-
acetamide (7b)
Obtained according to general procedure C from 3b (1.00 equiv,
2.00 g, 5.77 mmol) and purified by column chromatography (SiO2;
pentane–EtOAc, 10:1).
19F NMR (189 MHz, CDCl3): d = –75.88.
HRMS (APCI+): m/z [M + H+] calcd for C16H18F3N2O2: 327.1320;
found: 325.1147.
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414
J. F. Teichert et al.
PAPER
(E)-N-{2-[1-Benzyl-2-(3-hydroxyprop-1-enyl)-1H-indol-3-
yl]ethyl}-2,2,2-trifluoroacetamide (8b)
115.73 (q, J = 288.2 Hz), 110.40, 109.30, 68.29, 54.78, 40.41,
30.70, 23.96.
Obtained according to general procedure D from 7b (1.00 equiv,
0.285 g, 0.604 mmol) and purified by column chromatography
(SiO2; pentane–EtOAc, 1:1).
19F NMR (376 MHz, CDCl3): d = –75.98.
HRMS (APCI): m/z [M – OCO2Me] calcd for C16H16F3N2O:
309.1215; found: 309.1199.
Yield: 0.172 g (0.427 mmol, 71%); white solid; Rf = 0.50 (pentane–
EtOAc, 1:1).
(E)-3-{1-Benzyl-3-[2-(2,2,2-trifluoroacetamido)ethyl]-1H-in-
dol-2-yl}allyl Methyl Carbonate (9b)
Obtained according to general procedure E from 8b (1.00 equiv,
1H NMR (400 MHz, CDCl3): d = 7.59 (d, J = 7.7 Hz, 1 H), 7.33–
7.10 (m, 6 H), 7.00 (d, J = 7.0 Hz, 2 H), 6.71–6.54 (m, 2 H), 6.18
(dt, J = 16.1, 5.3 Hz, 1 H), 5.37 (s, 2 H), 4.28 (d, J = 5.2 Hz, 2 H),
3.65 (dd, J = 13.4, 6.8 Hz, 2 H), 3.19 (t, J = 7.1 Hz, 2 H).
13C NMR (101 MHz, CDCl3): d = 137.61, 137.15, 134.73, 134.59,
128.80, 127.56, 127.37, 125.87, 122.68, 119.98, 118.80, 118.33,
109.88, 109.60, 63.47, 47.31, 40.42, 24.04. COCF3 resonances not
observed.
0.230 g, 0.572 mmol).
Yield: 0.257 g (0.558 mmol, 98%); yellow foam.
1H NMR (201 MHz, CDCl3): d = 7.65 (d, J = 6.9 Hz, 1 H), 7.41–
7.10 (m, 6 H), 7.09–6.98 (m, 2 H), 7.10–6.95 (m, 2 H), 6.12 (dt,
J = 16.2, 6.1 Hz, 1 H), 5.38 (s, 2 H), 4.76 (d, J = 6.1 Hz, 2 H), 3.79
(s, 3 H), 3.66 (dd, J = 13.2, 6.7 Hz, 2 H), 3.19 (t, J = 7.0 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 155.39, 137.39, 137.36, 133.54,
128.74, 127.53, 127.47, 127.34, 125.82, 123.01, 122.57, 120.03,
118.55, 110.79, 109.83, 68.12, 54.76, 47.29, 40.33, 24.10. COCF3
resonances not observed.
19F NMR (376 MHz, CDCl3): d = –76.00.
HRMS (ESI+): m/z [M + Na+] calcd for C22H21F3N2O2Na:
425.1447; found: 425.1432.
(E)-N-{2-[1-Benzyl-2-(3-hydroxyprop-1-en-1-yl)-5-methoxy-
1H-indol-3-yl]ethyl}-2,2,2-trifluoroacetamide (8c)
Obtained according to general procedure D from 7c (1.00 equiv,
0.270 g, 0.538 mmol) and purified by column chromatography
(SiO2; pentane–EtOAc, 1:1).
19F NMR (189 MHz, CDCl3): d = –75.95.
HRMS (APCI): m/z [M – OCO2Me] calcd for C22H20F3N2O:
385.1528; found: 385.1507.
(E)-3-{1-Benzyl-5-methoxy-3-[2-(2,2,2-trifluoroacetamido)eth-
yl]-1H-indol-2-yl}allyl Methyl Carbonate (9c)
Obtained according to general procedure E from 8c (1.00 equiv,
0.137 g, 0.317 mmol).
Yield: 0.158 g (0.366 mmol, 68%); white solid; Rf = 0.5 (pentane–
EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): d = 7.26 (d, J = 6.7 Hz, 3 H), 7.08 (d,
J = 8.6 Hz, 1 H), 7.03 (s, 1 H), 6.98 (d, J = 6.0 Hz, 2 H), 6.91 (br s,
1 H), 6.83 (d, J = 8.2 Hz, 1 H), 6.58 (d, J = 16.2 Hz, 1 H), 6.15 (d,
J = 15.8 Hz, 1 H), 5.31 (s, 2 H), 4.25 (s, 2 H), 3.85 (s, 3 H), 3.62 (d,
J = 5.6 Hz, 2 H), 3.14 (br s, 2 H).
13C NMR (101 MHz, CDCl3): d = 157.38 (q, J = 37.6 Hz), 154.40,
137.70, 135.12, 134.11, 132.39, 128.75, 127.92, 127.30, 125.80,
118.89, 115.83 (q, J = 287.4 Hz), 112.75, 110.70, 109.22, 100.08,
63.40, 55.83, 47.34, 40.29, 24.06.
Yield: 0.142 g (0.290 mmol, 91%); yellow foam.
1H NMR (201 MHz, CDCl3): d = 7.35–7.20 (m, 3 H), 7.11 (d,
J = 8.9 Hz, 1 H), 7.05 (d, J = 2.3 Hz, 1 H), 7.03–6.96 (m, 2 H), 6.85
(dd, J = 8.9, 2.4 Hz, 1 H), 6.79–66.0 (m, 2 H), 6.07 (dt, J = 16.2,
6.1 Hz, 1 H), 5.33 (s, 2 H), 4.74 (dd, J = 6.1, 1.2 Hz, 2 H), 3.85 (s,
3 H), 3.77 (s, 3 H), 3.65 (dd, J = 13.2, 6.7 Hz, 2 H), 3.14 (t,
J = 7.0 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 157.15 (q, J = 37.0 Hz), 155.41,
154.49, 137.48, 133.95, 132.65, 128.75, 127.82, 127.34, 127.08,
125.79, 122.74, 115.76 (q, J = 287.2 Hz), 113.38, 110.74, 110.39,
100.00, 68.18, 55.70, 54.78, 47.41, 40.24, 24.14.
19F NMR (376 MHz, CDCl3): d = –75.94.
HRMS (ESI+): m/z [M + Na+] calcd for C23H23F3N2O3Na:
455.1553; found: 455.1539.
19F NMR (189 MHz, CDCl3): d = –75.93.
HRMS (ESI+): m/z [M + Na+] calcd for C25H25F3N2O5Na:
Conversion of Allylic Alcohols 8 into Allylic Carbonates 9;
General Procedure E
513.1608; found: 513.1585.
The appropriate allylic alcohol 8 (1.00 equiv) and anhydrous pyri-
dine (1.50 equiv) were dissolved in CH2Cl2 (2 mL/mmol) and the
reaction mixture was cooled to 0 °C. Methyl chloroformate (1.10
equiv) was added dropwise and the reaction mixture was stirred for
16 h, while allowing it to warm to 21 °C. When TLC indicated full
conversion of the starting material, the mixture was washed with aq
2 M HCl (3 × 2 mL/mmol) and dried over MgSO4. After filtration
and removal of all volatiles under reduced pressure, the desired
products 9 were obtained in sufficient purity.
Allylic Amidation of 9 To Give b-Carbolines 10; General Proce-
dure F
The appropriate allylic carbonate 9 (1.00 equiv) was dissolved in di-
oxane (50 mL/mmol) and Cs2CO3 (2.00 equiv) was added. The re-
action was stirred for 16 h at 100 °C. After cooling, H2O (50 mL/
mmol) was added and the mixture was extracted with Et2O (3 × 20
mL/mmol). After drying over MgSO4 and removal of all volatiles
under reduced pressure, the crude product was purified by column
chromatography to give the desired products 10.
(E)-Methyl 3-{1-Methyl-3-[2-(2,2,2-trifluoroacetamido)ethyl]-
1H-indol-2-yl}allyl Carbonate (9a)
Obtained according to general procedure E from 8a (1.00 equiv,
0.160 g, 0.490 mmol).
2,2,2-Trifluoro-1-[9-methyl-1-vinyl-3,4-dihydro-1H-pyrido-
indol-2(9H)-yl]ethanone (10a)
Obtained according to general procedure F from 9a (1.00 equiv,
0.020 g, 0.052 mmol) and purified by column chromatography
(SiO2; pentane–EtOAc, 10:1). The product was isolated as a mix-
ture of two isomers (ratio 1:7).
Yield: 0.185 g (0.481 mmol, 98%); yellow foam.
1H NMR (400 MHz, CDCl3): d = 7.62–7.55 (m, 1 H), 7.32–7.25 (m,
2 H), 7.17–7.10 (m, 1 H), 6.84–6.72 (m, 2 H), 6.19 (dt, J = 16.2,
6.2 Hz, 1 H), 4.85 (dd, J = 6.2, 1.4 Hz, 2 H), 3.83–3.82 (s, 2 H),
3.73 (s, 3 H), 3.60 (q, J = 6.8 Hz, 2 H), 3.13 (t, J = 7.1 Hz, 2 H).
13C NMR (101 MHz, CDCl3): d = 157.14 (q, J = 36.5 Hz), 155.47,
137.51, 133.42, 127.18, 126.88, 122.84, 122.70, 119.66, 118.37,
Yield: 0.013 g (0.043 mmol, 82%); white solid; Rf = 0.95 (pentane–
EtOAc, 10:1).
1H NMR (201 MHz, CDCl3): d (major isomer) = 7.57–7.45 (m,
1 H), 7.38–7.23 (m, 2 H), 7.23–7.06 (m, 1 H), 6.23 (br d,
Synthesis 2012, 44, 409–416
© Thieme Stuttgart · New York

PAPER
Functional b-Carboline Building Blocks
415
J = 5.2 Hz, 1 H), 6.17–5.95 (m, 1 H), 5.48 (d, J = 10.0 Hz, 1 H),
5.09 (d, J = 17.0 Hz, 1 H), 4.17 (br d, J = 14.1 Hz, 1 H), 3.71–3.47
(m, 4 H), 3.12–2.74 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 133.05, 130.56, 129.98, 125.93,
122.02, 121.22, 119.47, 118.26, 109.07, 107.83, 51.60, 39.91,
29.86, 22.15. COCF3 resonances not observed.
19F NMR (189 MHz, CDCl3): d = –68.55 (minor), –68.99 (major).
HRMS (APCI): m/z [M + H+] calcd for C16H16F3N2O: 309.1209;
2 h, the reaction mixture was cooled to 0 °C, and acrylaldehyde
(0.212 mL, 3.18 mmol, 1.50 equiv) was added. After warming to
r.t., the reaction was quenched by addition of sat. Na2S2O3 (10 mL),
the mixture washed with H2O (3 × 10 mL) and extracted with Et2O
(3 × 20 mL). After drying over MgSO4, all volatiles were removed
under reduced pressure to give the crude product, which was puri-
fied by column chromatography (SiO2; pentane–EtOAc, 7:3) to
give 12.
Yield: 0.523 g (1.299 mmol, 45%); yellow solid; Rf = 0.90 (pen-
tane–EtOAc, 8:2).
found: 309.1220.
1H NMR (400 MHz, CDCl3): d = 8.14 (br s, 1 H), 7.62 (d,
J = 7.6 Hz, 1 H), 7.37–7.10 (m, 6 H), 6.97 (d, J = 6.6 Hz, 2 H), 6.04
(ddd, J = 17.0, 10.4, 5.0 Hz, 1 H), 5.56 (d, J = 5.0 Hz, 1 H), 5.44 (d,
J = 4.6 Hz, 2 H), 5.33–5.11 (m, 2 H), 3.64 (dd, J = 11.9, 5.0 Hz,
3 H), 3.37–3.08 (m, 2 H).
13C NMR (101 MHz, CDCl3): d = 157.52 (q, J = 37.6 Hz), 137.81,
137.69, 136.81, 135.86, 128.63, 127.27, 127.24, 125.66, 122.47,
119.71, 118.37, 115.84 (q, J = 288.4 Hz), 115.52, 109.84, 109.69,
67.47, 46.83, 40.60, 22.47.
1-{9-Benzyl-1-vinyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-
yl}-2,2,2-trifluoroethanone (10b)
Obtained according to general procedure F from 9b (1.00 equiv,
0.037 g, 0.080 mmol) and purified by column chromatography
(SiO2; pentane–EtOAc, 10:1). NMR analysis indicated the presence
four isomers in a ratio 1.5:5:1.5:1. When investigated by variable-
temperature 19F NMR spectroscopy, two of the observed resonances
coalesce at 80 °C, while one of the other set of two resonances dis-
appeared.
Yield: 0.023 g (0.061 mmol, 76%); white solid; Rf = 0.85 (pentane–
EtOAc, 10:1).
19F NMR (376 MHz, CDCl3): d = –75.67.
HRMS (ESI+): m/z [M + Na+] calcd for C22H21F3N2O2Na:
1H NMR (201 MHz, CDCl3): d (major rotamers) = 7.53–7.41 (m,
1 H), 7.31–7.00 (m, 7 H), 6.95–6.83 (m, 1 H), 6.10–1.03 (m, 1 H),
6.01–5.81 (m, 1 H), 5.45–5.25 (m, 2 H), 5.18 (d, J = 10.3 Hz, 1 H),
5.13–4.87 (m, 1 H), 4.20–4.00 (m, 1 H), 3.63–3.42 (m, 1 H), 3.08–
2.72 (m, 2 H).
425.1447; found: 425.1456.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
13C NMR (50 MHz, CDCl3): d (major rotamers) = 137.19, 136.86,
132.94, 128.99, 128.84, 127.54, 126.08, 125.78, 122.34, 121.24,
120.29, 119.74, 118.34, 109.96, 47.01, 29.70, 22.18. COCF3 reso-
nances not observed.
19F NMR (189 MHz, CDCl3): d = –68.91 (1.5), –68.97 (5), –69.04
(1.5), –70.17 (1).
Acknowledgment
This work was financially supported by the Dutch National Re-
search School ‘combination catalysis controlled by chemical de-
sign’ (NRSC-Catalysis). M.F.-M. thanks the Spanish Ministry of
Science and Innovation (MICINN) for a postdoctoral fellowship.
HRMS (ESI+): m/z [M + H+] calcd for C22H20F3N2O: 385.1522;
found: 385.1511.
References
1-{9-Benzyl-6-methoxy-1-vinyl-3,4-dihydro-1H-pyrido[3,4-
b]indol-2(9H)-yl}-2,2,2-trifluoroethanone (10c)
Obtained according to general procedure F from 9c (1.00 equiv,
0.025 g, 0.051 mmol) and purified by column chromatography
(SiO2; pentane–EtOAc, 10:1). NMR analysis indicated the presence
four isomers in a ratio 2:6:2:1. See also comment to 10b.
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Weihofen, R. Chem. Commun. 2007, 675.
Yield: 0.017 g (0.042 mmol, 82%); white solid; Rf = 0.65 (pentane–
EtOAc, 10:1).
1H NMR (400 MHz, CDCl3): d (major peaks only) = 7.44–6.77 (m,
8 H), 6.11 (d, J = 5.4 Hz, 1 H), 6.07–5.93 (m, 1 H), 5.50–4.98 (m,
4 H), 4.25–4.12 (m, 1 H), 3.85 (s, 3 H), 3.67–3.54 (m, 1 H), 3.11–
2.94 (m, 1 H), 2.93–2.78 (m, 1 H).
13C NMR (101 MHz, CDCl3): d = 155.97 (q, J = 35.2 Hz), 154.29,
136.96, 132.96, 131.19, 128.98, 128.83, 127.52, 126.06, 125.95,
121.13, 116.52 (q, J = 287.7 Hz), 112.17, 110.77, 108.02, 100.46,
55.90, 51.76, 47.14, 39.92, 22.23.
19F NMR (376 MHz, CDCl3): d = –68.91 (2), –68.96 (6), –69.02 (2),
–70.18 (1).
HRMS (ESI+): m/z [M + H+] calcd for C23H22F3N2O2: 415.1628;
found: 415.1631.
N-{2-[1-Benzyl-2-(1-hydroxyallyl)-1H-indol-3-yl]ethyl}-2,2,2-
trifluoroacetamide (12)
N-[2-(1-Benzyl-1H-indol-3-yl)ethyl]-2,2,2-trifluoroacetamide (3b;
1.00 equiv, 1.00 g, 2.89 mmol) was dissolved in Et2O (10 mL) and
cooled to 0 °C. BuLi (3.97 mL, 6.35 mmol, 2.50 equiv) was added
dropwise and the reaction mixture was allowed to warm to r.t. After
(18) Bartels, B.; Garcia-Yebra, C.; Helmchen, G. Eur. J. Org.
Chem. 2003, 1097.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 409–416

416
J. F. Teichert et al.
PAPER
CF3
(19) Spiess, S.; Welter, C.; Franck, G.; Taquet, J. P.; Helmchen,
G. Angew. Chem. Int. Ed. 2008, 47, 7652.
(20) Kiener, C. A.; Shu, C. T.; Incarvito, C.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 14272.
CF3
O
HN
O
HN
BuLi (2.5 equiv), Et2O, 0 °C to r.t.
acrolein (1.5 equiv), Et2O, 0 °C to r.t.
OH
(21) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
15164.
(22) Marković, D.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129,
11680.
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49, 2486.
(24) Mingoia, Q. Gazz. Chim. Ital. 1930, 60, 509.
(25) N-Benzyltryptamine 7b could also be trapped with acrolein
after lithiation to give secondary allylic alcohol 12 (Scheme
6). See the experimental section for details.
N
N
Bn
Bn
7b
12
45%
Scheme 6
(26) Betzer, J. F.; Delaloge, F.; Muller, B.; Pancrazi, A.; Prunet,
J. J. Org. Chem. 1997, 62, 7768.
(27) Shi, C.; Ojima, I. Tetrahedron 2007, 63, 8563.
Synthesis 2012, 44, 409–416
© Thieme Stuttgart · New York