Borane-catalyzed indole synthesis through intramolecular hydroamination

Article abstract of DOI:10.1039/c6dt04725d

The reaction of 2-alkynyl anilines with catalytic amounts of B(C₆F₅)₃ (5 mol%) resulted in the formation of 2-substituted indoles according to an intramolecular hydroamination in good to excellent yields. Reaction intermediates as well as products were characterized by NMR spectroscopy and by X-ray crystallography. The domino hydroamination/hydrogenation sequence allowed the efficient synthesis of tetrahydroquinoline 8 in good yield.

Full text of DOI:10.1039/c6dt04725d

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DOI: 10.1039/C6DT04725D
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ARTICLE
Borane-catalyzed indole synthesis through intramolecular
hydroamination
Sebastian Tussing,a Miriam Ohland,a Garrit Wicker,a Ulrich Flörkeb and Jan Paradies*a
Received 00th January 20xx,
Accepted 00th January 20xx
The reaction of 2-alkynyl anilines with catalytic amounts of B(C6F5)3 (5 mol%) resulted in the formation of 2-substituted
indoles according to an intramolecular hydroamination in good to excellent yields. Reaction intermediates as well as
products were characterized by NMR spectroscopy and by x-ray crystallography. The domino hydroamination/hydro-
genation sequence allowed the efficient synthesis of tetrahydroquinoline 8 in good yield.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Bn
N
Bn
N
Introduction
25 °C
C6D6
H
+ B(C6F5)3
(1.0 equiv.)
+ B(C6F5)3
Ph
The activation of small molecules by frustrated Lewis pairs
(FLP) has attracted worldwide interest.1 Especially, the splitting
of molecular hydrogen2 has become major application of FLPs
for the reduction of carbon-carbon multiple bonds,3 electron-
deficient alkenes4, imines5 and even carbonyl groups.6 Among
other small molecules7 especially alkynes display a rich
chemistry when exposed to boranes or FLPs. Alkynes readily
react with strongly electrophilic boranes to furnish
H
Ph
1a
2a
3a
2a
quant.
Scheme 1. Intramolecular hydroamination initiated by B(C6F5)3.
Bn
Bn
N
Bn
N
B(C6F5)3
N
H
H
H
+ B(C6F5)3
carboboration products4c, whereas the presence of Lewis
8
bases results in the formation of stable onium borates.8n, 9 The
catalytic cycloisomerization of enynes8b and the catalytic inter-
Ph
B(C6F5)3
Ph
Ph
1a
2a
1a•2a
and intramolecular hydroamination of terminal alkynes8a,
10
Bn
Bn
H
proton
transfer
has been achieved although the conversion of onium borate
intermediates is quite challenging. Terminal alkynes found
increased attention in the FLP-catalyzed hydroamination
/hydrogenation sequence8a, 10 whereas the catalytic conversion
of internal alkynes has not been reported so far. Here we
present the application of internal alkynes in the FLP-catalyzed
intramolecular hydroamination to furnish substituted
heterocycles such as indole and tetrahydroquinoline
derivatives.
N
N
B(C6F5)3
+
Ph
Ph
2a
3a
4
H
B(C6F5)3
Scheme 2. Mechanistic proposal for the B(C6F5)3-catalyzed intramolecular hydro-
amination for the synthesis of 3a.
The 11B NMR spectrum of this mixture displayed a resonance
at 18.7 ppm which accounts for the presence of a weak Lewis-
adduct 1a•2a (Scheme 2). Nevertheless, slow conversion could
be observed at room temperature and resulted indeed in the
Results and Discussion
quantitative formation of the indole 3a as indicated by the
1
doublet in the H NMR spectrum at 6.71 ppm (3JHH = 0.7 Hz).
We started our investigation with the reaction of N-benzyl-2-
amino tolane (1a) with 1 equivalent of B(C6F5)3 in C6D6
(Scheme 1).
This intramolecular hydroamination probably proceeds by the
reversible formation of the FLP consisting of the aniline
derivative and borane followed by borane-induced activation
of the triple bond (Scheme 2). Subsequent 5-endo-dig
cyclization results in the zwitterionic indole derivative
undergoes protodeborylation8a,
4
which
8b, 10
to yield the indole with
concomitant regeneration of the borane catalyst. The
formation of the zwitterionic intermediate is supported by the
solid state structure of the ammonium borate
5 resulting from
deprotonation of
(Figure 1).
4
with 2,2,6,6-tetramethylpiperidine (TMP)
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The analysis unambiguously confirms the formation of the 3-
borylated indole arising from the intramolecular 5-endo-dig
cyclization. The trigonal planar coordination of the nitrogen
atom (sum of angles 358.4°) and the short distance of C131-
C138 of 1.362(4) Å support the formation of the aromatic
indole structure. The significant pyramidalization of the boron
atom (sum of angles 326.9°) warrants for the formation of the
borate anion. The negative charge is neutralized by the 2,2,6,6-
tetramethylpiperidinium cation which most likely resulted
from the deprotonation of the zwitterionic intermediate
Scheme 2).
4 (see
These observations served as starting point for the exploration
of the catalytic intramolecular hydroamination for the
synthesis of indoles. We selected 2-amino tolane derivatives
bearing different groups on the amino and on the acetylene
unit to investigate the generality of this method (Table 1). The
amino substituents were selected to provide steric bulk and to
modulate the electronic properties for the hydroamination/
deborylation sequence. Accordingly, removable and
electronically diverging amino-protecting groups e.g. Bn, PMB,
Boc, Cbz, trifluoroacetyl, tosyl and allyl were introduced. First
catalytic experiments were conducted with the N-benzyl
derivative 1a for 4h, which underwent slow intramolecular
hydroamination at ambient temperature. Upon heating to 70
°C for 1h the reaction showed quantitative yields on NMR scale
and 72% isolated yield in the presence of 5 mol% B(C6F5)3
(table 1, entry 1). Reduction of the catalyst loadings to 2.5
mol% resulted in a substantial decrease in yield to 30% (entry
2). The change of the borane to the less Lewis-acidic boranes
2b and 2c affected no conversion of the alkyne 1a (entries 3
and 4). Therefore, we selected B(C6F5)3 in 5 mol% catalyst
loading as optimum for further catalytic experiments.
Pleasingly, the PMB-derivative 1b as well as the phenyl-
derivative 1c were susceptible to the B(C6F5)3-catalyzed
hydroamination at 70 °C (entries 5 and 6), whereas the phenyl
derivative 1c showed full conversion also at ambient
temperature in less than 1h. The products 3b and 3c were
isolated in 63% yield each. The Boc-substituted 2-amino tolane
1d did not undergo the intramolecular 5-endo-dig cyclization
but resulted in the Boc-deprotection and formation of the
strong and catalytically inactive B/N Lewis-adduct (entry 7).
Protective groups which are more stable towards Lewis acids
were investigated (1e, 1f, 1g, entries 8-10). In each case the
cyclization did not occur probably due the significantly reduced
nucleophilicity of the nitrogen atom. The adduct formation
was not observed for the COCF3 substituted amino alkyne 1f as
evidenced by 11B NMR spectroscopy. Nevertheless, the
substrate showed no reactivity. The amino alkynes 1e and 1g
formed Lewis-adducts with resonances in the 11B NMR
spectrum at –4.7 ppm and 1.4 ppm, respectively. Upon
subsequent heating both samples showed decomposition to
several not further characterized species at higher
temperatures. The allyl derivative 1h formed a Lewis-adduct as
Figure 1. Piperidiunium borate 5 obtained by the reaction of 1a with one equivalent of
the FLP consisting of B(C6F5)3/TMP. Selected bond lengths: B1-C131 1.629(5) Å, C131-
C138 1.362(4) Å (only one of two molecules in the unit cell is displayed for clarity;
solvent molecules and selected hydrogen atoms are omitted for clarity).11
Table 1. Borane-catalyzed indole synthesis through intramolecular hydroamination.
R1
R
BArF
3
NH
BArF
:
3
N
(5 mol%)
R2
B(C6F5)3 (2a)
B(2,4,6ꢀF3ꢀC6H2)3 (2b)
B(2,6ꢀF2ꢀC6H3)3 (2c)
70 °C,
toluene
4h
R2
H
1
3
entry
R1
R2
indole
BArF
Yield
[%]a
3
1
2
Bn
Bn
Ph
3a
3a
3a
3a
3b
3c
3d
3e
3f
2a
2ab
2b
2c
72 (99)
(30)
Ph
3
Bn
Bn
Ph
Ph
n.r.
n.r.
4
5
PMB
Ph
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
63 (95)
63 (99)
decom.
decom.
n.r.
6
Ph
7
CO2tBu
CO2Bn
COCF3
SO2tol
allyl
Bn
Ph
8
Ph
9
Ph
Ph
10
11
12
13
14
3g
3h
3i
decom.
n.r.
Ph
4-OMe-C6H4
4-Cl-C6H4
Bu
92 (95)
71 (99)
84 (99)
Bn
3j
Bn
3k
a
numbers in parentheses refer to NMR yields using hexamethyl benzene as internal
standard; b reaction was performed with 2.5 mol% 2a; n.r.: no reaction
a)
b)
C110
C109
C14
C9
C115
N1
C15
C8
C1
C101
N1
C7
C108
C107
evidenced by the resonance at
−
4.9 ppm in the 11B NMR
spectrum. In contrast to 1a-1c this Lewis adduct could not be
split by heating to 70 °C or 90 °C so that corresponding N-
allylated indole 3h was not obtained. The structures of 3a and
3b were unambiguously confirmed by x-ray crystal structure
analysis. The molecular structure of 3a features a distance of
1.360(3) Å between C107-C108, which is in good agreement
for a C-C double bond in indoles. The nitrogen atom is almost
Figure 2. Molecular structures of 3a a) selected distances: N1-C115 1.456(2) Å; N1-
C108 1.391(2) Å; C107-C108 1.360(3) Å; selected angles: C115-N1-C108 126.5(17)°;
C108-N1-C101 108.05(16)°; C115-N1-C101 124.40(15)°; N1-C108-C109-C110 56.05°
(the second molecule of 3a in the unit cell and hydrogen atoms were omitted for
clarity); and 3b b) selected distances: N1-C15 1.4522(18) Å; N1-C8 1.3891(18) Å; C7-C8
1.367(2) Å; selected angles: C1-N1-C15 123.16(12)°; C15-N1-C8 128.06(12)°; C1-N1-C8
108.53(12)°; N1-C8-C9-C14 49.9 °.11
2 | Dalton Trans., 2016, 00, 1-3
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ARTICLE
1
evidenced from the H NMR spectrum revealing a resonance a
4.47 ppm in C6D6. The zwitterionic product was characterized
7
by multidimensional NMR spectroscopy and by crystal
structure analysis (Figure 3). The heterocyclic ring is planar
exhibiting alternating bond lengths between 1.322 Å and 1.450
Å typical for isoquinolines. Notably, the initial benzylic carbon
atom C108 is planarized (sum of angles 360°) showing a short
bond to N1 of 1.322(5) Å which is indicative for a trigonal
planar carbon center. Similarly, N1 displays trigonal planar
coordination with a sum of angels of 359.9°, which results in
the overall planarization of the aromatic heterocycle. The
borate moiety exhibits tetrahedral structure with a deviation
of 35.1° from 360°. The formation of the isoquinoline structure
is remarkable in two ways. First, the scaffold of the heterocycle
must be the result of the 6-endo-dig attack of the nitrogen
atom on the activated triple bond. However, Stephan has
utilized the terminal alkyne derivative in earlier studies but he
obtained the five-membered isoindoline as a result of the 5-
exo-dig cyclization.10 This result may be explained by the
better stabilization of the positive charge upon triple bond
activation and formation of the isoquinoline scaffold and by
the lesser steric demand of terminal alkynes. Second, the
Scheme 3. Stoichiometric reaction of the benzyl amino alkynes 6a and 6b with B(C6F5)3.
C131
C141
B1
C109
C121
C101
N1
C151
C102
C108
C107
formation of the zwitterionic isoquinoline derivative
7
apparently arose from the FLP-mediated oxidation with
simultaneous loss of molecular hydrogen. To this point it is
unclear if the oxidation occurs before or after the cyclization.
So far all experiments devoted to answer this question were
inconclusive. With the aim to suppress the dehydrogenation
we exposed the reaction of 6b to an atmosphere of hydrogen
(Scheme 4). While protodeborylation was inhibited under the
previously described conditions, the reaction showed catalytic
turnover with the use of 80 bar hydrogen and 20 mol% B(C6F5)3
Figure 3. Molecular structure of 7. Selected bond lengths and angles: C102-C107
1.414(5) Å, C107-108 1.386(5) Å, C108-N1 1.322(5) Å, N1-C109 1.399(5) Å, C109-C101
1.382(5) Å, C101-C102 1.450(5) Å, N1-C108-C107 121.5(4)°, C101-C109-N1 120.6(4),
N1-C109-C111 111.3(3)°, C131-B1-C141 111.90(3)°, C141-B1-C151 111.7(3)°, C151-B1-
C131 101.3(3)° (only one of two molecules in the elemental cell is depicted, hydrogen
atoms were omitted for clarity).11
(
2a). Indeed, when the reaction was conducted at 100 °C for
24 h the tetrahydroisoquinoline
yield.
8 could be isolated in 61%
Scheme 4. FLP-catalyzed hydroamination/hydrogenation sequence for the synthesis of
tetrahydrosisoquinoline 8.
Conclusions
We have demonstrated the FLP-catalyzed intramolecular
hydroamination of internal alkynes providing access to indoles
and tetrahydroquinonlines in good to excellent yields and
comparably mild conditions. The reaction proceeds exclusively
through 5- and 6-endo-dig cyclization with protodeborylation
being the rate determining step as indicated from the
characterization and isolation of the onium borate
trigonal planar (sum of angles 359.6°) and indicates the
aromatic character of the heterocycle. The phenyl substituent
is tilted out of plane by 56.05° to avoid steric clashes with the
C3 hydrogen atom. The solid state structure of 3b is almost
isostructural to 3a. The trigonal planar environment of the
nitrogen atom (sum of angles 359.7°) and the short C7-C8
bond of 1.367(2) Å support the structure of the aromatic
heterocycle. The phenyl ring is less tilted out of plane by 6 ° by
steric repulsion. In both structures the benzyl-type substituent
is turned out of plane by 83.74° and 78.33° for 3a and 3b
respectively.
intermediate
5. The observation of the dehydrogenation
product 7 in the 6-endo-dig cyclization led to the development
of a new domino hydroamination/hydrogenation reaction for
the synthesis of tetrahydroisoquinolines.
Furthermore, we investigated the applicability of the
hydroamination of internal alkynes for the synthesis of
isoquinolines from the benzyl amino alkynes 6a and 6b
(Scheme 3). Whereas the bisbenzyl amine 6a formed the
inactive Lewis-adduct with 2a the phenyl-derivative 6b
underwent an unexpected cyclization/dehydrogenation
sequence. The production of molecular hydrogen was
Experimental
x-Ray crystallography
Bruker AXS SMART APEX CCD diffractometer, graphite
monochromator, (Mo) = 0.71073 Å, T = 130(2) . Data
collection 1.5° <  < 27.9°, Data reduction and absorption
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corrections were performed with SAINT and SADABS.11 Full- (m, 1H, HAr), 7.41 – 7.35 (m, 2H, HAr), 7.24 – 7.19 (m, 1H, HAr),
matrix least-squares refinement based on F2.12 All non- 7.17 – 7.12 (m, 1H, HAr), 7.08 – 7.02 (m, 4H, HAr), 6.99 – 6.92
hydrogen atoms were refined anisotropically. All H atom (m, 3H, HAr), 6.84 – 6.77 (m, 2H, HAr), 6.71 (d, 4JHH = 0.7 Hz, 1H,
positions were clearly derived from difference Fourier maps HOlefin), 4.97 (s, 2H, NCH2); 13C-NMR (126 MHz, C6D6, 303 ) δ =
and then refined at idealized positions riding on their parent 142.0 (C), 138.8 (C), 138.7 (C), 133.4 (C), 129.5 (CH), 129.2 (C),
C/N atoms with Uiso = 1.2 Ueq(C/N) or 1.5Ueq (CH3) and C-H 129.0 (CH), 128.8 (CH), 128.1 (CH), 127.3 (CH), 126.2 (CH),
0.95-0.99 Å and N-H 0.99 Å. All CH3-hydrogen atoms were 122.5 (CH), 121.2 (CH), 120.7 (CH), 111.0 (CH), 103.1 (CH), 47.8
allowed to rotate but not to tip. The severely disordered DCM (CH2).
solvent molecule of 7 could not be modelled appropriately and N-para-methoxybenzyl-2-phenyl indole (3b) Cyclohexane/
thus was treated with the SQUEEZE facility of PLATON.13 For ethyl acetate 50:1, white solid, 63%, single crystal for X-ray
3a,
5 as well as 7 there are two crystallographically analysis was grown by condensation of cyclohexane to a
independent formula units per asymmetric unit each. All saturated solution of 3b in dichloromethane. 1H-NMR (500
relevant crystallographic data and details of data collection are MHz, C6D6, 303 ) δ = 7.79 – 7.72 (m, 1H, HAr), 7.46 – 7.41 (m,
given in the supplementary information. Crystallographic data 2H, HAr), 7.25 – 7.17 (m, 2H, HAr), 7.15 – 7.12 (m, 1H, HAr), 7.12
4
for all compounds have been deposited with the Cambridge – 7.04 (m, 3H, HAr), 6.75 – 6.72 (m, 2H, HAr), 6.72 (d, JHH = 0.7
Crystallographic Data Centre as supplementary no. CCDC- Hz, 1H, HOlefin), 6.61 – 6.55 (m, 2H, HAr), 4.98 (s, 2H, NCH2), 3.21
1518476 (3b), 1518477 (3a), 1518478 (5) and 1518479 (7
). (s, 3H, OCH3); 13C-NMR (126 MHz, C6D6, 303 ) δ = 159.3 (C),
Copies of the data can be obtained free of charge on 141.9 (C), 138.8 (C), 133.6 (C), 130.6 (C), 129.5 (CH), 129.2 (C),
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, U 128.8 (CH), 128.1 (CH), 127.4 (CH), 122.4 (CH), 121.2 (CH),
(fax: (+44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
120.7 (CH), 114.5 (CH), 111.1 (CH), 103.1 (CH), 54.7 (CH3), 47.3
(CH2).
N-phenyl-2-phenyl indole (3c)
General information
Cyclohexane/ ethyl acetate 25:1, yellow oil, 63%. 1H-NMR (500
MHz, C6D6, 303 ) δ = 7.76 – 7.70 (m, 1H, HAr), 7.30 – 7.26 (m,
3H, HAr), 7.24 (m, 1H, HAr), 7.20 – 7.16 (m, 1H, HAr), 7.03 – 6.98
(m, 2H, HAr), 6.98 – 6.88 (m, 6H, HAr), 6.82 (d, 4JHH = 0.5 Hz, 1H,
HOlefin); 13C-NMR (126 MHz, C6D6, 303 ) δ = 140.9 (C), 139.9
(C), 139.1 (C), 133.3 (C), 129.4 (CH), 129.3 (CH), 129.2 (C),
128.5 (CH), 128.4 (CH), 127.5 (CH), 127.2 (CH), 122.9 (CH),
121.3 (CH), 121.2 (CH), 111.1 (CH), 104.5 (CH).
When necessary preparations were carried out in oven dried
glassware under an atmosphere of inert gas (Argon 5.0, Air
Liquide) employing both Schlenk line techniques and
a
Glovebox Systems inert atmosphere glovebox. For NMR scale
experiments Teflon cap sealed J Young NMR tubes were used.
Table run experiments where performed in 10 ml headspace
vials with PTFE/ butyl rubber crimp caps. Deuterated solvents
were vacuum transferred from sodium/benzophenone
(benzene-d6, toluene-d8) or CaH2 (CDCl3, CD2Cl2), degassed by
2 freeze-pump-thaw cycles and stored over 3 Å molecular
sieves. Hydrogen 6.0 (AirLiquide) was purified through a
Johnson Matthey Model HIG 35XL gas purifier. Substrates for
hydroamination reactions were prepared as described in the
N-benzyl-2-para-methoxyphenyl indole (3i) Cyclohexane/
ethyl acetate 50:1, clear oil, 92%. 1H-NMR (500 MHz, C6D6, 303
) δ = 7.78 – 7.75 (m, 1H, HAr), 7.33 – 7.29 (m, 2H, HAr), 7.25 –
7.21 (m, 1H, HAr), 7.18 – 7.13 (m, 1H, HAr), 7.10 – 7.05 (m, 1H,
HAr), 7.01 – 6.93 (m, 3H, HAr), 6.86 – 6.81 (m, 2H, HAr), 6.71 (d,
4JHH = 0.8 Hz, 1H, HOlefin), 6.67 – 6.63 (m, 2H, HAr), 5.01 (s, 2H,
HAr), 3.25 (s, 3H, CH3); 13C-NMR (126 MHz, C6D6, 303 ) δ =
160.1 (C), 141.9 (C), 138.9 (C), 138.7 (C), 130.8 (CH), 129.3 (C),
129.0 (C), 127.3 (CH), 126.2 (CH), 125.7 (CH), 122.2 (CH), 121.0
supporting information. B(C6F2H3)3
prepared as described earlier.
(2c), B(C6F3H2)3 (2b) were
General procedure for hydroamination to indoles
In a glovebox the amino alkyne (1a-k, 0.5 mmol, 1.00 eq.) and (CH), 120.7 (CH), 114.4 (CH), 110.9 (CH), 102.5 (CH), 54.8 (CH3),
B(C6F5)3 (2a, 12.8 mg, 0.025 mmol, 0.05 eq.) were dissolved in 47.7 (CH2).
toluene (2.0 ml). The solution was transferred to a headspace N-benzyl-2-para-chlorophenyl indole (3j) Cyclohexane/
vial with PTFE/ butyl rubber crimp cap and magnetic stirring dichloromethane 20:1, clear oil, 71%. 1H-NMR (500 MHz, C6D6,
bar and the sample was heated for the given time and 303 ) δ = 7.76 – 7.69 (m, 1H, HAr), 7.24 – 7.19 (m, 1H, HAr),
temperature. After cooling to room temperature a minimum 7.18 – 7.12 (m, 1H, HAr), 7.08 – 7.02 (m, 3H, HAr), 6.98 – 6.93
amount of silica was added and the solvent was evaporated to (m, 5H, HAr), 6.78 – 6.72 (m, 2H, HAr), 6.59 (d, 4JHH = 0.7 Hz, 1H,
dryness. The powder was subjected to column HOlefin), 4.87 (s, 2H, CH2); 13C-NMR (126 MHz, C6D6, 303 ) δ =
chromatography. In a glovebox an additional sample of the 140.52 (C), 138.91 (C), 138.50 (C), 134.29 (C), 131.66 (C),
amino alkyne (1a-k, 0.100 mmol, 1.00 eq.), B(C6F5)3 (2a, 2.6 130.60 (CH), 129.02 (CH), 128.99 (C), 128.35 (CH), 127.41 (CH),
mg, 0.005 mmol, 0.05 eq.) and hexamethyl benzene (1.6 mg, 126.06 (CH), 122.76 (CH), 121.25 (CH), 120.90 (CH), 110.94
0.010 mmol, 0.1 eq.) was prepared in deuterated benzene (0.5 (CH), 103.39 (CH), 47.69 (CH2).
ml), transferred to a NMR tube with Young type Teflon tap, N-benzyl-2-butylindole (3k) Cyclohexane/ dichloromethane
20:1, clear oil, 6d, 84%. 1H-NMR (500 MHz, C6D6, 303 ) δ =
heated and analyzed by NMR spectroscopy.
N-benzyl-2-phenyl indole (3a) Cyclohexane, pale white solid, 7.75 – 7.71 (m, 1H, HAr), 7.24 – 7.19 (m, 1H, HAr), 7.18 – 7.14
72%, single crystal for X-ray analysis was grown by (m, 1H, HAr), 7.08 – 7.05 (m, 1H, HAr), 6.97 – 6.91 (m, 3H, HAr),
condensation of methanol to a saturated solution of $$ in 6.75 – 6.71 (m, 2H, HAr), 6.40 – 6.37 (m, 1H, CH), 4.83 (s, 2H,
diethyl ether. 1H-NMR (500 MHz, C6D6, 303 ) δ = 7.76 – 7.72 NCH2), 2.43 – 2.37 (m, 2H, CH2), 1.53 – 1.44 (m, 2H, CH2), 1.23
4 | Dalton Trans., 2016, 00, 1-3
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– 1.14 (m, 2H, CH2), 0.78 (t, J = 7.4 Hz, 3H, CH3); 13C-NMR (126 129.32 (CH, CPh), 128.80 (CH, CPh), 127.48 (CH, CPh), 126.95 (CH,
MHz, C6D6, 303 ) δ =
CPh), 126.89 (CH, CPh), 126.02 (CH, CPh), 125.41 (C, C-8), C-B and
C-F were not observed; 1H/15N-HMBC (500/51 MHz, CD2Cl2,
303 ) δ = 9.07/212.3; 11B-NMR (160 MHz, CD2Cl2, 303 ) δ =
−15.56 (s); 19F-NMR (282 MHz, CD2Cl2) δ = -119.37 – -119.97
(m, 1F, Fortho), -128.16 – -128.68 (m, 2F, Fortho), -128.68 –
-129.11 (m, 1F, Fortho), -133.05 – -133.53 (m, 1F, Fortho), -136.33
Synthesis of [3a-B(C6F5)3][HTMP] (5)
In a glovebox the amino alkyne (1a, 14.2 mg, 0.050 mmol, 1.00
eq), B(C6F5)3 (2a, 25.6 mg, 0.050 mmol, 1.00 eq) and 2,2,6,6-
tetramethylpiperidine (7.1 mg, 0.050 mmol, 1.00 eq) were
dissolved in CD2Cl2 (0.5 ml), transferred to a NMR tube with
Young type teflon tap, heated to 70 °C for 2 h and objected to
NMR spectroscopy. Suitable crystals for X-ray single crystal
structure analysis were grown by condensation of pentanes
into the dichloromethane solution. 1H-NMR (500 MHz, CD2Cl2,
303 ) δ = 7.53 – 7.49 (m, 1H, HAr), 7.25 (s, 2H, HAr), 7.17 – 7.07
–
-136.75 (m, 1F, Fortho), -160.83 – -161.18 (m, 1F,
Fpara), -161.43 – -161.76 (m, 1F, Fpara), -161.92 – -162.20 (m, 1F,
Fpara), -164.76 – -165.18 (m, 1F, Fmeta), -165.77 – -166.09 (m,
1F, Fmeta), -166.51 – -166.85 (m, 2F, Fmeta), -167.07 – -167.37
(m, 1F, Fmeta), -167.37 – -167.73 (m, 1F, Fmeta).
Synthesis of tetrahydrohydroisoquinoline 8
(m, 6H, HAr), 7.01 – 6.96 (m, 1H, HAr), 6.91 – 6.86 (m, 2H, HAr),
2
6.74 – 6.70 (m, 2H, HAr), 5.02 (d, JHH = 16.8 Hz, 1H, CH2), 4.95 In a GC-vial equipped with magnetic stirring bar amino alkyne
(d, 2JHH = 16.8 Hz, 1H, CH2), 3.74 (s, 2H, NH2, TMP), 1.74 – 1.65 6b (44.2 mg, 0.16 mmol, 1.00 eq.) and B(C6F5)3 (16.4 mg, 0.032
(m, 2H, CH2, TMP), 1.59 – 1.51 (m, 4H, CH2, TMP), 1.21 (s, 12H, mmol, 0.20 eq.) were dissolved in toluene (0.7 ml). The sample
CH3, TMP); 13C-NMR (126 MHz, CD2Cl2, 303 ) δ = 148.9 (C), was pressurized with 80 bar H2 and heated to 100 °C for 24 h.
142.3 (C), 139.4 (C), 137.9 (C), 137.2 (C), 136.1 (C), 135.3 (C), A small part of the sample was transferred to a NMR tube
131.8 (CH), 131.4 (CH), 131.3 (CH), 128.7 (CH), 127.2 (CH), equipped with Young type Teflon tap, the solvent was
127.2 (CH), 127.1 (CH), 126.7 (CH), 126.4 (CH), 123.1 (CH), exchanged to C6D6 and the sample was analyzed by NMR
119.4 (CH), 118.4 (CH), 110.1 (CH), 60.4 (C, TMP), 47.3 (CH2, spectroscopy showing quantitative yield. The solvent of the
benzyl), 35.9 (CH2, TMP), 28.3 (CH3), 16.1 (CH2, TMP); 11B-NMR combined fractions was evaporated under reduced pressure
(160 MHz, CD2Cl2, 303 ) δ = −
15.56 (s); 19F-NMR (282 MHz, and the residue was purified by column chromatography
CD2Cl2) δ = -124.63 – -125.13 (m, 1F, Fortho), -127.05 – -127.47 (cyclohexane) to yield the product as brown solid (27 mg,
(m, 1F, Fortho), -129.36 – -129.68 (m, 1F, Fortho), -133.17 – 0.095 mmol, 61 %). 1H NMR (500 MHz, CD2Cl2, 303 ): δ = 7.30
-133.76 (m, 2F, Fortho), -135.82 – -136.30 (m, 1F, Fortho), -163.24 – 7.26 (m, 1H, H-4), 7.24 – 7.21 (m, 2H, H-5 and HPh), 7.21 –
– -163.53 (m, 1F, Fpara), -163.90 – -164.20 (m, 1F, Fpara), -164.60 7.19 (m, 1H, HPh), 7.19 – 7.15 (m, 2H, H-6 und HPh), 7.15 – 7.12
–
-164.92 (m, 1F, Fpara), -166.12 – -166.43 (m, 1F, (m, 1H, HPh), 7.12 – 7.09 (m, 2H, HPh), 7.07-7.03 (m, 1H, H-7),
Fmeta), -166.68 – -167.03 (m, 1F, Fmeta), -167.37 – -167.95 (m, 6.83 – 6.80 (m, 2H, HPh), 6.75 – 6.70 (m, 1H, HPh), 5.16 (dd,
3JHaHb = 5.6, 3.3 Hz, 1H, H-10), 4.61 (d, 2JHaHb = 14.7 Hz, 1H, 1 H-
3F, Fmeta), -168.04 – -168.40 (m, 1F, Fmeta).
2
2), 4.56 (d, JHaHb = 14.7 Hz, 1H, 1 H-2), 3.49 (dd, JHaHb = 15.1,
Synthesis of isoquinoline 7
5.7 Hz, 1H, 1 H-9), 3.16 (dd, JHaHb = 15.2, 3.2 Hz, 1H, 1 H-9); 13
C
In a glovebox a screw cap vial equipped with magnetic stirring
bar was charged with the amino alkyne (6b, 28.3 mg, 0.100
mmol, 1.00 eq.), B(C6F5)3 (2a, 51.2 mg, 0.100 mmol, 1.00 eq.)
and toluene (1.5 ml) and the resulting solution was heated to
90 °C for 2 h. Upon cooling to room temperature the
zwitterionic product precipitated as fine white needles and
was isolated by filtration (74.8 mg, 0.094 mmol, 94%). Suitable
crystals for X-ray single crystal structure analysis were grown
by condensation of pentanes into a saturated solution of the
zwitterionic product in dichloromethane/toluene (1:2).
1H-NMR (500 MHz, CD2Cl2, 303) δ = 9.07 (s, 1H, H-2), 8.73 –
8.67 (m, 1H, H-4), 8.09 – 8.04 (m, 1H, H-7), 7.89 – 7.82 (m, 1H,
H-5), 7.81 – 7.74 (m, 1H, H-6), 7.39 – 7.31 (br m, 1H, HPh), 7.32
– 7.28 (m, 1H, HPh), 7.31 – 7.24 (br m, 1H, HPh), 7.24 – 7.12 (m,
2H, HPh), 7.09 – 7.02 (br m, 1H, HPh), 7.02 – 6.94 (br m, 2H,
HPh), 6.97 – 6.92 (m, 1H, HPh), 6.81 – 6.70 (br m, 1H, HPh); 1H-
NMR (500 MHz, CD2Cl2, 283 ) δ = 9.08 (s, 1H), 8.71 – 8.66 (m,
1H, H-4), 8.09 – 8.05 (m, 1H, H-7), 7.88 – 7.83 (m, 1H, H-5),
7.80 – 7.75 (m, 1H, H-6), 7.37 – 7.32 (m, 1H, HPh), 7.32 – 7.25
(m, 2H, HPh), 7.23 – 7.18 (m, 2H, HPh), 7.06 – 7.01 (m, 1H, HPh),
7.01 – 6.96 (m, 2H, HPh), 6.96 – 6.91 (m, 1H, HPh), 6.77 – 6.72
(m, 1H, HPh); 13C-NMR (126 MHz, CD2Cl2, 303 ) δ = 147.98 (C),
147.04 (CH, C-2), 145.70 (C, C-3), 143.75 (C), 135.39 (CH, C-5),
133.70 (C), 133.19 (CH), 131.52 (CH), 130.50 (CH, C-7), 130.28
(CH), 130.15 (CH, C-4), 130.12 (CH, C-6), 129.56 (CH, CPh),
NMR (126 MHz, CD2Cl2, 303 ): δ = 149.6 (Cq-12), 144.0 (Cq-
11), 135.7 (Cq-3), 134.4 (Cq-8), 129.5 (2 CHPh), 128.6 (2 CHPh),
128.3 (CH-6), 127.3 (CH-7), 127.0 (1 CHPh), 126.83 (2 CHPh),
126.78 (CH-5), 126.5 (CH-4), 117.5 (CHPh), 113.6 (2 CHPh), 58.6
(CH-10), 48.2 (CH2-2), 37.3 (CH2-9).
Acknowledgements
The German Science Foundation (DFG) is gratefully
acknowledged for the financial support to J.P. (PA 1562/6-1).
Notes and references
1
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ARTICLE
Dalton Transactions
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The catalytic metal-free intramolecular hydroamination for the synthesis of
indoles and tetrahydroisoquinolines was achieved.