Straight Access to Indoles from Anilines and Ethylene Glycol by Heterogeneous Acceptorless Dehydrogenative Condensation

Article abstract of DOI:10.1021/acs.joc.7b02722

The development of original strategies for the preparation of indole derivatives is a major goal in drug design. Herein, we report the first straight access to indoles from anilines and ethylene glycol by heterogeneous catalysis, based on an acceptorless dehydrogenative condensation, under noninert conditions. In order to achieve high selectivity, a combination of Pt/Al₂O₃ and ZnO have been found to slowly dehydrogenate ethylene glycol generating, after condensation with the amine and tautomeric equilibrium, the corresponding pyrrole-ring unsubstituted indoles.

Full text of DOI:10.1021/acs.joc.7b02722

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Note
Straight Access to Indoles from Anilines and Ethylene Glycol by
Heterogeneous Acceptorless Dehydrogenative Condensation
Pedro Juan Llabrés-Campaner, Rafael Ballesteros-Garrido, Rafael Ballesteros, and Belen Abarca
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02722 • Publication Date (Web): 11 Dec 2017
Downloaded from http://pubs.acs.org on December 12, 2017
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Straight Access to Indoles from Anilines and Ethylene Glycol by Heterogeneous Accep-
torless Dehydrogenative Condensation
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Pedro Juan LlabresꢀCampaner, Rafael BallesterosꢀGarrido*, Rafael Ballesteros and Belén Abarca.
Dpto. de Química Orgánica, Facultad de Farmacia Universidad de Valencia, Vicent Andres Estelles s/n
46100 Burjassot
KEYWORDS Indoles • Heterogeneous Catalysis • Aceptorless Dehydrogenative Condesation• Ethylene
glycol activation • ZnO
ABSTRACT: The development of original strategies for the preparation of indole derivatives is a major
goal in drug design. Herein, we report the first straight access to indoles from anilines and ethylene glyꢀ
col by heterogeneous catalysis, based on an acceptorless dehydrogenative condensation, under nonꢀinert
conditions. In order to achieve high selectivity, a combination of Pt/Al2O3 and ZnO have been found to
slowly dehydrogenate ethylene glycol generating, after condensation with the amine and tautomeric
equilibrium, the corresponding pyrroleꢀring unsubstituted indoles.
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Indole scaffold is present in a large number of important compounds in pharmaceutical chemistry.1a
Thus, significant strategies have been reported for the synthesis of this heterocycle.1bꢀd For example,
Fischer,2a Reissert,2b Grandberg,2c or Bischler2d original methodologies allowed the preparation of inꢀ
doles bearing different substituents on the pyrrole ring. However, for the synthesis of pyrroleꢀring unꢀ
substituted indoles, just a few examples are reported. LeimgruberꢀBatcho3aꢀc strategy developed by Coꢀ
rey3d or Madelung4a modification developed by Saegusa4b are some examples where C2ꢀC3 unsubstitutꢀ
ed indoles are prepared. A straight and simple approach to this heterocycle free from hydrazine or halo
carbonyl derivatives still represents a challenge. Ethylene glycol and aniline (Figure 1) appear to be the
most ideal reagents for generate pyrroleꢀring unsubstituted indoles.5 It has been reported that at high
temperatures (350 ºC) these two reagents can yield to indole in gas phase.6aꢀb Interestingly, some authors
have reported that diols and anilines can be converted into indoles with homogeneous Ir/Ru catalyst.6cꢀf
However, neat ethylene glycol did not work under these conditions with free aniline or afforded low
yields6e that could be improved by adding equimolecular amount of SnCl2 using RuCl3 as catalyst.6f In
the course of our studies we discovered that a combination of a classical hydrogenating catalyst Pd/C
and large excess of metallic Zn or ZnO were able to activate ethylene glycol.7 It is important to note the
high stability of ethylene glycol and the possibility of double functionalization limits the efficiency of
the transformation.8 If a mono dehydrogenation of ethylene glycol can be performed, in presence of
anilines and avoiding Borrowing Hydrogen (BH) path,9 indoles should be obtained, through a tautomerꢀ
ism followed by conventional acylation/elimination reaction (Figure 1).
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Under BH conditions few examples are known with ethylene glycol and anilines.8a,10 However, Kempe
has recently reported on the use of Acceptorless Borrowing Hydrogen (BH) reaction11aꢀc (called Accepꢀ
torless Dehydrogenative Condensation or ADC11d) for the preparation of pyridines and pyrroles.
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Herein we report a heterogeneous acceptorless dehydrogenative condensation for the preparation of inꢀ
doles from neat ethylene glycol and anilines. This methodology allows the preparation of pyrroleꢀring
unsubstituted indoles with high efficiency.
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Figure 1. Indole synthesis through ADC/tautomeric approach.
The catalyst screening was performed with the common catalysts employed for hydrogenation, under
heterogeneous conditions, which is indeed required for a BH reaction (Pt/Al2O3, Ru/Al2O3 and Pd/C)
using pꢀtoluidine as aniline. Initial tests with the previous catalyst afforded negative results (Table 1).
Table 1. Catalyst screening.
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ZnO was introduced as coꢀcatalyst to activate the diol. In our previous studies Zn7a and ZnO7c were sucꢀ
cessfully employed to activate ethylene glycol. ZnO is known to activate alcohols12 and (as nanopartiꢀ
cle) has been reported as a catalyst for organic reactions.12 When the catalyst was combined with ZnO,
conversion increased, ZnOꢀPt/Al2O3 combination revealed as the most powerful catalyst. 0.6 M concenꢀ
tration of amine in ethylene glycol (4 mmol of 1a in 6 mL) was found ideal for high conversion and
yield. With different conditions side products appeared (See S1 for detailed scope). Amino alcohol 3 and
dimers 4 and 5 were the major side products, being able to be rationalized by a BH path (vide infra).
Watanabe reported on dimers formation 4 and 5 with anilines and ethylene glycol under RuCl3 catalyꢀ
sis.6e,6f However, their presence could only be detected when the reaction was carried out with Pd/C. For
elevated conversions and yields 24h were required. When the temperature was reduced to 150ºC conꢀ
version decreased. All reactions were carried out in presence of air and moisture, no specific conditions
were required.
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In Table 2 the scope with different anilines is presented. In all cases the presence of electron donating
groups induced the formation of the indole. Reaction with compound 1b afforded diꢀmethylated indole
2b in 81% isolated yield. Dimethoxy and trimethoxy derivatives 2c and 2d were isolated in high yields
(84% and 88%, entries 3 and 4). Surprisingly, reaction with aniline 1e afforded moderate yield (43%
isolated yield for indole 2e). This result pointed out this methodology requires the presence of donor
substituents in the aromatic ring. Benzodioxol and benzodioxane anilines 1f and 1g afforded indoles 2f
and 2g in excellent yields (2g was obtained in presence of an isomer mixture of 75:25). Naphthyl amine
1h afforded the corresponding indole 2h in 90% isolated yield. Although deactivated anilines like nitro
or cyano derivatives did not afford any conversion, with fluorinated aniline 1i bisꢀindoles 6 (due to the
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symmetry of compound 6 Z or E configuration cannot be determined) were obtained in moderate yield
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(36% yield), this result pointed out that reaction mechanism involved different features (vide infra).
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Table 2. Scope of the methodology using different anilines. Isolated yields are shown.
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In Figure 2, rational mechanism is presented. In first step, ethylene glycol is transformed into the correꢀ
sponding monoꢀaldehyde 13 7 by means of Pt/Al2O3 in presence of ZnO as activating agent (conversion
dramatically decreased when smaller amount of ZnO are employed, Table S1). Nevertheless, 7 has nevꢀ
er been isolated under these conditions.14 It has been reported that a competitive oxidative pathway15
with O2 could be also responsible for the obtention of aldehydes from alcohols. However, when the reꢀ
action was performed in absence of O2 (all solvents and reagents were degassed with argon) similar reꢀ
sults were obtained. The presence of molecular hydrogen was also confirmed by GC (by taking a samꢀ
ple of the internal gas of the flask after the reaction, see SI) being this another evidence of the ADC
path. The relatively long reaction time (24h) and also the absence of 7 may indicate that this first step is
the rate limiting one. This hypothesis can be supported by the fact that this step must be mediated by
both catalysts, while all the subsequent steps do not require catalyst necessarily. Then, the amine generꢀ
ates the corresponding imine. Under normal BH/HA conditions, this imine would be reꢀhydrogenated to
afford compound 3 (Figure 2, grey path). However, employing ethylene glycol, a tautomeric equilibrium
of this imine in combination with Pt/Al2O3 limited reꢀhydrogenation capacity, yields to a different comꢀ
pound undergoing indole formation. Madsen, Williams, and Bruneau have reported on a similar tautoꢀ
meric feature with amino alcohols under BH reactions in homogeneous phase.6c,8a,16 The use of ZnO
nanoparticles as a catalyst has recently been reported.12fꢀg In our case, the small particle size and the
solubility17 of this oxide may be responsible of an easier coꢀparticipation between ZnO and Pt/Al2O3 in
the first step of the catalytic cycle. The formation of just 3, 4 or 5 as side products clearly indicates that
the CꢀN bond formation is the first step; as no side products derived from an initial cyclization (forꢀ
mation of CꢀC bond and then formation of the CꢀN bond) have ever been observed.
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4,00
3,50
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Time (s)
0
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10000 15000 20000
Figure 2. Rational mechanism and kinetic study (Inset).
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By evaluating the rate of aniline conversion with three different catalysts, we could determine how slow
kinetics help in the formation of indole 2a. This rate (Figure 2, inset) for Pd/C was higher than for
Pt/Al2O3. With Pd/C the selectivity towards 3, 4 and 5 also increased. Indeed, the faster the dehydroꢀ
genation of ethylene glycol, the faster the obtention of side products derived from the BH cycle (3, 4
and 5).6e When double quantity of ZnO with Pt/Al2O3 was employed the rate also increased, but the seꢀ
lectivity was similar to the standard conditions. The kinetic study also indicated that between the two
Pt/Al2O3 conditions (more or less ZnO) no significant differences were found in terms selectivity and
conversion at long times. However, as noted, with Pd/C kinetics and selectivity were completely differꢀ
ent. Under our conditions and without the possibility of reꢀhydrogenation (due to the Pd/C), the forꢀ
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mation of dimers may be explained through accumulation of imine in the reaction (see SI for more deꢀ
tails). Competitive experiment between aniline 1d and 1i (Scheme 1, top) clearly indicated that electron
rich one reacts faster as no trace of 6 was observed. When ethylene glycol was replaced by 1,2ꢀ
propanediol (8) small conversion with 1d was obtained at 175 ºC. By increasing reaction time (48h),
indole 9 was obtained as unique compound. Although compound 8 oxidation may afford two possible
products (10 and 10’’) that are under tautomeric equilibrium (Scheme 1, bottom), the imine formation is
faster with aldehydes and the methyl substituent is only present at position 3 in 9.18
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O
F
O
Pt/Al2O3
ZnO
O
O
O
O
NH2
N
NH2
HO
OH
H
2d > 95%a
1d
1i
Pt/Al2O3
ZnO
48 h
O
O
O
O
O
O
N
H
NH2
HO
OH
8
9 87%
1d
H3C
HO
H3C
HO
H3C
O
OH
O
OH
10''
10'
10
Scheme 1. Competitive experience and 1,2ꢀpropanediol (8) test. (a) 1HꢀNMR yield.
The indole formation was also explored with different Nꢀsubstituted anilines (11, 13 and 15) and mꢀ
phenylenediamine (16) (Scheme 2). Nꢀmethylated aniline 11 afforded indole 12 in good yield. When
tetrahydroquinolines 13a and 13b were employed, the corresponding indoles were obtained in moderatꢀ
ed (14a, 50% isolated yield) to excellent yields (14b, 89% isolated yield). However, when indoline 15
was submitted to the reaction conditions, no indole was formed.19ꢀ20 With mꢀphenylenediamine (16),
excellent yield (87%) was obtained for the bisꢀindole 17.
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Scheme 2. Nꢀsubstituted indoles and bisꢀindole 17.
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As it has been outlined before, our methodology allows the transformation of ethylene glycol into the
corresponding monoaldehyde 7. In the literature bisꢀindoles are present in many natural products i.e.
Streptindole 21a (18) or Arsindoline B21b (19) (Scheme 3, top). Retrosynthetic analysis suggests that with
our methodology, and employing indole 2e as reagent, alcohol 20 may be accessible. As proof of the
presence of 7, we attempted the standard reaction starting from 2e. Only a 5% of compound 20 was obꢀ
tained, however, by increasing temperature and catalyst loading we were able to achieve 23% yield of
20, which can be transformed into 18 and 19 by esterification.22 Despite the low yield, it is important to
highlight that we have been able to access natural products Streptindole’s and Arsindoline B’s precursor
20 in two steps from simple building blocks like aniline and ethylene glycol.
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Scheme 3. 2ꢀhydroxyacetaldehyde (7) as precursor of natural products, yields are given for isolated
compound.
In conclusion, herein we present a new access towards pyrroleꢀring unsubstituted indoles based on a
heterogeneous ADC reaction between anilines and ethylene glycol. The combination of Pt/Al2O3 and
ZnO has been found to be able to slowly transform glycol into the corresponding 2ꢀ
hydroxyacetaldehyde (7) by means of dehydrogenation. In addition, we have been able to capture this
intermediate into a natural product precursor (20). Tautomeric equilibrium of the imine intermediate has
revealed crucial for the indole formation. This reaction is possible due to monoꢀactivation of ethylene
glycol that takes place thanks to the combination of Pt/Al2O3 and ZnO. This is an original heterogeneꢀ
ous approach towards pyrroleꢀring unsubstituted indoles by an atom efficient protocol. The complemenꢀ
tarity between air and moisture stability and economical catalysts (Pt/Al2O3 and ZnO) represents a difꢀ
ferent and efficient approach towards indoles.
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Experimental Section
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Materials and Measurements
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Starting materials, if commercially available, were purchased and used as such. H and (1H decoupled) 13C nuclear
magnetic resonance (NMR) spectra were recorded at 300 and 75 MHz. Chemical shifts are reported in δ units, parts
per million (ppm), and were measured relative to the signals for residual chloroform. Coupling constants (J) are
given in Hz. COSY and HSQC experiments were performed for new compounds. IR spectra were recorded using
FTꢀIR ATR. HRMS were recorded using TOF electrospray ionization (ESIꢀpositive). The solvents used were of
spectroscopic or equivalent grade. Water was twice distilled and passed through a Millipore apparatus. All reaction
mixtures were filtered through a 0.45 ꢁm PTFE 25 mm Syringe Filter.
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General Procedure
4 mmol of aniline (indole, THQ or indoline), 1.7% of Pt/Al2O3 (273 mg), 4.5% of ZnO nanoparticles (250 mg)
(<100 nm particle size (DLS), <40 nm avg. part. size (APS), 20 wt.% in H2O) and 6 mL of ethylene glycol were
mixed manually inside a 50 mL QuickꢀThread Glass Reaction Tube. Then it was sealed with an EasyꢀOn PTFE Cap
and put into a Carousel 12 Plus Reaction Station at 175 ºC for 24 h. The reaction mixture was cooled to room temꢀ
perature and it needed to be opened carefully to depressurize the tube. After that, 30 mL of ethyl acetate were addꢀ
ed, and the crude was filtered through a 0.45 ꢁm PTFE filter. The reaction mixture was extracted with distilled waꢀ
ter (3x20 mL) and the organic layer was dried with Na2SO4, filtered and concentrated affording the reaction crude
1
that was checked by HꢀNMR. Crude reaction was purified by column chromatography using Merck 60 (0.040ꢀ
0.063 mm) silicagel and a mixture of hexane (5): ethyl acetate (1) as eluent.
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5-Methylindole (2a) : 360 mg, 70% yield, powder, mp 59 – 60 ºC. H NMR (300 MHz, CDCl3) δ: 7.44 (m, 2H),
7.26 (d, J= 8.5 Hz, 1H), 7.12 (d, J= 3.0 Hz, 1H), 6.44 (d, J= 3.0 Hz, 1H), 2.39 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ: 148.0 (1C, C), 138.6 (1C, C), 134.0 (1C, C), 130.2 (1C, CH), 121.2 (2C, CH), 119.4 (1C, CH), 94.8 (1C, CH),
20.9 (1C, CH3).
1
4,6-Dimethylindole
(
2b
)
24: 463 mg, 81% yield, oil. H NMR (300 MHz, CDCl3) δ: 8.01 (bs, 1H), 7.13 (m, 1H),
7.04 (s, 1H), 6.78 (s, 1H), 6.52 (ddd, J= 3.1; 2.1; 0.9 Hz, 1H), 2.54 (s, 3H), 2.44 (s, 3H). 13C NMR (75 MHz,
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CDCl3) δ: 136.1 (1C, C), 132.0 (1C, C), 129.9 (1C, C), 125.7 (1C, C), 122.9 (1C, CH), 122.0 (1C, CH), 108.6(1C,
4
5
CH), 101.1 (1C, CH), 21.8 (1C, CH3), 18.8 (1C, CH3).
5,6-Dimethoxyindole
(
2c)25: 725 mg, 84% yield, powder. mp 150 ꢀ 151 ºC. H NMR (300 MHz, CDCl3) δ: 8.06
6
7
1
8
9
(bs, 1H), 7.10 (s, 1H), 7.08 (dd, J= 3.1; 2.4 Hz, 1H), 6.89 (s, 1H), 6.45 (ddd, J= 3.0; 2.1; 0.9 Hz, 1H), 3.92 (s, 3H),
3.90 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 147.2 (1C, C), 145.3 (1C, C), 130.3 (1C, C), 122.8(1C, CH), 120.7 (1C,
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C), 102.4 (2C, CH), 94.6 (1C, CH), 56.4 (1C, CH3), 56.3 (1C, CH3).
1
4,5,6-Trimethoxyindole
(
2d
)
: 842 mg, 88% yield, oil. H NMR (300 MHz, CDCl3) δ: 8.07 (bs, 1H), 7.04 (dd, J=
3.3; 2.4 Hz, 1H), 6.65 (d, J=0.8 Hz, 1H), 6.65 (ddd, J= 3.2; 2.2; 0.9 Hz, 1H), 4.11 (s, 3H), 3.88 (s, 6H). 13C NMR
(75 MHz, CDCl3) δ: 151.3 (2C, C), 146.1 (1C, C), 132.9 (1C, C), 122.3(1C, CH), 115.1 (1C, C), 100.5 (1C, CH),
89.6 (1C, CH), 61.7 (1C, CH3), 60.8 (1C, CH3), 56.4 (1C, CH3). HRMS (ESIꢀTOF) m/z: [M+H+] Calctd for
C11H14NO3 208.0968; Found: 208.0957. IR (ATR): 3381, 2842, 1601 cmꢀ1.
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1H-Indole (2e) : 201 mg, 43% yield, mp 53 – 54 ºC. H NMR (300 MHz, CDCl3) δ: 7.68 (ddt, J= 7.8; 1.6; 0.8
Hz, 1H), 7.41 (ddd, J= 8.1; 1.9; 1.0 Hz, 1H), 7.25ꢀ7.19 (m, 2H), 7.17ꢀ7.11 (m, 1H), 6.59ꢀ6.56 (m, 1H). 13C NMR
(75 MHz, CDCl3) δ: 135.9 (1C, C), 128.0 (1C, C), 124.2 (1C, CH), 122.1 (1C, CH), 120.9 (1C, CH), 119.8 (1C,
CH), 111.1 (1C, CH), 102.8 (1C, CH).
5H-[1,3]Dioxolo[4,5-f]indole (2f)
27 : 644 mg 86% yield, oil. 1H NMR (300 MHz, CDCl3) δ: 8.01 (bs, 1H), 7.07
(dd, J= 3.1; 2.5 Hz, 1H), 7.02 (s, 1H), 6.84 (s, 1H), 6.44 (ddd, J= 3.1; 2.1; 0.9 Hz, 1H), 5.93 (s, 2H). 13C NMR (75
MHz, CDCl3) δ: 145.0 (1C, C), 143.1 (1C, C), 130.7 (1C, C), 122.9 (1C, CH), 121.8 (1C, C), 102.9 (1C, CH), 100.7
(1C, CH2), 99.2 (1C, CH), 92.0 (1C, CH).
2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole
(
2g) (75%)28 and 2,3ꢀdihydroꢀ7Hꢀ[1,4]dioxino[2,3ꢀe]indole
1
(
2g’) (25%)28: 560 mg, 80% yield, oil. H NMR (300 MHz, CDCl3) δ: 8.02 (bs, 1H, NH 2g’), 7.87 (bs, 1H, NHꢀ
2g), 7.12 (m, 1H, Hꢀ1: 2g’), 7.10ꢀ7.07 (m, 2H, Hꢀ1 and Hꢀ7, 2g), 6.88 (d, J= 8.7 Hz, 1H, Hꢀ6 2g’) 6.87 (s, 1H. Hꢀ4,
2g), 6.78 (d, J= 8.7 Hz, 1H, Hꢀ5, 2g’), 6.55 (ddd, J= 3.0; 2.2; 0.9 Hz, 1H, Hꢀ2, 2g’), 6.39 (ddd, J= 3.1; 2.0; 0.9 Hz,
1H, Hꢀ2, 2g), 4.39 (m, 2H, OCH2 2g’), 4.33ꢀ4.23 (m, 6H, OCH2 2g and 2g’). 13C NMR (75 MHz, CDCl3) δ: 124.0,
106.9, 102.1, 98.3, 65.05, 64.7, 64.4.
1H-Benz[g]indole (2h)
29: 603 mg, 90% yield, powder. mp 168 ꢀ 169 ºC. 1H NMR (300 MHz, CDCl3) δ: 8.85 (bs,
1H), 7.97 (t, J= 8.4 Hz, 2H), 7.75 (d, J= 8.7 Hz, 1H), 7.53 (m, 2H), 7.45 (ddd, J= 8.1; 7.0; 1.3 Hz, 1H), 7.26 (t, J=
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2.8 Hz, 1H), 6.71 (dd, J= 3.0; 2.1 Hz, 1H). 13C NMR (75 MHz, CDCl3). δ: 130.5 (2C, C), 129.0 (1C, CH), 125.6
(1C, CH), 124.0 (1C, CH), 123.9(1C, C), 122.4 (1C, CH), 121.9(1C, C), 120.9 (1C, CH), 120.8 (1C, CH), 119.5
(1C, CH), 104.4 (1C, CH).
2-((4-Methylphenyl)amino)ethanol (3
)30: traces, oil. 1H NMR (300 MHz, CDCl3) δ: 7.01 (d, J=8.6 Hz, 2H), 6.60 (d,
J=8.5 Hz, 2H), 3.82 (t, J= 5.2 Hz, 2H), 3.28 (t, J= 5.2 Hz, 2H), 2.85 (bs, 1H), 2.25 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ: 145.8(1C, C), 129.9 (2C, CH), 127.5 (1C, C), 113.7 (2C, CH), 61.4 (1C, CH2), 46.8 (1C, CH2), 20.5 (1C,
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CH3).
7c
N,N’-Bis(4-methylphenyl)-1,2-ethanediamine
(4
)
:
traces, oil. 1H NMR (300 MHz, CDCl3) δ: 7.01 (d, J= 8.0
Hz, 4H), 6.64 (d, J= 8.4 Hz, 4H), 3.39 (s, 4H), 2.25 (s, 6H). 13C NMR (75 MHz, CDCl3) δ: 145.1 (2C, C), 130.0
(4C, CH), 128.0 (2C, C), 114.0 (4C, CH), 44.2 (2C, CH2), 20.5 (2C, CH3). HRMS (ESIꢀTOF) m/z: [M+H+] Calcd
for C16H21N2 241.1699; Found 241.1688. IR (ATR): 2918, 2858, 1616 cmꢀ1.
1
1,4-Bis(4-methylphenyl)-piperazine
(
5
)7c: traces, oil. H NMR (300 MHz, CDCl3) δ: 7.11 (d, J= 8.6 Hz, 4H),
6.91 (d, J= 8.5 Hz, 4H), 3.30 (s, 8H), 2.29 (s, 6H). 13C NMR (75 MHz, CDCl3) δ: 149.3 (2C, C), 129.8 (6C, C and
CH), 116.9 (4C, CH), 50.2 (4C, CH2), 20.6 (2C, CH3). HRMS (ESIꢀTOF) m/z: [M+H+] Calctd for C18H23N2
267.1856; Found: 267.1844. IR (ATR): 2953, 2855, cmꢀ1.
1,2-Bis(6-fluoro-1H-indol-1-yl)ethene (6) (Z/E configuration remains undetermined): 423 mg, 36% yield, oil.
1H NMR (300 MHz, Acetoneꢀd6) δ: 7.54 (m, 4H), 7.46 (d, J= 3.2 Hz, 2H), 7.44 (m, 2H), 6.99 (m, 2H), 6.68 (d, J=
3.1 Hz, 2H). 13C NMR (75 MHz, Acetoneꢀd6) δ: 164.5 (2C, d, J= 244.0 Hz, C), 132.4 (4C, C), 122.3 (2C, CH),
115.3 (2C, CH), 111.6 (2C, d, J= 21.4 Hz, CH), 106.6 (2C, d, J= 25.7, CH), 97.4 (2C, CH). HRMS (ESIꢀTOF) m/z:
[M+H+] Calctd for C18H14F2N2 295.1041; Found: 295.1040. IR (ATR): 3377(H2O), 3003, 2926, 1603, 1567 cmꢀ1.
1
4,5,6-Trimethoxy-3-methyl-1H-indole
(9
): 751 mg, 87% yield, oil. H NMR (300 MHz, CDCl3) δ: 7.77 (bs,
1H), 6.56 (d, J= 0.6 Hz, 1H), 6.24 (dt, J= 2.0; 0.9 Hz, 1H), 4.07 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 2.39 (d, J= 1.0
Hz, 3H). 13C NMR (75 MHz, CDCl3) δ: 150.3 (1C, C), 145.3 (1C, C), 136.7 (1C, C), 133.1 (1C, C), 133.1 (1C, C),
115.9 (1C, C), 98.0 (1C, CH), 89.5 (1C, CH), 61.6 (1C, CH3), 60.7 (1C, CH3), 56.5 (1C, CH3), 13.7 (1C, CH3).
HRMS (ESIꢀTOF) m/z: [M+H+] Calcd for C12H16NO3 222.1125; Found 222.1127. IR (ATR): 3361, 2926, 1626 cmꢀ
1
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1,5-Dimethyl-1H-indole
(
12
)
: 446 mg, 77% yield, oil. H NMR (300 MHz, CDCl3) δ: 7.47 (dt, J= 1.6; 0.8 Hz,
4
5
6
7
8
9
1H), 7.27 (d, J= 8.3 Hz, 1H), 7.11 (dd, J= 8.3; 1.6 Hz, 1H), 7.05 (d, 3.1 Hz, 1H), 6.45 (dd, J= 3.1; 0.8 Hz, 1H), 3.80
(s, 3H), 2.52 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 135.3 (1C, C), 128.9 (1C, CH), 128.8 (1C, C), 128.5 (1C, C),
123.2 (1C, CH), 120.6 (1C, CH), 109.0 (1C, CH), 100.4 (1C, CH), 32.9 (1C, CH3), 21.5 (1C, CH3).
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5,6-Dihydro-4H-pyrrolo-[3,2,1-ij]-quinoline(14a) : 315 mg, 50% yield, oil. H NMR (300 MHz, CDCl3) δ:
7.37 (dd, J= 7.9; 0.8 Hz, 1H), 7.00 (d, J= 3.0 Hz, 1H), 6.94 (dd, J= 7.9; 7.1 Hz, 1H), 6.84 (dd, J= 7.1; 0.9 Hz, 1H),
6.37 (d, J= 3.0 Hz, 1H), 4.09 (t, J= 5.7 Hz, 2H), 2.93 (t, J= 6.1 Hz, 2H), 2.17 (m, 2H). 13C NMR (75 MHz, CDCl3)
δ: 134.3 (1C, CH), 126.1(1C, CH), 126.0 (1C, C), 122.0 (1C, C), 119.8 (1C, CH), 118.7 (1C, CH), 118.3(1C, CH),
100.5 (1C, CH), 44.3 (1C, CH2), 24.9 (1C, CH2), 23.1 (1C, CH2).
1
8-Methoxy-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline
(
14b): 663 mg, 89% yield, oil. H NMR (300 MHz,
CDCl3)δ: 7.05 (d, J= 2.9 Hz, 1H), 6.91 (d, J= 2.2 Hz, 1H), 6.62 (dd, J= 1.5; 0.6 Hz, 1H), 6.36 (d, J= 2.9 Hz, 1H),
4.13 (t, J= 5.7 Hz, 2H), 3.84 (s, 3H), 2.96 (dd, J= 8.9; 3.4 Hz, 2H), 2.28ꢀ2.17 (m, 2H). 13C NMR (75 MHz, CDCl3)
δ: 154.84 (1C, C), 126.34 (1C, CH), 125.8 (1C, C), 122.7(2C, C), 109.4 (1C, CH), 100.1 (1C, CH), 99.9 (1C, CH),
56.2 (1C, CH3), 44.2 (1C, CH2), 25.0 (1C, CH2), 23.2 (1C, CH2). HRMS (ESIꢀTOF) m/z: [M+H+] Calcd for
C12H14NO: 188.1070; Found 188.1066. IR (ATR): 2938, 1618, 1495 cmꢀ1.
1,6-Dihydropyrrolo[2,3-e]indole (
17)33: 542 mg, 87% yield, oil. 1H NMR (300 MHz, MeOD) δ: 7.35 (d, J= 8.6
Hz, 1H), 7.17 (m, 2H), 7.11 (d, J= 3.1 Hz, 1H), 6.71 (dd, J= 3.1; 0.8 Hz, 1H), 6.53 (d, J= 3.1 Hz, 1H). 13C NMR (75
MHz, MeOD) δ: 134.2 (1C, C), 130.2 (1C, C), 122.4 (1C, CH), 121.36 (1C, C), 121.1 (1C, CH), 115.6 (1C, CH),
114.8 (1C, C), 106.0 (1C, CH), 103.2 (1C, CH), 98.7 (1C, CH).
21d
1
2,2-Di(1H-indol-3-yl)ethan-1-ol
(
20
)
220 mg, 23% yield, oil. H NMR (300 MHz, CDCl3) δ: 8.03 (bs, 1H),
7.61 (d, J= 8.0 Hz, 2H), 7.38 (dt, J= 8.2; 0.9 Hz, 2H), 7.19 (ddd, J= 8.2; 7.1; 1.2 Hz, 2H), 7.11 (dd, J= 2.3; 0.6 Hz,
2H), 7.07 (ddd, J= 8.0; 7.0; 1.0 Hz, 2H), 4.80 (t, J= 6.2 Hz, 1H), 4.31 (d, J= 6.2 Hz, 2H). 13C NMR (125 MHz,
CDCl3) δ: 136.7 (2C, C), 127.1 (2C, C), 122.7 (2C, CH), 122.3 (2C, CH), 119.61 (2C, CH), 119,6 (2C, CH), 116.4
(2C, CH), 111.35 (2C, CH), 66.0 (1C, CH2), 37.3 (1C, CH).
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ASSOCIATED CONTENT
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Complete screening of conditions, complete mechanistic analysis and spectroscopic characterization.
This material is available free of charge via the Internet at http://pubs.acs.org.
Notes
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The authors declare no competing financial interests.
AUTHOR INFORMATION
Corresponding Author
rafael.ballesteros-garrido@uv.es
Author Contributions
The manuscript was written through contributions of all authors.
Funding Sources
This work was financially from University of Valencia (Spain) (UVꢀINVꢀAE 15ꢀ332846).
ACKNOWLEDGMENT
R. BꢀG is much indebted to the Postdoctoral fellow 2013 of the Ministerio de Economía y Competiꢀ
tividad (Spain, FPDIꢀ2013ꢀ17464). We are especially grateful to “Central Service for Experimental Reꢀ
search” (SCSIE) of University of Valencia and NANBIOSIS platform. Pr. H. Garcia and Dr. J. Albero
(ITQ, UPV) are acknowledged for their help with the GC molecular hydrogen determination. We grateꢀ
fully acknowledge the suggestions and advice from the referees and the editor in order to improve the
quality of this contribution.
REFERENCES
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(13)
2ꢀHydroxyacetaldehyde (7) is particular molecule also known as glycolaldehyde. It has
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PhysChem,
2015,
16,
2226–2236.
It
can
be
obtained
from
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Chem. Int. Ed. 2017, 56, 3050 –3054.
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