β-Amino alcohols from anilines and ethylene glycol through heterogeneous Borrowing Hydrogen reaction

Article abstract of DOI:10.1016/j.tet.2017.08.006

Borrowing Hydrogen (BH), also called Hydrogen Autotransfer (HA), reaction with neat ethylene glycol represents a key step in the preparation of β-amino alcohols. However, due to the stability of ethylene glycol, mono-activation has rarely been achieved. Herein, a combination of Pd/C and ZnO is reported as heterogeneous catalyst for this BH/HA reaction. This system results in an extremely air and moisture stable, and economic catalyst able to mono-functionalize ethylene glycol in water, without further activation of the diol. In this work, different diols and aromatic amines have been explored affording a new approach towards amino alcohols. This study reveals how the combination of two solid species can afford interesting catalytic properties in heterogeneous phase. ZnO activates ethylene glycol while Pd/C is the responsible of the BH/HA cycle. This catalytic system has also been found useful to dehydrogenate indoles affording indolines that undergo in situ BH/HA cycle prior to re-aromatization, representing a tandem heterogeneous process.

Full text of DOI:10.1016/j.tet.2017.08.006

Accepted Manuscript
β-Amino alcohols from anilines and ethylene glycol through heterogeneous Borrowing
Hydrogen reaction
Pedro J. Llabres-Campaner, Rafael Ballesteros-Garrido, Rafael Ballesteros, Belén
Abarca
PII:
S0040-4020(17)30826-8
10.1016/j.tet.2017.08.006
TET 28900
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 June 2017
Revised Date: 25 July 2017
Accepted Date: 3 August 2017
Please cite this article as: Llabres-Campaner PJ, Ballesteros-Garrido R, Ballesteros R, Abarca Belé, β-
Amino alcohols from anilines and ethylene glycol through heterogeneous Borrowing Hydrogen reaction,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.08.006.
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ACCEPTED MANUSCRIPT
β-Amino Alcohols from Anilines and Ethylene Glycol through Heterogeneous Borrowing
Hydrogen Reaction
Pedro J. Llabres-Campaner, Rafael Ballesteros-Garrido*, Rafael Ballesteros and Belén Abarca
Departament de Química Orgànica, Universitat de València, Av. Vicent Andrés Estellés s/n, 46100
Burjassot, Valencia, Spain. Rafael.ballesteros-garrido@uv.es
Abstract
Borrowing Hydrogen (BH), also called Hydrogen Autotransfer (HA), reaction with neat ethylene
glycol represents a key step in the preparation of β-amino alcohols. However, due to the stability of
ethylene glycol, mono-activation has rarely been achieved. Herein, a combination of Pd/C and ZnO is
reported as heterogeneous catalyst for this BH/HA reaction. This system results in an extremely air
and moisture stable, and economic catalyst able to mono-functionalize ethylene glycol in water,
without further activation of the diol. In this work, different diols and aromatic amines have been
explored affording a new approach towards amino alcohols. This study reveals how the combination
of two solid species can afford interesting catalytic properties in heterogeneous phase. ZnO activates
ethylene glycol while Pd/C is the responsible of the BH/HA cycle. This catalytic system has also
been found useful to dehydrogenate indoles affording indolines that undergo in situ BH/HA cycle
prior to re-aromatization, representing a tandem heterogeneous process.
Pd/C, ZnO
150 ºC
Water
R
OH
OH
+
R
HO
N
NH2
H
H2-Pd/C
ZnO
Pd/C
ZnO
up to 88% yield
H2O
R
OH
+
R
OH
O
N
NH2
1

ACCEPTED MANUSCRIPT
Introduction
The development of green processes in organic synthesis represents a major goal nowadays.1
From atom economy2 to the use of environmentally friend reagents, many different strategies
can be employed for the development of green reactions. Borrowing Hydrogen (BH)
reactions3,4 (also called Hydrogen Autotransfer (HA) reactions5) (Figure 1, top) represent a
unique opportunity for the creation of molecular complexity with extremely high atom
economy and, in many cases, under green principles. Important results concerning the
preparation of secondary unsymmetrical amines, starting from primary amines and alcohols,
are reported. Recently, Michlik and Kempe6 employed this methodology for the preparation
of pyrroles coupling two BH/HA processes with amino alcohols. The preparation of β-amino
alcohols (vicinal or 1,2-amino alcohols) by means of BH/HA reactions under heterogeneous
catalysis is a major goal due to the relevance of these compounds.7,8 In addition, efficient
preparation of
β-amino alcohols derived from anilines is a key step in the preparation of
important compounds like pyrroles.6 Retrosynthetic analysis indicates that under controlled
BH/HA conditions aniline and ethylene glycol may lead towards
β
-amino alcohols (Figure 1,
bottom).
H
NH2
NH2
N
R
HO
R
R
+
CAT
O
CAT-H2
N
R
+
Heterogeneous catalysis?
H
N
N
H2
+
HO
Ar
OH
Ar
O
H
-amino alcohol
β
this work
Figure 1. BH/HA strategy for the preparation of unsymmetrical amines (up) and retro synthetic approach to β-
amino alcohols with ethylene glycol (down).
2

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However, in the literature, Kempe has reported this reaction in 32% yield with transition
metal complex as catalyst starting from anilines and in presence of an excess of ethylene
glycol.6a Börner also reported on monoaminations with an homogeneous Iridium pincer
catalyst in excellent yields.6b Another important reaction reported by Williams with a
secondary amine (phenyl benzyl amine) yielded 70% under homogeneous Ru catalysis.9
Watanabe also reported on the formation of indoles and cyclic compounds under similar
conditions, the formation of cyclic compounds was also reported by Beller.10 Those examples
are by far the most efficient ones with ethylene glycol and any other alternative found in the
literature requires 300ºC or transformation of ethylene glycol into a better reagent with
diethyl carbonate.11,12 Even more, diols are also used to generate typically cyclic compounds
like pyrrolidines that came from functionalization of both alcohols.9 In view of this, single
functionalization of ethylene glycol is challenging and relevant. Herein, we report our recent
advances on the use of BH/HA reactions to obtain
β-amino alcohols, based on a
heterogeneous catalysis. The catalytic system is formed by Pd/C and ZnO, and different aryl
amines have been reacted with ethylene glycol, in order to test the scope of this
heterogeneous catalysis, less common in BH/HA processes.13
The challenge in the use of ethylene glycol as reagent relies on its stability compared to
benzylic alcohols that are normally used in BH/HA reactions. It is important to enhance that
diols are rarely used because they trend to react twice, yielding dimers or cyclic compounds.10
The choice of the catalyst represents the key of the process, because an extremely powerful
catalyst may be able to di-oxidize the glycol or the final β-amino alcohol, leading to different
products as Milstein reported.14 Thus, preparing
reagent remains a challenge.
β
-amino alcohols using ethylene glycol as
3

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Results and Discussion
Recently, in our group, we developed a tandem process of hydrogenation and BH/HA in
alcohol/water mixtures at high temperature with metallic Zn as reducing agent and under
Pd/C catalysis.15 Understanding that Pd/C could undergo BH/HA cycle, we firstly
investigated these conditions. However, the presence of Zn(0) as electron donor represented
non-green conditions, so we thought about ZnO as an activating agent for the glycol. Zinc
oxide is an amphoteric material that can activate alcohols.16-22 Indeed, under our previous
studies, Zn(0) was transformed in situ into ZnO. There are a few reports in the literature
indicating that ZnO nanoparticles can act as catalyst23 it is almost stable over the catalysis,
cheap and can be recovered with de Pd/C after reaction, being a greener reagent compared to
metal Zn.
The first screening of conditions was performed at 200ºC and 64h, observing complete
degradation of the starting aniline
1 and no traces of β-amino alcohol. Either with Zn or ZnO,
24 or 64 hours were extremely hard conditions and induced complete transformation of the
product without any selectivity (Table 1, entries 1 to 3). Surprisingly, when we reduced the
temperature to 150ºC, excellent conversion and selectivity was observed, and the
corresponding β-amino alcohol 2a was isolated in 88% yield (Table 1, entry 4 and Figure S1).
Evaluating the kinetics of the reaction, 24 h was found to be efficient for high conversions
and selectivity (Table 1, entries 4 to 8), moreover, no degradation of the product was
observed at longer times. Reaction was clear yielding to product 2a with small traces of
dimeric compounds (Table S2). The 1:1 solvents ratio was also optimal, as long as any
modification induced lower conversion (Table 1, entries 8 to 10).
In this reaction, ethylene glycol is employed also as solvent, however, the absence of water
afforded no conversion (Table 1, entry 9). Any other modifications of these conditions
afforded lower conversions. When comparing Pd/C with common commercial heterogeneous
BH/HA catalysts Pt/Al2O3 or Ru/Al2O313 (Table 1, entries 17 and 18), moderate conversions
4

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and selectivities were observed under the same conditions. As long as catalyst support may
have significant influence, more specific Pt/C and Ru/C were also evaluated. However, the
overall conversion and selectivity were smaller (See SI for complete details).
Table 1. Screening conditions for the preparation of β-amino alcohol 2a by Heterogeneous BH/HA Reaction
Entry
1
1
T
Time
64h
64h
24h
24h
0,5h
6h
EG
6 mL
6 mL
6 mL
6 mL
6 ml
6 ml
6 ml
6 mL
12 mL
0,25 ml
6 ml
6 ml
6 ml
6 ml
6 ml
6 ml
6 ml
6 ml
6 ml
Water
6 mL
6 mL
6 mL
6 ml
6 ml
6 ml
6 ml
6 ml
0 mL
6 ml
6 ml
6 ml
6 ml
6 ml
6 ml
6 ml
6 ml
6 ml
6 ml
Catalyst
Pd/C 7%
Pd/C 7%
Pd/C 7%
Pd/C 7%
Pd/C 7%
Pd/C 7%
Pd/C 7%
Pd/C 7%
Pd/C 7%
Pd/C 7%
Pd/C 7%
Pd/C 7%
Pd/C 7%
Pd/C 7%
Pd/C 3%
Pt/Al2O3 7%
Ru/Al2O3 7%
Pt/C 7%
Additive
Zn 3eq.
Conversiona
99%
99%
99%
92%
0%
Selectivity
0%
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol
2 mmol
1 mmol
1mmol
1 mmol
1mmol
1 mmol
200ºC
200ºC
200ºC
150ºC
150ºC
150ºC
150ºC
150ºC
150ºC
150ºC
150ºC
150ºC
150ºC
150ºC
150ºC
150ºC
150ºC
150ºC
150ºC
2
ZnO 3eq.
ZnO 3eq.
ZnO 3eq.
ZnO 3eq.
ZnO 3eq.
ZnO 3eq.
ZnO 3eq.
ZnO 3eq.
ZnO 3eq.
no ZnO
0%
3
0%
98% (88%)b
4
5
0%
6
67%
90%
99%
0%
71%
82%
90%
0%
7
12h
64h
24h
64h
24h
24h
24h
24h
24h
24h
24h
24h
24h
8
9
10
11
12
13
14
15
16
17
18
19
<5%
<5%
50%
56%
99%
50%
47%
21%
81%
71%
99%
99%
99%
80%
66%
75%
80%
71%
37%
65%
ZnO 1eq.
ZnO 2eq.
ZnO 4eq.
ZnO 3eq.
ZnO 3eq.
ZnO 3eq.
ZnO 3eq.
ZnO 3eq.
Ru/C 7%
a. Conversion obtained by 1H-NMR. Selectivity measured towards 2a. b. Isolated yield after purification.
The stability of the catalytic system was evaluated by means of PXRD before and after the
reaction observing no significant changes (Figure S2). Reuses without any cleaning of the
catalyst, just removing by decantation the liquid phase and adding amine and solvents again,
afforded 70% of conversion up to three rounds. ICP analysis indicated no significant Pd or Zn
leaching after the reaction. However, small modification on the ZnO particle size was
5

ACCEPTED MANUSCRIPT
detected that may explain this decrease in combination of the inevitable loss of catalyst during
the decantation (see the SI for more details). Hot filtration test confirmed a complete
heterogeneous process (Scheme S3).
Once optimized the reaction conditions for the preparation of β-amino alcohol 2a, the scope
of the reaction was studied (Figure 2). In view of the major challenge that represents diols in
BH/HA processes different aromatic amines were selected as reagents in order to avoid any
side reactions on the initial amine as Williams reported with some amino alcohols.10 In
general, all reagents afforded moderated to good conversion and selectivity.
1
Figure 2. Scope of the catalysis using different aryl amines. Structure of side compounds (
3
-
5
). H-NMR and
isolated yields (brackets) are shown.
6

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First, different mono-methyl anilines were submitted to the conditions, affording compounds
2a-2i. Conversion decreased with steric hindrance at the ortho position, but in all cases β-
amino alcohols were isolated in moderate yields. Compound 2j, derived from aniline, was
also obtained in 65%. When the substituents were strong electron withdrawing groups no
conversion was observed (2k
fluorine allowed the isolation of the desired amino alcohols 2n
23% isolated yields). Trifluoromethyl and trifluoromethoxyl groups were also employed and
afforded alcohols 2q 2r and 2s in moderate yields. Amino alcohols 2t 2u 2v and 2w contain
methoxyl groups. In almost all cases, side products traces (indoles and/or dimers and 5,
,
2l and 2m). However, moderate withdrawing groups like
,
2o and 2p (34%, 32% and
,
,
,
3
4
Table S2) could be isolated. These compounds are known to appear when ethylene glycol and
anilines are heated and are the main responsible of yield dicrease.10
We also wanted to explore to possibility of inducing strain in the amine by using 1,2,3,4-
tetrahydroquinoline (
6) as long as in our previous work we determine that this compound
generates indole in a more efficient way.15 When the reaction was performed with
6
the
amount of indole increased (Figure 3) yielding to compounds 7a in 45% yield and 7b in 45%.
With a methoxide derivative
16 % (isolated yields).
8
similar behavior was observed, yielding 9a in 18% and 9b in
1
Figure 3. Heterogeneous BH/HA reactions with tetrahydroquinolines
6
and
8
. Yields obtained by H-NMR and
isolated yields.
7

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In view of these results, a rational mechanism could be proposed for this reaction. The
formation of amino alcohols follows a typical BH/HA pathway, being Pd/C the responsible
for the hydrogenation/dehydrogenation process. In addition, as it has been shown in Table 1,
ZnO is required to activate alcohol. Many examples reported in the literature with diols under
homogeneous4,24 or heterogeneous13 catalysis afford the double functionalization.25 This
avoids the formation of amino alcohols yielding to diamines, either inter- or intra-molecular
as it is the case when Pd/MgO is used as catalyst with ethylene glycol as reported by Corma.26
Kempe and Williams methodologies6,9 are the unique successful conditions for this
challenging mono activation of ethylene glycol. These methodologies employed an excess of
ethylene glycol (significantly smaller than in our conditions, 3 eq6 or 5 eq9) and solvents.
However, by using our systems, even having a large excess of glycol (it is indeed co-solvent
with water), we are able to obtain the amino alcohols without anhydrous conditions.
In Figure 4, the rational mechanism is represented. Normal BH/HA pathway is employed for
the formation of amino alcohol. Ethylene glycol is transformed into the corresponding mono-
aldehyde by means of Pd/C in presence of ZnO as activating agent (conversion decreases
when smaller amount of ZnO are employed, Table 1 entries 12 and 13). The relatively long
reaction times required (24h) and also the absence of 2-hydroxyacetaldehyde in the crude may
indicate that this first process is the rate limiting one. This hypothesis may be supported by
the fact that this step must be mediated by both heterogeneous catalysts, while all the
subsequent steps require just Pd/C. In addition, ZnO may be partially soluble under our
conditions.27 The interaction between both catalyst may be facilitated thanks to this solubility
combined with the excess (300%) of ZnO. Then, the amine generates the corresponding imine
that is reduced yielding to the β-amino alcohol closing BH/HA cycle. However, with ethylene
glycol, a tautomeric equilibrium of this imine can yield to a different compound that may
undergo indole formation or dimers. Williams9 and Bruneau24 reported on a similar
tautomeric feature with amino alcohols under BH/HA reactions in homogeneous phase. When
8

ACCEPTED MANUSCRIPT
imine is generated, the tautomeric pathway implicates a migration of the double bond. This
migration is also well known in the literature and employed in the Voigth reaction for the
preparation of β
-amino ketones.28 This takes place through the aliphatic chain yielding to an
enol that is formally a hidden indole. In order to capture intermediates, 1,2-diamino benzene
was employed to give alcohol 1029a in excellent yield by means of condensation, suggesting
once again that the imine is an intermediate, even if it has not been detected in any example.
Figure 4. Rational mechanism and key intermediates
9

ACCEPTED MANUSCRIPT
Indole formation has been found more efficient using
6
compared to anilines that requires
activation of the aromatic ring (Figure 5). Rigidity in
6
induces an intermediate with the
adequate geometry leading to a more efficient indole formation. In anilines, free rotation may
difficult the achieving of this intermediate and is responsible of smaller yields. Even if the
formation of the indole reduces the yield of the amino alcohol, a straight synthesis of indoles
also represents a major advancement in catalysis. However, the formation of indole cannot be
produced by over reaction of the corresponding
β-amino alcohol. When compound 7a was
submitted to the reaction conditions, no conversion was observed (Scheme S4).
Figure 5. Structural differences in indole formation between 1,2,3,4-tetrahydroquinoline (6) and p-toluidine (1)
intermediates.
In order to verify this mechanism some tests were performed (See the SI for more details). To
add evidences of imine tautomerism, deuteration essays in reactions were carried out. The
6
D/H ratios agree with this double bond migration (Scheme S1). Alcohol 7a was also oxidized
under Swern conditions yielding to an aldehyde that evolved spontaneously to 7b proving that
this aldehyde is extremely reactive under our reaction conditions (Scheme S2). However,
imine intermediates were not isolated, compared with Corma results.27 This is also in
agreement with the inability of the catalyst to dehydrogenate β-amino alcohols (Scheme S4).
Diols and anilines can be transformed into indoles with homogenous catalysis, but normally
diols have methyl substituents.29b,29c
10

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Finally, tandem reactions were tested. In view of the difficulty that requires activation of
ethylene glycol, we considered that under these conditions we may be able to hydrogenate
indoles (Figure 6). Under heterogeneous conditions, this kind of reaction is proposed without
this hydrogenation step.30 However, Williams and Beller31 reported on the pre-formation of
indolines as a part of a more functional BH/HA cycle and end up by re-aromatization towards
and alkylated indole.
Figure 6. Tandem functional BH/HA cycles.
To check this, we performed reactions with indole (11), indoline (12) and 5-methoxy indole
(
13). In all cases amino alcohols were isolated, proving that our catalyst was able to
hydrogenate the five-member ring generating an amine that could undergo BH/HA cycle. The
combined selectivity of 14a or 15a-b proves that Pd/C, ZnO combination is a powerful
-
b
catalyst that is not only able to activate ethylene glycol but also dehydrogenate/hydrogenate
indoles.
11

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Conclusion
The combination of Pd/C and ZnO has been proved to be an adequate heterogeneous catalyst
for the single-alcohol activation of ethylene glycol in presence of aromatic amines under
BH/HA cycles in water/ethylene glycol mixture. We have prepared a large family of β-amino
alcohols by a new protocol. In addition, major secondary products of this reaction are indoles,
and even their low yield, it represents also a major input on a straight synthesis of these
heterocycles. The present methodology reveals to be useful as long as it is air and moisture
stable. Furthermore, we have proved that Pd/C, ZnO is also able to hydrogenate indoles to
indolines inducing tandem BH/HA reactions all of them driven by a heterogeneous catalyst.
All these reactions are possible by a mono-activation of ethylene glycol that takes place
thanks to the combination of Pd/C and ZnO and an excess of glycol. This is the unique
heterogeneous approach towards
β-amino alcohols with high atom efficiency (due to the
BH/HA process), and without derivatization of glycol. The complementarity between BH/HA
common economical catalyst (Pd/C) with and alcohol activation agents (ZnO) represents a
different approach towards extremely stable poly alcohols. Further studies are undergoing
with the aim reducing the amount of ethylene glycol as well as the use of different diols.
Experimental Methods
General procedure:
1 mmol of amine, 0.07 mmol of Pd/C, 3 mmol of ZnO, 6 mL of distilled water and 6 mL of
ethylene glycol were mixed manually inside a 20mL Teflon flask. Then it was sealed into a
steel autoclave and introduced in a preheated oven at 150ºC for 24h. The reaction mixture was
cooled to room temperature, 25mL of distilled water were added and the crude was filtered
through a 0.2µm Teflon filter. The reaction mixture was extracted with ethyl acetate 3x15ml
and organic layers were combined, dried with Na2SO4, filtered and concentrated affording the
reaction crude that was cheeked by NMR. Crude reaction was purified by chromatotron (1
12

ACCEPTED MANUSCRIPT
mm, silica, from hexane to hexane/AcOEt 1:3) affording pure
β
-amino alcohols. Similar
conditions were employed with tetrahydroquinolines
6 and 8. Tandem reactions were
performed under the same conditions employing indoles or indoline instead of aniline. For all
isolated compounds in this work that are new: name, structure, isolated yield, physical aspect
1
13
and characterization by H-NMR, C-NMR, HRMS and IR are shown. For those products
that are already described in the literature: name, structure, isolated yield, physical aspect, and
1
13
characterization by H-NMR and C-NMR are shown. An isolated yield defined as “traces”
is referred to an amount of isolated product between 1 and 5 mg, considering this range of
values not enough to give a representative yield.
1
2-(4-Methylphenylamino)ethanol
(
2a)32 Isolated yield: 130 mg (88%). Oil. H 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
13
(t, J= 5.2 Hz, 2H), 2.85 (bs, 1H), 2.25 (s, 3H). C 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,
CH3).
33
1
2-(3-Methylphenylamino)ethanol (2b
)
Isolated yield: 60 mg (39%). Oil. H NMR (300
MHz, CDCl3) δ: 7.00 (dd, J=11.0; 5.1 Hz, 1H), 6.44 (m, 3H), 3.71 (t, J=5.2 Hz, 2H), 3.19 (t,
J=5.2 Hz, 2H), 2.82 (s, 1H), 2.20 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 148.4 (1C, C), 139.5
(1C, C), 129.6(1C, CH), 119.4 (1C, CH), 114.4 (1C, CH), 110.9 (1C, CH), 61.7 (1C, CH2),
46.7 (1C, CH2), 22.0 (1C, CH3).
2-(2-Methylphenylamino)ethanol (
2c)34 Isolated yield: 44 mg (28%). Oil. 1H NMR (300 MHz,
CDCl3) δ: 7.12 (m, 2H), 6.69 (m, 2H), 3.87 (t, J= 5.1 Hz, 2H), 3.35 (t, J= 5.1 Hz, 2H), 2.18 (s,
13
3H). C NMR (75 MHz, CDCl3) δ: 146.1 (1C, C), 130.4 (1C, CH), 127.2(1C, CH), 122.7
(1C, C), 117.6(1C, CH), 110.2 (1C, CH), 61.3 (1C, CH2), 46.1 (1C, CH2), 17.6 (1C, CH3).
1
2-(2,3-Dimethylphenylamino)ethanol
(
2d) Isolated yield: 30 mg (22%). Oil. H NMR (300
MHz, CDCl3) δ: 7.04 (t, J = 7.8 Hz, 1H), 6.64 (d, J = 7.5 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H),
13

ACCEPTED MANUSCRIPT
13
3.87 (t, J = 5.2, 2H), 3.34 (t, J = 5.2, 2H), 2.30 (s, 3H), 2.09 (s, 3H). C NMR (75 MHz,
CDCl3) δ: 146.1 (1C, C), 136.9 (1C, C), 126.3(1C, CH), 121.2 (1C, C), 120.0(1C, CH), 108.6
(1C, CH), 61.4 (1C, CH2), 46.5 (1C, CH2), 20.8 (1C, CH2), 12.7 (1C, CH3). HRMS for
C10H15NO [M+H+]: calculated: 166.1220; found: 166.1219. IR (ATR): 3409, 2943, 2878,
1589, 1506, 1476, 1458, 1317, 1283, 1141, 1060, 765, 713.
1
2-(2,4-Dimethylphenylamino)ethanol
(
2e) Isolated yield: 30 mg (23%). Oil. H NMR (300
MHz, CDCl3) δ 6.94 (d, J = 8.1 Hz, 1H), 6.91 (s, 1H), 6.58 (d, J = 8.0 Hz, 1H), 3.86 (t, J =
5.2, 2H), 3.33(t, J = 5.2, 2H), 2.24 (s, 3H), 2.15 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 143.8
(1C, C), 131.3 (1C, CH), 127.5 (1C, CH), 127.0 (1C, C), 123.0 (1C, C), 110.6 (1C, CH), 61.4
(1C, CH2), 46.5 (1C, CH2), 20.7 (1C, CH3), 17.6 (1C, CH3). HRMS for C10H15NO [M+H+]:
calculated: 166.1226; found: 166.1217. IR (ATR): 3403, 2918, 1618, 1514, 1457, 1378, 1314,
1269, 1219, 1144, 1061, 875, 804, 772, 607.
1
2-(3,4-Dimethylphenylamino)ethanol
(
2f) Isolated yield: 43 mg (30%). Oil. H NMR (300
MHz, CDCl3) δ: 6.96 (d, J=8.0 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 6.44 (dd, J=8.0;2.5, 1H), 3.81
13
(t, J=5.4 Hz, 2H), 3.28 (t, J=5.3 Hz, 2H), 2.72 (s, 1H), 2.21 (s, 3H), 2.17 (s, 3H). C NMR
(75 MHz, CDCl3) δ: 146.3 (1C, C), 137.5 (1C, C), 130.5 (1C, CH), 126.2 (1C, C), 115.4 (1C,
CH), 110.9 (1C, CH), 61.4 (1C, CH2), 46.7 (1C, CH2), 20.1 (1C, CH3), 18.8 (1C, CH3).
HRMS for C10H15NO [M+H+]: calculated: 166.1226; found: 166.1225. IR (ATR): 3354,
2917, 2861, 1616, 1507, 1448, 1319, 1262, 1217, 1059, 1021, 852, 803, 703.
1
2-(3,5-Dimethylphenylamino)ethanol
(
2g) Isolated yield: 41 mg (30%). Oil. H NMR (300
MHz, CDCl3) δ: 6.43 (s, 1H), 6.31 (s, 2H), 3.80 (t, J=5.2 Hz, 2H), 3.28 (t, J=5.2 Hz, 2H), 2.27
13
(s, 6H). C NMR (75 MHz, CDCl3) δ: 148.3 (1C, C), 139.1 (2C, C), 120.1(1C, CH), 111.4
(2C, CH), 61.4 (1C, CH2), 46.3 (1C, CH2), 21.6 (2C, CH3). HRMS for C10H15NO [M+H+]:
calculated: 166.1226; found: 166.1219. IR (ATR): 3381, 2927, 2842, 1601, 1574, 1504, 1456,
1373, 1346, 1329, 1302, 1241, 1212, 1194, 1131, 1095, 1058, 1011, 938, 872, 831, 800, 743,
718.
14

ACCEPTED MANUSCRIPT
-(2,5-Dimethylphenylamino)ethanol 2h) Isolated yield: 53 mg (39%). Oil. H NMR (300
1
2
(
MHz, CDCl3) δ: 6.87 (d, J=7.4 Hz, 1H), 6.44 (d, J=7.5 Hz, 1H), 6.40 (s, 1H), 3.78 (t, J=5.3
Hz, 2H), 3.26 (t, J=5.3 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ: 146.2 (1C, C), 137.6 (1C, C),
130.5(1C, CH), 120.1 (1C, C), 118.6(1C, CH), 111.5 (1C, CH), 61.7 (1C, CH2), 46.3 (1C,
CH2), 21.9 (1C, CH3), 17.4 (1C, CH3). HRMS for C10H15NO [M+H+]: calculated: 166.1226;
found: 166.1220. IR (ATR): 3405, 3014, 2919, 1614, 1581, 1519, 1456, 1422, 1376, 1297,
1272, 1206, 1167, 1139, 1058, 1000, 877, 842, 793.
1
2-(2,6-Dimethylphenylamino)ethanol
(
2i)34 Isolated yield: 20 mg (12%). Oil. H NMR (300
MHz, CDCl3) δ: 7.01 (d, J= 7.4 Hz, 2H), 6.86 (dd, J= 7.9; 7.0 Hz, 1H), 3.80 (t, J= 5.0 Hz,
2H), 3.15 (t, J= 5.0 Hz, 2H), 2.73 (bs, 1H), 2.33 (s, 6H). 13C NMR (75 MHz, CDCl3) δ: 145.1
(1C, C), 130.2 (1C, C), 129.1 (2C, CH), 122.8 (1C, CH), 62.3 (1C, CH2), 50.6 (1C, CH2),
18.5 (2C, CH3).
2-Phenylaminoethanol (
2j)35 Isolated yield: 89 mg (65%). Oil. 1H NMR (300 MHz, CDCl3) δ:
7.14-7.06 (m, 2H), 6.69-6.62 (m, 1H), 6.60 (dd, J= 8.6; 1.0 Hz, 2H), 3.71 (t, J= 5.3 Hz, 2H),
13
3.19 (t, J= 5.3 Hz, 2H). C NMR (75 MHz, CDCl3) δ: 148.2 (1C, C), 129.4 (2C, CH), 118.0
(1C, CH), 113.4 (2C, CH), 61.3 (1C, CH2), 46.2 (1C, CH2).
1
2-(4-Fluorophenylamino)ethanol
(
2n)36 Isolated yield: 52 mg (34%). Oil. H NMR (300
MHz, CDCl3) δ: 6.90-6.85 (m, 2H), 6.60-6.55 (m, 2H), 3.82 (m, 2H), 3.24 (t, J= 5.3 Hz, 2H).
13C NMR (75 MHz, CDCl3) δ: 164.0 (1C, C), 160.1 (1C, C), 114.6 (1C, C), 114.4 (1C, C),
115.8 (1C, C), 115.4 (1C, C), 61.4 (1C, CH2), 46.2 (1C, CH2).
1
2-(3-Fluorophenylamino)ethanol
(
2o) Isolated yield: 50 mg (32%). Oil. H NMR (300 MHz,
CDCl3) δ: 7.03 (td, J=8.1; 6.7 Hz, 1C), 6.34 (m, 2H), 6.26 (dt, J=11.5; 2.3 Hz, 1C), 3.76 (t,
J=5.2 Hz, 2H), 3.21 (t, J=5.2 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ: 162.5 (1C, C),
149.8(1C, C), 130.4 (1C, CH), 109.1(1C, CH), 104.4 (1C, CH), 99.9 (1C, CH), 61.1 (1C,
CH2), 45.94 (1C, CH2). HRMS for C8H10FNO [M+H+]: calculated: 156.0819; found:
15

ACCEPTED MANUSCRIPT
156.0807. IR (ATR): 3351, 2929, 1617, 1588, 1510, 1495, 1459, 1334, 1286, 1175, 1149,
1054, 997, 963, 828, 756, 681.
1
2-(2-Fluorophenylamino)ethanol
(
2p) Isolated yield: 35 mg (23%). Oil. H NMR (300 MHz,
CDCl3) δ: 7.00 (m, 2H), 6.76 (td, J=8.4; 1.5 Hz, 1H), 6.66 (m, 1H), 3.86 (t, J=5.2 Hz, 2H),
13
3.35 (t, J=5.2 Hz, 2H). C NMR (75 MHz, CDCl3) δ: 153.6 (1C, C), 150.4(1C, C), 124.8
(1C, CH), 117.6 (1C, CH), 114.9(1C, CH), 112.9 (1C, CH), 61.4 (1C, CH2), 46.0 (1H, CH2).
HRMS for C8H11FNO [M+H+]: calculated: 156.0825; found: 156.0811. IR (ATR): 3402,
1620, 1514, 1544, 1336, 1297, 1252, 1188, 1061, 1033, 741.
1
2-(2-Trifluoromethylphenylamino)ethanol
(
2q) Isolated yield: 84 mg (41%). Oil. H NMR
(300 MHz, CDCl3) δ: 7.87 (ddd, J= 7.9; 1.6; 0.6 Hz, 1H), 7.26 (m, 1H), 6.64 (m, 2H), 2.11 (t,
J= 4.6 Hz, 2H), 3.92 (t, J= 4.6 Hz, 2H). 13C NMR (75 MHz, CDCl3)δ: 168.5 (1C, C),
150.7(1C, C), 134.5 (1C, CH), 131.6 (1C, CH), 116.9 (1C, CH), 116.4 (1C, CH), 110.5 (1C,
C), 66.2 (1C, CH2), 61.6 (1C, CH2). HRMS for C9H10F3NO [M-2H+]: calculated: 204.0631;
found: 204.0625. IR (ATR): 3473, 3368, 1682, 1614, 1587, 1561, 1487, 1455, 1291, 1240,
1161, 1131, 1065, 751, 702, 665.
1
2-(3-Trifluoromethylphenylamino)ethanol
(
2r)37 Isolated yield: 101 mg (50%). Oil. H NMR
(300 MHz, CDCl3) δ: 7.10 (t, J= 7.9 Hz, 1H), 6.82-6.77 (m, 1H), 6.67 (s, 1H), 6.61 (dd, J=
8.2; 2.3Hz, 1H), 3.67 (t, J= 5.2 Hz, 2H), 3.15 (t, J= 5.2 Hz, 2H). 13C NMR (75 MHz, CDCl3)
δ: 148.5 (1C, CF3), 129.8(1C, CH), 126.2 (1C, C), 122.6 (1C, C), 116.3 (1C, CH), 114.3 (1C,
CH), 109.3 (1C, CH), 61.1 (1C, CH2), 45.8 (1C, CH2).
1
2-(2-Trifluoromethoxyphenylamino)ethanol
(
2s) Isolated yield: 59 mg (28%). Oil. H NMR
(300 MHz, CDCl3) δ: 7.07 (m, 2H), 6.70 (dd, J= 8.5; 1.5 Hz, 1H), 6.62 (m, 1H), 3.78 (t, J=
5.2 Hz, 2H), 3.28 (t, J= 5.2 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ: 140.9 (1C, C), 134.9 (1C,
C), 128.1 (1C, CH), 121.4 (1C, CH), 117.4 (1C, CH), 112.8 (1C, CH), 61.5 (1C, CH2), 46.0
(1C, CH2). HRMS for C9H10F3NO2 [M+H+]: calculated: 222.0736; found: 222.0729. IR
16

ACCEPTED MANUSCRIPT
(ATR): 3420, 2930, 2360, 1614, 1515, 1457, 1330, 1246, 1215, 1166, 1042, 923, 745, 669,
630, 604.
1
2-(2-Methoxyphenylamino)ethanol
(
2t)38 Isolated yield: 108 mg (65%). Oil. H NMR (300
MHz, CDCl3) δ: 6.88 (td, J= 7.6; 1.6 Hz, 1H), 6.79 (dd, J= 7.9; 1.5 Hz, 1H), 6.72 (dd, J= 7.5;
1.6 Hz, 1H), 6.66 (dd, J= 7.8; 1.5 Hz, 1H), 3.75 (s, 3H), 3.74 (t, J= 5.3 Hz, 2H), 3.32 (t, J= 5.3
Hz, 2H).13C NMR (75 MHz, CDCl3) δ: 147.3 (1C, C), 138.1 (1C, C), 121.3 (1C, CH), 117.1
(1C, CH), 110.4(1C, CH), 109.7 (1C, CH), 61.4 (1C, CH3), 55.5 (1C, CH2), 46.0 (1C, CH2).
2-(4-Methoxyphenylamino)ethanol (
2u)35 Isolated yield: 115 mg (70%). Oil.1H NMR (300
MHz, CDCl3) δ: 6.76 (d, J= 9.2 Hz, 2H), 6.58 (d, J= 8.8 Hz, 2H), 3.74 (t, J= 5.2 Hz, 2H), 3.73
13
(s, 3H), 3.25 (t, J= 5.2 Hz, 2H). C NMR (75 MHz, CDCl3) δ: 152.8 (1C, C), 142.5 (1C, C),
115.1 (2C, CH), 114.9 (1C, CH), 61.3 (1C, CH3),55.8 (1C, CH2), 47.1 (1C, CH2).
1
2-(3,5-Dimethoxylphenylamino)ethanol
(
2v) Isolated yield: 22 mg (11%). Oil. H NMR (300
MHz, CDCl3) δ: 5.92 (t, J=2.1 Hz, 1H), 5.87 (s, 1H), 5.86 (s, 1H), 3.82 (t, J=5.2 Hz, 2H), 3.75
13
(s, 6H), 3.27 (t, J=5.3 Hz, 2H). C NMR (75 MHz, CDCl3) δ: 161.9 (2C, C), 149.9 (1C, C),
92.5 (2C, CH), 90.6 (1C, CH), 61.3 (1C, CH3), 55.3 (2C, CH2), 46.5 (1C, CH2). HRMS for
C10H15NO3 [M+H+]: calculated: 198.1125; found: 198.1113. IR (ATR): 3384, 2938, 2839,
1613, 1507, 1456, 1235, 1203, 1176, 1151, 1127, 1059, 808.
1
2-(3,4-Dimethoxylphenylamino)ethanol
(
2w) Isolated yield: 35 mg (18%). Oil. H NMR (300
MHz, CDCl3) δ: 6.74 (d, J= 8.5 Hz, 1H), 6.30 (d, J= 2.6 Hz, 1H), 6.20 (dd, J= 8.5; 2.6 Hz,
13
1H), 3.84-3.81 (m, 5H), 3.80 (s, 3H), 3.26 (t, J= 5.2 Hz, 2H). C NMR (75 MHz, CDCl3) δ:
150.1 (1C, C), 142.9 (1C, C), 142.2(1C, C), 113.3 (1C, CH), 104.4 (1C, CH), 99.8 (1C, CH),
61.4 (1C, CH2), 56.8 (1C, CH3), 55.9 (1C, CH3), 47.3 (1C, CH2). HRMS for C10H15NO3
[M+H+]: calculated: 198.1125; found: 198.1125. IR (ATR): 3383, 2940, 2832, 1616, 1515,
1463, 1232, 1210, 1168, 1139, 1024, 797, 611.
5-Methylindole
(
3a)39 Isolated yield: traces. Oil. 1H NMR (300 MHz, CDCl3) δ: 7.44 (m, 2H),
13
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). C
17

ACCEPTED MANUSCRIPT
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
6-Methylindole
(
3b) and 4-Methylindole
(
3b’)40 Isolated yield: 23 mg (17%, mixture). Oil. H
NMR (300 MHz, CDCl3) δ: 8.15 (bs, 1H), 8.01 (bs, 1H), 7.54 (d, J= 8.1 Hz, 1H’), 7.16 (m,
5H), 6.97 (d, J= 8.3 Hz, 1H’), 6.93 (d, J= 7.2 Hz, 1H), 6.58 (s, 1H), 6.51 (s, 1H’), 2.58 (s,
13
3H), 2.48 (s, 3H’). C NMR (75 MHz, CDCl3) δ: 136.4 (1C’, C), 135.6 (1C, C), 131.9 (1C,
C), 130.4 (1C’, C), 127.9(1C’, C), 125.7 (1C, C), 123.6 (1C, CH), 122.2 (1C, CH), 121.7
(1C’, CH), 120.4 (1C’, CH), 120.0 (1C, CH), 111.1 (1C, CH), 108.7 (1C, CH), 102.5 (1C’,
CH), 101.2 (1C, CH), 21.8 (1C, CH3), 18.9 (1C’, CH3).
1
7-Methylindole
(
3c)41 Isolated yield: 27 mg (20%). Oil. H NMR (300 MHz, CDCl3) δ: 8.07
(bs, 1H), 7.51 (d, J= 7.5 Hz, 1H), 7.22 (s, 1H), 7.09-6.97 (m, 2H), 6.57 (s, 1H), 2.52 (s, 3H).
13C NMR (75 MHz, CDCl3) δ: 131.2 (1C, C), 123.9 (2C, CH and C), 122.63 (2C, CH), 120.2
(1C, CH), 118.6(1C, CH), 103.3 (1C, CH), 16.8 (1C, CH3).
1
6,7-Dimethylindole
(
3d)42 Isolated yield: traces. Oil. H NMR (300 MHz, CDCl3) δ: 7.40 (d,
13
J=8.0 Hz, 1H), 7.16 (m, 1H), 6.96 (d, J=8.1, 1H), 6.51 (dd, J=3.2; 2.1, 1H), 2.41 (s, 6H). C
NMR (75 MHz, CDCl3) δ: 129.4 (2C, C), 123.5 (1C, CH), 122.80 (1C, CH), 117.85 (1C,
CH), 103.2 (1C, CH), 19.4 (1C, CH3), 13.3 (1C, CH3).
1
5,7-Dimethylindole
(
3e)43 Isolated yield: traces. Oil. H NMR (300 MHz, CDCl3) δ: 7.29 (bs,
13
1H), 7.18 (m, 1H), 6.84 (bs, 1H), 6.48 (dd, J=3.1; 2.1, 1H), 2.47 (s, 3H), 2.42 (s, 3H). C
NMR (75 MHz, CDCl3) δ: 133.3(1C, C), 131.3 (1C, C), 127.4 (1C, C), 124.42 (1C, CH),
124.0 (1C, CH), 119.9 (1C, C), 102.8 (1C, CH), 21.5 (1C, CH3), 16.8 (1C, CH3).
5,6-Dimethylindole (3f) (
44 and 4,5-Dimethylindole 3f’)45 Isolated yield: traces (mixture). Oil.
1H NMR (300 MHz, CDCl3) δ: 8.05 (bs, 1H), 7.96 (bs, 1H’), 7.40 (s, 1H’), 7.16 (m, 3H), 7.10
(t, J= 2.8 Hz, 1H’), 7.01 (d, J= 8.2 Hz, 1H), 6.54 (ddd, J= 3.1; 2.1; 0.9 Hz, 1H), 6.44 (ddd, J=
13
3.0; 2.0; 0.9 Hz, 1H’), 2.47 (s, 3H), 2.37 (s, 3H), 2.36 (s, 3H’), 2.35 (s, 3H’). C NMR (75
MHz, CDCl3) δ: 134.4 (2C, C), 128.6 (2C, C), 127.7 (2C, C), 126.6 (2C, C), 124.8 (1C, CH),
18

ACCEPTED MANUSCRIPT
123.8 (1C, CH), 123.4 (1C’, CH), 120.8 (1C’, CH), 111.5 (1C’, CH), 108.2 (1C, CH), 102.0
(1C’, CH), 101.1 (1C, CH), 20.6 (1C’, CH3), 19.6 (1C’, CH3), 19.4 (1C, CH3), 15.6 (1C,
CH3).
1
4,6-Dimethylindole
(
3g)46 Isolated yield: 38 mg (32%). 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, 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, CH), 101.1 (1C, CH),
21.8 (1C, CH3), 18.8 (1C, CH3).
1
4,7-Dimethylindole
(
3h)42 Isolated yield: traces. Oil. H NMR (300 MHz, CDCl3)δ: 7.22 (m,
1H), 6.93 (d, J=7.2 Hz, 1H), 6.86 (d, J=7.1 Hz, 1H), 6.60 (m, 1H), 2.56 (s, 3H), 2.48 (s, 3H).
13C NMR (75 MHz, CDCl3) δ: 135.1 (1C, C), 127.9 (1C, C), 127.4(1C, C), 123.3 (1C, CH),
122.6 (1C, CH), 120.1 (1C, CH), 117.7 (1C, C), 101.79 (1C, CH), 18.7 (1C, CH3), 16.6 (1C,
CH3).
1
4,6-Dimethoxyindole
(
3v)47 Isolated yield: traces. Oil. H NMR (300 MHz, CDCl3) δ: 8.03
(bs, 1H), 6.99 (dd, J=3.2; 2.3 Hz, 1H), 6.57 (ddd, J= 3.1; 2.2; 0.8 Hz, 1H), 6.50 (dd, J= 1.8;
13
0.8 Hz, 1H), 6.24 (d, J= 1.9 Hz, 1H), 3.93 (s, 3H), 3.84 (s, 3H). C NMR (75 MHz, CDCl3)
δ: 157.7 (1C, C), 153.8 (1C, C), 137.3 (1C, C), 121.3 (1C, CH), 113.2 (1C, C), 99.9 (1C, CH),
91.8 (1C, CH), 86.9 (1C, CH), 55.8 (1C, CH3), 55.5 (1C, CH3).
5,6-Dimethoxyindole (
3w)48 Isolated yield: 36 mg (20%). Oil. 1H NMR (300 MHz, CDCl3) δ:
8.06 (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;
13
0.9 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H). C NMR (75 MHz, CDCl3) δ: 147.2 (1C, C), 145.3
(1C, C), 130.3 (1C, C), 122.8(1C, CH), 120.7 (1C, C), 102.4 (2C, CH), 94.6 (1C, CH), 56.4
(1C, CH3), 56.3 (1C, CH3).
1
N,N’-Bis(4-methylphenyl)-1,2-ethanediamine
(
4a) Isolated yield: traces. Oil. H 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),
19

ACCEPTED MANUSCRIPT
44.2 (2C, CH2), 20.5 (2C, CH3). HRMS for C16H20N2 [M+H+]: calculated: 241.1699; found:
241.1688. IR (ATR): 2918, 2858, 1616, 1517, 1464, 1317, 1296, 1256, 1182, 1127, 806.
49
1
N,N’-Bis(2-methylphenyl)-1,2-ethanediamine
(
4c
)
Isolated yield: 13 mg (24%). Oil. H
NMR (300 MHz, CDCl3) δ: 7.15 (t, J=7.6 Hz, 2H), 7.08 (d, J=7.2 Hz, 2H), 6.70 (m, 4H), 3.50
13
(s, 4H), 2.13 (s, 6H). C NMR (75 MHz, CDCl3) δ: 130.4 (2C, CH), 127.3 (2C, CH), 122.7
(4C, C), 117.8(2C, CH), 110.2 (2C, CH), 43.4 (2C, CH2), 17.7 (2C, CH3)
1
N,N’-Bis(2,4-dimethylphenyl)-1,2-ethanediamine
(
4e)49 Isolated yield: traces. Oil. H NMR
(300 MHz, CDCl3) δ: 6.87 (d, J=8.1 Hz, 2H), 6.83 (s, 2H), 6.53 (d, J=8.0 Hz, 2H), 3.38 (s,
4H), 2.16 (s, 6H), 2.03 (s, 6H). 13C NMR (75 MHz, CDCl3) δ: 143.7 (2C, C), 131.3 (2C, CH),
127.5 (2C, CH), 126.9 (2C, C), 110.5 (2C, CH), 43.7 (2C, CH2), 20.5 (2C, CH3), 17.6 (2C,
CH3).
N,N’-Bis(3,5-dimethylphenyl)-1,2-ethanediamine
(
4g) Isolated yield: traces. Oil. 1H NMR
13
(300 MHz, CDCl3) δ: 6.40 (s, 2H), 6.29 (s, 4H), 3.36 (s, 4H), 2.24 (s, 12H). C NMR (75
MHz, CDCl3) δ: 148.1 (2C, C), 138.2 (4C, C), 120.1(2C, CH), 111.3 (4C, CH), 43.7 (2C,
CH2), 21.6 (4C, CH3). HRMS for C18H24N2 [M+H+]: calculated: 269.2012; found: 269.2016.
IR (ATR): 2916., 2358, 2342, 1652, 1601, 1558, 1540, 1520, 1506, 1489, 1472, 1456, 1338,
1186, 819, 772.
1
N,N’-Bis(3-fluorophenyl)-1,2-ethanediamine
(
4o) Isolated yield: traces. Oil. H NMR (300
13
MHz, CDCl3) δ: 7.14-7.09 (m, 2H), 6.48-6.28 (m, 6H), 3.39 (s, 4H). C NMR (75 MHz,
CDCl3) δ: 164.2 (d,
J
= 243.4 Hz, 2C, C), 149.0 (d,
J
= 10.6 Hz, 2C, C), 130.6 (d,
J = 10.2
Hz, 2C, CH), 109.2 (d,
J
= 2.5 Hz, 2C, CH), 104.8 (d,
J
= 21.5 Hz, 2C, CH), 100.1 (d, J =
25.3 Hz, 2C, CH), 43.3 (2C, CH2). HRMS for C14H14F2N2 [M+H+]: calculated: 249.1198;
found: 249.1202. IR (ATR): 1616, 1589, 1507, 1496, 1175, 1150, 830, 757, 682.
1
N,N’-Bis(2-trifluoromethoxyphenyl)-1,2-ethanediamine
(
4s) Isolated yield: traces. Oil. H
NMR (300 MHz, CDCl3) δ: 7.19-7.12 (m, 4H), 6.77 (dd, J=8.5; 1.5 Hz, 2H), 6.73-6.66 (m,
13
2H), 3.46 (s, 4H). C NMR (75 MHz, CDCl3)δ: 140.4 (2C, C), 136.6 (2C, C), 127.9 (2C,
20

ACCEPTED MANUSCRIPT
CH), 122.7(2C, C), 121.3 (2C, CH), 117.1(2C, CH), 112.1 (2C, CH), 42.7 (2C, CH2). HRMS
for C16H14F6N2O2 [M+H+]: calculated: 381.1032; found: 381.1012. IR: 3454, 2928, 1612,
1558, 1514, 1472, 1328, 1248, 1217, 1166, 1043, 920, 772, 746, 674, 630, 606.
1
1,4-Bis(4-methylphenyl)-piperazine
(
5a) Isolated yield: traces. Oil. H NMR (300 MHz,
13
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). C
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 for C18H22N2 [M+H+]: calculated: 267.1856; found: 267.1844.
IR (ATR): 2953, 2919, 2855, 2820, 2360, 2343, 1743, 1615, 1515, 1489, 1452, 1384, 1317,
1293, 1265, 1229, 1211, 1180, 1150, 1041, 939, 823, 813, 771.
1
1,4-Bis(3-methylphenyl)-piperazine
(
5b) Isolated yield: traces. Oil. H NMR (300 MHz,
CDCl3) δ: 7.19 (t, J= 7.9 Hz, 2H), 6.81 (m, 4H), 6.73 (d, J=7.3 Hz, 2H), 3.33 (s, 8H), 2.35 (s,
6H). 13C NMR (75 MHz, CDCl3) δ: 151.5 (2C, C), 139.0 (2C, C), 129.2 (2C, CH), 121.1 (2C,
CH), 117.35 (2C, CH), 113.6 (2C, CH), 49.7 (4C, CH2), 21.9 (2C, CH3). HRMS for C18H22N2
[M+H+]: calculated: 267.1856; found: 267.1844. IR (ATR): 2826, 1604, 1583, 1494, 1448,
1242, 995, 955, 690, 609.
1
1,4-Bis(2-methylphenyl)-piperazine
(
5c) Isolated yield: traces. Oil. H NMR (300 MHz,
CDCl3) δ: 7.20 (m, 4H), 7.11, (d, J=7.90 Hz, 2H), 7.01 (t, J=7.2 Hz, 2H), 3.08 (s, 8H), 2.37 (s,
6H). 13C NMR (75 MHz, CDCl3) δ: 151.8 (2C, C), 132.8 (2C, C), 131.3 (2C, CH), 126.7 (2C,
CH), 123.3(2C, CH), 119.3 (2C, CH), 52.4 (4C, CH2), 18.1 (2C, CH3). HRMS for C18H22N2
[M+H+]: calculated: 267.1856; found: 267.1854. IR (ATR): 2946, 2823, 1596, 1490, 1442,
1372, 1253, 1222, 1142, 1112, 1039, 945, 767, 722.
1
1,4-Bis(2,3-dimethylphenyl)-piperazine
(
5d) Isolated yield: traces. Oil. H NMR (300 MHz,
CDCl3) δ: 7.11 (t, J=7.7 Hz, 2H), 7.00 (d, J=7.6 Hz, 2H), 6.92 (d, J=7.4 Hz, 2H), 3.05 (s, 8H),
13
2.29 (s, 6H), 2.28 (s, 6H). C NMR (75 MHz, CDCl3) δ: 151.9 (2C, C), 138.1 (2C, C),
131.5(2C, C), 125.9 (2C, CH), 125.1(2C, CH), 116.9 (2C, CH), 52.9 (2C, CH2), 20.8 (2C,
CH3), 14.2 (2C, CH3). HRMS for C20H26N2 [M+H+]: calculated: 295.2169; found: 295.2163.
21

ACCEPTED MANUSCRIPT
IR (ATR): 2949, 2814, 2744, 1580, 1507, 1475, 1449, 1373, 1315, 1272, 1233, 1219, 1140,
1085, 1028, 994, 944, 775, 717.
1
1,4-Bis(2,4-dimethylphenyl)-piperazine
(
5e) Isolated yield: traces. Oil. H NMR (300 MHz,
CDCl3) δ 7.03 (m, 6H), 3.04 (s, 8H), 2.33 (s, 6H), 2.30 (s, 6H).13C NMR (75 MHz, CDCl3) δ
149.4 (2C, C), 132.8 (4C, C), 127.2(2C, CH), 119.2 (2C, CH), 52.7 (4C, CH2), 20.8 (2C,
CH3), 17.9 (2C, CH3). HRMS for C20H26N2 [M+H+]: calculated: 295.2169; found: 295.2175.
IR (ATR): 2943, 2813, 2359, 2343, 1504, 1447, 1370, 1353, 1311, 1293, 1257, 1234, 1220,
1163, 1143, 1125, 1044, 961, 947, 913, 888, 812, 755, 720, 668.
1
1,4-Bis(3,4-dimethylphenyl)-piperazine
(
5f) Isolated yield: 23 mg (20%). Oil. H NMR (300
MHz, CDCl3) δ: 7.06 (d, J= 8.2 Hz, 2H), 6.82 (d, J=2.4 Hz, 2H), 6.75 (dd, J=8.2, 2.6 Hz, 2H),
3.29 (s, 8H), 2.26 (s, 6H), 2.20 (s, 6H). 13C NMR (75 MHz, CDCl3) δ: 149.8 (2C, C),
137.3(2C, C), 130.4 (2C, CH), 128.5(2C, C), 118.5 (2C, CH), 114.2 (2C, CH), 50.3 (4C,
CH2), 20.4 (2C, CH3), 18.9 (2C, CH3). HRMS for C20H26N2 [M+H+]: calculated: 295.2169;
found: 295.2170. IR (ATR): 2963, 2919, 2822, 1616, 1504, 1447, 1336, 1235, 1178, 1156,
1127, 1023, 1000, 961, 872, 850, 807, 703.
1
1,4-Bis(3,5-dimethylphenyl)-piperazine
(
5g) Isolated yield: 33 mg (27%). Oil. H NMR (300
13
MHz, CDCl3) δ: 6.64 (s, 4H), 6.58, (s, 2H), 3.33 (s, 8H), 2.32 (s, 6H). C NMR (75 MHz,
CDCl3) δ: 151.5(2C, C), 138.4 (2C, CH), 122.5 (4C, C), 114.5 (4C, CH), 49.9 (8C, CH2), 21.8
(4C, CH3). HRMS for C20H26N2 [M+H+]: calculated: 295.2169; found: 295.2168. IR (ATR):
2978, 2830, 2802, 1596, 1451, 1438, 1384, 1343, 1257, 1198, 1153, 1011, 827, 696, 685.
1
1,4-Bis(2,5-dimethylphenyl)-piperazine
(
5h) Isolated yield: 25 mg (20%). Oil. H NMR (300
MHz, CDCl3) δ: 7.09 (d, J=7.5 Hz, 2H), 6.92 (s, 2H), 6.83 (d, J=7.5 Hz, 2H), 3.07 (s, 8H),
2.33 (s, 6H), 2.32 (s, 6H). 13C NMR (75 MHz, CDCl3) δ: 151.7 (2C, C), 136.2 (2C, C), 131.1
(2C CH), 129.5 (2C, C), 123.9 (2C, CH), 120.1(2C, CH), 52.4 (4C, CH2), 21.4 (2C, CH3),
17.7 (2C, CH3).HRMS for C20H26N2 [M+H+]: calculated: 295.2159, found: 295.2167. IR:
2946, 2920, 2812, 1504, 1448, 1370, 1238, 1219, 1145, 1126, 992, 804, 772.
22

ACCEPTED MANUSCRIPT
1,4-Bis(2,3-dimethoxyphenyl)-piperazine
(
5w) Isolated yield: traces. Oil. 1H NMR (300 MHz,
CDCl3) δ: 6.82 (d, J= 8.7 Hz, 2H), 6.66 (bs, 2H), 6.53 (dd, J= 8.6; 2.6 Hz, 2H), 3.89 (s, 6H),
13
3.85 (s, 6H), 3.28 (s, 8H). C NMR (75 MHz, CDCl3) δ: 149.7 (4C, C), 112.2 (2C, CH),
108.5 (4C, C), 103.4 (2C, CH), 56.4 (2C, CH3), 56.0 (2C, CH3), 51.3 (4C, CH2). HRMS for
C20H26N2O4 [M+H+]: calculated: 359.1965; found: 359.1963. IR (ATR): 2943, 2836, 2803.
1
N-(2-Hydroxyethyl)-1,2,3,4-tetrahydroquinoline
(
7a)49 Isolated yield: 79 mg (45%). Oil. H
NMR (300 MHz, CDCl3) δ: 7.26-6.36 (m, 4H), 3.70-3.10 (m, 6H), 2.75 (t, J= 6 Hz, 2H), 1.91
13
(m, 2H). C NMR (75 MHz, CDCl3) δ: 146.0(1C, C), 129.5 (1C, CH), 127.2 (1C, CH),
123.02 (1C, C), 116.6(1C, CH), 111.5 (1C, CH), 60.1 (1C, CH2), 54.3 (1C, CH2), 50.5 (1C,
CH2), 28.2 (1C, CH2), 23.03 (1C, CH2).
50
1
5,6-Dihydro-4H-pyrrolo-[3,2,1-ij]-quinoline
(
7b
)
Isolated yield: 70 mg (45%). 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,
13
2H), 2.93 (t, J= 6.1 Hz, 2H), 2.17 (m, 2H). C 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
3,4-Dihydro-6-methoxy-1(2H)-quinolinethanol
(
9a) Isolated yield: 39 mg (18%). Oil. H
NMR (300 MHz, CDCl3) δ: 6.66 (m, 2H), 6.59 (m, 1H), 3.79 (t, J= 5.7 Hz, 2H), 3.73 (s, 3H),
13
3.37 (t, J= 5.7 Hz, 2H), 3.25-3.20 (m, 2H), 2.77 (t, J= 6.5 Hz, 2H), 2.01-1.89 (m, 2H). C
NMR (75 MHz, CDCl3) δ: 151.7 (1C, C), 140.7 (1C, C), 125.0 (1C, C), 115.3 (1C, CH),
113.7(1C, CH), 112.7 (1C, CH), 59.9 (1C, CH3), 55.9 (1C, CH2), 55.5 (1C, CH2), 50.3 (1C,
CH2), 28.3 (1C, CH2), 22.2 (1C, CH2). HRMS for C12H17NO2 [M+H+]: calculated: 208.1332;
found: 208.1326. IR (ATR): 3355, 2929, 1502, 1464, 1429, 1334, 1296, 1265, 1238, 1201,
1151, 1036, 1004, 922, 879, 843, 796, 721, 670, 631.
5,6-Dihydro-8-methoxy-4H-pyrrolo[3,2,1-ij]quinoline (9b) Isolated yield: 30 mg (16%). Oil.
1H 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=
23

ACCEPTED MANUSCRIPT
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=
13
8.9; 3.4 Hz, 2H), 2.28-2.17 (m, 2H). C 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 for C12H13NO [M+H+]:
calculated: 188.1070; found: 188.1066. IR (ATR): 2938, 1618, 1601, 1495, 1436, 1394, 1342,
1298, 1261, 1234, 1218, 1140, 1047, 1031, 830, 799, 716.
1H-Benzimidazole-2-methanol (10)
28,51 Isolated yield: 103 mg (70%). Yellow powder, m.p.=
1
169.5-170.5 ºC. H NMR (300 MHz, CD3OD) δ: 7.60-7.48 (m, 2H), 7.27-7.15 (m, 2H), 4.85
(s, 2H).13C NMR (75 MHz, CD3OD) δ: 157.6 (1C, C), 139.9 (2C, C), 122.6 (2C, CH), 117.6
(2C, CH), 58.7 (1C, CH2).
2,3-Dihydro-1H-indole-1-ethanol (14a) & 2-Indol-1-yl-ethanol (
14b)52 Isolated yield: 43 mg
(26%, mixture). Oil. 1H NMR (300 MHz, CDCl3) δ: 7.67-7.63 (m, 1H-b), 7.38 (dd, J= 8.2; 0.8
Hz, 1H-b), 7.26-7.19 (m, 1H-a), 7.16 (d, J= 3.2 Hz, 1H-a), 7.15-7.06 (m, 3H-a,b), 6.72 (td,
J=7.5; 0.9 Hz, 1H-a), 6.57 (d, J= 7.8 Hz, 1H-a, 6.53 (dd, J= 3.1; 0.8 Hz, 1H-a), 4.27 (t, J= 5.3
Hz, 2H-b), 3.93 (t, J= 5.3 Hz, 2H-b), 3.80 (t, J= 5.4 Hz, 2H-a), 3.39 (t, J= 8.3 Hz, 2H-a), 3.23
13
(t, J= 5.3 Hz, 2H-a), 3.00 (t, J= 8.3 Hz, 2H-a). C NMR (75 MHz, CDCl3) δ: 152.8 (1C, C),
136.2 (1C, C), 130.2 (1C, C), 128.8 (1C, C), 128.5 (1C, CH-a), 127.5 (1C, CH-a,b), 124.7
(1C, CH-a,b), 121.8 (1C, CH-a), 121.2 (1C, CH-b), 119.7 (1C, CH-a,b), 118.6 (1C, CH-a),
109.4 (1C, CH-b), 107.6 (1C, CH-a), 101.6 (1C, CH-b), 62.0 (1C, CH2-b), 60.3 (1C, CH2-a),
54.0 (1C, CH2-a), 52.8 (1C, CH2-a), 48.9 (1C, CH2-b), 28.8 (1C, CH2-a).
1
2-(5-Methoxyindolin-1-yl)ethanol
(
15a) Isolated yield: 22 mg (11%). Oil. H NMR (300
MHz, CDCl3) δ: 6.78-6.75 (m, 1H), 6.66 (dd, J= 8.5; 2.6 Hz, 1H), 6.53 (d, J=8.5 Hz, 1H),
3.81 (t, J= 5.4 Hz, 2H), 3.75 (s, 3H), 3.35 (t, J= 8.1 Hz, 2H), 3.18 (t, J= 5.4 Hz, 2H), 2.97 (t,
13
J= 8.1 Hz, 2H), 2.24 (bs, 1H). C NMR (75 MHz, CDCl3) δ: 153.8(1C, C), 132.0 (2C, C),
112.1(2C, CH), 108.5 (1C, CH), 60.2 (1C, CH2), 56.2 (1C, CH2), 54.8 (1C, CH3), 54.1 (1C,
CH2), 29.1 (1C, CH2). HRMS for C11H15NO2 [M+H+]: calculated: 194.1176; found:
24

ACCEPTED MANUSCRIPT
194.1171. IR (ATR): 3361, 2934, 2830, 1620, 1594, 1576, 1488, 1449, 1435, 1397, 1360,
1236, 1190, 1150, 1051, 1030, 939, 864, 833, 798, 753, 724.
1
2-(5-Methoxy-1H-indol-1-yl)ethanol
(
15b) Isolated yield: 20 mg (10%). Oil. H NMR (300
MHz, CDCl3) δ: 7.25 (d, J= 8.9 Hz, 1H), 7.12 (d, J= 3.1 Hz, 1H), 7.10 (d, J= 2.4 Hz, 1H),
6.88 (dd, J= 8.9; 2.5 Hz, 1H), 6.44 (dd, J= 3.1; 0.8 Hz, 1H), 4.23 (t, J= 5.3 Hz, 2H), 3.91 (t, J=
13
5.3 Hz, 2H), 3.85 (s, 3H). C NMR (75 MHz, CDCl3) δ: 154.3 (1C, C), 131.6 (1C, C),
129.2(1C, C), 129.0 (1C, CH), 112.2 (1C, CH), 110.2 (1C, CH), 102.8(1C, CH), 101.3 (1C,
CH), 62.2 (1C, CH2), 56.0 (1C, CH2), 49.0 (1C, CH3). HRMS for C11H13NO2 [M+H+]:
calculated: 192.1019; found: 192.1013. IR (ATR): 3409, 2940, 2831, 1621, 1487, 1449, 1237,
1190, 1150, 1063, 1030, 799, 721.
Associated Content
Supporting Information.
1
Additional information, complete table of Figure 2, additional mechanistic experiments, H-
and 13C-NMR spectra of all compounds (PDF).
Author Information
Corresponding Author:
*E-mail: rafael.ballesteros-garrido@uv.es
Notes
The authors declare no competing financial interest.
Acknowledgements
R. B-G is much indebted to the Postdoctoral fellow 2013 of the “Ministerio de Economía y
Competitividad” (Spain, FPDI-2013-17464). This work was financially supported by the “Ministerio
de Ciencia e Innovación” (Spain) (Project CONSOLIDER-INGENIO SUPRAMED CSD 2010-
25

ACCEPTED MANUSCRIPT
00065 and from University of Valencia (Spain) (UV-INV-AE 15-332846)). Acknowledgments to the
“Central Services for Experimental Research” (SCSIE) of University of Valencia and NANBIOSIS
platform. We gratefully acknowledge the suggestions and advice from the referee in order to improve
the quality of this contribution.
References
1.
Li C-J, Trost BM PNAS 2008;105:13197–13202.
2.
3.
4.
Trost BM Angew. Chem. Int. Ed. 1995;34:259–281.
Watson AJA, Williams JMJ. Science 2010;329:635–636.
Hamid MHSA, Slatford PA, Williams JMJ. Adv. Synth. Catal. 2007;349:1555-
1575.
5.
Guillena G, Ramon DJ, Yus M. Chem. Rev. 2010;110:1611-1641.
a) Michlik S, Kempe R. Nat. Chem. 2013;5:140-144. b) Andrushko N. Andrushko
V. Roose P. Moonen K. Börner A. ChemCatChem, 2010;2:640–643.
Bergmeier SC. Tetrahedron 2000;56:2561-2576.
6.
7.
8.
Ager DA, Prakash I, Schaad DR. Chem. Rev. 1996;96:835-876.
Hamid MHMS, Allen CL, Lamb GW, Maxwell AC, Maytum HC, Watson AJA,
Williams, JMJ. J. Am. Chem. Soc. 2009;131:1766-1774.
a) Tsuji Y, Huh KT, Watanabe Y. J. Org. Chem. 1987;52:1673-1680. b) Bähn S.
Tillack A. Imm S. Mevius K. Michalik D. Hollmann D. Neubert L. Beller M.
ChemSuSChem, 2009;2:551-557.
9.
10.
11.
12.
13.
Selva M, Perosa A, Fabris M. Green Chem. 2008;10:1068-1077.
Shivarkar AB, Gupte SP, Chaudhari RV. SYNLETT, 2006;9:1374-1378.
Shimizu KI. Catal. Sci. Technol. 2015;5:1412-1427.
26

ACCEPTED MANUSCRIPT
Gnanaprakasam B, Balaraman E, Ben-David Y, Milstein D. Angew. Chem. Int. Ed.
14.
2011;50:12240-12244.
15.
16.
17.
18.
19.
Abarca B, Adam R, Ballesteros R. Org. Biomol. Chem. 2012;10:1826-1833.
Kolboe S. J. Catal. 1972;27:379-388.
Müller HD, Steinbach F. Nature 1970;225:728-729.
Vohs JM, Barteau A. Surf. Sci. 1989;221:590-608.
Nokkosmäski MI, Kuoppala ET, Leppämäki EA, Krausse AOI. J. Anal. Appl.
Pyrol. 2000;55:119-131.
20.
a) Nakajima T, Tanabe K, Yamaguchi T, Matsuzaki I, Mishima S. Appl. Catal.
1989; 52:237-248.
21.
22.
Kolodziejczak-Radzimska A, Jesionowski T. Materials 2014;7:2833-2881.
Lacroix SD, Pennycook A, Liu S, Eisenhart TT, Marr AC. Catal. Sci. Technol.
2012;2:288-290.
23.
24.
a) Hassanpour A. Khanmiri R.H. Abolhasani J. Synthetic Commun. 2015;45:727-
733. (b) Dinparast L. Valizadech H. Monatsh. Chem. 2015;146:313–319
a) Labed A, Jiang F, Labed I, Lator A, Peters M, Achard M, Kabouche A,
Kabouche, Z, Sharma GVM, Bruneau C. Chem. Cat. Chem. 2015;7:1090-1096.
b) Yang Q, Wang Q, Yu, Z. Chem. Soc. Rev. 2015;44:2305-2329.
Marsella JA. J. Organomet. Chem. 1991;407:97-105.
25.
26.
27.
Corma A, Ródenas T, Sabater MJ. Chem. Eur. J. 2010;16:254-260.
ZnO has been reported to be soluble in hot ethylene glycol this is in agreement with
our ICP results see SI 3.1: Wang J. Chen Y. Shen W. Zhu Z. Xu Y. Fang Y. Catal
Comun. 2017;89:52-55.
28.
(a) Voight, K. J. Prakt. Chem. 1886;34:1-27; (b) Wang, Z. Comprehensive Organic
Name Reactions and Reagents “Voight reaction”, 2010; 2888-2891.
27

ACCEPTED MANUSCRIPT
a) Lorentz-Petersen L, Nordstrom L, Madsen R, Eur. J. Org. Chem. 2012;34:6752-
29.
6759; b) Xing J, Jia X. Adv. Mat. Res. 2011:668-671; c) Tursky M, Lorentz-
Petersen LLR, Olsen LB, Madsen R. Org. Biomol. Chem. 2010;8:5576–5582; this
methodology has also been explored by c) Zhang M, Xie F, Wang XT, Yan F,
Wang T, Chen M, Ding Y. RSC Adv. 2013;3:6022-6029.
Siddiki SMAH, Kon K, Shimizu KI. Green Chem. 2015;17:173-177.
Baehn S, Imm S, Mevius K, Neubert L, Tillack A, Williams MJJ, Beller M. Chem.
Eur. J. 2010;16:3590-3593.
30.
31.
32.
33.
Shafir A, Lichtor P, Buchwald S. J. Am. Chem. Soc. 2007;129:3490-3491.
Yin H, Jin M, Chen W, Chen C, Zheng L, Wei P, Han S. Tetrahedron Lett.
2012;53:1265-1270.
34.
35.
36.
37.
38.
Bhanu Prasad BA, Gilbertson SR. Org. Lett. 2009;11:3710-3713.
Yang M, Liu F. J. Org. Chem.2007;72:8969-8971.
Haldar P, Ray J. Org. Lett., 2005;7:4341-4343.
Shi M, Chen Y. J. Fluorine Chem. 2003;122:219-227.
Yin Y, Zheng K, Eid N, Howard S, Jeong J, Yi F, Guo J, Min Park C, Bibian M,
Wu W, Hernandez P, Park H, Wu Y, Luo J, LoGrasso P, Feng Y. J. Med. Chem.
2015;58:1846-1861.
39.
40.
Thansandote P, Hulcoop D, Langer M, Lautens M. J. Org. Chem. 2009;74:1673-
1678.
(a) 3b: Taydakov I, Dutova T, Sidorenko E, Krasnoselsky, SS. Chem. of
Heterocycl. Comp. 2011;47:425-434. (b). 3b’ Dobbs A. J. Org. Chem.
2001;66:638-641.
41.
42.
Hartung C, Fecher A, Chapell B, Snieckus V. Org. Lett. 2003;5:1899-1902.
Cho CS, Lim HK, Shim SC, Kim TJ, Choi H-J. Chem. Commun. 1998:995-996.
28

ACCEPTED MANUSCRIPT
43.
44.
Ezquerra J, Pedregal C, Lamas C, Barluenga J, Pérez M, García-Martín MA,
González JM. J. Org. Chem.1996;61:5804-5812.
Brown KL, Chanda T, Zou S, Valente EJ. Nucleos. Nucleot. Nucl. 2005;24:1147-
1165.
45.
46.
Thies N, Hrib C, Haak E. Chem. Eur. J. 2012;18:6302-6308.
Onajole O, Pieroni M, Tipparaju S, Lun S, Stec J, Chen G, Gunosewoyo H, Guo, H,
Ammerman N, Bishai W, Kozikowski A. J. Med. Chem. 2013;56:4093-4103.
Bratulescu G. Tetrahedron Lett. 2008;49:984-986.
47.
48.
De Luca L, De Grazia S, Ferro S, Gitto R, Christ F, Debyser Z, Chimirri A. Eur. J.
Med. Chem. 2011;46:756-764.
49.
50.
Matsumura T, Nakada M. Tetrahedron Lett. 2014;55:1412-1415.
Zhuangzhi S, Chun Z, Si L, Delin P, Shengtao D, Yuxin C, Ning J. Angew. Chem.
Int. Ed. 2009;48:4572-4576.
51.
52.
Voigt M, Smuda M, Pfahler C, Glomb M. J. Agric. Food Chem. 2010;58:5685-
5691.
Schiffner JA, Wöste TH, Oestreich M. Eur. Joc. Chem. 2010;1:174-182.
29