Tethered NHC Ligands for Stereoselective Alkyne Semihydrogenations

Article abstract of DOI:10.1055/s-0036-1590112

A copper(I)-catalyzed semihydrogenation of internal alkynes has been developed. A variety of oxygen- and nitrogen-tethered N-heterocyclic carbene (NHC) complexes have been investigated, leading to a highly Z-selective transformation. The catalyst is generated from inexpensive copper(I) chloride in situ and allows catalytic semihydrogenation down to 10 bar H₂.

Full text of DOI:10.1055/s-0036-1590112

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–M
paper
A
F. Pape, J. F. Teichert
Paper
Synthesis
Tethered NHC Ligands for Stereoselective Alkyne Semihydrogenations
Felix Pape
Johannes F. Teichert*
Institut für Chemie, Technische Universität Berlin,
Straße des 17. Juni 115, 10623 Berlin, Germany
johannes.teichert@chem.tu-berlin.de
Received: 04.01.2017
Accepted after revision: 09.02.2017
(formal) transfer of H2
H
O
O
Published online: 13.12.2016
DOI: 10.1055/s-0036-1590112; Art ID: ss-2017-z0008-op
H
R
R'
R
R'
Abstract A copper(I)-catalyzed semihydrogenation of internal alkynes
has been developed. A variety of oxygen- and nitrogen-tethered N-het-
erocyclic carbene (NHC) complexes have been investigated, leading to
a highly Z-selective transformation. The catalyst is generated from inex-
pensive copper(I) chloride in situ and allows catalytic semihydrogena-
tion down to 10 bar H2.
Cu–H
catalyst
H
R'
H
R'
R
R
Key words alkynes, dihydrogen, copper, stereoselectivity, hydroge-
nation, NHC ligands
hydrosilane (Si−H)
vs.
dihydrogen (H2)
• requires proton source
• stoichiometric Si waste
• mild conditions
• atom-economic
• high pressure required
The use of dihydrogen (H2) has been advocated for cata-
lytic reductive transformations with transition metal cata-
lysts to reduce the waste generated with commonly em-
ployed stoichiometric hydride sources such as boron or alu-
minum hydrides, hydrosilanes, or hydrostannanes.1 The use
of H2 in catalysis with copper hydrides exemplifies this
case: generally formed in situ from stoichiometric hydro-
silanes, a wide variety of catalytic (asymmetric) transfor-
mations can be effected with copper(I) hydride complexes;
and the overall reductive processes are well established
synthetic methods (Scheme 1).2–5 More recently, a number
of studies have been directed at the replacement of hydro-
silanes with H2, for example, in hydrogenation of carbonyl
groups6,7 or alkyne semihydrogenation.8–15 Key structural
feature for H2 activation in all of these instances was the
presence of a copper–oxygen bond in the active catalyst,
which presumably allows for an efficient H2 activation by
heterolytic cleavage of the H–H bond.16
Scheme 1 Reductive transformations with copper(I) hydride catalysts;
use of hydrosilanes or dihydrogen as stoichiometric reducing agent
semihydrogenations giving the corresponding Z-alkenes
such as 3. In addition, the catalyst displayed remarkable
chemoselectivity, as ketones like the acetophenone 1 were
not reduced under the reaction conditions. This absence of
reactivity is remarkable, as carbonyl compounds generally
are good substrates for the related hydrosilylation.2–5
Two main obstacles in the original study prompted us to
further investigate the tethered copper catalyst: 1) high H2
pressure of up to 100 bar was required for efficient catalysis
and 2) as copper(I) precursor, mesitylcopper(I)17 was need-
ed for best results. As pointed out in our earlier study,10 me-
sitylcopper(I) is difficult to purify and prone to decomposi-
tion in air and moisture. Both factors, however, have a
strong influence on catalyst activity and selectivity. Herein,
we would like to report our studies toward solving both re-
strictions in copper(I)-catalyzed alkyne semihydrogenation
with tethered NHC ligands.
To this end, we have introduced a copper(I) complex
with a tethered N-heterocyclic carbene (NHC) ligand bear-
ing an alkoxide, thus forging the Cu–O bond in an intramo-
lecular fashion as in the proposed complex 2 (Scheme 2).10
This catalyst design allows for highly stereoselective alkyne
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

B
F. Pape, J. F. Teichert
Paper
Synthesis
quired at this stage, displaying one of the limitations of the
current system. It was shown that the catalyst based upon
mesitylcopper(I) is more active than the present CuCl sys-
tem, as the former still gave full conversion of 4 at 20 bar H2
(entry 13). However, it should be noted that employment of
CuCl circumvents the need of the tedious preparation of
mesitylcopper(I) and manipulations in the glovebox. No re-
action was observed in the absence of a copper source.18
O
O
BnO
cat. 2
H2
3
BnO
H
3
1
3
H
84%
Z only
N
N
• excellent Z-stereoselectivity
• chemoselectivity (ketone stays intact)
• high pressure needed (100 bar)
Mes
Cu
Table 1 Optimization of Copper(I)-Catalyzed Alkyne Semihydrogena-
O
• catalyst preparation from labile mesitylcopper(I)
tion of Tolanea
2
formed in situ
5.0 mol% [Cu]
7.5 mol% 5a
15 mol% n-BuLi
H2
–
PF6
Scheme 2 Chemo- and stereoselective alkyne semihydrogenation
with tethered NHC copper(I) catalysts
H
Ph
N
N
H
Mes
Ph
THF, temp, 5 h
Ph
Ph
(Z)-6
HO
4
5a
Catalyst Optimization
Entry
Cu source
Conditions
Conv. (%)b
To optimize the copper(I)-catalyzed alkyne semihydro-
genation under the abovementioned aspects, we first inves-
tigated the possible replacement of mesitylcopper(I) by
more stable copper(I) salts. The semihydrogenation of
tolane (4) to (Z)-stilbene (6) served as the test reaction
(Table 1). In all cases, excellent stereoselectivity to (Z)-6 was
maintained, highlighting the hallmark advantages of cop-
per catalysts in alkyne semihydrogenation reactions.8–12
Emanating from our previous results,10 we commenced
with imidazolinium salt 5a as NHC precursor, requiring two
equivalents of base with regard to 5a. With a special atten-
tion to stable and readily available copper(I) sources, cop-
per(I) halides and copper(I) cyanide were investigated first
(Table 1, entries 1–4). Under forcing conditions (100 bar H2,
60 °C), only copper(I) chloride led to conversion to (Z)-6
(>99% after 5 h reaction time, entry 1), whereas copper(I)
bromide and copper(I) cyanide were not active catalysts
(entries 2–4). To probe whether low solubility of the cop-
per(I) salts in THF was the cause for the absent reactivity,
copper(I) triflate benzene complex was tested, however,
this also did not yield any turnover (entry 5). Two cationic
tetrakis(acetonitrile)copper(I) complexes bearing weakly
coordinating counterions, on the other hand, displayed
again full conversion of the internal alkyne 4 (entries 6 and
7). Taking into account the much lower price of copper(I)
chloride, we decided to investigate the temperature and H2
pressure required for the alkyne semihydrogenation with
this copper(I) precursor. It was found that for active cataly-
sis, a temperature of 60 °C was necessary, as the reaction at
40 °C – sufficient with mesitylcopper(I) as precursor10 – led
to no conversion of 4 (entry 8). Full consumption of 4 was
maintained to pressures down to 40 bar H2, lowering the
pressure even further led to diminished conversion to 4
(30% at 30 bar H2, no conversion at 20 bar H2; entries 10–
12). While these pressures are significantly lower than in
our previous study, still high pressure equipment is re-
1
2
CuCl
100 bar H2, 60 °C
100 bar H2, 60 °C
100 bar H2, 60 °C
100 bar H2, 60 °C
100 bar H2, 60 °C
100 bar H2, 60 °C
100 bar H2, 60 °C
100 bar H2, 40 °C
50 bar H2, 60 °C
40 bar H2, 60 °C
30 bar H2, 60 °C
20 bar H2, 60 °C
20 bar H2, 60 °C
>99
<1
CuBr
3
CuBr·SMe2
CuCN
<1
4
<1
5
CuOTf·C6H6
Cu(MeCN)4BF4
Cu(MeCN)4PF6
CuCl
<1
6
>99
>99
<1
7
8
9
CuCl
>99
>99
30
10
11
12
13
CuCl
CuCl
CuCl
<1
MesCuc,d
>99
a Unless otherwise noted, the amounts of (E)-6 and over-reduced alkane
were <1% (GC analysis).
b Determined by GC analysis.
c MesCu: mesitylcopper(I).
d 6 mol% 5a and 6 mol% n-BuLi were used.
Investigation of Ligands
Under the optimized conditions for the alkyne semihy-
drogenation, the influence of the tethered NHC ligands was
investigated next, making use of their modular setup (Fig-
ure 1).19,20 To obtain clear knowledge of even small reactivi-
ty differences, ligands were subsequently tested at various
pressures from 50 to 10 bar H2 at 60 °C in THF (Figure 1 and
Table 2). In the semihydrogenation of tolane (4), the alkox-
ide tethers of NHC precursors were systematically elongat-
ed from ethoxy 5a to pentoxy 5d substituents (Table 2, en-
tries 1 to 4), revealing that the four carbon containing teth-
er in 5c enabled complete semihydrogenation of 4 down to
a H2 pressure of 10 bar (Table 1, entry 3), which represents
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

C
F. Pape, J. F. Teichert
Paper
Synthesis
the highest activity in this study. Lowering the pressure
even further led to diminished conversion of 4, with no ac-
tivity observed at 5 bar H2. This reactivity trend with re-
gards to tether length does not correspond to our previous
findings,10 in which the two carbon tethered 5a showed the
highest activity. This underscores that the copper(I) source
and the respective counterions play an important role for
catalyst activity and the optimal ligand required. Hence, an
involvement of the chloride counterions in the active cata-
lyst seems likely. Next to building upon a cheaper and sta-
ble copper(I) source, the present protocol also allows for ef-
ficient alkyne semihydrogenations to be carried out at sig-
nificantly lower H2 pressure than our previous catalyst
design. However, the present catalysts do not achieve effi-
cient conversions at the ultimately desirable and more
practical pressure of 1 bar, meaning high pressure equip-
ment is still required. Full conversion to (Z)-6 at 20 bar H2
was also observed with phenylalanine-derived 5e (Table 2,
entry 5). Changing the tether to phenoxides 5f and 5g or a
tertiary alcohol 5h led to inactive catalysts (entries 6 to 8).
Similarly, the nature of the heterocyclic backbone has a
strong influence on the activity, as imidazolium-, pyrimi-
dinium-, and benzimidazolium-based ligands derived from
5i–k did not lead to efficient catalysis (entries 9–11). When
the N-aryl substituent was systematically varied it was
found that neither the variation of steric 5l, 5p or electronic
factors 5m, 5n or both 5o had a positive influence on the
conversion (entries 12 to 16). When the N-alkylimidazolin-
ium salts 5q–s were tested (entries 17–19), the correspond-
ing copper(I) complexes showed low activity in the alkyne
semihydrogenation.
All ligands yielding inactive alkyne semihydrogenation
catalysts at 50 bar H2 were subsequently tested at 100 bar
H2 (precursors 5f–k,m–p,s; Table 2, last column), to clarify
whether these particular ligands were principally suitable
for H2 activation and the general catalytic alkyne semihy-
drogenation. Of these catalysts tested, only the ones based
upon NHC precursors 5f, 5m, 5o, and 5s showed significant
activity at 100 bar H2. This demonstrates that, as a whole,
some variability is tolerated by the copper catalyst to acti-
vate H2, as phenoxide precursor 5f, bearing an oxygen teth-
er with a different pKa value for the O–H bond allows for
alkyne semihydrogenation, as well as electron-withdraw-
ing and electron-donating compounds 5m, 5o, and 5s.
However, in the latter two cases, a supportive effect
through extra coordinating ether groups cannot be ruled
out at this stage.
Of particular note is the aniline-tethered precursor 5t,
which also enables the alkyne semihydrogenation (Table 2,
entry 20). To the best of our knowledge, only copper(I)
complexes bearing a copper–oxygen bond had been suc-
cessfully used in H2 activation and subsequent catalysis.21
The fact that a semihydrogenation with this ligand precur-
–
–
–
–
PF6
PF6
PF6
PF6
Bn
N
N
N
N
N
N
N
N
( )n
HO
HO
HO
HO
n = 1, 5a
n = 2, 5b
n = 3, 5c
n = 4, 5d
5e
5f
5g
–
–
–
–
PF6
PF6
PF6
PF6
N
N
N
N
N
N
N
N
HO
HO
HO
HO
5j
5h
5i
5k
–
–
–
–
PF6
PF6
PF6
PF6
i-Pr
N
N
N
N
N
N
N
N
F3C
MeO
i-Pr
OMe
HO
HO
HO
HO
5l
5m
5n
5o
–
–
–
–
–
PF6
PF6
PF6
PF6
PF6
N
N
N
N
N
N
N
N
N
N
Bn
t-Bu
n-Bu
MesHN
HO
HO
HO
OPh HO
5t
5p
5q
5r
5s
Figure 1 Precursors for tethered NHC ligands used in this study
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

D
F. Pape, J. F. Teichert
Paper
Synthesis
–
–
Table 2 Ligand Screening for Alkyne Semihydrogenation
PF6
PF6
N
–
PF6
N
5.0 mol% CuCl
7.5 mol% 5
N
N
N
Mes
Bn
2 equiv i-Pr2NEt
2 equiv BnNH2
N
Mes
15 mol% n-BuLi
H
H
H
Ph
H2
BnHN
MesHN
Ph
H
MeCN, 60 °C, 19 h
TsO
Ph
Ph
9
8
5t
Ph
THF, 60 °C, 5 h
H
H
not observed
Ph
(Z)-6
26%
4
7
Scheme 3 Synthesis of 5t
Entry
Ligand
Conversion (%)a
precursor 50 bar H2 30 bar H2 20 bar H2 10 bar H2 100 bar H2
1
2
5a
5b
5c
5d
5e
5f
>99b
>99
>99
>99e
>99
<1
30b
>99
>99
>99e
>99
–
<1b
<1
>99
<1
>99e
–
–
>99b
–
–
3
>99c,d
–
–
4
–
5
<1
–
–
>99e
<1
<1
16
<1
<1
–
Figure 2 Crystal structure of 5t; H atoms and the PF6– counterion have
been omitted for clarity
6
7
5g
5h
5i
<1
–
–
–
8
<1
–
–
–
9
<1
–
–
–
10
11
12
13
14
15
16
17
18
19
20
5j
<1
–
–
–
Substrate Scope
5k
5l
<1
–
–
With the optimized reaction conditions in hand for the
alkyne semihydrogenation, we set out to investigate the
substrate scope with our improved catalyst system. In pre-
liminary studies, we found that although the semihydroge-
nation of unfunctionalized alkynes such as tolane (4, see
Table 1) is feasible at low H2 pressures reaching 10 bar,
somewhat higher pressures were required for substrates
bearing coordinating functional groups. In order to main-
tain generally applicable high conversions of the alkynes 10
without having to optimize the pressure needed for every
single substrate, 50 bar of H2 were applied. In all cases, only
pure Z-isomers of 11 were detected (Scheme 4). The alkyne
semihydrogenation protocol is applicable to diarylalkynes 4
and 10a–d, which can be converted to the corresponding
(Z)-stilbenes 6, 11a–d in high yields, irrespective of elec-
tron-withdrawing groups (CF3 in 11a) or electron-donating
groups (OMe in 11d). In the case of bromostilbene (11b), 7%
of debromination of 11b was detected, most probably due
to a slight excess of n-butyllithium present in the reaction
mixture. Aryl alkyl alkynes 10e–j are suitable substrates for
the semihydrogenation as well: pentynol-derived com-
pounds 10e–i can successfully be converted to the corre-
sponding Z-alkenes 11e–i in good to excellent yields. Again,
in the preparation of phenyl bromides 11f and 11j, small
amounts of debrominated products were detected (7% and
1%, respectively). While E-alkenes were never observed, a
5% of over-reduced alkane was produced along with meth-
oxy-substituted 11h. Acetophenone derivative 10i dis-
played partial reduction of the ketone (17% stilbene bearing
a benzyl alcohol) as well as relatively high over-reduction to
the alkane (24%). While the parent catalyst did not show
>99
7
<1
–
–
–
5m
5n
5o
5p
5q
5r
–
–
>99e
<1
>99e
<1
–
<1
–
–
–
<1
–
–
–
<1
–
–
–
>99e
>99
<1
<1
>99
–
–
–
<1
–
–
–
5s
5t
–
48
>99
>99
>99
>99
<1
a Determined by GC analysis.
b Compare Table 1.
c At 8 bar H2: 91% conversion of 4.
d At 5 bar H2: <1% conversion of 4.
e Less than 5% of 7 was detected.
sor is feasible even at H2 pressures down to 20 bar shows
that other copper–heteroatom bonds and tethered frame-
works could potentially be exploited for H2 activation.22
This is especially noteworthy as a related copper(I)/NHC an-
ilido complex (IPrCuNHPh) has been shown to be inactive
towards a reaction with H2.23 The synthesis of 5t needs
some further elaboration: originally, the preparation of im-
idazolium salt 9 bearing a benzylamine from tosylate 820
was envisaged (Scheme 3). However, the only product iso-
lated after tedious separation was the rearranged imidaz-
olinium 5t bearing two alkyl substituents on the heterocy-
cle. The structure of 5t was unambiguously determined by
NMR spectroscopy and X-ray crystal structure analysis (Fig-
ure 2).24,25
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

E
F. Pape, J. F. Teichert
Paper
Synthesis
any carbonyl reduction of 11i (see Scheme 2),10 it is evident
that the present catalyst does not display an equally high
functional group tolerance, mirroring the findings of relat-
ed studies.12,15 Finally, dialkylalkynes 10k and 10l can suc-
cessfully be converted into Z-alkenes 11k and 11l; however,
for complete conversion elevated H2 pressure of 85 bar had
to be applied. Protected Z-allyl alcohols such as 11l are use-
ful building blocks for organic synthesis, and a highly ste-
reoselective preparation as displayed in our case is desir-
able. In a similar vein, the semihydrogenation of propargyl
silane 10m was attempted, but no significant conversion to
an alkene was observed. Instead, the formation of 5% phen-
ylpropyne indicated a possible stoichiometric desilylation
mediated by the copper complex. Generally, the observed
high stereoselectivity indicates a reaction mechanism pass-
ing through copper(I) hydride intermediates, in which the
alkynes can stereospecifically insert to give a transient vi-
nylcopper(I) compound.26,27
In summary, we have developed an easy access to cop-
per(I) catalyst for alkyne semihydrogenations of internal
alkynes. A wide variety of oxygen- and nitrogen-tethered
NHC ligands have been investigated and the present proto-
col allows for the catalyst to be prepared in a practical man-
ner in situ from copper(I) chloride, circumventing previous-
ly necessary catalyst generation in the glovebox. Further-
more, it was shown that the alkyne semihydrogenation of a
variety of alkynes can be effected at lower pressure than
the parent system reaching 8 bar H2, while maintaining ex-
cellent Z-selectivity for the alkene products.
All reactions were carried out in flame dried glassware under a N2 at-
mosphere using standard Schlenk techniques. Analytical TLC was per-
formed on silica gel 60 G/UV254 aluminum sheets (Macherey-Nagel).
Flash column chromatography was performed on silica gel Davisil
LC60A (40–63 μm, pore size 60 Å, Grace) using the indicated solvents.
NMR spectra were recorded on AV400 or AV500 instruments
(Bruker). Chemical shifts are reported in parts per million (ppm) and
are referenced to the residual solvent resonance as the internal stan-
dard. Data are reported as follows: chemical shift, multiplicity (stan-
dard abbreviations), coupling constants (Hz), integration. Melting
points were determined using a Leica Galen III melting point appara-
tus (Wagner & Munz). IR spectra were recorded on a Cary 630 FT-IR
spectrometer equipped with an ATR unit (Agilent Technologies) or on
a FT/IR-4100 spectrophotometer (Jasco). Mass spectra (HRMS) were
obtained from the Analytical Facility at the Institut für Chemie at
Technische Universität Berlin (ESI/APCI: LTQ Orbitrap XL, Thermo Sci-
entific; EI: GC-system 5975C, HP-5MS, Agilent Technologies). Reac-
tions under microwave irradiation were performed in a Discover SP
(CEM). Liquid substrates for hydrogenation reactions were degassed
prior to use.
5.0 mol% CuCl
7.5 mol% 5c
15 mol% n-BuLi
50 bar H2
H
R2
H
R2
R1
THF, 60 °C, 18 h
R1
10a–m
(Z)-6, (Z)-11a–m
H
R = H, 6, 78%a
H
R = CF3, 11a, 77%a
R = Br, 11b, 83%b
R = Cl, 11c, 84%c
R = OMe, 11d, 87%
R
R
O
THF and 1,4-dioxane were dried over sodium/benzophenone and dis-
tilled under an N2 atmosphere prior to use. Toluene was dried over so-
dium and distilled under an N2 atmosphere prior to use. Et3N, CH2Cl2,
Et2O, and 1,2-dichloroethane were dried over CaH2 and distilled un-
der a N2 atmosphere prior to use. MeCN (99.9%, extra dry), DMF
(99.8%, extra dry), 2-Me-THF (99%, extra dry), and chlorobenzene
(99.8%, extra dry) were purchased from Acros. Benzene (puriss., abso-
lute) and tert-butyl methyl ether (anhyd, 99.8%) were purchased from
Sigma Aldrich. Solvents (technical grade) for extraction/chromatogra-
phy (EtOAc, cyclohexane, CH2Cl2, Et2O, tert-butyl methyl ether) were
distilled under reduced pressure prior to use.
H
R = H, 11e, 89%
H
H
R = Br, 11f, 92%b
R = CF3, 11g, 86%
R = OMe, 11h, 91%c
BnO
BnO
H
H
H
C4H9
Br
All hydrogenation reactions were carried out in glass vials (50 ×
14 mm, Schütt), equipped with a magnetic stir bar, a rubber septum
and a needle (0.90 × 50 mm, Braun) in autoclaves BR-100 or BR-300
(including the appropriate heating blocks; Berghof). The autoclave
was purged with N2 (3 × 10 bar) before the vials were placed in the
autoclave under a counterflow of N2. The autoclave was purged with
N2 (1 × 1 bar, 3 × 10 bar) and H2 (3 × 20 bar) before the appropriate H2
pressure was applied (pressure is given as initial pressure before heat-
ing). The heating block was preheated before the autoclave was placed
inside. After the respective reaction time, the autoclave was allowed
to cool to r.t. and H2 was released. The autoclave was purged with N2
(3 × 10 bar) before the vials were taken out. The reaction mixture was
filtered through a small plug of silica (4 × 0.6 cm, tert-butyl methyl
ether as eluent), and all volatiles were removed under reduced pres-
sure. Reactions were subsequently analyzed either by GC or NMR.
11i
100% conv.
24% alkane
11j
93%b
17% benzyl alcohol
H
H
H
OTIPS
Ph
SiMe3
H
C5H11
C5H11
BnO
11k
11l
86%d,e
10m
no conversiond,f
86%d
Scheme 4 Copper(I)-catalyzed alkyne semihydrogenation, substrate
scope. Unless otherwise noted, the ratio of Z/E/alkane is >99:1:1. a Reac-
tion time 5 h. b ≤7% dehalogenation observed. c 5% alkane observed.
d Reaction at 85 bar H2. e Contains 3% starting material, reaction was
run for 66 h. f Formation of 5% phenylpropyne observed.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

F
F. Pape, J. F. Teichert
Paper
Synthesis
An elaborate introduction to the experimental part, including the
preparation of starting materials and individual ligands, screening,
and control experiments, is provided in the Supporting Information.
solved in H2O (15 mL/mmol) followed by extraction with EtOAc
(3 × 15 mL/mmol). To the aqueous phase was added KPF6 (2 equiv)
and the resulting emulsion was stirred at r.t. (for reaction time, see
the corresponding substrate). The mixture was extracted with CH2Cl2
(3 × 7 mL/mmol), the combined organic layers were washed with
brine (15 mL/mmol), dried (MgSO4), and filtered. Removal of all vola-
tiles under reduced pressure and purification of the resulting residue
via flash column chromatography yielded the desired imidazolinium
hexafluorophosphates.
Synthesis of Ligands
General Procedures for the Stepwise Synthesis of Dihydroimidaz-
olium Hexafluorophosphates
Synthesis of 2-Oxoacetates; General Procedure 1
3-(2-Hydroxyphenyl)-1-mesityl-4,5-dihydro-1H-imidazol-3-ium
Hexafluorophosphate (5f)
Following
a
literature procedure,20 ethyl 2-chloro-2-oxoacetate
(1.2 equiv) was added dropwise to a solution of the corresponding
amine (1 equiv) and pyridine (1.2 equiv) in CH2Cl2 (1 M) at 0 °C. The
resulting mixture was stirred at r.t. until full conversion of the start-
ing material was detected (TLC analysis, for reaction time, see the cor-
responding substrate). The mixture was diluted with EtOAc
(1 mL/mmol) at r.t. and successively washed with 1 M aq HCl
(2 × 2 mL/mmol), sat. aq NaHCO3 (2 mL/mmol), and brine
(2 mL/mmol). The combined organic layers were dried (Na2SO4), fil-
tered, and all volatiles were removed under reduced pressure to yield
the corresponding 2-oxoacetates.
Prepared from the corresponding hydrochloride salt.28 To a solution
of the hydrochloride salt (0.19 g, 0.61 mmol, 1.0 equiv) in H2O
(20 mL) was added KPF6 (222 mg, 1.21 mmol, 1.98 equiv). The result-
ing suspension was stirred at r.t. for 15 h and extracted with CH2Cl2
(3 × 20 mL). The combined organic phases were dried (MgSO4). Filtra-
tion and removal of all volatiles under reduced pressure yielded 5f
(198 mg, 0.464 mmol, 76%) as a pale brown solid; mp 203 °C.
IR (ATR): 3520 (w), 1627 (m), 1600 (m), 1271 (m), 1254 (m), 819 (s),
753 (s), 555 cm–1 (s).
1H NMR (500 MHz, CD2Cl2): δ = 2.33 (s, 6 H), 2.34 (s, 3 H), 4.30–4.37
(m, 2 H), 4.65–4.71 (m, 2 H), 6.83 (br s, 1 H), 7.03–7.08 (m, 3 H), 7.13
(dd, J = 8.2, 1.2 Hz, 1 H), 7.22–7.25 (m, 1 H), 7.27 (dd, J = 8.0, 1.5 Hz, 1
H), 8.53 (s, 1 H).
13C NMR (125 MHz, CD2Cl2): δ = 17.8, 21.2, 50.8, 51.3, 118.0, 122.1,
122.2, 123.3, 129.9, 130.5, 130.6, 135.5, 141.6, 148.5, 158.0.
19F NMR (470 MHz, CD2Cl2): δ = –72.55 (d, J = 711 Hz).
31P NMR (202 MHz, CD2Cl2): δ = –144.3 (sept, J = 711 Hz).
HRMS (ESI): m/z calcd for C18H21N2O+ [(M – PF6–)+]: 281.1648; found:
Synthesis of Oxalamides; General Procedure 2
Following a literature procedure,10 a mixture of the corresponding 2-
oxoacetate (1.00 equiv) and the corresponding amino alcohol
(1.25 equiv) in CH2Cl2 (0.4 M) was stirred at reflux until full conver-
sion of the starting material was detected (TLC analysis, for reaction
time, see the corresponding substrate). The mixture was diluted with
EtOAc (2.5 mL/mmol) at r.t. and washed with 1 M aq HCl (1 M,
5 mL/mmol) and brine (5 mL/mmol), respectively. The combined or-
ganic layers were dried (Na2SO4), filtered, and all volatiles were re-
moved under reduced pressure to yield the corresponding oxal-
amides.
281.1646.
3-(2-Hydroxy-2-methylpropyl)-1-mesityl-4,5-dihydro-1H-imidaz-
Synthesis of Diamines; General Procedure 3
ol-3-ium Hexafluorophosphate (5h)
Following a literature procedure,10 LiAlH4 (4 equiv) was suspended in
THF (1.4 M). A solution of the corresponding oxalamide (1 equiv) in
THF (0.3 M) was added dropwise at 0 °C. The reaction mixture was
heated at reflux until full conversion of the starting material was de-
tected (TLC analysis, for reaction time, see the corresponding sub-
strate). The reaction was quenched by the addition of H2O
(2 mL/mmol) and 2 M aq NaOH (3.5 mL/mmol) at 0 °. The resulting
precipitate was removed by filtration over Celite. The layers were sep-
arated and the aqueous phase was extracted with tert-butyl methyl
ether (3 × 5 mL/mmol). The combined organic layers were dried
(Na2SO4) and filtered. Removal of all volatiles under reduced pressure
yielded the corresponding diamines.
Prepared from the corresponding hydrochloride.29 Prepared in analo-
gy to 5f. Compound 5h (174 mg, 0.428 mmol, 70%) was obtained as a
yellow solid; mp 201 °C.
IR (ATR): 3579 (m), 3040 (w), 2976 (w), 1636 (m), 1265 (m), 1193
(m), 821 cm–1 (s).
1H NMR (500 MHz, DMSO-d6): δ = 1.19 (s, 6 H), 2.26 (s, 6 H), 2.27 (s, 3
H), 3.45 (3.45, 2 H), 4.13–4.21 (m, 2 H), 4.24–4.32 (m, 2 H), 5.01 (s, 1
H), 7.04 (s, 2 H), 8.68 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 17.2, 20.5, 30.0, 50.5, 51.0, 57.8,
69.2, 129.4, 131.2, 135.4, 139.3, 159.7.
19F NMR (470 MHz, DMSO-d6): δ = –70.14 (d, J = 711 Hz).
31P NMR (202 MHz, DMSO-d6): δ = –144.19 (sept, J = 713 Hz).
HRMS (ESI): m/z calcd for C16H25N2O+ [(M – PF6–)+]: 261.1961; found:
Synthesis of 4,5-Dihydroimidazolium Hexafluorophosphates;
General Procedure 4
261.1954.
Following
a
literature procedure,10 the corresponding diamine
(1 equiv) was dissolved in Et2O (0.2 M) and HCl (2 M solution in Et2O,
1 equiv) was added dropwise at 0 °C. The resulting suspension was
stirred at r.t. (for reaction time, see the corresponding substrate). Re-
moval of all volatiles under reduced pressure yielded the correspond-
ing ammonium hydrochlorides as solids. The ammonium hydrochlo-
ride (1 equiv) was suspended in toluene (0.3 M) and trimethyl ortho-
formate (5 equiv) was added. The reaction mixture was heated at
90 °C until full conversion of the starting material was detected (NMR
analysis, for reaction time, see the corresponding substrate). All vola-
tiles were removed under reduced pressure, the precipitate was dis-
1-(2-Hydroxyethyl)-3-mesityl-3,4,5,6-tetrahydropyrimidin-1-ium
Hexafluorophosphate (5j)
A
solution of 1-mesityl-1,4,5,6-tetrahydropyrimidine30 (0.40 g,
2.0 mmol, 1.0 equiv) and 2-bromoethanol (0.14 mL, 2.0 mmol,
1.0 equiv) in DMF (10 mL) was heated at 100 °C for 5 d. All volatiles
were removed under reduced pressure, the resulting yellow oil was
dissolved in H2O (30 mL), and extracted with EtOAc (3 × 30 mL). To
the aqueous phase was then added KPF6 (0.73 g, 3.9 mmol, 2.0 equiv)
and the resulting brown emulsion was stirred at r.t. for 3 h. The aque-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

G
F. Pape, J. F. Teichert
Paper
Synthesis
ous phase was extracted with CH2Cl2 (3 × 15 mL), the combined ex-
tracts were dried (MgSO4), and filtered. Purification of the resulting
residue via flash column chromatography (SiO2, CH2Cl2/MeOH 30:1)
yielded 5j (346 mg, 0.882 mmol, 45%) as an orange oil, which was
crystallized from CH2Cl2/pentane at –20 °C; mp 98 °C; Rf = 0.21 (SiO2,
CH2Cl2/MeOH 14:1).
1H NMR (500 MHz, CDCl3): δ = 1.44 (t, J = 7.1 Hz, 3 H), 4.43 (q,
J = 6.7 Hz, 2 H), 7.64 (d, J = 8.5 Hz, 2 H), 7.78 (d, J = 8.6 Hz, 2 H), 9.01 (s,
1 H).
13C NMR (125 MHz, CDCl3): δ = 14.1, 64.2, 119.8, 124.0 (q, J = 272 Hz),
126.7 (q, J = 3.7 Hz), 127.5 (q, J = 33 Hz) 139.4, 154.2, 160.8.
19F NMR (470 MHz, CDCl3): δ = –62.3 (s).
HRMS (EI): m/z calcd for C11H10F3NO3 [(M+)]: 261.0607; found:
IR (ATR): 3593 (w), 2925 (w), 1655 (m), 1306 (w), 1053 (w), 827 (s),
556 cm–1 (s) .
1H NMR (500 MHz, CDCl3): δ = 2.18–2.22 (m, 6 H), 2.26–2.29 (m, 3 H),
2.33 (mc, 2 H), 2.75 (br s, 1 H), 3.51–3.56 (m, 2 H), 3.58–3.66 (m, 4 H),
3.78–3.84 (m, 2 H), 6.92 (s, 2 H), 7.53–7.57 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 17.3, 19.0, 21.1, 43.4, 45.8, 57.7, 57.8,
130.1, 135.0, 136.7, 140.2, 154.2.
19F NMR (470 MHz, DMSO-d6): δ = –70.18 (d, J = 711 Hz).
31P NMR (202 MHz, CDCl3): δ = –144.5 (sept, J = 712 Hz).
HRMS (ESI): m/z calcd for C15H23N2O+ [(M – F6–)+]: 247.1805; found:
261.0617.
N1-(2-Hydroxyethyl)-N2-[4-(trifluoromethyl)phenyl]oxalamide was
prepared from ethyl 2-oxo-2-{[4-(trifluoromethyl)phenyl]amino}ace-
tate (2.8 g, 11 mmol, 1.0 equiv) and 2-aminoethanol (0.81 mL,
25 mmol, 1.3 equiv) in CH2Cl2 (75 mL) following General Procedure 2.
The reaction mixture was heated at reflux for 2.5 d and the mixture
was diluted with EtOAc (25 mL). Differing from General Procedure 2,
the white suspension was washed with 1 M aq HCl (50 mL), and fil-
tered through a glass frit. The white precipitate was washed with H2O
(2 × 50 mL) and dried under reduced pressure (60 °C/10 mbar).
N1-(2-Hydroxyethyl)-N2-[4-(trifluoromethyl)phenyl]oxalamide (2.5 g,
9.1 mmol, 85%) was obtained as a white solid and used without fur-
ther purification; mp 216 °C.
247.1802.
3-(2-Hydroxyethyl)-1-mesityl-1H-benzo[d]imidazol-3-ium Hexa-
fluorophosphate (5k)
IR (ATR): 3305 (m), 3284 (m), 1662 (m), 1529 (s), 1319 (s), 1171 (s),
1130 (s), 835 (m), 716 cm–1 (m).
1H NMR (500 MHz, DMSO-d6): δ = 3.29 (q, J = 6.1 Hz, 2 H), 3.50 (q,
J = 5.9 Hz, 2 H), 4.78 (t, J = 5.7 Hz, 1 H, OH), 7.72 (d, J = 8.5 Hz, 2 H),
8.05 (d, J = 8.5 Hz, 2 H), 8.87 (t, J = 5.9 Hz, 1 H), 11.0 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 42.0, 59.2, 120.5, 124.3 (q,
J = 271 Hz), 124.5 (q, J = 32 Hz), 126.0 (q, J = 3.3 Hz), 141.3, 159.2,
159.7.
Following a literature procedure,31 a solution of 1-mesityl-1H-ben-
zo[d]imidazole32 (0.46 g, 2.0 mmol, 1.0 equiv) and 2-chloroethanol
(0.18 mL, 2.7 mmol, 1.4 equiv) in MeCN (1 mL) was heated in a micro-
wave reactor (250 W) at 120 °C for 36 h. After cooling to r.t., all vola-
tiles were removed under reduced pressure, the resulting brown resi-
due was dissolved in H2O (30 mL), and extracted with EtOAc
(2 × 30 mL). To the aqueous phase was then added KPF6 (0.74 g,
4.0 mmol, 2.0 equiv) and the resulting emulsion was stirred at r.t. for
3 h. The aqueous phase was extracted with CH2Cl2 (3 × 15 mL), the
combined organic phases were washed with brine (30 mL) and dried
(MgSO4). Filtration and removal of all volatiles under reduced pres-
sure yielded 5k (0.66 g, 1.5 mmol, 79%) as a white solid; mp 124 °C.
19F NMR (470 MHz, DMSO-d6): δ = –60.5 (d, J = 8.9 Hz).
+
HRMS (APCI): m/z calcd for C11H12F3N2O3 [(M + H)+]: 277.0795;
found: 277.0797.
2-[(2-{[4-(Trifluoromethyl)phenyl]amino}ethyl)amino]ethan-1-ol was
prepared from N1-(2-hydroxyethyl)-N2-[4-(trifluoromethyl)phe-
nyl]oxalamide following a modified literature procedure.33 To a sus-
pension of N1-(2-hydroxyethyl)-N2-[4-(trifluoromethyl)phenyl]oxa-
lamide (2.0 g, 7.2 mmol, 1.0 equiv) in toluene (21 mL) was added
BH3·THF (1 M in THF, 22 mL, 22 mmol, 3.0 equiv) dropwise at 0 °C.
The mixture was stirred at 0 °C for 15 min and finally heated at
100 °C for 4 d. The reaction was quenched by the slow addition of sat.
aq NaHCO3 (40 mL) at 0 °C. The resulting emulsion was stirred at r.t.
for 30 min and the organic phase was extracted with tert-butyl meth-
yl ether (3 × 40 mL). The combined organic phases were extracted
with 2 M aq HCl (2 × 100 mL). The aqueous phase was neutralized
with aq NaOH and washed with CH2Cl2 (2 × 100 mL). Finally the aque-
ous phase was basified with NaOH to pH 14, extracted with CH2Cl2
(3 × 100 mL), and dried (Na2SO4). Filtration and removal of all vola-
tiles under reduced pressure yielded 2-[(2-{[4-(trifluoromethyl)phe-
nyl]amino}ethyl)amino]ethan-1-ol (1.6 g, 6.5 mmol, 90%) as a white
solid, which was used without further purification; mp 69 °C.
IR (ATR): 3590 (w), 3143 (w), 1557 (w), 1486 (w), 1228 (w), 1076 (w),
821 cm–1 (s) .
1H NMR (500 MHz, CDCl3): δ = 1.95 (s, 6 H), 2.38 (s, 3 H), 3.07 (br s, 1
H) 4.06 (t, J = 4.9 Hz, 2 H), 4.78 (t, J = 4.9 Hz, 2 H), 7.07 (s, 2 H), 7.23 (d,
J = 8.3 Hz, 1 H), 7.60 (mc, 1 H), 7.69 (mc, 1 H), 7.98 (d, J = 8.5 Hz, 1 H),
9.03 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 17.2, 21.3, 49.9, 59.5, 113.1, 114.2,
127.9, 128.0, 128.2, 130.2, 131.3, 131.9, 135.6, 141.9, 141.9.
19F NMR (470 MHz, CDCl3): δ = –72.11 (d, J = 715 Hz).
31P NMR (202 MHz, CDCl3): δ = –144.4 (sept, J = 714 Hz).
HRMS (ESI): m/z calcd for C18H21N2O+ [(M – PF6–)+]: 281.1648; found:
281.1642.
3-(2-Hydroxyethyl)-1-[4-(trifluoromethyl)phenyl]-4,5-dihydro-
1H-imidazol-3-ium Hexafluorophosphate (5m)
Ethyl 2-oxo-2-{[4-(trifluoromethyl)phenyl]amino}acetate was pre-
pared from p-(trifluoromethyl)aniline (1.5 mL, 12 mmol, 1.0 equiv),
pyridine (1.2 mL, 14 mmol, 1.2 equiv), and ethyl 2-chloro-2-oxoace-
tate (1.6 mL, 14 mmol, 1.2 equiv) following General Procedure 1. The
reaction mixture was stirred at r.t. for 18 h and heated at reflux for
further 25 h. Purification by flash column chromatography (SiO2, gra-
dient cyclohexane/CH2Cl2 1:1 to 0:1) yielded ethyl 2-oxo-2-{[4-(tri-
fluoromethyl)phenyl]amino}acetate (3.0 g, 11 mmol, 96%) as a light
brown solid; mp 138 °C; Rf = 0.80 (SiO2, cyclohexane/EtOAc 1:1).
IR (ATR): 2838 (w), 1616 (m), 1543 (m), 1456 (m), 1315 (m), 1089 (s),
1059 (s), 909 (m), 817 cm–1 (s).
1H NMR (500 MHz, CDCl3): δ = 2.06 (s, 1 H), 2.12–2.34 (m, 1 H), 2.77–
2.84 (m, 2 H), 2.87–2.94 (m, 2 H), 3.25 (mc, 2 H), 3.65–3.71 (m, 2 H),
4.43–4.58 (m, 1 H), 6.62 (mc, 2 H), 7.39 (mc, 2 H).
13C NMR (125 MHz, CDCl3): δ = 43.2, 48.2, 51.1, 61.3, 112.0, 119.0 (q,
J = 33 Hz), 125.1 (q, J = 270 Hz), 126.7 (q, J = 3.7 Hz), 150.9.
19F NMR (470 MHz, CDCl3): δ = –61.0 (d, J = 7.0 Hz).
IR (ATR): 3333 (m), 1706 (m), 1545 (m), 1298 (m), 1110 (s), 1064 (s),
838 (m), 500 cm–1 (m).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

H
F. Pape, J. F. Teichert
Paper
Synthesis
HRMS (ESI): m/z calcd for C11H16F3N2O+ [(M + H)+]: 249.1209; found:
249.1208.
1H NMR (500 MHz, DMSO-d6): δ = 3.27 (mc, 2 H), 3.49 (mc, 2 H), 3.73
(s, 3 H), 4.78 (t, J = 5.3 Hz, 1 H), 6.91 (mc, 2 H), 7.72 (mc, 2 H), 8.75 (t,
J = 5.9 Hz, 1 H), 10.5 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 41.9, 55.2, 59.2, 113.8, 121.9,
130.7, 156.1, 158.1, 160.2.
3-(2-Hydroxyethyl)-1-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1H-
imidazol-3-ium hexafluorophosphate (5m) was prepared from 2-[(2-
{[4-(trifluoromethyl)phenyl]amino}ethyl)amino]ethan-1-ol (0.61 g,
2.4 mmol, 1.0 equiv) following General Procedure 4. The reaction
mixture was stirred with HCl (2 M solution in Et2O, 1.2 mL, 2.4 mmol,
1.0 equiv) in Et2O for 15 min. The mixture was then stirred with
trimethyl orthoformate (1.3 mL, 12 mmol, 5.0 equiv) at 90 °C for 16 h
and the emulsion with KPF6 (0.91 g, 4.9 mmol, 2.0 equiv) was stirred
for 1.5 h. Purification by flash column chromatography (SiO2, CH2Cl2/
MeOH 25:1) yielded 5m (243 mg, 0.601 mmol, 25%) as a light brown
solid; mp 88 °C; Rf = 0.40 (SiO2, CH2Cl2/MeOH 19:1).
HRMS (EI): m/z calcd for
C
11H14N2O4 [(M)+]: 238.0948; found:
238.0946.
2-({2-[(4-Methoxyphenyl)amino]ethyl}amino)ethan-1-ol was pre-
pared differing from General Procedure 3. LiAlH4 (1.9 g, 49 mmol,
4.0 equiv) was suspended in THF (75 mL) and N1-(2-hydroxyethyl)-
N2-(4-methoxyphenyl)oxalamide (3.2 g, 12 mmol, 1.0 equiv) was
added portionwise under a counterflow of N2. The reaction mixture
was heated at reflux for 10 h. 2-({2-[(4-Methoxyphenyl)amino]eth-
yl}amino)ethan-1-ol (2.7 g, 13 mmol, quant) was obtained as a yellow
solid and used without further purification; mp 69 °C.
IR (ATR): 3605 (w), 3348 (w), 3113 (w), 1659 (m), 1615 (m), 1326 (m),
1070 (m), 820 (s), 555 cm–1 (s).
1H NMR (500 MHz, DMSO-d6): δ = 3.67–3.75 (m,
4 H), 4.19 (t,
IR (ATR): 3349 (m), 2910 (m), 2837 (s), 2713 (m), 1511 (m), 1233 (m),
1033 (s), 808 cm–1 (s).
1H NMR (500 MHz, CDCl3): δ = 2.78 (mc, 2 H), 2.86 (mc, 2 H), 3.18 (mc,
2 H), 3.66 (mc, 2 H), 3.73–3.75 (m, 3 H), 6.60 (mc, 2 H), 6.78 (mc, 2 H).
13C NMR (125 MHz, CDCl3): δ = 44.8, 48.6, 51.2, 55.9, 61.2, 114.5,
J = 10.3 Hz, 2 H), 4.43 (t, J = 10.3 Hz, 2 H), 5.16 (t, J = 4.8 Hz, 1 H), 7.59
(d, J = 8.5 Hz, 2 H), 7.89 (d, J = 8.5 Hz, 2 H), 9.53 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 47.8, 49.0, 51.1, 57.2, 117.6, 124.0
(q, J = 272 Hz), 125.8 (q, J = 32 Hz), 127.0 (q, J = 3.6 Hz), 139.8, 155.6.
19F NMR (470 MHz, DMSO-d6): δ = –60.6 (s), –70.2 (d, J = 712 Hz).
31P NMR (202 MHz, DMSO-d6): δ = –144.2 (sept, J = 712 Hz).
HRMS (ESI): m/z calcd for C12H14F3N2O+ [(M – PF6–)+]: 259.1053;
115.0, 142.7, 152.4.
HRMS (ESI): m/z calcd for C11H19N2O2 [(M)+]: 211.1441; found:
+
211.1441.
found: 259.1053.
3-(2-Hydroxyethyl)-1-(4-methoxyphenyl)-4,5-dihydro-1H-imidazol-
3-ium hexafluorophosphate (5n) was prepared from 2-({2-[(4-Meth-
oxyphenyl)amino]ethyl}amino)ethan-1-ol (2.6 g, 12 mmol, 1.0 equiv)
following General Procedure 4. The reaction mixture was stirred with
HCl (2 M solution in Et2O, 0.43 mL, 0.86 mmol, 1.0 equiv) in Et2O/CH2Cl2
(1:1, 60 mL) for 3 h. Trimethyl orthoformate was added (6.7 mL,
62 mmol, 5.0 equiv) and the resulting mixture was stirred at 90 °C for
16 h and the emulsion with KPF6 (4.5 g, 25 mmol, 2.0 equiv) was
stirred for 21 h. The resulting brown residue was suspended in CH2Cl2
(20 mL), collected on a glass frit, and washed with cold CH2Cl2
(2 × 20 mL). Evaporation of the solvent afforded 5n (1.6 g, 4.3 mmol,
35%) as a white solid; mp 122 °C.
3-(2-Hydroxyethyl)-1-(4-methoxyphenyl)-4,5-dihydro-1H-imidaz-
ol-3-ium Hexafluorophosphate (5n)
Ethyl 2-[(4-methoxyphenyl)amino]-2-oxoacetate was prepared from
p-anisidine (3.0 g, 24 mmol, 1.0 equiv), pyridine (2.4 mL, 29 mmol,
1.2 equiv), and ethyl 2-chloro-2-oxoacetate (3.3 mL, 29 mmol,
1.2 equiv) following General Procedure 1. The reaction mixture was
stirred at r.t. for 18 h. Purification by flash column chromatography
(SiO2, gradient cyclohexane/tert-butyl methyl ether 2:1 to 0:1) yield-
ed ethyl 2-[(4-methoxyphenyl)amino]-2-oxoacetate (4.6 g, 21 mmol,
84%) as a light brown solid; mp 95 °C; Rf = 0.60 (SiO2, cyclohex-
ane/EtOAc 1:1).
IR (ATR): 1646 (m), 1521 (m), 1506 (m), 1438 (w), 1252 (m), 1032
(m), 816 cm–1 (s).
1H NMR (500 MHz, DMSO-d6): δ = 3.59–3.65 (m, 2 H), 3.65–3.70 (s, 2
H), 3.78 (s, 3 H), 4.10 (mc, 2 H), 4.36 (mc, 2 H), 5.14 (br s, 1 H), 7.07
(mc, 2 H), 7.35 (mc, 2 H), 9.18 (s, 1 H).
IR (ATR): 3357 (m), 2991 (w), 2942 (w), 2907 (w), 1722 (m), 1691 (s),
1539 (m), 1509 (s), 1290 (s), 1019 (s), 834 (s), 697 cm–1 (s).
1H NMR (500 MHz, CDCl3): δ = 1.42 (t, J = 7.1 Hz, 3 H), 3.80 (s, 3 H),
4.40 (q, J = 7.1 Hz, 2 H), 6.89 (mc, 2 H), 7.56 (mc, 2 H), 8.80 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 48.5, 48.5, 50.7, 55.5, 57.2, 114.9,
13C NMR (125 MHz, CDCl3): δ = 14.1, 55.6, 63.8, 114.5, 121.5, 129.7,
119.3, 129.6, 154.8, 157.6.
153.8, 157.3, 161.3.
19F NMR (470 MHz, DMSO-d6): δ = –70.2 (d, J = 711 Hz).
31P NMR (202 MHz, DMSO-d6): δ = –144.2 (sept, J = 712 Hz).
+
HRMS (ESI): m/z calcd for C11H14NO4 [(M + H)+]: 224.0917; found:
224.0915.
N1-(2-Hydroxyethyl)-N2-(4-methoxyphenyl)oxalamide was prepared
+
HRMS (APCI): m/z calcd for C12H17N2O2 [(M – PF6–)+]: 221.1285;
from
ethyl
2-[(4-methoxyphenyl)amino]-2-oxoacetate
(4.4 g,
found: 221.1279.
20 mmol, 1.0 equiv) and 2-aminoethanol (1.5 mL, 25 mmol,
1.3 equiv) following General Procedure 2. The reaction mixture was
heated at reflux for 14 h and the mixture was diluted with EtOAc
(200 mL). Differing from General Procedure 2 the organic phase was
washed with 6 M aq HCl (100 mL) and the aqueous phase was ex-
tracted with CH2Cl2 (2 × 250 mL). The combined organic phases were
washed with brine (100 mL) and dried (Na2SO4). N1-(2-Hydroxyeth-
yl)-N2-(4-methoxyphenyl)oxalamide (3.5 g, 15 mmol, 74%) was ob-
tained as a white solid and used without further purification;
mp 194 °C.
3-(2-Hydroxyethyl)-1-(2-methoxyphenyl)-4,5-dihydro-1H-imidaz-
ol-3-ium Hexafluorophosphate (5o)
Following a literature procedure,34 a mixture of o-anisidine (2.5 mL,
22 mmol, 2.0 equiv) and 2-bromoethylamine hydrobromide (2.3 g,
11 mmol, 1 equiv) in toluene (20 mL) was heated at reflux for 8 h and
stirred for further 5 d at r.t. in an open flask. To the orange precipitate
was added H2O (8 mL) and tert-butyl methyl ether (5 mL) and the re-
sulting emulsion was washed with aq 50 wt% KOH (2.5 mL). The lay-
ers were separated, the aqueous phase was saturated with NaCl, ex-
tracted with tert-butyl methyl ether (2 × 8 mL), and the combined or-
ganic layers were dried (Na2SO4). Filtration, removal of all volatiles
IR (ATR): 3306 (w), 3283 (m), 2957 (w), 2839 (w), 1651 (s), 1597 (m),
1526 (s), 1412 (m), 1175 (m), 1029 (s), 818 (s), 754 cm–1 (m).
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F. Pape, J. F. Teichert
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Synthesis
and purification by flash column chromatography (SiO2, gradient
CH2Cl2/MeOH 19:1 to 14:1) yielded N1-(2-methoxyphenyl)ethane-
1,2-diamine (1.5 g, 8.7 mmol, 79%) as an orange oil.
1H NMR (500 MHz, CDCl3): δ = 1.29 (br s, 2 H), 2.96 (t, J = 5.8 Hz, 2 H),
3.21 (t, 3J = 5.8 Hz, 2 H), 3.85 (s, 3 H), 4.48 (br s, 1 H), 6.64 (dd, J = 7.8,
1.4 Hz, 1 H), 6.68 (td, J = 7.7, 1.5 Hz, 1 H), 6.78 (dd, J = 7.9, 1.3 Hz, 1 H),
6.87 (td, 3J = 7.6, 1.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 41.4, 46.6, 55.4, 109.5, 109.9, 116.5,
121.3, 138.3, 147.0.
HRMS (ESI): m/z calcd for C9H15N2O+ [(M + H)+]: 167.1179; found:
167.1180.
3-(2-Hydroxyethyl)-1-phenyl-4,5-dihydro-1H-imidazol-3-ium
Hexafluorophosphate (5p)
Ethyl 2-oxo-2-(phenylamino)acetate was prepared from aniline
(1.0 mL, 11 mmol, 1.0 equiv), pyridine (1.1 mL, 13 mmol, 1.2 equiv),
and ethyl 2-chloro-2-oxoacetate (1.5 mL, 13 mmol, 1.2 equiv) follow-
ing General Procedure 1. The reaction mixture was stirred at r.t. for
2.5 h. Ethyl-2-oxo-2-(phenylamino)acetate (2.1 g, 11 mmol, quant)
was obtained as a pale pink solid and used without further purifica-
tion; mp 59 °C.
1H NMR (500 MHz, CDCl3): δ = 1.41–1.45 (m, 3 H), 4.39–4.45 (m, 2 H),
7.19 (mc, 1 H), 7.38 (mc, 2 H), 7.64 (mc, 2 H), 8.87 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 14.1, 63.9, 120.0, 125.7, 129.4, 136.5,
154.0, 161.2.
The data are in accordance with the literature.35
1-(2-methoxyphenyl)-4,5-dihydro-1H-imidazole was prepared ac-
cording to a literature procedure.36 A solution of N1-(2-methoxyphe-
nyl)ethane-1,2-diamine (1.9 g, 12 mmol, 1.0 equiv) and pTsOH·H2O
(44 mg, 0.23 mmol, 2 mol%) in triethyl orthoformate (7.7 mL,
46 mmol, 4.0 equiv) was heated at 150 °C for 18 h. The resulting
brown solution was diluted with H2O (13 mL), extracted with CH2Cl2
(3 × 15 mL), and the combined organic layers were dried (MgSO4). Fil-
tration, removal of all volatiles under reduced pressure and purifica-
tion via Kugelrohr distillation (201 °C/0.89 mbar) yielded 1-(2-meth-
oxyphenyl)-4,5-dihydro-1H-imidazole (1.5 g, 8.4 mmol, 73%) as a
pale yellow oil.
1H NMR (500 MHz, CDCl3): δ = 3.68 (t, J = 9.7 Hz, 2 H), 3.82 (s, 3 H),
3.89 (t, 3J = 9.5 Hz, 2 H), 6.80–6.86 (m, 1 H), 6.86–6.93 (m, 2 H), 6.93–
7.01 (m, 1 H), 7.74 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 48.2, 53.5, 55.6, 111.9, 118.3, 121.2,
123.0, 130.3, 150.6, 153.6.
+
HRMS (ESI): m/z calcd for C10H12NO3 [(M + H)+]: 194.0812; found:
194.0804.
The data are in accordance with the literature.38
N1-(2-Hydroxyethyl)-N2-phenyloxalamide was prepared from ethyl
2-oxo-2-(phenylamino)acetate (1.8 g, 9.1 mmol, 1.0 equiv) and 2-am-
inoethanol (0.68 mL, 11 mmol, 1.3 equiv) following General Proce-
dure 2. The reaction mixture was heated at reflux for 45 h and the
mixture was diluted with EtOAc (23 mL). Differing from General Pro-
cedure 2, the organic phase was filtered through a glass frit and the
organic phase as well as the white residue were washed each with 1
M aq HCl (45 mL). The residue was washed with H2O (45 mL) and the
organic phase was washed with brine (45 mL) and dried (Na2SO4). Fil-
tration, removal of all volatiles and drying under reduced pressure of
the combined solids yielded N1-(2-hydroxyethyl)-N2-phenyloxal-
amide (1.7 g, 8.2 mmol, 91%) as a white solid, which was used with-
out further purification; mp 158 °C.
HRMS (ESI): m/z calcd for C10H13N2O+ [(M + H)+]: 177.1022; found:
177.1019.
IR (ATR): 3411 (w), 3310 (m), 3287 (m), 1659 (s), 1523 (s), 1447 (s),
1055 (m), 756 (s), 480 cm–1 (s).
3-(2-Hydroxyethyl)-1-(2-methoxyphenyl)-4,5-dihydro-1H-imidazol-
3-ium hexafluorophosphate (5o) was prepared according to a litera-
ture procedure.37 A solution of 1-(2-methoxyphenyl)-4,5-dihydro-
1H-imidazole (1.4 g, 7.7 mmol, 1.0 equiv) and 2-bromoethanol
(0.76 mL, 11 mmol, 1.4 equiv) in MeCN (37 mL) was heated at 85 °C
for 17 h. The resulting white precipitate was collected on a glass frit
and washed with tert-butyl methyl ether (2 × 15 mL) yielding the cor-
responding 4,5-dihydro-1H-imidazol-3-ium bromide (806 mg,
2.68 mmol, 35%), which (398 mg, 1.32 mmol, 1.00 equiv) was dis-
solved in H2O (20 mL). To the aqueous phase was added KPF6 (486 mg,
2.64 mmol, 2.00 equiv) and the resulting colorless emulsion was
stirred at r.t. for 15 h. The aqueous phase was extracted with CH2Cl2
(3 × 10 mL), and the combined organic layers were dried (MgSO4). Fil-
tration and removal of all volatiles yielded 5o (462 mg, 1.26 mmol,
96%) as a colorless oil that crystallized over time; mp 71 °C.
1H NMR (500 MHz, DMSO-d6): δ = 3.28 (mc, 2 H), 3.50 (mc, 2 H), 4.77
(t, J = 5.4 Hz, 1 H), 7.13 (t, J = 7.1 Hz, 1 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.81
(d, J = 7.8 Hz, 2 H), 8.79 (mc, 1 H), 10.6 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 41.9, 59.2, 120.4, 124.4, 128.6,
137.6, 158.6, 160.0.
HRMS (EI): m/z calcd for
C
10H12N2O3 [(M)+]: 208.0842; found:
208.0847.
2-{[2-(Phenylamino)ethyl]amino}ethan-1-ol was prepared from N1-
(2-hydroxyethyl)-N2-phenyloxalamide. Differing from General Proce-
dure 3, LiAlH4 (1.2 g, 30 mmol, 4.0 equiv) was suspended in THF
(48 mL)
and
N1-(2-hydroxyethyl)-N2-phenyloxalamide
(1.6 g,
7.6 mmol, 1.0 equiv) was added portionwise under a counterflow of
N2. The reaction mixture was heated at reflux for 40 h. 2-{[2-(Phenyl-
amino)ethyl]amino}ethan-1-ol (1.2 g, 6.6 mmol, 86%) was obtained
as a pale yellow oil and used without further purification.
IR (ATR): 3568 (w), 3400 (w), 1640 (m), 1599 (m), 1251 (m), 827 (s),
756 (s), 554 cm–1 (s).
1H NMR (500 MHz, DMSO-d6): δ = 3.66–3.69 (m, 4 H), 3.90 (s, 3 H),
4.07–4.13 (m, 2 H), 4.35–4.41 (m, 2 H), 5.10–5.15 (m, 1 H), 7.08 (mc, 1
H), 7.22–7.26 (m, 1 H), 7.34–7.39 (m, 2 H), 9.01 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 47.9, 50.1, 50.4, 56.1, 57.1, 112.8,
121.0, 122.7, 125.1, 128.5, 151.6, 157.6.
19F NMR (470 MHz, DMSO-d6): δ = –70.15 (d, J = 711 Hz).
31P NMR (202 MHz, DMSO-d6): δ = –144.2 (sept, J = 712 Hz).
HRMS (ESI): m/z calcd for C12H17N2O2+ [(M – PF6–)+]: 221.1285; found:
IR (ATR): 3332 (br, m), 2847 (m), 1601 (s), 1499 (m), 1053 (m), 748
(s), 692 cm–1 (s).
1H NMR (500 MHz, CDCl3): δ = 2.74–2.78 (m, 2 H), 2.83–2.88 (m, 2 H),
3.20–3.25 (m, 2 H), 3.67 (mc, 2 H), 6.62 (mc, 2 H), 6.71 (mc, 1 H), 7.17
(mc, 2 H).
13C NMR (125 MHz, CDCl3): δ = 43.2, 48.3, 51.1, 60.6, 112.9, 117.5,
129.3, 148.3.
HRMS (ESI): m/z calcd for C10H17N2O+ [(M + H)+]: 181.1335; found:
181.1333.
221.1286.
3-(2-Hydroxyethyl)-1-phenyl-4,5-dihydro-1H-imidazol-3-ium hexa-
fluorophosphate (5p) was prepared from 2-{[2-(phenylamino)eth-
yl]amino}ethan-1-ol (1.0 g, 5.6 mmol, 1.0 equiv) following General
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

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F. Pape, J. F. Teichert
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Synthesis
Procedure 4. The reaction mixture was stirred with HCl (2 M solution
in Et2O, 2.8 mL, 5.6 mmol, 1.0 equiv) in Et2O for 50 min. The mixture
was then stirred with trimethyl orthoformate (3.1 mL, 28 mmol,
5.0 equiv) at 90 °C for 41 h and the emulsion with KPF6 (2.1 g,
11 mmol, 2.0 equiv) was stirred for 16 h. The title compound
(544 mg, 1.62 mmol, 29%) was obtained as a brown solid and used
without further purification; mp 64 °C.
IR (ATR): 3257 (w), 2917 (m), 2848 (m), 2630 (w), 2484 (w), 1724 (m),
1462 (m), 1265 (s), 1061 (s), 704 cm–1 (m).
1H NMR (500 MHz, CDCl3): δ = 1.07 (s, 9 H), 2.63–2.68 (m, 2 H), 2.68–
2.71 (m, 2 H), 2.71–2.75 (m, 2 H), 3.61 (mc, 2 H).
13C NMR (125 MHz, CDCl3): δ = 29.0, 42.1, 49.8, 50.4, 51.3, 60.9.
HRMS (ESI): m/z calcd for C8H21N2O+ [(M + H)+]: 161.1648; found
161.1644.
IR (ATR): 3600 (w), 3125 (w), 2941 (w), 1646 (m), 1598 (m), 1521 (m),
1268 (m), 1215 (m), 818 (s), 756 (s), 555 cm–1 (s).
1H NMR (500 MHz, DMSO-d6): δ = 3.64–3.68 (m, 2 H), 3.68–3.72 (m, 2
H), 4.11–4.18 (m, 2 H), 4.36–4.42 (m, 2 H), 5.14 (t, J = 5.4 Hz, 1 H),
7.31 (mc, 1 H), 7.40 (mc, 2 H), 7.51 (mc, 2 H), 9.36 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 47.9, 48.6, 50.8, 57.2, 117.3, 126.0,
129.8, 136.4, 155.0.
19F NMR (470 MHz, DMSO-d6): δ = –70.15 (d, J = 712 Hz).
31P NMR (202 MHz, DMSO-d6): δ = –144.2 (sept, J = 713 Hz).
HRMS (ESI): m/z calcd for C11H15N2O+ [(M – PF6–)+]: 191.1179; found:
1-(tert-Butyl)-3-(2-hydroxyethyl)-4,5-dihydro-1H-imidazol-3-ium
hexafluorophosphate (5q) was prepared from 2-{[2-(tert-butylami-
no)ethyl]amino}ethan-1-ol (138 mg, 0.861 mmol, 1.0 equiv) follow-
ing General Procedure 4. The reaction mixture was stirred with HCl
(2 M solution in Et2O, 0.43 mL, 0.86 mmol, 1.0 equiv) in Et2O for 1 h.
The mixture was then stirred with trimethyl orthoformate (0.45 mL,
4.1 mmol, 5.0 equiv) at 90 °C for 14 h and the emulsion with KPF6
(0.32 g, 1.7 mmol, 2.1 equiv) was stirred for 16 h. Purification via
flash column chromatography (SiO2, CH2Cl2/MeOH 30:1) yielded 5q
(50 mg, 0.16 mmol, 18%) as a brown solid; mp 119 °C; Rf = 0.18 (SiO2,
CH2Cl2/MeOH 19:1).
191.1174.
IR (ATR): 3590 (w), 2962 (w), 2877 (w), 1653 (s), 1305 (m), 1056 (m),
819 cm–1 (s).
1H NMR (500 MHz, DMSO-d6): δ = 1.33 (s, 9 H), 3.48 (t, J = 4.8 Hz, 2
H), 3.59 (mc, 2 H), 3.91 (mc, 4 H), 5.02 (t, J = 5.3 Hz, 1 H), 8.44 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 27.4, 44.9, 47.9, 49.9, 55.7, 57.2,
156.0.
19F NMR (470 MHz, DMSO-d6): δ = –70.16 (d, J = 712 Hz).
31P NMR (202 MHz, DMSO-d6): δ = –144.2 (sept, J = 713 Hz).
HRMS (ESI): m/z calcd for C9H19N2O+ [(M – PF6–)+]: 171.1492; found:
1-(tert-Butyl)-3-(2-hydroxyethyl)-4,5-dihydro-1H-imidazol-3-ium
Hexafluorophosphate (5q)
Ethyl 2-(tert-butylamino)-2-oxoacetate was prepared from tert-bu-
tylamine (3.2 mL, 31 mmol, 1.0 equiv), pyridine (2.9 mL, 36 mmol,
1.2 equiv), and ethyl 2-chloro-2-oxoacetate (4.1 mL, 37 mmol,
1.2 equiv) following General Procedure 1. The reaction mixture was
stirred at r.t. for 14 h. Ethyl 2-(tert-butylamino)-2-oxoacetate (4.4 g,
25 mmol, 82%) was obtained as a pale yellow oil and used without
further purification.
171.1491.
1H NMR (500 MHz, CDCl3): δ = 1.32–1.37 (m, 3 H), 1.37–1.41 (m, 9 H),
4.29 (mc, 2 H), 6.95 (br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 14.0, 28.3, 52.0, 63.2, 155.7, 161.5.
HRMS (EI): m/z calcd for C8H15NO3 [(M)+]: 173.1046; found:
173.1049.
1-Butyl-3-(2-hydroxyethyl)-4,5-dihydro-1H-imidazol-3-ium
Hexafluorophosphate (5r)
+
Ethyl 2-(butylamino)-2-oxoacetate was prepared from n-butylamine
(3.0 mL, 30 mmol, 1.0 equiv), pyridine (2.9 mL, 37 mmol, 1.2 equiv),
and ethyl 2-chloro-2-oxoacetate (4.1 mL, 36 mmol, 1.2 equiv) follow-
ing General Procedure 1. The reaction mixture was stirred at r.t. for
14 h. Ethyl 2-(butylamino)-2-oxoacetate (5.0 g, 29 mmol, 95%) was
obtained as a pale yellow oil and used without further purification.
The data are in accordance with the literature.39
N1-(tert-Butyl)-N2-(2-hydroxyethyl)oxalamide was prepared from
ethyl 2-(tert-butylamino)-2-oxoacetate (4.3 g, 25 mmol, 1.0 equiv)
and 2-aminoethanol (2.1 mL, 35 mmol, 1.4 equiv) following General
Procedure 2. The reaction mixture was heated at reflux for 16 h. N1-
(tert-Butyl)-N2-(2-hydroxyethyl)oxalamide (1.8 g, 9.3 mmol, 37%)
was obtained as a white solid and used without further purification;
mp 103 °C.
IR (ATR): 3279 (w), 2960 (w), 2936 (w), 1735 (m), 1683 (s), 1292 (m),
1195 (s), 1013 (m), 864 cm–1 (w).
1H NMR (500 MHz, CDCl3): δ = 0.92 (t, J = 7.3 Hz, 3 H), 1.37 (mc, 5 H),
1.54 (mc, 2 H), 3.33 (q, J = 6.7 Hz, 2 H), 4.33 (mc, 2 H), 7.10 (br s, 1 H).
IR (ATR): 3299 (s), 2972 (w), 2929 (w), 1653 (s), 1509 (s), 1454 (m),
1219 (m), 1056 (m), 754 (m), 719 cm–1 (m).
1H NMR (500 MHz, CDCl3): δ = 1.38 (s, 9 H), 2.58–2.87 (m, 1 H), 3.47
(mc, 2 H), 3.75 (mc, 2 H), 7.39 (s, 1 H), 8.00 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 28.4, 42.6, 51.7, 61.6, 158.9, 161.4.
13C NMR (125 MHz, CDCl3): δ = 13.7, 14.1, 20.1, 31.3, 39.7, 63.2, 156.7,
161.0.
+
HRMS (EI): m/z calcd for C8H15NO3 [(M)+]: 173.1046; found:
173.1051.
N1-Butyl-N2-(2-hydroxyethyl)oxalamide was prepared from ethyl 2-
(butylamino)-2-oxoacetate (4.3 g, 25 mmol, 1.0 equiv) and 2-ami-
noethanol (2.1 mL, 35 mmol, 1.4 equiv) following General Procedure
2. The reaction mixture was heated at reflux for 16 h. N1-Butyl-N2-(2-
hydroxyethyl)oxalamide (2.8 g, 15 mmol, 60%) was obtained as a
white solid and used without further purification; mp 139 °C.
+
HRMS (ESI): m/z calcd for C8H17N2O3 [(M + H)+]: 189.1234; found:
189.1233.
2-{[2-(tert-Butylamino)ethyl]amino}ethan-1-ol was prepared ac-
cording to General Procedure 3. LiAlH4 (1.4 g, 37 mmol, 4.0 equiv)
was suspended in THF (55 mL) and N1-(tert-butyl)-N2-(2-hydroxyeth-
yl)oxalamide (1.7 g, 9.2 mmol, 1.0 equiv) was added portionwise un-
der a counterflow of N2. The reaction mixture was heated at reflux for
IR (ATR): 3294 (s), 2953 (m), 2872 (m), 1649 (s), 1528 (s), 1439 (m),
1063 (m), 758 cm–1 (m) .
2 d.
2-{[2-(tert-Butylamino)ethyl]amino}ethan-1-ol
(610 mg,
1H NMR (500 MHz, CDCl3): δ = 0.93 (t, J = 7.4 Hz, 3 H), 1.37 (sext,
J = 7.4 Hz, 2 H), 1.51–1.58 (m, 2 H), 2.65 (br s, 1 H), 3.31 (mc, 2 H), 3.50
(mc, 2 H), 3.78 (t, J = 5.4 Hz, 2 H), 7.56 (br s, 1 H), 7.99 (br s, 1 H).
3.8 mmol, 41%) was obtained as a yellow oil that crystallized over
time and used without further purification; mp 54 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

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F. Pape, J. F. Teichert
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Synthesis
13C NMR (125 MHz, CDCl3): δ = 13.8, 20.1, 31.3, 39.6, 42.7, 61.7, 159.8,
160.8.
IR (ATR): 3578 (w), 3071 (w), 1660 (m), 1588 (m), 1495 (m), 1234
(m), 1054 (s), 818 (s), 766 (s), 555 cm–1 (s).
+
HRMS (ESI): m/z calcd for C8H17N2O3 [(M + H)+]: 189.1234; found:
189.1233.
1H NMR (500 MHz, DMSO-d6): δ = 3.50 (mc, 2 H), 3.59 (mc, 2 H), 3.85
(t, J = 4.8 Hz, 2 H), 3.96 (mc, 4 H), 4.19 (t, J = 4.9 Hz, 2 H), 5.06 (mc, 1
H), 6.96–7.01 (m, 3 H), 7.32 (mc, 2 H), 8.50–8.55 (m, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 46.7, 48.3, 48.5, 49.8, 57.0, 64.2,
114.7, 121.2, 129.6, 157.8, 158.7.
19F NMR (470 MHz, DMSO-d6): δ = –70.15 (d, J = 711 Hz).
31P NMR (202 MHz, DMSO-d6): δ = –144.2 (sept, J = 713 Hz).
HRMS (ESI): m/z calcd for C13H19N2O2+ [(M – PF6–)+]: 235.1441; found:
2-{[2-(Butylamino)ethyl]amino}ethan-1-ol was prepared following
General Procedure 3. LiAlH4 (2.7 g, 60 mmol, 4.0 equiv) was suspend-
ed in THF (90 mL) and N1-butyl-N2-(2-hydroxyethyl)oxalamide (2.8 g,
15 mmol, 1.0 equiv) was added portionwise under a counterflow of
N2. The reaction mixture was heated at reflux for 2 d. 2-{[2-(Butyl-
amino)ethyl]amino}ethan-1-ol (1.8 g, 11 mmol, 76%) was obtained as
a yellow oil and used without further purification.
235.1437.
IR (ATR): 3267 (br, m), 2957 (m), 2932 (m), 2872 (m), 1634 (m), 1466
(m), 1295 (m), 1054 (m), 810 cm–1 (w) .
1-Benzyl-3-[2-(mesitylamino)ethyl]-4,5-dihydro-1H-imidazol-3-
ium Hexafluorophosphate (5t)
1H NMR (400 MHz, CDCl3): δ = 0.86 (t, J = 7.3 Hz, 3 H), 1.28 (sext,
J = 7.4 Hz, 2 H), 1.37–1.47 (m, 2 H), 2.40 (br s, 2 H), 2.55 (mc, 2 H),
2.64–2.74 (m, 6 H), 3.59 (mc, 2 H).
13C NMR (125 MHz, CDCl3): δ = 14.0, 20.5, 32.2, 49.0, 49.5, 49.7, 51.4,
60.8.
1-Mesityl-3-[2-(tosyloxy)ethyl]-4,5-dihydro-1H-imidazol-3-ium
hexafluorophosphate (8) was prepared according to a literature pro-
cedure.41 To a solution of 5a (1.59 g, 4.20 mmol, 1 equiv) and Et3N
(0.87 mL, 6.3 mmol, 1.5 equiv) in CH2Cl2 (15 mL) was added a solution
of TsCl (1.2 g, 6.3 mmol, 1.5 equiv) in CH2Cl2 (6 mL) dropwise at r.t.
The resulting solution was stirred at r.t. for 16 h and diluted with
EtOAc (12 mL). All volatiles were removed under reduced pressure
and the residue was purified via flash column chromatography
(SiO2, CH2Cl2/acetone 30:1). 1-Mesityl-3-[2-(tosyloxy)ethyl]-4,5-di-
hydro-1H-imidazol-3-ium hexafluorophosphate (8; 1.1 g, 2.1 mmol,
49%) was obtained as a white solid; mp 154 °C.
HRMS (ESI): m/z calcd for C8H21N2O+ [(M + H)+]: 161.1648; found:
161.1644.
1-Butyl-3-(2-hydroxyethyl)-4,5-dihydro-1H-imidazol-3-ium hexa-
fluorophosphate (5r) was prepared from 2-{[2-(butylamino)eth-
yl]amino}ethan-1-ol (0.40 g, 2.5 mmol, 1.0 equiv) following General
Procedure 4. The reaction mixture was stirred with HCl (2 M solution
in Et2O, 1.3 mL, 2.5 mmol, 1.0 equiv) in Et2O for 1 h. The mixture was
then stirred with trimethyl orthoformate (1.3 mL, 12 mmol,
5.0 equiv) at 90 °C for 14 h and the emulsion with KPF6 (924 mg,
5.0 mmol, 2 equiv) was stirred for 16 h. Purification by flash column
chromatography (SiO2, CH2Cl2/MeOH 50:1) yielded 5r (223 mg,
0.705 mmol, 28%) as a brown oil; Rf = 0.1 (SiO2, CH2Cl2/MeOH 16:1).
IR (ATR): 3357 (w), 2991 (w), 2942 (w), 1722 (m), 1691 (s), 1509 (s),
1290 (s), 1173 (s), 1019 (s), 834 (s), 697 cm–1 (s).
1H NMR (500 MHz, DMSO-d6): δ = 2.22 (s, 6 H), 2.27 (s, 3 H), 2.45 (s, 3
H), 3.86 (t, J = 4.7 Hz, 2 H), 4.14 (mc, 4 H), 4.37 (t, J = 4.7 Hz, 2 H), 7.05
(s, 2 H), 7.53 (d, J = 8.3 Hz, 2 H), 7.85 (d, J = 8.3 Hz, 2 H), 8.78 (s, 1 H).
IR (ATR): 3590 (w), 2962 (w), 2877 (w), 1653 (s), 1526 (w), 1461 (w),
1305 (m), 1056 (m), 819 cm–1 (s).
1H NMR (500 MHz, DMSO-d6): δ = 0.91 (t, J = 7.4 Hz, 3 H), 1.29 (tq,
J = 7.8, 7.7 Hz, 2 H), 1.52–1.59 (m, 2 H), 3.42 (t, J = 7.2 Hz, 2 H), 3.45 (t,
J = 5.0 Hz, 2 H), 3.57 (t, J = 5.0 Hz, 2 H), 3.88 (mc, 4 H), 5.04 (s, 1 H),
8.42 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 17.0, 20.5, 21.1, 46.7, 48.5, 50.6,
66.3, 127.6, 129.3, 130.3, 130.9, 132.0, 135.4, 139.4, 145.4, 159.8.
19F NMR (470 MHz, DMSO-d6): δ = –70.15 (d, J = 712 Hz).
31P NMR (202 MHz, DMSO-d6): δ = –144.2 (sept, J = 712 Hz).
HRMS (ESI): m/z calcd for C21H27N2O3S+ [(M – PF6–)+]: 387.1737;
found: 387.1743.
13C NMR (125 MHz, DMSO-d6): δ = 13.4, 18.9, 28.5, 46.8, 47.8, 48.0,
49.8, 57.0, 157.9.
Following a literature procedure,42 to a solution of 1-mesityl-3-[2-(to-
syloxy)ethyl]-4,5-dihydro-1H-imidazol-3-ium hexafluorophosphate
(8; 446 mg, 0.838 mmol, 1.00 equiv) in MeCN (3.5 mL) was added
successively i-Pr2NEt (0.18 mL, 1.7 mmol, 2.0 equiv) and benzylamine
(0.29 mL, 1.7 mmol, 2.0 equiv). The resulting mixture was heated at
60 °C for 19 h. The volatiles were removed under reduced pressure
and the resulting residue was purified by flash column chromatogra-
phy (SiO2, CH2Cl2/acetone 50:1) to afford 5t (103 mg, 0.220 mmol,
26%) as a yellow oil that crystallized over time; mp 52 °C.
19F NMR (470 MHz, DMSO-d6): δ = –70.17 (d, J = 711 Hz).
31P NMR (202 MHz, DMSO-d6): δ = –144.2 (sept, J = 712 Hz).
HRMS (ESI): m/z calcd for C9H19N2O+ [(M – PF6–]+: 171.1492; found:
171.1490.
3-(2-Hydroxyethyl)-1-(2-phenoxyethyl)-4,5-dihydro-1H-imidazol-
3-ium Hexafluorophosphate (5s)
Following a literature procedure,37 a solution of 1-(2-phenoxyethyl)-
4,5-dihydro-1H-imidazole40 (626 mg, 3.29 mmol, 1.00 equiv) and 2-
bromoethanol (0.33 mL, 4.7 mmol, 1.4 equiv) in MeCN (15 mL) was
heated at 85 °C for 2 d. All volatiles were removed under reduced
pressure, the resulting yellow oil was dissolved in H2O (50 mL), and
extracted with EtOAc (3 × 50 mL). To the aqueous phase was then
added KPF6 (1.2 g, 6.6 mmol, 2.0 equiv) and the resulting colorless
emulsion was stirred at r.t. for 65 h. The aqueous phase was extract-
ed with CH2Cl2 (3 × 25 mL), the combined organic extracts were dried
(MgSO4), and filtered. Purification of the resulting colorless residue by
flash column chromatography (SiO2, CH2Cl2/MeOH 19:1) yielded 5s
(854 mg, 2.25 mmol, 68%) as a colorless oil that crystallized over
time; mp 52 °C; Rf = 0.08 (SiO2, CH2Cl2/MeOH 14:1).
IR (ATR): 3360 (w), 2962 (w), 1660 (m), 1437 (m), 1303 (m), 1215
(m), 819 (s), 554 cm–1 (s).
1H NMR (500 MHz, CD2Cl2): δ = 2.17 (s, 6 H), 2.19 (s, 3 H), 2.92 (br s, 1
H) 3.11 (t, J = 5.8 Hz, 2 H), 3.63 (t, J = 5.7 Hz, 2 H), 3.77 (dd,
Janti = 13.2 Hz, Jsyn = 11.6 Hz,
2
H), 3.98 (dd, Janti = 13.4 Hz,
Jsyn = 11.7 Hz, 2 H), 4.56 (s, 2 H), 6.79 (s, 2 H), 7.29–7.33 (m, 2 H),
7.37–7.44 (m, 3 H), 8.03 (s, 1 H).
13C NMR (125 MHz, CD2Cl2): δ = 18.2, 20.7, 45.5, 48.4, 49.2, 49.5, 52.7,
129.1, 129.7, 129.7, 129.9, 130.9, 132.5, 133.0, 142.2, 157.9.
19F NMR (470 MHz, CD2Cl2): δ = –72.16 (d, J = 711 Hz).
31P NMR (202 MHz, CD2Cl2): δ = –144.3 (sept, J = 707 Hz).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

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F. Pape, J. F. Teichert
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+
HRMS (ESI): m/z calcd for C21H28N3 [(M – PF6–)+]: 322.2278; found:
322.2276.
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Alkyne Semihydrogenation; General Procedure
A 5 mL glass vial was charged with CuCl (0.02 mmol, 5 mol%) and li-
gand precursor 5c (0.03 mmol, 7.5 mol%). The vial was evacuated and
refilled with N2 (3 ×). THF was added (1 mL for solid substrates; 1.5
mL for liquid substrates), the mixture was stirred for 2 min at r.t. fol-
lowed by the addition of n-BuLi (0.06 mmol, 15 mol%). The resulting
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septum was punctured with a needle, the vial was placed in an auto-
clave and the mixture stirred (750 rpm) under H2 pressure (50 bar,
unless otherwise noted). After completion of the reaction, all volatiles
were removed under reduced pressure and the crude mixture was
purified by column chromatography to give the desired product 11.
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Representative Alkyne Semihydrogenation Product: (Z)-1-Bromo-
4-(hex-1-en-1-yl)benzene (11j)
The title compound was prepared from 1-bromo-4-(hex-1-yn-1-
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0.022 mmol, 4.9 mol%), 5c (13.5 mg, 0.0332 mmol, 7.36 mol%) and n-
BuLi (2.65 M, 0.025 mL, 0.066 mmol, 15 mol%) following the General
Procedure for alkyne semihydrogenation. Before adding the substrate,
the catalyst solution was stirred for 5 min at r.t. The reaction mixture
was stirred under H2 (50 bar) at 60 °C for 18 h. Purification via filtra-
tion through a small plug of silica gel (4 × 0.6 cm), elution with pen-
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yielded 11j (100 mg, 0.418 mmol, 93%) as a colorless oil.
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see: Cao, H.; Chen, T.; Zhou, Y.; Han, D.; Yin, S.-F.; Han, L.-B. Adv.
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1H NMR (500 MHz, CDCl3): δ = 0.90 (t, J = 7.3 Hz, 3 H), 1.36 (mc, 2 H),
1.43 (mc, 2 H), 2.29 (mc, 2 H), 5.70 (dt, J = 11.7, 7.3 Hz, 1 H), 6.33 (mc, 1
H) 7.14 (mc, 2 H), 7.45 (mc, 2 H).
13C NMR (125 MHz, CDCl3): δ = 14.1, 22.5, 28.4, 32.2, 120.4, 127.7,
130.5, 131.3, 134.2, 136.8.
HRMS (EI): m/z calcd for C12H15Br+ [(M+)]: 238.0352; found: 238.0357.
Further examples of semihydrogenation products 11 (Scheme 4) are
provided in the Supporting Information.
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Acknowledgment
J.F.T. acknowledges support by the Fonds der Chemischen Industrie
through a Liebig-Stipendium. F.P. is supported by a predoctoral schol-
arship of the Berlin International Graduate School of Natural Sciences
and Engineering (BIG-NSE). This work was supported by a postdoc-
toral fellowship to J.F.T. by the Daimler and Benz foundation. We
thank Dr. Elisabeth Irran (TU Berlin) for support with the crystal
structure analysis. Dr. Sebastian Kember and Samantha Voges (TU
Berlin) are thanked for assistance with NMR spectroscopy. Prof. Dr.
Martin Oestreich (TU Berlin) is kindly thanked for generous support.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1590112.
S
u
p
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ortiInfogrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M

M
F. Pape, J. F. Teichert
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–M