New insight into the role of a base in the mechanism of imine transfer hydrogenation on a Ru(ii) half-sandwich complex

Article abstract of DOI:10.1039/c3dt32733g

Asymmetric transfer hydrogenation (ATH) of cyclic imines using [RuCl(η⁶-p-cymene)TsDPEN] (TsDPEN = N-tosyl-1,2- diphenylethylenediamine) was tested with various aliphatic (secondary, tertiary) and aromatic amines employed in the HCOOH-base hydrogen donor mixture. Significant differences in reaction rates and stereoselectivity were observed, which pointed to the fact that the role of the base in the overall mechanism could be more significant than generally accepted. The hydrogenation mixture was studied by nuclear magnetic resonance (NMR), Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and vibrational circular dichroism (VCD) with infrared spectroscopy. The results suggested that the protonated base formed an associate with the active ruthenium-hydride species, most probably via a hydrogen bond with the sulfonyl group of the complex. It is assumed that the steric and electronic differences among the bases were responsible for the results of the initial ATH experiments.

Full text of DOI:10.1039/c3dt32733g

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New insight into the role of a base in the mechanism
of imine transfer hydrogenation on a Ru(II)
half-sandwich complex†
Cite this: Dalton Trans., 2013, 42, 5174
Marek Kuzma,*a Jiří Václavík,b Petr Novák,a Jan Přech,b Jakub Januščák,b
Jaroslav Červený,a Jan Pecháček,b Petr Šot,b Beáta Vilhanová,b Václav Matoušek,b
Iryna I. Goncharova,c Marie Urbanovád and Petr Kačerb
Asymmetric transfer hydrogenation (ATH) of cyclic imines using [RuCl(η6-p-cymene)TsDPEN] (TsDPEN =
N-tosyl-1,2-diphenylethylenediamine) was tested with various aliphatic (secondary, tertiary) and aromatic
amines employed in the HCOOH–base hydrogen donor mixture. Significant differences in reaction rates
and stereoselectivity were observed, which pointed to the fact that the role of the base in the overall
mechanism could be more significant than generally accepted. The hydrogenation mixture was studied
by nuclear magnetic resonance (NMR), Fourier transform ion cyclotron resonance mass spectrometry
(FT-ICR MS) and vibrational circular dichroism (VCD) with infrared spectroscopy. The results suggested
that the protonated base formed an associate with the active ruthenium-hydride species, most probably
via a hydrogen bond with the sulfonyl group of the complex. It is assumed that the steric and electronic
differences among the bases were responsible for the results of the initial ATH experiments.
Received 15th November 2012,
Accepted 24th January 2013
DOI: 10.1039/c3dt32733g
www.rsc.org/dalton
gaseous hydrogen (asymmetric hydrogenation, AH), or by
hydrogen obtained in situ from an organic molecule, such as
Introduction
Enantiomerically pure compounds are of vital importance for propan-2-ol or formic acid, which is present in the reaction
a broad range of life sciences and fine chemical products, par- mixture (asymmetric transfer hydrogenation, ATH). The AH of
ticularly for pharmaceuticals and agrochemicals. For the man- functionalized ketones is typically carried out with the organo-
ufacture of chiral compounds starting from achiral precursors, metallic complexes of rhodium and ruthenium bearing dipho-
enantioselective catalysis has become a valuable and versatile sphine ligands.3 Unfunctionalized ketones are efficiently
synthetic route.
reduced over ruthenium-diphosphine/β-diamine complexes.4
Catalytic enantioselective synthesis is according to Rouhi1 For ATH, several active ruthenium-arene, iridium-Cp and
one of the most important synthetic methods for the pro- rhodium-Cp (Cp = cyclopentadienyl) complexes based on
duction of chiral compounds. One of those methods, catalytic β-diamines and β-amino alcohols have been described.5
asymmetric hydrogenation, plays an outstanding role both on
a laboratory and an industrial scale.2 Enantioselective hydro- hydrogenation employing transition metals can operate.6 ATH
genation of the CvC double bond has historically attracted using [RuCl(η6-p-cymene)TsDPEN] (TsDPEN
N-tosyl-1,2-
the most interest. diphenylethylenediamine) (1 in Scheme 1) with HCOOH
There are a variety of mechanisms through which catalytic
=
Nowadays, the asymmetric hydrogenation of ketones and requires the presence of a base such as t-BuOK or triethyl-
imines plays comparably an important role from the practical amine (TEA), which serves as an acceptor of HCl from 1.7 A 16
point of view. The reduction can be conducted either by e− unsaturated complex (3)8 is formed, which can be in situ
protonated and form a solvate (4).9 In the presence of HCOOH,
ruthenium hydride 2 is formed.8,10 This species is capable of
reducing prochiral ketones or imines (such as dihydroiso-
aLaboratory of Molecular Structure Characterization, Institute of Microbiology, v.v.i.,
Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20 Prague 4,
quinolines, DHIQs) to optically enriched alcohols or amines
(tetrahydroisoquinolines, THIQs). The outcome is complex 4
(in an equilibrium with 3), which is converted back to species
2 by reacting with the formate anion.
In the ATH of ketones it has been shown that selection of
the base can affect the reaction’s enantioselectivity.11 However,
Czech Republic. E-mail: kuzma@biomed.cas.cz
bDepartment of Organic Technology, Institute of Chemical Technology, Technická 5,
166 28 Prague 6, Czech Republic
cDepartment of Analytical Chemistry, ICT Prague, Czech Republic
dDepartment of Physics and Measurements, ICT Prague, Czech Republic
†Electronic supplementary information (ESI) available: Additional spectroscopic
data. See DOI: 10.1039/c3dt32733g
5174 | Dalton Trans., 2013, 42, 5174–5182
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molecules in the set. The diastereoselectivity was also within
the range of 65–70% de for aromatic bases (pyrrole, pyridine),
but the use of imidazole showed zero selectivity. Based on
these results, we assumed that the differences in diastereos-
electivity were related to the steric requirements of the bases
applied.
A similar experiment was conducted with 1-methyl-3,4-di-
hydroisoquinoline (6). The differences in reaction rates were
very significant and also followed the groups of tertiary, sec-
ondary and aromatic bases. However, in this case the rate with
DIPEA was slightly higher than with TEA. Interestingly, enan-
tioselectivity was not changed appreciably when various bases
were used. This is in contrast with the observations made with
substrate (R)-5.
It was clear that the base dramatically influenced the reac-
tion performance for no apparent reason. We therefore set out
to investigate the observed phenomena closely by utilizing
spectroscopic methods.
Spectroscopic studies
To get further information concerning the structure of species
present in the solution, a mixture of complex 1, HCOOH and
TEA was studied by NMR spectroscopy. Different ratios of TEA
and HCOOH ranging from pure HCOOH to 1 : 10 were exam-
ined (Fig. 1).
Scheme 1 Suggested catalytic cycle for the ATH of a protonated dihydroiso-
quinoline (DHIQ-H+) using catalyst 1.
no mechanistic rationale was proposed and research in this
direction has been rather limited. The presented work is
focused on the influence of a base on the ATH of cyclic imines
and is complemented with a mechanistic study.
When only HCOOH (1 eq.) was added to 1, the Ru hydride
species (2) could be detected but it underwent rapid decompo-
sition. Adding excess HCOOH led to catalyst breakdown,
although after a certain period of time complex 1 reappeared,
meaning that HCOOH did not destroy the catalyst irreversibly.
Addition of TEA had a positive effect on the formation of
hydride 2 (Fig. 1) but increasing the TEA : HCOOH ratio above
5 : 1 did not lead to any appreciable increase of the concen-
tration of 2. Under such conditions, the aromatic region of
Results and discussion
Kinetic experiments
We started our investigation by the ATH of (R)-1,4-dimethyl- 1H NMR spectra consisted of three sets of four individual
3,4-dihydroisoquinoline ((R)-5) followed in situ by NMR. Di- signals belonging to three different p-cymene moieties, which
astereomeric products formed during the reaction were readily can be attributed to (a) hydride 2, (b) a compound identified
1
distinguishable by H NMR. Several bases were tested in com- as ruthenium formate [Ru(HCOO−)(η6-p-cymene)TsDPEN],10a
bination with HCOOH as a hydrogen source and the results and (c) a species that was assumed to be a second diastereo-
are summarized in Table 1.
mer of the ruthenium hydride. The latter has also been
Substantially different reaction rates were observed with observed in the case of ruthenium tethered complexes12 and
various bases. The highest was for tertiary amines, i.e. TEA, the hypothesis is further supported by the fact that no second
N,N-diisopropyl(ethyl)amine (DIPEA) and 1,4-diazabicyclo- hydridic species was observed with an achiral p-toluenesulfo-
[2.2.2]octane (DABCO). In the case of TEA, the rate was over nylethylenediamine ligand as shown by Ikariya et al.10a In con-
1
four times higher than in the trial with DIPEA. Secondary trast, in the H NMR spectrum of precatalyst 1, all protons of
amines (morpholine, piperidine and pyrrolidine) performed the p-cymene moiety resonated in a narrow region (Fig. S1†13).
with even lower rates. The rate was surprisingly high for One interpretation of such significant changes might be that
pyrrole (an aromatic heterocycle) when compared to pyrroli- the coordination mode of p-cymene was changed. However,
dine because the rates obtained with other aromatic bases the 1JC–H direct interaction constants of p-cymene in complexes
(imidazole and pyridine) were very low.
1 and 2 were very similar (Table S1†13) and the slight differ-
Selection of a base also distinctively affected the asym- ences were therefore ascribed to different electron-donating
metric bias of the reaction. The lowest diastereomeric excess abilities of the chloride and hydride ligands. This measure-
(de) was observed for DIPEA, followed by TEA and DABCO. Sec- ment thus disproved our initial assumption of p-cymene
1
ondary amines (piperidine, morpholine and pyrrole) per- decoordination since more profound changes of JC–H con-
formed with around 65% de and the highest value was stants would be expected. An explanation based on subsequent
obtained for pyrrolidine, which is one of the smallest experiments is proposed at the end of this study (vide infra).
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Table 1 Results of the asymmetric transfer hydrogenation of (R)-5 and 6 using catalyst 1 and HCOOH with various bases
Substrate (R)-5
Substrate 6
Amine type
Tertiary
Amine
TEAd
pKa1
ka
deb [%]
55.5
ka
eec [%]
83.9
10.8
1.0000
1.0000
DIPEAe
11.4
8.7
0.2442
0.2335
46.1
63.8
1.1650
0.4932
84.0
82.7
DABCOf
Secondary
Aromatic
Morpholine
Piperidine
8.3
0.2144
0.2059
65.6
65.1
0.1156
0.2383
78.9
82.1
11.0
Pyrrolidine
Pyrrole
11.2
0
0.0594
0.1423
0.0042
0.0064
71.5
65.5
0
0.2726
79.2
—
0
Imidazole
Pyridine
7.0
5.2
0
—
69.3
0.0006
n.d.g
a Zero order rate constants relative to TEA. From the time-conversion plot, the linear region was used for the least squares linear regression
analysis to determine the k values. b Diastereomeric excess, determined by NMR. c Enantiomeric excess, determined by GC after pre-column
derivatization. d Triethylamine. e N,N-Diisopropyl(ethyl)amine. f 1,4-Diazabicyclo[2.2.2]octane. g The amount of the product was too low to
determine ee.
In the next stage, we utilized Fourier transform ion cyclo-
tron resonance mass spectrometry with electrospray ionization
in positive mode (ESI+-FT-ICR MS) to observe active hydride
species 2. Since the NMR experiments showed that it was
formed in the prevalence of TEA, similar conditions were
applied (TEA : HCOOH = 5 : 2).
The mass spectrum contained three isolated ion clusters
(Fig. 2 and Table 2). The most intense ion cluster in the spec-
trum contained a monoisotopic ion with m/z 595.1500. Analyz-
ing the ion cluster and the isotope relative ratio allowed us to
reveal the molecular formula C31H35N2O2RuS, which well
agreed with the measured data (Table 2). The species was
identified as a [M − H]+ ion of the 16 e− Ru complex (3) that is
formed from 1 by elimination of HCl.14 The second most
intense ion cluster in the spectrum contained a monoisotopic
ion with m/z 698.2855 reflecting the elemental composition
Fig. 1 Spectra of 1 upon adding pure HCOOH or a mixture of HCOOH and TEA
in various ratios.
C37H52N3O2RuS.
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Fig. 3 Three hypothetical associates of TEA with 1. The amine (a) coordinates
to the Ru atom of 1, (b) forms a hydrogen bond with the NH2 group of the
ligand, or (c) forms a hydrogen bond with the sulfonyl group.
Application of ESI as an ion source can be accompanied by
formation of artificial in-source ions as a consequence of ion–
ion or ion–solvent reactions. However, they can be eliminated
by dilution and no substantial changes in the MS spectrum
after a 1000-fold dilution of the measured solution with pure
acetonitrile were detected (Fig. S2†13). Therefore, we believe
that the detected ions reflected the true solution composition.
To support our hypothesis based on the association of the
base with the complex, we repeated the ESI+-FT-ICR MS
measurements with DIPEA and DABCO. In both cases, three
clusters were observed (Table 2, Fig. S3 and S4†13). The one
corresponding to 3 was present in both spectra. The second
and third clusters showed the presence of “2-base” and
“1-base” associates, respectively. Thus, it was further con-
firmed that also other bases could bind to the Ru complex.
Although the experiments pointed to catalyst–base associ-
ates, it was not clear how the amines could be bound to 1 and
2. Three hypothetical situations were initially considered (see
Fig. 3):
Fig. 2 ESI+-FT-ICR MS spectrum of species formed from 1 in the presence of
HCOOH and TEA.
Table 2 Monoisotopic masses obtained from ESI+-FT-ICR MS measurements
with TEA, DIPEA and DABCO
Monoisotopic mass (m/z)
Error
[ppm]
Identified
species
Measured
Theoretical
Formula
TEA
595.1500
698.2855
732.2475
DIPEA
595.1490
698.2851
732.2466
1.7
0.6
1.2
C31H35N2O2RuS
C37H52N3O2RuS
C37H51N3O2RuSCl
3
2 + base
1 + base
595.1499
726.3150
760.2756
DABCO
595.1499
709.2662
743.2256
595.1490
726.3164
760.2779
1.5
1.9
3.0
C31H35N2O2RuS
C39H56N3O2RuS
C39H55N3O2RuSCl
3
(a) The base coordinates to the ruthenium central atom.
(b) The base forms an N⋯H–N hydrogen bond with the
NH2 group of the TsDPEN ligand.
2 + base
1 + base
(c) The base is protonated and forms an N+–H⋯OvS hydro-
gen bond with the sulfonyl group of the TsDPEN ligand.
Hydride 2 is a coordinatively saturated complex and thus
one of its ligands would have to decoordinate in order to
accept the base as a ligand. Since both hydride and TsDPEN
ligands are required to maintain the catalytic activity of the
complex, the only remaining situation would be a ring slip-
page, e.g. η6 to η4 (ref. 10a and 15) as depicted in Fig. 3a.
However, this scenario was ruled out by NMR measurements
595.1490
709.2647
743.2262
1.5
2.1
0.8
C31H35N2O2RuS
C37H49N4O2RuS
C37H48N4O2RuSCl
3
2 + base
1 + base
The molecular formula of 2 is C31H36N2O2SRu, which
differs from the ion cluster by C6H16N. Because the reaction
mixture contained TEA (C6H15N), this cluster could be
explained as 2 associated with TEA. Similarly, the third cluster
(m/z 732.2475) was assigned to precatalyst 1 associated with
TEA.
1
as the JC–H interaction constants of p-cymene would necess-
arily change upon its decoordination (vide supra).
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piperidine, respectively, and a negative signal at 1153 cm−1
,
which was identified as C–N stretching vibration of the proto-
nated base. However, the C–N vibrations are typically located
at lower wavenumbers. The observed shift may be explained by
the fact that the base was bound to the Ru complex. Moreover,
as the protonated base is not chiral itself and cannot be
observed in a VCD spectrum, the VCD signal supported the
hypothesis of a complex–base associate. In combination with
the distinct change of the vibrations of the SO2 group observed
in VCD, this observation suggested a hydrogen bond of the
N+–H⋯OvS type connecting the SO2 group of TsDPEN and
the protonated base. For the sake of completeness, additional
assignment of the measured VCD signal is given in ESI.†
Hypothesis (c) was conditional on the presence of a proto-
nated base that could form a hydrogen bond. In the case of
+
piperidine, deformation vibrations of the NH2 group were
observed in the IR spectrum at 1600 cm−1 (Fig. 4). Since the
N–H bond of protonated TEA can only undergo stretching
vibrations at shorter wavelengths, the deformation vibrations
could not be expected in VCD spectra. Therefore, additional
FT-IR spectra were measured for 1 and 1 + HCOOH/TEA in the
range of 4000–2000 cm−1 (Fig. S5†13). Unfortunately, we
refrained from drawing conclusions based on these data due
to their unsatisfactory quality. Protonation of TEA was there-
fore assumed from its similarity with piperidine regarding
structure and acidic properties.
The stark difference between the 1H NMR spectra of 1
(Fig. S1†13) and 1 + HCOOH/TEA (Fig. 1) was also interpreted
based on the knowledge obtained. TEA, presumably bound to
the complex, changed the proton shielding and symmetry of
the system, which resulted in the p-cymene ligand being mani-
Fig. 4 VCD and IR absorbance spectra of 1 in DMSO-d6 and upon addition of
HCOOH/piperidine (5/2) and HCOOH/TEA (5/2) mixtures. VCD noise is depicted
in dashed lines.
fested as four individual doublets instead of
multiplet.
a narrow
Diffusion ordered spectroscopy (DOSY) and NOE-based
NMR measurements were carried out to examine the base–
catalyst interaction. Unfortunately, no conclusive results could
be obtained due to several complications arising from the
composition of the mixture. The HCOOH–triethylamine
mixture is in excess to the catalyst and therefore we were
usually confronted with very strong ridges in the spectra
coming from intense signals of TEA. Further, the lifetime of 2
is relatively short (about 8–10 hours), which prevented us from
running experiments that are long enough to get a reasonable
signal-to-noise ratio for the catalyst present as a minority.
Finally, the complex-bonded TEA does not exhibit separate
resonances different from the HCOOH–TEA complex, which
prevented us from performing some selective experiments
and/or selective suppression of the intense signals.
Therefore, the higher amount of the HCOOH–triethylamine
mixture over the catalyst was detrimental to the DOSY experi-
ments. The processing of a DOSY experiment consists of the
analysis of the NMR signal attenuation of particular mixture
components. The loss of signal intensity depends on the
power of magnetic gradients and the slope is proportional to
the diffusion coefficient. We expect the presence of bonded
and non-bonded TEA species, which both possess NMR
Options (b) and (c) required further investigation and there-
fore we directed our experiments towards vibrational circular
dichroism (VCD). VCD spectra were measured together with IR
absorption as the method enables simultaneous acquisition of
both (Fig. 4). The rather low signal-to-noise ratio in VCD was
inevitably caused by an intensive stream of gaseous CO2 that
was formed when 1 was mixed with the HCOOH–base mix-
tures. Due to
a high level of spectral noise within
1700–1550 cm−1, the VCD spectra were not interpreted in this
region.
Strong bands in the IR absorption spectrum of 1 at 1275
and 1133 cm−1 were assigned to asymmetric and symmetric
vibrations of the SO2 group of TsDPEN. In the VCD spectrum,
these vibrations were identified as negative patterns at 1272
and 1129 cm−1. When the HCOOH–base mixtures were added,
two pronounced changes were observed. Firstly, a new band
appeared in VCD at 1211 and 1213 cm−1 for TEA and piper-
idine, respectively, which was assigned to asymmetric stretch-
ing of the SO2 group combined with another vibration of a
group nearby. Secondly, an exciton couplet appeared in VCD
with a positive signal at 1178 and 1176 cm−1 for TEA and
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signals of the same chemical shifts. Therefore, the analysis of speculated that the molecules of the catalytic complex and (R)-
the DOSY spectrum would require a detection of minor 5 are structurally more prone to interfere with the base, result-
changes in the attenuation curve of the signals of TEA caused ing in more apparent influence of the base on the reaction
by bonded TEA, which is unrealistic in the case of predominat- performance.
ing non-bonded TEA. The DOSY spectra, which were
measured, demonstrated mainly TEA signals with no unequi-
vocal demonstration of TEA being bonded to the complex.
When the complex and HCOOH–triethylamine were in an
Conclusions
Together with the aforementioned results we can draw a con-
clusion that it is likely that the base binds to the catalytic
complex by forming an N+–H⋯OvS hydrogen bond with the
SO2 group of the ligand. As a consequence, the selection of the
base can have an influence on the reaction rate and enantio-
selectivity of the ATH of cyclic imines. The influence of the
base on the enantioselectivity of the ATH of ketones, as
observed earlier,11 can be explained in the same fashion.
In the mechanistic pathways described so far, the base
solely serves as an acceptor of the chloride ligand from the
RuII precatalyst. The implications of this work thus sup-
plement those parts of the reaction mechanism that have
already been clarified, and allow for a rational optimization of
the ATH reaction conditions that would suit concrete
substrates.
equimolar ratio, the conversion of 1 to 2 was not complete and
the mixture composition no longer corresponded to the reac-
tion conditions.
The NOE measurements were likewise complicated by the
excess of triethylamine. Since only a small part of the total
amount of triethylamine forms the described associate with
the Ru complex, it could not be observed under such
conditions.
Eventually, the findings allowed us to offer an explanation
for the differences in reactivity and/or selectivity observed in
the ATH of (R)-5 and 6. Similarly to the base, the substrate is
also protonated and enters the transition states from an ener-
getic minimum in which it is bonded to the oxygen atom of
the sulfonyl group (Fig. 5a).16 The base can compete with the
substrate for this site, which might explain its influence on the
reaction rate.17
Enantioselectivity is a result of a fine interplay between the
substrate and the η6-aromate of the catalyst, which is based on
CH–π interactions. The presence of a base in the vicinity of the
aromatic ligand and the substrate molecule (Fig. 5b) may
affect the free energy of Si (G‡S) and/or Re (G‡R) transition states
(sterically, electronically, or by a combination of both), thereby
changing the enantioselectivity since the ee value is factually
dependent on the difference ΔG‡R/S. Regarding different trends
of de and ee in the case of (R)-5 and 6, respectively, it is
Experimental
Chemicals
[RuCl(η6-p-cymene)TsDPEN],
(2R)-2-phenylpropan-1-amine
(99%), phosphorus oxychloride (99%), acetanhydride (≥98%),
formic acid (≥96%), triethylamine (≥99%), N,N-diisopropyl-
(ethyl)amine (99.5%), 1,4-diazabicyclo[2.2.2]octane (≥99%),
pyridine (≥99.0%), pyrrole (98%), imidazole (≥99%), pyrroli-
dine (≥99%), morpholine (≥99%), piperidine (99%) were pur-
chased from Sigma-Aldrich (Steinheim, Germany). DMSO-d6
(99.8 atom%D), CD3CN (99.5 atom%D), and CDCl3 (99.8 atom
%D) were purchased from ARMAR Chemicals. Toluene (p.a.),
chloroform (p.a.), acetonitrile (p.a.), xylene (p.a.) and diethyl
ether (p.a.) were obtained from Penta (Czech Republic).
Instrumentation
NMR. NMR spectra were measured on a Varian UNITYInova-
400 spectrometer (399.89 MHz for 1H and 100.55 MHz for
13C), a Bruker AVANCE III 400 MHz spectrometer (400.00 MHz
for 1H and 100.58 MHz for 13C) and a Bruker AVANCE III
600 MHz spectrometer (600.23 MHz for 1H and 150.93 MHz
for 13C) in CD3CN, DMSO-d6, and CDCl3 at 303 K. The residual
signal of the solvent was used as an internal standard (CD3CN:
δH 1.931 ppm, δC 1.265 ppm, DMSO-d6: δH 2.500 ppm, δC
1
39.60 ppm, CDCl3: δH 7.265 ppm, δC 77.00 ppm). H NMR, 13C
NMR, COSY, gHSQCAD, and gHMBCAD spectra were measured
using standard manufacturers’ software (Varian Inc., Palo Alto,
U.S.A. and Topspin 2.1, Bruker Biospin GmbH, Rheinstetten,
Germany). 1D NMR spectra were zero filled to fourfold data
points and multiplied by window function (for H NMR with
two-parameter double-exponential Lorentz–Gauss function, for
Fig. 5 (a) The base hinders the substrate by competing for the sulfonyl site;
(b) the base is involved in the supramolecular structure of the diastereomeric
transition state, thus affecting its free energy.
1
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13C NMR line broadening 1 Hz was applied) before Fourier into an NMR tube and a solution of 1 (97 μL) was added
transformation to improve resolution. Chemical shifts are thereto. Then substrate 6 (12 mg, 83 μmol) dissolved in CD3CN
1
given in δ scale [ppm] and coupling constants in Hz. Digital was added to reach a total volume of 800 μL. H spectra were
resolution enabled us to report chemical shifts of protons to 3 acquired at regular intervals. Conversion was determined by
and coupling constants to 1 and carbon chemical shifts to 2 integration. After the reaction, a saturated solution of sodium
decimal places.
FT-ICR MS. Mass spectrometric experiments were per- was subsequently extracted with diethyl ether, dried over mag-
formed on commercial APEX-Ultra FTMS instrument nesium sulfate and evaporated to dryness. The residue was
carbonate (1 mL) was added to the reaction mixture, which
a
equipped with a 9.4 T superconducting magnet and a Dual II reconstituted to acetonitrile (1 mL), (1R)-(−)-menthyl chloro-
ESI/MALDI ion source (Bruker Daltonics, Billerica, MA) using formate (10.0 μL, 0.13 mmol) and triethylamine (20.0 μL,
electrospray ionization in the positive mode (ESI+). The flow 0.14 mmol) were added and the sample was analyzed on GC
rate was 1 μL min−1 and the temperature of dry gas (nitrogen) for the determination of enantiomeric excess (ee).
was set to 200 °C. Mass spectra were obtained by accumulating
FT-ICR MS. Catalyst 1 (5.1 mg) was dissolved in acetonitrile
ions in the storage hexapole for 0.1 s and running the quadru- (550 μL) and water (40 μL). The base (triethylamine: 9.2 μL,
pole mass filter in non mass-selective (Rf-only) mode so that 66 μmol; DIPEA: 11.6 μL, 66 μmol; DABCO: 7.4 mg, 66 μmol)
ions of a broad m/z range (200–2500) were passed to the FTMS and HCOOH (0.5 μL, 13 μmol) were added thereto and the
analyzer cell. The accumulation time in a collision cell was set solution was stirred for 5 minutes. Prior to the FT-MS measure-
to 0.2 s, the ICR cell was opened for 1500 μs and 8 experiments ment an aliquot (1 μL) of the solution was dissolved in pure
were collected for one spectrum. The instrument was externally acetonitrile (1 mL).
calibrated using singly charged arginine clusters and as a
Circular dichroism. A stock solution of 1 (21.0 mg) was pre-
result, the typical mass accuracy was ≤3.0 ppm. After the ana- pared by dissolving it in DMSO-d6 (300 μL) and VCD and IR
lysis the spectra were apodized using sin apodization with one absorbance spectra of the solution (75 μL) were measured. The
zero fill. The interpretation of mass spectra was done using base (triethylamine: 2.30 μL, 16.5 μmol; piperidine: 1.63 μL,
the DataAnalysis version 3.4 software package (Bruker Dal- 16.5 μmol) and HCOOH (1.56 μL, 0.04 mmol) were added to
tonics, Billerica MA) and mMass.18
Circular dichroism. The VCD spectra were measured using a acquired.
the sample and spectra of the resulting mixtures were
Bruker IFS-66/S spectrometer equipped with a PMA 37 VCD/
FT-IR. A stock solution of 1 in CHCl3 (66 mg mL−1) was pre-
IRRAS module containing a BaF2 polarizer, a ZnSe photoelastic pared. The solution of 1 (0.5 mL) was mixed with triethylamine
modulator, an MCT detector and a filter restricting frequencies (72.5 μL, 0.52 mmol) and HCOOH (49.0 μL, 1.30 mmol). IR
to <1800 cm−1, as described previously.19 For all measure- spectra of pure 1 and of the mixture were measured in a
ments an A145 Bruker cuvette with BaF2 windows and a cuvette with a path length of 0.1 mm.
100 μm pathlength were used. All spectra were measured at a
Preparative procedures
resolution of 8 cm−1, averaging 8 blocks, each containing 2240
interferometric scans with a zero filling factor of 4.
Synthesis of [(R)-2-phenylpropyl]acetamide. (R)-2-Phenylpro-
FT-IR. Infrared spectra were obtained on an FT-IR NICOLET pane-1-amine (3.00 g, 22.2 mmol) was dissolved in toluene
6700 spectrometer. Measurements were conducted within the (12 mL). Under stirring, acetanhydride (2.40 mL, 22.2 mmol)
range of 4000–2000 cm−1 with 32 scans per spectrum. Spectra was added dropwise. The solution was then refluxed for
were obtained and interpreted using OMNIC v7.3 software.
2 hours. The remaining oil was distilled (bp 142–145 °C at
2–3 mmHg) to afford the product. Yield: 3.73 g, 95%. H NMR
(399.87 MHz, CDCl3, 303 K): δH 1.265 (3H, d, J = 7.0 Hz, H-6),
1
Spectroscopic studies
Kinetic experiments. Procedure for the ATH of (R)-5: A stock 1.892 (3H, s, H-1), 2.934 (1H, m, H-5), 3.227 (1H, ddd, J = 4.9,
solution of 1 (28 mg mL−1) was prepared. HCOOH (83 μL, 8.7, 13.5 Hz, H-4u), 3.621 (1H, ddd, J = 6.1, 6.9, 13.5 Hz, H-4d),
2.2 mmol) and a base (2.5 eq.) were premixed in DMSO-d6 to a 5.554 (1H, br s, H-3), 7.198 (2H, m, H-ortho), 7.229 (1H, m,
total volume of 600 μL and a solution of 1 (10 μL) was added H-para), 7.323 (2H, m, H-meta); 13C NMR (100.55 MHz, CDCl3,
thereto. The mixture was transferred into the NMR tube and 303 K): δC 19.34 (q, C-6), 23.06 (q, C-1), 39.58 (d, C-5), 46.14 (t,
1
placed in the NMR. H NMR spectra were measured using the C-4), 126.65 (d, C-para), 127.10 (d, C-ortho), 128.65 (d, C-meta),
WET pulse sequence for presaturation of strong signals. 143.98 (s, C-ipso), 170.38 (s, C-2).
During the initial period, an appropriate saturation waveform
Synthesis
of
(R)-1,4-dimethyl-3,4-dihydroisoquinoline
was generated for elimination of signals of HCOOH and the ((R)-5). N-[(R)-2-Phenylpropyl]acetamide (3.57 g, 20.1 mmol)
base. Then substrate (R)-5 (7.0 mg, 44 μmol) dissolved in and phosphorus oxychloride (9.4 mL, 0.1 mol) were dissolved
DMSO-d6 was added to reach a total volume of 700 μL. 1H in dry xylene (100 mL) and stirred at 180 °C for 3 hours. The
spectra were acquired at regular intervals. Conversion and de reaction mixture was carefully added to ice water and the solu-
were determined by integration.
tion was filtered. The filtrate was neutralized with water solu-
Procedure for the ATH of 6: A stock solution of 1 (5.2 mg tion of NaOH (20%). The product was extracted with diethyl
mL−1) was prepared. HCOOH (62 μL, 2.2 mmol) and a base ether (3 × 20 mL) and combined organic phases were washed
(2.5 eq.) were premixed in CD3CN, the mixture was transferred with water (3 × 20 mL), dried over anhydrous MgSO4 and the
5180 | Dalton Trans., 2013, 42, 5174–5182
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volatiles were concentrated in a vacuum to yield a dark oil. The
crude product was distilled under reduced pressure (bp
Acknowledgements
104–110 °C/2–3 mmHg). Yield: 2.02 g, 63%. 1H NMR This work has been financially supported by the Grant Agency
(399.87 MHz, CDCl3, 303 K): δH 1.232 (3H, d, J = 7.0 Hz, of the Czech Republic (Grant GACR 104/09/1497 and P106/12/
4-CH3), 2.391 (3H, t, J = 1.5 Hz, 1-CH3), 2.825 (1H, m, H-4), 1276), and by a grant for long-term conceptual development of
3.434 (1H, ddq, J = 1.5, 8.9, 15.5 Hz, H-3u), 3.726 (1H, ddq, J = Institute of Microbiology RVO: 61388971. We would like to
1.5, 5.8, 15.5 Hz, H-3d), 7.245 (1H, m, H-5), 7.284 (1H, m, H-7), thank Miroslava Novotná from Laboratory of Molecular Spec-
7.385 (1H, m, H-6), 7.478 (1H, m, H-8); 13C NMR (100.55 MHz, troscopy, ICT Prague, for providing the equipment and assist-
CDCl3, 303 K): δC 17.28 (q, 4-CH3), 23.15 (q, 1-CH3), 29.86 (d, ance with measuring the FT-IR experiments.
C-4), 54.06 (t, C-3), 125.27 (d, C-8), 125.42 (d, C-5), 126.54 (d,
C-7), 128.62 (s, C-8a), 130.78 (d, C-6), 142.23 (s, C-4a), 164.01
(s, C-1).
Notes and references
Synthesis of N-(2-phenylethyl)acetamide. Phenethylamine
(5.0 g, 41 mmol) and triethylamine (7.3 mL, 51 mmol) were
dissolved in dichloromethane (150 mL). The reaction mixture
was stirred and acetyl chloride (3.6 mL, 50 mmol) was added
dropwise during 15 min at 25 °C. The mixture was further
stirred at 45 °C for 30 minutes. Water was added to the reac-
tion mixture, which was cooled to room temperature. The
organic phase was separated, washed with 5% hydrochloric
acid (100 mL), 5% solution of sodium carbonate (100 mL) and
water (100 mL), then dried over anhydrous magnesium sul-
phate and concentrated on a rotary evaporator (10 torr, 60 °C).
The product was obtained in the form of honey-like oil. Yield:
6.5 g, 97%. 1H NMR (399.87 MHz, CDCl3, 303 K): δH 1.928 (3H,
s, H-1), 2.811 (2H, t, J = 7.0 Hz, H-5), 3.498 (2H, dt, J = 5.8, 7.0
Hz, H-4), 5.813 (1H, br s, H-3), 7.186 (2H, m, H-ortho), 7.221
(1H, m, H-para), 7.301 (2H, m, H-meta); 13C NMR (100.55 MHz,
CDCl3, 303 K): δC 23.11 (q, C-1), 35.55 (t, C-5), 40.64 (t, C-4),
126.42 (d, C-para), 128.55 (d, C-meta), 128.63 (d, C-ortho),
138.83 (s, C-ipso), 170.10 (s, C-2).
1 A. M. Rouhi, Chem. Eng. News, 2004, 82, 47–62.
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Synthesis of 1-methyl-3,4-dihydroisoquinoline (6). N-(2-Phe-
nylethyl)acetamide (12.0 g, 73.6 mmol) and tetraphosphorus
decaoxide (190 g, 0.67 mol) were dissolved in dry xylene
(250 mL) under an argon atmosphere. The mixture was stirred
at 160 °C for 6 hours and then hydrolyzed with water (200 mL)
after cooling down to room temperature. The solution was
acidified by addition of concentrated hydrochloric acid
(20 mL). The aqueous phase was separated and washed with
toluene (3 × 40 mL). Solid impurities were removed by fil-
tration and the solution was alkalized with a concentrated
solution of sodium hydroxide (280 g) in water. The product
precipitated in the form of a milky emulsion, which was
extracted with toluene (5 × 40 mL). Combined organic extracts
were washed with water (50 mL) and brine (50 mL), dried over
anhydrous magnesium sulfate and concentrated on a rotary
evaporator (10 torr, bath temp. 65 °C). The obtained brown oil
was distilled under reduced pressure (120 °C, 8 torr) to afford
the product in the form of slightly yellowish oil. Yield: 5.2 g,
1
49%. H NMR (400.00, MHz, CDCl3, 303.2 K): δH 2.374 (3H, t,
J = 1.5 Hz, 1-CH3), 2.689 (2H, m, H-4), 3.652 (2H, tq, J = 7.5, 1.5
Hz, H-3), 7.163 (1H, m, H-5), 7.275 (1H, m, H-7), 7.323 (1H,
ddd, J = 7.4, 7.4, 1.4 Hz, H-6), 7.462 (1H, dd, J = 7.6, 1.4 Hz,
H-8); 13C NMR (100.58 MHz, CDCl3, 303.2 K): δC 23.17 (1-CH3),
25.96 (C-4), 46.85 (C-3), 125.19 (C-8), 126.78 (C-7), 127.32 (C-5),
129.49 (C-8a), 130.45 (C-6), 137.32 (C-4a), 164.14 (C-1).
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17 We are aware of the fact that a significant contribution can
also be made by the base during the formation of hydride
2. However, the hydride formation was beyond the focal
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currently underway.
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5182 | Dalton Trans., 2013, 42, 5174–5182
This journal is © The Royal Society of Chemistry 2013