Thiyl radical mediated racemization of benzylic amines

Article abstract of DOI:10.1002/ejoc.200600120

Thiyl radical mediated reversible H abstraction from the stereogenic center α to the nitrogen atom is a mild method to racemize benzylic amines. Owing to the sensitivity of atomtransfer reactions to enthalpic effects, a knowledge of both the S-H and the α-C-H bond dissociation energies is fundamental to select the thiol that is appropriate to abstract the hydrogen atom from a given amine. In the absence of experimental data, theoretical calculations supply a useful predictive tool. The experiments described here are helpful in delineating the optimal conditions that have to be fulfilled for the racemization to proceed in a reasonable time in the presence of either a stoichiometric or a catalytic amount of thiol. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600120

FULL PAPER
DOI: 10.1002/ejoc.200600120
Thiyl Radical Mediated Racemization of Benzylic Amines
Stéphanie Escoubet,[a] Stéphane Gastaldi,[a] Nicolas Vanthuyne,[b] Gérard Gil,[b]
Didier Siri,[c] and Michèle P. Bertrand*[a]
Keywords: Amines / Density functional calculations / Racemization / Radical reactions
Thiyl radical mediated reversible H abstraction from the ste-
reogenic center α to the nitrogen atom is a mild method to
racemize benzylic amines. Owing to the sensitivity of atom-
transfer reactions to enthalpic effects, a knowledge of both
the S–H and the α-C–H bond dissociation energies is funda-
mental to select the thiol that is appropriate to abstract the
hydrogen atom from a given amine. In the absence of experi-
mental data, theoretical calculations supply a useful predic-
tive tool. The experiments described here are helpful in de-
lineating the optimal conditions that have to be fulfilled for
the racemization to proceed in a reasonable time in the pres-
ence of either a stoichiometric or a catalytic amount of thiol.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
catalyzed dehydrogenation of amines and that of the related
hydrogen transfer to imines have been investigated by
Bäckvall. These reactions have been applied to the racemi-
zation of benzylic amines at 110 °C in toluene.[5]
Introduction
As stated by Ebbers et al. in 1997,[1] in a general review
devoted to the racemization of organic compounds: “Not-
withstanding the revolutionary advances in asymmetric
synthesis, the resolution of racemates is still the most im-
portant approach to the industrial synthesis of optically
pure compounds [...] The main disadvantage of a resolution
compared to an enantioselective synthesis is the maximum
theoretical yield of 50%. Therefore racemization of the un-
wanted isomer is of critical importance for economically
and environmentally acceptable resolutions.” If one ignores
α-amino acid derivatives,[2] the racemization of amines is
mainly performed by processes involving oxidation/re-
duction[1,3] (60%) or base-catalysis[1,4] (30%). The latter
often necessitates rather harsh conditions, which do not tol-
erate additional sensitive functional groups. Redox pro-
cesses going through prochiral imines or iminium ion inter-
mediates can be performed either under heterogeneous or
homogeneous catalysis. The mechanism of the ruthenium-
Thiols are very good hydrogen atom donors[6] and, at the
same time, thiyl radicals are able to abstract hydrogen
atoms from electron-rich C–H bonds.[7] They also act as
efficient polar reversal catalysts in numerous radical reac-
tions.[8] The epimerization of stereogenic centers α to an
oxygen atom in cyclic systems has been reported by
von Sonntag and by Roberts,[9] and we have recently shown
that thiyl radicals are able to mediate the cleavage of allylic
amines.[10] The reaction is likely to proceed through hydro-
gen abstraction from the allylic position α to the nitrogen
atom, according to Scheme 1. The backward hydrogen
transfer from the thiol to the carbon atom γ to the nitrogen
atom in the intermediate delocalized radical leads to an en-
amine, which gives rise to a thioaminal under stoichiomet-
ric conditions. The latter is hydrolyzed upon acidic workup.
[a] Laboratoire de Chimie Moléculaire Organique, UMR 6517
“Chimie, Biologie, et Radicaux Libres”, Boite 562, Université
Paul Cézanne, Aix-Marseille III, Faculté des Sciences St
Jérôme,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex
20, France
E-mail: michele.bertrand@univ.u-3mrs.fr
[b] Laboratoire de Stéréochimie Dynamique et Chiralité, UMR
6180 “Chirotechnologies: Catalyse et Biocatalyse”, Université
Paul Cézanne, Aix-Marseille III, Faculté des Sciences St
Jérôme,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex
20, France
Scheme 1.
[c] Laboratoire de Chimie Théorique et Modélisation Moléculaire,
UMR 6517, Université de Provence, Faculté des Sciences St
Jérôme,
Following on from this study, we have investigated the
thiyl radical mediated reversible H abstraction from chiral
benzylic amines, since this reaction should provide an at-
tractive methodology to racemize these activated amines
under mild conditions (Scheme 2).
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex
20, France
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Thiyl Radical Mediated Racemization of Benzylic Amines
FULL PAPER
cal experiments were performed as follows: a benzene solu-
tion of amine (0.063–0.64 ) containing the selected thiol
(1.2 or 0.2 equiv.) was heated at reflux for 6–7 h in the pres-
ence of AIBN (an overall quantity of 20 mol-% of AIBN
was divided into three equal portions, which were added
successively every 2 h). After concentration, the residue was
diluted with HCl (1 ) and the solution was washed with
Et2O. The aqueous phase was basified with saturated so-
dium carbonate and extracted with Et2O. The pure amine
was isolated after drying with MgSO4 and concentration.
Due to the scale (approximately 100 mg of substrate), the
isolated yields for the recovery of the amine after acid/base
purification seldom exceeded 70%, except for the most lipo-
philic amine in the series (2). Yields determined by 1H
NMR spectroscopy using pentamethylbenzene as internal
standard are given in parentheses.
As stated above, the choice of thiol is crucial. According
to literature data, the α-C–H BDE is 357 kJmol–1 in diben-
zylaniline and 372 kJmol–1 in tribenzylamine.[14] Instead of
taking any of these nonbranched amines as reference, we
reasoned that the α-C–H BDE in chiral benzylic amines
should not be very different from the α-C–H BDE in allylic
amines (the α-C–H BDE in N-allylic amines varies between
320 and 330 kJmol–1 according to DFT calculations[10b]).
This is the reason why we started studying the reactivity of
thiocresol with respect to amine 1, using the experimental
conditions that had proved efficient for H abstraction from
allylic amines.[10] Compound 1 was found to be almost com-
pletely racemized in 6 h (14% ee; Entry 1). Acetophenone
(5) was detected in 3% yield as a side-product. The latter
most probably results from oxidation of the intermediate
α-amino radical. These radicals are reputedly potent one-
electron reducing agents, with ionization potentials that ri-
val those of alkali metals.[15,16]
Scheme 2.
The forward hydrogen atom transfer from the amine to
the electrophilic thiyl radical is particularly favored on the
grounds of polar effects since it generates a strongly nucleo-
philic carbon-centered radical. However, the opposite po-
larity of the two radical species, which accelerates the hy-
drogen atom transfers, is not the only requirement. The S–
H and the C–H bond dissociation energies (BDEs) should
match each other in such a way that none of the key hydro-
gen transfers is too slow for the reaction to proceed in a
reasonable time, and without undesired side-products being
formed.
We describe herein the results obtained with α-phen-
ethylamines 1–3, amide 4, and amines 8–11 (Figure 1). The
influence of both experimental conditions (temperature,
solvent, concentration of the reagents), and structural pa-
rameters (substitution at the nitrogen atom, nature of the
thiol) has been investigated.
The result reported in Entry 1 was obtained after 6 h in
the presence of 1.2 equiv. of thiocresol. Reducing the
number of equivalents of thiol by a factor of six (Entry 2/
Entry 1) led to 28% ee for the recovered amine after 7 h at
reflux. Multiplying the concentration by a factor of 2 or 10
did not change the results very much under stoichiometric
conditions (cf. Entries 3 and 4 with Entry 1). Monitoring of
the reaction by chiral HPLC led us to the conclusion that
Figure 1. Structures of compounds 1–11.
Results and Discussion
The racemization experiments were performed on terti- stoichiometric conditions and a concentration between
ary, secondary, and primary amines 1, 2, and 3. Amine 1 0.067 and 0.13  was a rather good compromise.
was obtained from the commercially available (R)-1-phen-
As reported in Table 1 (Entries 6–9), the nature of the
ethylamine (3) in 68% yield (94–90% ee depending on the thiol was investigated with amine 1. Racemization was com-
experiment) by an Eschweiler–Clarke methylation pro- pleted in 6 h with both thiophenol and n-OctSH under stoi-
cedure.[11] Amine 2 was prepared in 59% yield (92% ee) by chiometric conditions (ee values of 4 and 0%, respectively;
the addition of 3 to ethyl acrylate.[12] Amine 10 was pre- Entries 6 and 8). According to enthalpic effects, going from
pared in 77% yield (ee Ͼ 99%) by the double alkylation of TolS· to n-OctS· would increase kH and conversely should
(–)-(R)-2-aminophenylethanol with 1,5-dibromopentane.[13] decrease k–H. This was clearly demonstrated by the influ-
Its methylated derivative 11 was obtained in 80% yield (ee ence of the concentration in the case of the alkanethiol:
Ͼ 99%) upon treatment with NaH and MeI. The synthesis after 6 h, under catalytic conditions, the ee value was still
of these amines in racemic form was also performed accord- 80%, whereas amine 1 was totally racemized under stoi-
ing to the same protocols in order to optimize the analytical chiometric conditions (Entry 9/Entry 8). The effect was less
procedures.
pronounced in the case of TolSH (Entry 2/Entry 1). Thi-
The radical reactions were monitored and analyzed by ophenol was as efficient under stoichiometric conditions as
chiral HPLC. The results are summarized in Table 1. Typi- under catalytic conditions (Entry 6/Entry 7).
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S. Escoubet, S. Gastaldi, N. Vanthuyne, G. Gil, D. Siri, M. P. Bertrand
FULL PAPER
Table 1. Racemization of amines 1, 2, 3, amide 4, and amines 10 and 11.
[a] nd = not determined. [b] ee = 16% after 3 h. [c] (ee)0 = 94%. [d] (ee)0 = 92%. [e] (ee)0 = 86%. [f] (ee)0 Ͼ 97%. [g] (ee)0 Ͼ 99%.
Thus, a wide range of thiols can be used to racemize amount of thiol) to prevent side reactions of the α-ami-
tertiary benzylic amines in the presence of 1.2 equiv. of noalkyl radical.
thiol. The requirement regarding the relative strength of S–
The variation of ee value vs. time was also monitored.
H and C–H bonds is stricter when the thiol is used in cata- In the presence of a stoichiometric amount of thiol, the
lytic amounts (0.2 equiv.) with respect to the substrate since racemization proceeded slightly faster for the secondary
the rate of the backward transfer is divided by a factor of amine 2 than for the tertiary amine 1. The racemization of
six, like the thiol concentration.
1 proceeded slightly faster with OctSH than with TolSH
The secondary amine 2 was also racemized within 7 h (see Supporting Information).
using either a stoichiometric or a catalytic amount of thio-
According to literature data, acetylation strengthens the
cresol (0 or 38% ee depending on the experimental condi- α-C–H BDE by approximately 17 kJmol–1 for aliphatic
tions; Entry 10/Entry 11). Racemization was nearly com- amines.[17] The stereogenic center in the acetylated deriva-
plete in 6 h with a stoichiometric amount of thiophenol. tive 4 could not be epimerized whatever thiol was used
However, with octanethiol as the mediator degradation was (PhSH, TolSH, or even thioglycolic acid methyl ester, which
observed. The remaining amine (15%) was not significantly has a much stronger S–H bond; see Table 3) under stoichio-
racemized. This would indicate that, although n-OctS· is metric conditions (Entry 14). The absence of racemization
strong enough to abstract the α-hydrogen atom, the reverse is likely to result from the inability of any of the thiyl
step is too slow (even in the presence of a stoichiometric radical mediators used to abstract the α-hydrogen
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Thiyl Radical Mediated Racemization of Benzylic Amines
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atom because both enthalpic and polar effects are unfavor- lations were undertaken. According to Guo et al.,[21] the
able. best methods to calculate BDEs would be high-level theo-
The most intriguing results came from the primary amine retical methods such as G3 and CBS-Q; the G3B3(MP2)
3. In all cases a large amount of imine 6 was formed.[18] method also gives a quite good agreement with experimen-
The oxidation of the intermediate radical leading to the cor- tal values. However, for cost reasons, many groups have
responding carbenium ion, followed by condensation of the used pure DFT methods that have been shown to give reli-
primary amine according to Scheme 3, might account for able relative values in a series and therefore offer a good
the formation of 6.
compromise.[21,22] Both S–H BDEs and α-C–H BDEs in
amines 1, 3, and 7 (taken as a model for 2; Figure 1) were
first determined at the UB3P86/6-311++G(d,p)//UB3LYP/
6-31G(d) level of theory using the Gaussian 03 program.[23]
The UB3LYP/6-31G(d) basis set was used to optimize
geometries. Each optimized geometry was confirmed by
frequency calculations to be a real minimum. The enthalpy
of each species was calculated using the UB3P86/6-
311++G(d,p) electronic energy, and the zero-point vi-
brational energy and thermal corrections obtained at the
UB3LYP/6-31G(d) level using a scale factor of 0.9804.
The energies of the frontier orbitals, i.e., the SOMOs of
both the α-amino radicals and the thiyl radicals, are given
in Tables 2 and 3, respectively (nBuSH was taken as a model
for n-OctSH).
Scheme 3.
When thiocresol was used as the mediator, partial race-
mization occurred, 61% of amine 3 (60% ee) was recovered,
and 6 was detected in 14% yield by NMR spectroscopy
(Entry 15). It should be noted that a 14% yield of imine 6
corresponds to the consumption of 28% of amine 3. One
would have expected the best hydrogen atom donor, i.e.,
thiocresol to give the best results. However, thiophenol gave
slightly better results than thiocresol. When thiophenol was
used, either in stoichiometric or catalytic amounts, the rate
of recovery of amine 3 increased slightly and the recovered
amine was partially racemized [40% ee after 6 h under stoi-
chiometric conditions (Entry 16); 76% ee in the presence of
a catalytic amount of PhSH (Entry 17)].
Table 2. Calculated α-C–H BDEs, energies of the SOMOs of α-
amino radicals, and vertical ionization potentials.
An experiment was performed using a stoichiometric
amount of thiophenol at a concentration ten times higher
(Entry 18/Entry 16). The higher thiophenol concentration
should increase the rate of hydrogen transfer from the thiol
to the intermediate α-amino radical and thus render the
racemization process competitive with respect to the oxi-
dation of the α-amino radical. Racemization was completed
within 6 h and, as expected, the amount of 6 was signifi-
cantly decreased. The amount of 6 was not strictly repro-
ducible from one experiment to another, and careful degas-
sing of the reaction medium did not affect the results.
Changing the nature of the solvent did not change the
outcome of the reaction: no significant effect was registered
going from benzene to toluene, heptane, or even ethyl ace-
tate. Neither octanethiol nor methyl thioglycolate were ef-
ficient in racemizing amine 3. When octanethiol was used,
oxidative degradation of the amine was observed. In all
likelihood the return hydrogen transfer (k–H) is too slow,
and electron transfer oxidation (possibly with the disulfide
likely to be formed in the reaction medium) became the
major pathway.
[a] UB3P86/6-311++G(d,p)//UB3LYP/6-31G(d). [b] G3B3. [c]
G3B3(MP2).
It should be noted that according to the calculations re-
ported here, the α-C–H BDE increases with substitution at
the nitrogen atom, contrary to the above-mentioned general
assumption. The preferred conformations of the amine and
the corresponding α-amino radicals are given in Figures 2
and 3, respectively. In all cases the lowest-energy conformer
of the amine corresponds to the geometry where the α-C–
H bond is antiperiplanar with respect to the lone pair. Ac-
cording to NBO calculations,[26] the overlap between the
σ*C–H orbital and the lone pair stabilizes the system by
Theoretical Support
It long has been accepted that the α-C–H BDE increases around 30–37 kJmol–1 (Table 4). The interaction with the
when going from a tertiary to a secondary, and then to a π-bonds of the aromatic ring stabilizes the ground state by
primary amine.[19] However, recent data on α-C–H BDEs in less than 2.1 kJmol–1. These effects account for the varia-
aliphatic amines have shown that the degree of substitution tion of the C–H bond length in the series.
at the nitrogen atom has little effect on the BDE.[20] To
The case of amine 7 is somewhat special since two stable
confirm or refute our mechanistic speculations, BDE calcu- conformers were found for the ground state (their total en-
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S. Escoubet, S. Gastaldi, N. Vanthuyne, G. Gil, D. Siri, M. P. Bertrand
FULL PAPER
Table 3. Calculated and experimental values for S–H BDEs, and
energies of the SOMOs of thiyl radicals.
Table 4. Hyperconjugative effects affecting the α-C–H bond deter-
mined by the NBO method for the lowest-energy conformers of
amines 1, 7a, 7b (models for 2a and 2b), 3, 8, 10, and 11 calculated
at the UB3P86/6-311++G(d,p)//UB3LYP/6-31+G(d) level, and
bond lengths.
[a] This
work,
UB3P86/6-311++G(d,p)//UB3LYP/6-31G(d).
[b] This work, G3B3(MP2). [c] G3(MP2) calculated value at
298 K.[24a] [d] Experimental values.[24a] [e] Experimental value.[25] [f]
G3-calculated value at 298 K for nBuSH.[10b]
[a] In kJmol–1. [b] C–H bond lengths in Å.
298 K), and thus to a BDE value higher by about
11 kJmol–1 (although the rotational barrier is likely to be
very low). The data in Tables 2 and 4 indicate that 7 (and
by extrapolation 2) is closer to 1 than to 3. This is in agree-
ment with the observed reactivity.
Based on the interaction of the lone pair with the σ*C–H
orbital, one would expect 1 to be cleaved faster than 2,
which itself would be cleaved faster than 3. However, the
BDEs show the opposite trend. The variation of the C–H
BDE in the series is well accounted for by steric interactions
which prevent the radical from being planar and fully delo-
calized in the case of the secondary and the tertiary amines
(Figure 3). If spin delocalization at the aromatic ring car-
bon atoms is important in all cases, the overlap between the
lone pair and the singly occupied orbital is smaller when a
methyl group faces the aromatic ring.
Figure 2. Preferred conformations of amines 1, 3, and 7.
From the experimental measurements it was possible to
determine how much the S–H BDEs are underestimated by
the calculations (Table 3). However, the BDEs in the series
were not all measured according to the same experimental
method. We also had no experimental data to determine
how much the C–H BDEs were underestimated. So we had
in hand two independent reliable relative scales but it was
not obvious to superimpose them. Owing to the accuracy
of these calculations,[21] and in order to obtain more reliable
absolute values for the BDEs in the series of amines for
which we could not refer to any experimental measurement,
G3B3(MP2) calculations were performed for both the α-C–
H BDEs in amines 1–3 and the S–H BDEs (Tables 2 and
3). According to these data, in the case of amine 1 and, by
analogy, in the case of amine 2 (closer to 1 than to 3), the
forward H transfer should be endothermic whatever the
thiol is. Consequently, it should be rate-limiting. This is in
agreement with the racemization of 2 proceeding slightly
Figure 3. Preferred conformations of α-amino radicals 1·, 3·, and
7·.
ergies differ by 4 kJmol–1 at 298 K; at 80 °C the ratio of 7b/ faster than that of 1 in the presence of a stoichiometric
7a would be 80:20). The most stable conformer (7b) corre- amount of TolSH, since the forward hydrogen transfer is
sponds to the less stable conformation of the radical less endothermic. The fact that 1 is racemized faster by n-
(7 kJmol–1 total energy difference between 7b and 7a at OctSH than by TolSH points to the same conclusion.
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Thiyl Radical Mediated Racemization of Benzylic Amines
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Hydrogen abstraction reactions have been the object of Scope and Limits
many theoretical and empirical studies.[27] Special attention
The above comments should help in figuring out the
scope and limits of the reaction. As stated above, the back-
ward transfer may not be able to compete with the oxi-
dation process when the intermediate α-amino radical is
readily oxidized. In fact, this is the case for the cyclic pri-
mary benzylic amines 8 and 9. The reaction performed with
(R)-1-aminoindane (8) clearly shows that the starting mate-
rial is nearly totally degraded. The remaining substrate is
completely racemized. Due to favorable structural param-
eters, H abstraction is particularly favored and the resulting
radical has a high-lying SOMO (–4.2 eV). The value for its
vertical ionization potential is only 6.2 eV, therefore oxidat-
ive degradation is very fast in this case. A test was per-
formed on racemic 9 in order to check its stability toward
the reaction conditions; it was completely degraded under
our standard conditions.
Beyond the previously mentioned acylation, which com-
pletely inhibits H abstraction due to the strengthening of
the α-C–H BDE, we have performed some experiments on
amino alcohol derivatives (10 and 11) in order to analyze
the effect of the β-substituents. The results of the racemiza-
tion experiments are also reported in Table 1. The reactions
were performed under the standard conditions defined for
the other amines, and the ee value was analyzed after 6 h
at reflux in the presence of AIBN.
As shown in Figure 4, intramolecular hydrogen bonding
in 10 modifies the geometry in such a way that neither the
aromatic π-system nor the lone pair can fully participate in
the weakening of the α-C–H bond and the stabilization of
the incipient radical (Table 4). The N···H distance is 2.04 Å
and the delocalization of the lone pair in the antibonding
σ*O–H orbital stabilizes the system by 24.3 kJmol–1. All
these effects contribute to strengthening the α-C–H bond
[UB3P86/6-311++G(d,p)//UB3LYP/6-31G(d)-calculated
BDE = 347.8 kJmol–1], which means that the racemization
process is slowed down and the ee is still 72% after 6 h.
has been focused recently on hydrogen-transfer reactions
from a series of aliphatic thiols to a series of carbon-cen-
tered radicals selected with respect to their polar character.
High-level ab initio and DFT calculations using the curve-
crossing model confirm that the activation barrier is influ-
enced by both polar and enthalpic factors.[28,29] Unfortu-
nately, no calculations were carried out for α-amino
radicals, and the range of thiols did not include aromatic
thiols.
The reduction of the hydroxymethyl radical with thiols
was shown to be a reversible process. The rate constant for
the reaction of the penicillamine thiyl radical with 2-propa-
nol is 1.4 (0.3)×104 –1 s–1, and the rate constant for the
reverse hydrogen transfer is 1.2 (0.3)×108 –1 s–1 at
20 °C.[30,31] The rate constant for the H abstraction from
peptides by the methylthiyl radical was estimated to be
3×105 –1 s–1 by Rauk et al.[32]
From our estimate of the rate of racemization of amines
1 and 2 with thiocresol, one would expect the order of mag-
nitude of kH to be between 103 and 104 –1 s–1 for this thiol
(see Supporting Information).
The examination of the results also leads to the conclu-
sion that the backward H transfer is critical for the efficacy
of the racemization process. Only the most exothermic ones
enable the racemization to proceed in the presence of a
catalytic amount of thiol. As an example, in the presence
of 0.2 equiv. of thiol the backward transfer would become
too slow for the two-step chain mechanism to proceed with
the thiol having the strongest BDE, i.e., n-OctSH (Entry 9).
According to the calculations reported by Coote et al.,[28]
the smaller the enthalpy change, the closer are the acti-
vation barriers for the forward and the backward transfers.
A very narrow range between kH and k–H could be expected
for the reaction of octanethiol with amine 1. In the case of
amine 2, even in the presence of 1.2 equiv. of octanethiol,
the backward hydrogen transfer would not be able to com-
pete with oxidative degradation (Entry 13).
The least exothermic transfers from the thiol to the car-
bon-centered radical, i.e., those involved in the case of
amine 3, would not be fast enough to compete with the
oxidation of the radical leading to the formation of aceto-
phenone and imine 6.
One would have expected the α-amino radical having the
highest-lying SOMO to be oxidized faster. The similarity
between the energies of the SOMOs of the radicals derived
from 1 and 3, as confirmed by the similarity of their non-
adiabatic ionization potentials calculated at the UB3P86/6-
311++G(d,p)//UB3LYP/6-31G(d) level (6.4 eV for both
Figure 4. Influence of hydrogen bonding on the preferred confor-
mation of amine 10.
The results obtained with 11 as starting material suggest
radicals), leads us to discard such an explanation.[33] In the that the presence of the alkylated oxygen atom in the β-
case of amine 3, the fact that PhSH is slightly more efficient position still slows down the racemization process (ee =
than TolSH might originate from the contribution of polar 42% for PhSH; Entry 22), even though there is no impedi-
effects. Since the enthalpy change is similar (based on ex- ment to the antiparallel arrangement of the lone pair and
perimental values of S–H BDEs[24a]), the hydrogen transfers the α-C–H bond (cf. Table 4). The BDE is 340.8 kJmol–1
involving PhS·, which is more electrophilic than TolS· (elec- according to UB3P86/6-311++G(d,p)//UB3LYP/6-31G(d)
tron affinities, EA, of 225.5 and 215.4 kJmol–1,[24c] respec- calculations, which is slightly weaker than the α-C–H BDE
tively) might be slightly faster.
in 1.
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(R)-Ethyl 3-[N-(1-Phenylethyl)acetamido]propanoate (4): Acetyl
chloride (186 µL, 3.28 mmol) was added to a solution of 2 (330 mg,
1.49 mmol) and Et3N (457 µL, 3.28 mmol) in dichloromethane at
0 °C. The reaction mixture was warmed to room temperature over-
night and then diluted with water and extracted twice with EtOAc.
The combined organic fractions were washed with 1  HCl, brine
and dried (Na2SO4). The solution was concentrated to give 4
(360 mg, 1.37 mmol, 92%), which was used without further purifi-
cation. ee = 86%. Chiral HPLC conditions for the racemic mixture:
Chiralcel OD-H, hexane/ethanol (90:10), 1 mLmin–1. Detector: UV
(254 nm) and polarimeter. tR (R, +) = 11.10, tR (S, –) = 13.29, k
(R, +) = 2.64, k (S, –) = 3.36, α = 1.27, Rs = 2.34. 1H NMR
Conclusions
We have proposed a very simple method to racemize chi-
ral benzylic amines that is based on reversible H abstraction
at the stereogenic center by a thiyl radical. The competitive
oxidation of the intermediate α-amino radical makes the
method less efficient for primary amines than for secondary
and tertiary ones. It should be noted that in all cases, but
more particularly when the carbon-centered radical is easily
oxidized, the rate of H abstraction from the thiol by the
carbon-centered radical is a parameter of major importance
since it controls its lifetime. In this case, a stoichiometric (300 MHz, CDCl3, TMS; mixture of 2 rotamers in a 58:42 ratio):
δ = 7.19–7.48 (m, 5 H), 6.05 (q, J = 7.2 Hz, 0.42 H), 5.09 (q, J =
7.0 Hz, 0.58 H), 4.07 (q, J = 7.2 Hz, 0.84 H), 4.06 (q, J = 7.2 Hz,
1.16 H), 3.23–3.59 (m, 2 H), 2.29–2.57 (m, 2 H), 2.25 (s, 1.74 H),
2.19 (s, 1.26 H), 1.65 (d, J = 7.0 Hz, 1.74 H), 1.53 (d, J = 7.2 Hz,
1.26 H), 1.22 (t, J = 7.2 Hz, 1.26 H), 1.21 (t, J = 7.2 Hz, 1.74 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 14.5 (CH3), 16.9 (CH3),
18.5 (CH3), 21.1 (CH3), 22.3 (CH3), 22.5 (CH3), 33.8 (CH2), 35.6
(CH2), 39.0 (CH2), 40.3 (CH2), 51.2 (CH), 56.7 (CH), 60.7 (CH2),
61.1 (CH2), 127.0 (CH), 127.1 (CH), 127.9 (CH), 128.2 (CH), 128.9
(CH), 129.2 (CH), 140.4 (C), 140.9 (C), 171.1 (CO), 171.3 (CO),
172.3 (CO), 174.5 (CO) ppm.
amount of thiol is recommended in order to minimize side
reactions. Since polar effects can be considered to be
roughly equally favorable for all the reactions in the series,
theoretical calculations of α-C–H BDEs, which enable us to
quantify enthalpic factors, provide useful data to rationalize
the results and can be used as a predictive tool. Further
developments will be reported in due course.
Experimental Section
(R)-2-Phenyl-2-(piperidin-1-yl)ethanol (10): ee = 99%. Chiral HPLC
conditions for the racemic mixture: Chiralcel OG, hexane/isopro-
panol (90:10), 1 mLmin–1. Detector: UV (254 nm) and polarimeter.
tR (R, –) = 5.28, tR (S, +) = 7.36, k (R, –) = 0.70, k (S, +) = 1.38,
α = 1.96, Rs = 2.10.
General: All reactions were carried out under argon. Solvents were
degassed before use. 1H and 13C NMR spectra were recorded at
300 and 75 MHz, respectively. Chemical shifts are reported in ppm
and coupling constants given in Hz. Enantiomeric excesses (ee)
were determined by analytical chiral HPLC. The solvents for chiral
chromatography (n-hexane, 2-PrOH, EtOH) were of HPLC grade.
They were degassed and filtered through a Millipore membrane
(0.45 µm) before use. Cellulose tris(3,5-dimethylphenylcarbamate),
Chiralcel OD-H (250×4.6 mm), and cellulose tris(4-methylphen-
ylcarbamate), Chiralcel OG (250×4.6 mm), chiral stationary
phases are available from Chiral Technologies (Illkirch, France).
The chiral HPLC analyses were performed with a screening unit
composed of a Merck D-7000 system manager, a Merck–Lachrom
L-7100 pump, a Merck–Lachrom L-7360 oven, a Merck–Lachrom
L-7400 UV detector, and an on-line chiroptical detector (Jasco OR-
1590 polarimeter or Jasco CD-1595 circular dichrometer). The sign
reported in parentheses is the sign given by the on-line polarimeter
in the mobile phase used for the chiral HPLC analysis. Detailed
chromatographic conditions are reported below. Compounds 1, 2,
and 10 were prepared according to literature procedures.[11–13] All
other commercially available compounds were used without further
purification.
1-[(R)-2-Methoxy-1-phenylethyl]piperidine (11): NaH (60% in oil,
133 mg, 3.30 mmol) was added to a solution of 10 (454 mg,
2.20 mmol) in dry THF at 0 °C. After 20 min of stirring at 0 °C
and then 20 min at room temperature, iodomethane (144 µL,
2.31 mmol) was added at 0 °C. The reaction mixture was warmed
to room temperature overnight and then diluted with water and
extracted twice with Et2O. The combined organic fractions were
washed with water, brine, dried (Na2SO4), and concentrated. The
crude material was subjected to flash column chromatography on
silica gel (EtOAc/Et3N/pentane, 10:5:85) to give 11 (370 mg,
1.77 mmol, 80%). ee = 99%. Chiral HPLC conditions for the race-
mic mixture: Chiralcel OD-H, hexane, 1 mLmin–1. Detector: UV
(254 nm) and polarimeter. tR (S, +) = 8.19, tR (R, –) = 10.51, k (S,
+) = 1.57, k (R, –) = 2.29, α = 1.46, Rs = 3.47. 1H NMR (300 MHz,
CDCl3, TMS): δ = 7.20–7.40 (m, 5 H), 3.78 (dd, J = 5.7 and 9.8 Hz,
1 H), 3.66 (dd, J = 5.7 and 9.8 Hz, 1 H), 3.53 (pseudo-t, J = 5.7 Hz,
1 H), 3.31 (s, 3 H), 2.33–2.48 (m, 4 H), 1.49–1.64 (m, 4 H), 1.30–
1.43 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.0 (CH2),
26.6 (CH2), 52.3 (CH2), 59.3 (CH3), 70.1 (CH), 74.9 (CH2), 127.5
(CH), 128.4 (CH), 128.9 (CH), 140.1 (C) ppm.
(R)-N,N-Dimethyl-1-phenethylamine (1): ee = 94%. Chiral HPLC
conditions for the racemic mixture: Chiralcel OD-H, hexane/2-pro-
panol (99.8:0.2), 1 mLmin–1. Detector: UV (254 nm) and polarime-
ter. tR (R, +) = 5.44, tR (S, –) = 6.21, k (R, +) = 0.75, k (S, –) =
1.0, α = 1.33, Rs = 1.99.
General Procedure for the Racemization: A 0.06  solution of amine
(100 mg) and thiol (1.2 equiv. or 0.2 equiv.) in benzene was refluxed
for 6–7 h in the presence of AIBN (an overall quantity of 20 mol-%
of AIBN was divided into three equal portions, which were added
successively every 2 h). After concentration, the residue was diluted
with HCl (1 ) and the solution was washed with Et2O. The aque-
ous phase was basified with saturated aqueous sodium carbonate
and extracted with Et2O. The pure amine was isolated after drying
with MgSO4 and concentration.
(R)-Ethyl 3-(1-Phenylethylamino)propanoate (2): ee = 92%. Chiral
HPLC conditions for the racemic mixture: Chiralcel OD-H,
hexane/2-propanol (99:1), 1 mLmin–1. Detector: UV (254 nm) and
polarimeter. tR (S, –) = 8.34, tR (R, +) = 9.09, k (S, –) = 1.69, k
(R, +) = 1.93, α = 1.14, Rs = 0.72.
(R)-1-Phenethylamine (3): ee = 97%. Chiral HPLC conditions for
the racemic mixture: Chiralcel OD-H, hexane/2-propanol (90:10),
Computational Details: All the calculations were performed with
1 mLmin–1. Detection: UV (220 nm) and polarimeter. tR (R, +) = the Gaussian 03 software package.[24] Geometry optimizations were
6.19, tR (S, –) = 7.23, k (R, +) = 1.00, k (S, –) = 1.33, α = 1.33, Rs
= 1.31.
carried out, without constraints, at the UB3LYP/6-31G(d) level of
theory. Vibrational frequencies were calculated at the UB3LYP/6-
3248
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Eur. J. Org. Chem. 2006, 3242–3250

Thiyl Radical Mediated Racemization of Benzylic Amines
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Supporting Information (see footnote on the first page of this arti-
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[11]
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[13]
Acknowledgments
[14]
[15]
The authors express their deep gratitude to Dr. Vitaliy Timokhin
for his very valuable assistance and for rereading the manuscript,
and they thank Dr. S. Marque for helpful discussions.
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3249

S. Escoubet, S. Gastaldi, N. Vanthuyne, G. Gil, D. Siri, M. P. Bertrand
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Received: February 10, 2006
7221.
Published Online: May 22, 2006
3250
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3242–3250