Stereoselective Michael additions of lithiated ortho -sulfinylbenzyl carbanions derived from -amino nitriles

Article abstract of DOI:10.1080/17415993.2013.779698

Enantiomerically pure -substituted -amino ortho-sulfinylphenylacetonitriles have been readily prepared by the reaction of diastereoisomeric mixtures of -amino phenylacetonitriles with differently sized cycloalkenones and 2-methyl cyclopentenone in the pre

Full text of DOI:10.1080/17415993.2013.779698

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Stereoselective Michael additions
of lithiated ortho-sulfinylbenzyl
carbanions derived from α-amino
nitriles
José Luis García Ruanoa, Ana M. Martín-Castroa, Laura Morenoa,
Francisco Tatoa & Esther Torrentea
a Departamento de Química Orgánica, Universidad Autónoma de
Madrid, Cantoblanco, 28049 Madrid, Spain
Published online: 19 Apr 2013.
To cite this article: José Luis García Ruano, Ana M. Martín-Castro, Laura Moreno, Francisco
Tato & Esther Torrente (2013) Stereoselective Michael additions of lithiated ortho-sulfinylbenzyl
carbanions derived from α-amino nitriles, Journal of Sulfur Chemistry, 34:6, 559-565, DOI:
10.1080/17415993.2013.779698
To link to this article: http://dx.doi.org/10.1080/17415993.2013.779698
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Journal of Sulfur Chemistry, 2013
Vol. 34, No. 6, 559–565, http://dx.doi.org/10.1080/17415993.2013.779698
Stereoselective Michael additions of lithiated
ortho-sulfinylbenzyl carbanions derived from α-amino nitriles
José Luis García Ruano*, Ana M. Martín-Castro, Laura Moreno, Francisco Tato and
Esther Torrente
Departamento de Química Orgánica, UniversidadAutónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
(Received 29 January 2013; final version received 21 February 2013)
Enantiomerically pure α-substituted α-amino ortho-sulfinylphenylacetonitriles have been readily pre-
pared by the reaction of diastereoisomeric mixtures of α-amino phenylacetonitriles with differently sized
cycloalkenones and 2-methyl cyclopentenone in the presence of lithium bases. The reactions proceeded
with high levels of stereoselectivity, generating molecules containing up to three asymmetric carbon centers
in just one synthetic step.
Keywords: asymmetric synthesis; quaternary carbons; amino nitriles; Michael addition; remote stereo-
control by sulfoxides
1. Introduction
α, α-Disubstituted α-amino acids have been reported as glutamate agonists and antagonists (1), as
compounds involved in enzymatic processes related with plant growth (2), and also as molecules
capable of stabilizing protein secondary structures (3). Additionally, they are used as building
blocks for the synthesis of peptide hormones and enzymatic inhibitors (4). As a consequence of
their manifold applications, the search for new methods for their preparation is highly challenging.
As α-amino nitriles are among the most useful precursors for synthesizing α-amino acids (among
the reported methods for their preparation, a leading role is played by the reaction of aldimine-
derived α-amino nitriles with electrophiles under basic conditions, see e.g. (5)), all those methods
affording α, α-disubstituted α-amino nitriles also turn out to be of great interest (6). This prompted
us several years ago to develop a highly competitive method for the stereoselective syntheses of
a variety of α-substituted α-amino phenylacetonitriles (7), consisting in the completely stereose-
lective quaternization of the diastereoisomeric mixture resulting from the hydrocyanation of the
2-p-tolylsulfinylbenzaldimines, with different alkylating or acylating reagents in the presence of
*Corresponding author. Email: joseluis.garcia.ruano@uam.es
© 2013 Taylor & Francis

560 J.L. García Ruano et al.
potassium hexamethyldisilazide (KHMDS) (Scheme 1). These results proved the high efficiency
of the sulfinyl group as a remote chiral auxiliary capable of stabilizing the intervening carban-
ions in a totally diastereoconvergent process, the stereochemical outcome of which proved to be
independent of the configuration at the benzylic carbon atom of the substrates.
Scheme 1. Diastereoconvergent quaternization of amino nitriles derived from
2-p-tolulsulfinylbenzaldimines.
More recently we have demonstrated that this ability can be exploited for creating acyclic frag-
ments containing up to four contiguous stereocenters, all of them controlled by the sulfinyl group,
in one-pot reactions of lithiated chiral ortho-sulfinylbenzyl carbanions with prochiral Michael
acceptors and subsequent attack of a variety of electrophiles (Scheme 2) (8).
Scheme 2. Highly stereoselective Michael and tandem Michael-aldol reactions of
ortho-sulfinylbenzyl carbanions.
With all these results in hand, and bearing in mind the potential interest of α, α-disubstituted
α-amino nitriles with additional stereocenters in their framework, we initiated the study
of the nucleophilic behavior of the carbanions derived from amino [2-(p-tolylsulfinyl)
phenyl]acetonitriles in Michael-type addition reactions, which would broaden the scope of
applicability of these substrates. We report herein the results obtained in the conjugate addi-
tion reactions of cycloalkenones with the anion derived from (benzylamino) [2-(p-tolylsulfinyl)
phenyl]acetonitrile (1). Depending on the substitution pattern of the Michael acceptor employed
in the reaction, up to three contiguous stereocenters could be generated in the process (Scheme 3).
2. Results and discussion
The substrate of all the studied conjugate addition reactions, (benzylamino)
[2-(p-tolylsulfinyl)phenyl]acetonitrile, was prepared by hydrocyanation of the corresponding
2-p-tolylsulfinylbenzaldimine, as previously reported (7). Initially, we studied the reaction

Journal of Sulfur Chemistry 561
Scheme 3. Proposed strategy for the asymmetric synthesis of fragments containing up to three
stereocenters from amino nitriles.
Table 1. Reactions of [2S,(S)S] and [2R,(S)S]-(benzylamino) [2-(p-tolylsulfinyl)phenyl] acetonitrile (1a + 1b)
with different cycloalkenones.
Entry
Base (additive)
n
Time
Product
Equiv. of E+a
Yield (%)
dr (a:b)
1
2
3
4
5
6
KHMDS
KHMDS (18-crown-6 ether)
LiHMDS
1
1
1
1
2
3
2.5 h
1.5 h
0.5 h
5 min
5 min
5 min
2a + 2b
2a + 2b
2a + 2b
2a + 2b
3a + 3b
4a + 4b
3.0
3.0
3.0
1.5
1.5
1.5
37
n.d.b
60
56
87
90:10
n.d.b
> 98 : 2
> 98 : 2
> 98 : 2
90:10
LiHMDS
LiHMDS
LiHMDS
33
Note: aE+ indicates cycloalkenone.
bComplex reaction mixture.
of the diastereoisomeric mixture (dr 48:52) of [2S,(S)S] and [2R,(S)S]-(benzylamino) [2-(p-
tolylsulfinyl)phenyl]acetonitrile (1a + 1b) with cyclopent-2-enone under different experimental
conditions (Table 1, Entries 1–5).
In all the cases, a complete conversion of the substrate was observed by NMR of the crude
reaction mixtures, the adduct [2R,3S,(S)S]-2a being the major or only isolated product. When
the reaction was accomplished with KHMDS and 3 equiv. of cyclopentenone were used, the
mixture 2a and 2b (dr 90:10, Table 1, Entry 1) was isolated in 37% yield after 2.5 h. The addition
of 18-crown-6 ether for enhancing the reactivity of the anion led to the formation of complex
mixtures (Entry 2). Fortunately, both stereoselectivity and yield were improved by using lithium
hexamethyldisilazide (LiHMDS) as the base, yielding diastereomerically pure 2a in 60% yield
(Table 1, Entry 3). The reactivity with the lithium base was also higher and the reaction was almost
instantaneous by using only 1.5 equiv. of cyclopentenone (Table 1, Entry 4). These results proved
that all these reactions are diastereoconvergent regardless of the configuration of the benzylic
carbon of the substrate and the employed counterion.
The reaction of the carbanion generated from 1a + 1b with LiHMDS and cyclohex-2-enone
also proved to be completely diastereoselective affording only adduct 3a in good yield (Table 1,
Entry 5). The use of the larger cyclohept-2-enone (Table 1, Entry 6) produced erosion in the
diastereoselectivity (dr 90:10) giving the major isomer 4a in a lower yield, presumably due to its
high instability, which hindered its isolation and purification.
The absolute configuration of 2a was unequivocally determined as [2R,3S,(S)S] by X-ray
diffraction analysis of the compound 5a (crystallographic data (excluding structure factors) of

562 J.L. García Ruano et al.
5a have been deposited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 921152. Copies of the data can be obtained, free of charge, on appli-
cation to CCDC, Cambridge, UK (deposit@ccdc.cam.ac.uk)), obtained by treatment of 2a with
m-chloroperoxybenzoic acid. This compound was formed by the simultaneous m-CPBA oxi-
−
dation of the sulfinyl (into sulfonyl) and the NH (into N OH) groups, followed by attack of
the OH to the carbonyl group, affording the hemiacetal 5a (Scheme 4). As this sequence does
not affect the configuration of the stereogenic carbon atoms present in the starting sulfoxide
2a, the absolute configuration of the latter should be identical to that unequivocally determined
for 5a. Absolute configurations of compounds 3a and 4a, respectively, obtained as the only
and major diastereoisomer starting from cyclohexenone and cycloheptenone, were assigned as
that of 2a.
Scheme 4. Synthetic transformations for configurational assignment of 2a.
Next we studied the reaction of 3-methylcyclopent-2-enone with the 1a + 1b mixture, in order
toobtaincompoundscontaining two vicinal quaternary stereocenters, but it wasunsuccessful since
the unaltered starting material was recovered after long reaction times. By contrast, the reaction
of 1a + 1b with 2-methylcyclopent-2-enone under LiHMDS was complete affording a mixture of
only two diastereoisomers (6a and 6b) containing three stereocenters, two of them simultaneously
created in the process (Table 2). The stereoselectivity was observed to be closely dependent on the
quenching conditions. It was only moderate by using an aqueous solution of ammonium chloride
(Table 2, Entries 1 and 2) and was improved by the addition of MeOH (Entry 3). The best results
(dr 95:5) were achieved when a saturated HCl solution in MeOH was added to the reaction mixture
at −78◦C (Table 2, Entry 4). The loss of stereoselectivity when different quenching conditions
were employed was attributed to changes in the temperature during the hydrolysis step. When
10% HCl–MeOH was added onto the reaction mixture at −78◦C, protonation should occur on the
rigid chelated enolate (vide infra). Other quenching conditions took place at higher temperatures
which probably caused erosion in the stereoselectivity of the process.
Both diastereoisomers should differ only in the configuration of the stereogenic center next to
the carbonyl group (the other two will exhibit the same configurations as those at compound 2a).
Thus, taking into account that this must be a consequence of the equilibration of the intermediate
anion, we have assigned the configuration S to this center (Table 2) because this corresponds to the
most stable situation where the methyl group and the quaternary carbon are in a trans arrangement
in the cyclopentanone ring.

Journal of Sulfur Chemistry 563
Table 2. Reaction of [2S,(S)S] and [2R,(S)S]-(benzylamino) [2-(p-tolylsulfinyl)phenyl] acetoni-
trile (1a + 1b) with 2-methylcyclopent-2-enone.
Entry
Time (h)
Hydrolysis conditions
Equiv. E+a
Yield (%)
dr (a:b)
1
2
3
4
5
0.5
0.5
1.0
1.0
0.5
Aq. sat. NH4Cl
Aq. sat. NH4Clb
Sat. NH4Cl–MeOH
10% HCl–MeOH
10% HCl–MeOHc
3.0
3.0
3.0
1.5
1.5
54
54
53
53
53
73:27
70:30
86:14
95:5
55:45
Note: aE+ indicates cycloalkenone.
bInverse addition (carbanion was added onto the Michael acceptor).
cThe reaction mixture was added onto the methanolic solution.
3. Mechanistic proposal
The stereochemical results obtained in the above described reactions can be explained as follows.
Thereactionoftheepimericmixtureofaminonitriles(1a and 1b)withLiHMDSinitiallygenerates
the boat-like chelated sp3 carbanionic species Ia (Scheme 5), with the metal associated with both
the sulfinyl oxygen and the benzylic carbon atom. The favored arrangement of the substituents
around the carbanionic carbon had been previously established as that indicated for I in Scheme 5
by theoretical calculations (7). This arrangement minimizes the dipolar repulsion between S→O
and C:N bonds and is stabilized by the n2–d0 interactions between the lone electron pair at nitrogen
and the empty d orbitals at sulfur (9). Such as it had been postulated for the acylation processes of
other sulfinylbenzyl carbanions (10), the carbonyl oxygen atom of cycloalkenones may coordinate
with the cation Li+, thus breaking the initial boat-like chelate I and generating a new intermediate
speciesII. Intramolecularadditionfrom II wouldafford III withtheR configurationatthebenzylic
stereocenter, coincident with that observed for the major or exclusive diastereoisomers obtained
in these reactions. Simultaneously, the S configuration of the C-β atom at the cycloalkenone ring
can also be predicted from this approach (Scheme 5).
From the above results, we can conclude that the ortho-sulfinyl group has proved to be a
highly efficient chiral auxiliary for the Michael addition of tertiary benzylic carbanions derived
from benzyl α-amino nitriles, affording enantiomerically pure α, α-disubstituted α-amino nitriles
connected to additional stereocenters. Currently, we are developing the in situ trapping of the
enolates formed in the conjugate addition with different types of electrophiles. The results will
be reported in due course.
4. Experimental section
4.1. Typical procedure for Michael addition reaction of (benzylamino)
[2-(p-tolylsulfinyl)phenyl]acetonitrile
To a solution of diastereoisomeric 48:52 mixture of [2S,(S)S] and [2R,(S)S]-(benzylamino)
[2-(p-tolylsulfinyl)phenyl]acetonitrile (1a + 1b, 36.1 mg, 0.1 mmol) in anhydrous THF (1.5 ml)

564 J.L. García Ruano et al.
Scheme 5. Mechanistic proposal accounting for the stereochemical outcome of Michael
additions of carbanions derived from 1a + 1b to cycloalkenones.
at −78◦C under argon was added LiHMDS (1M in THF) (120 μl, 0.12 mmol). The mixture was
stirred at −78◦C for 5 min and then 0.15 mmol of the corresponding Michael acceptor was added
dropwise. The reaction was monitored by TLC. Upon transformation of the starting material,
the reaction was hydrolyzed using the method indicated in each case. The mixture was extracted
with CH2Cl2 (3 × 5 ml), dried (Na2SO4), and the solvent was evaporated. The diastereoisomeric
mixture was purified by flash column chromatography or by Combiflash system using a normal
phase column (ISCOꢀ); the used eluent was indicated in each case.
5. Supporting information
Characterization data for sulfinyl derivatives 2a, 3a, 4a, 4b, 6a, 6b, and compound 5a are described
in the supporting information.
Acknowledgements
Financial support of this work by the Ministerio de Ciencia y Tecnología (CTQ2012-35957), UAM-Comunidad de Madrid
(CCG08UAM/PPQ-4235) and Comunidad de Madrid (AVANCAT, S-2009-PPQ-1634) are gratefully acknowledged.
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