Asymmetric strecker synthesis of α-arylglycines

Article abstract of DOI:10.1021/jo200528s

A practically simple three-component Strecker reaction for the asymmetric synthesis of enantiopure α-arylglycines has been developed. Addition of a range of aryl-aldehydes to a solution of sodium cyanide and (S)-1-(4- methoxyphenyl)ethylamine affords highly crystalline (S,S)-α-aminonitriles that are easily obtained in diastereomerically pure form. Heating the resultant (S,S)-α-aminonitriles in 6 M aqueous HCl at reflux resulted in cleavage of their chiral auxiliary fragments and concomitant hydrolysis of their nitrile groups to afford enantiopure (S)-α-arylglycines. The enantiopurities of these (S)-α-arylglycines were determined via derivatization of their corresponding methyl esters with 2-formylphenylboronic acid and (S)-BINOL, followed by ¹H NMR spectroscopic analysis of the resultant mixtures of diastereomeric iminoboronate esters.

Full text of DOI:10.1021/jo200528s

ARTICLE
pubs.acs.org/joc
Asymmetric Strecker Synthesis of r-Arylglycines
Yolanda Pꢀerez-Fuertes,† James E. Taylor,† David A. Tickell,† Mary F. Mahon,‡ Steven D. Bull,*,†
and Tony D. James*,†
†Department of Chemistry and ‡Bath X-ray Crystallographic Suite, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
S Supporting Information
b
ABSTRACT:
A practically simple three-component Strecker reaction for the asymmetric synthesis of enantiopure R-arylglycines has been
developed. Addition of a range of aryl-aldehydes to a solution of sodium cyanide and (S)-1-(4-methoxyphenyl)ethylamine affords
highly crystalline (S,S)-R-aminonitriles that are easily obtained in diastereomerically pure form. Heating the resultant (S,S)-R-
aminonitriles in 6 M aqueous HCl at reflux resulted in cleavage of their chiral auxiliary fragments and concomitant hydrolysis of
their nitrile groups to afford enantiopure (S)-R-arylglycines. The enantiopurities of these (S)-R-arylglycines were determined via
1
derivatization of their corresponding methyl esters with 2-formylphenylboronic acid and (S)-BINOL, followed by H NMR
spectroscopic analysis of the resultant mixtures of diastereomeric iminoboronate esters.
’ INTRODUCTION
An alternative approach to using asymmetric catalysis is to use
enantiomerically pure amines as chiral auxiliaries to perform
diastereoselective Strecker reactions. The resulting R-aminoni-
triles can then be hydrolyzed and their auxiliary fragments
removed to form enantiopure R-arylglycines. A number of
different enantiomerically pure amines have been used as chiral
auxiliaries for the asymmetric synthesis of R-aryl-aminonitriles.1
Enantiopure 1-phenylethylamine (1) is one of the most common
chiral auxiliaries for the asymmetric Strecker synthesis of R-
amino acids.12 However, while a number of procedures have
been developed that afford diastereomerically enriched R-aryl-
aminonitriles,13 its use is limited due to the difficulty of selectivity
removing the auxiliary fragment. 1-Phenylethylamine (1) frag-
ments are usually cleaved by hydrogenolysis;12 however, this
approach has been reported to be unsuccessful for R-arylglycines
due to competing cleavage of the R-aryl-aminonitrile stereocenter.14
Panse reported that a modified procedure in which cyanogen
bromide (CNBr) was added to preformed imines derived from
aryl-aldehydes and (S)-1-phenylethylamine (1) allowed access to
N-bromo-R-aminonitriles. The diastereomerically enriched
N-bromo-R-aminonitriles were then deprotected by dehydro-
bromination to form benzylic imines that were hydrolyzed to
afford the desired R-arylglycines. However, the ee of the resulting
R-arylglycines were moderate (50% ee) due to partial racemiza-
tion during the deprotection step (Scheme 1a).13j
Enantiomerically pure R-arylglycines are non-proteinogenic
R-amino acids that are found within the structures of many
biologically active compounds. For example, R-arylglycine frag-
ments are found in β-lactam antibiotics such as amoxicillin,
cephalexin, and cefadroxil, and there are three separate R-
arylglycine fragments contained within the structure of the
glycopeptide antibiotic vancomycin.1 They have also been widely
used as privileged chiral building blocks for the preparation of
drug-like molecules that exhibit a wide range of biological
activities.2 Consequently, a variety of methodologies have been
developed for their asymmetric synthesis,3 including approaches
that employ chiral auxiliaries,4 transition metal catalysts,5
organocatalysts,6 and biocatalysts.7
The asymmetric Strecker reaction is one of the most widely
employed methods for synthesizing R-aminonitriles that can be
hydrolyzed to give R-amino acids.8 A number of catalytic
enantioselective Strecker reactions to form R-aryl-aminonitriles
that employ either metal-based catalysts9 or organocatalysts10
have been reported in recent years. While many of these catalytic
protocols have been shown to afford enantiopure R-aryl-amino-
nitriles in good yield, they often employ expensive chiral catalysts
or require multistep syntheses of chiral ligands. Furthermore, the
majority of these catalytic protocols require the use of trimethyl-
silyl cyanide (TMSCN) as a nucleophile, which is an expensive,
volatile, toxic reagent that is difficult to use on scale-up.11 Many
of these catalytic protocols also require a two-step process,
involving nucleophilic addition of a cyanide equivalent to a
preformed imine. Finally, the substrate specificity profile of a
number of these catalytic protocols is limited, which can lead to
the formation of scalemic R-arylglycines that are difficult to
purify to greater than 95% enantiomeric excess (ee).
Enantiopure 2-phenylglycinol (2) has been widely used as an
effective chiral auxiliary for the synthesis of R-aryl-aminonitriles
in reasonable diastereomeric excess (de).15 Cleavage of the
2-phenylglycinol fragment of these R-aminonitriles required a
Received: March 23, 2011
Published: May 31, 2011
r
2011 American Chemical Society
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Scheme 1. Chiral Amines Previously Used As Auxiliaries for
the Asymmetric Synthesis of r-Arylglycines
Scheme 2. (S)-1-(4-Methoxyphenyl)ethylamine as a Chiral
Auxiliary for the Asymmetric Synthesis of (S)-R-Phenylgly-
cine Methyl Ester Hydrochloride
The auxiliary initially provided R-aryl-aminonitriles with modest
de (40% de), although the major diastereoisomer could be
isolated in 65% yield after recrystallization. The oxidative clea-
vage of the auxiliary using sodium periodate was compatible with
the synthesis of R-arylglycines, providing R-phenylglycine in
56% yield (Scheme 1e).18
As part of our studies19 we required rapid access to a series of
enantiopure R-arylglycines and decided to investigate the po-
tential of using (S)-1-(4-methoxyphenyl)ethylamine (10) as a
chiral auxiliary in the asymmetric Strecker reaction. A review of
the literature revealed that Singh and co-workers had reported a
single example of its use, involving Lewis acid (BF3 Et2O or
3
LiClO4) catalyzed addition of TMSCN to preformed imine (6)
to give chiral R-aminonitrile 7 in 60% de. The corresponding R-
phenylglycine methyl ester was then obtained via a two-step
deprotection sequence. First, treatment of R-aminonitrile 7 with
either 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) or ceric
ammonium nitrate (CAN) resulted in the oxidative removal of
the chiral auxiliary fragment. R-Phenylnitrile 8 was then hydro-
lyzed to its corresponding R-phenylglycine methyl ester 9a via
treatment with methanolic HCl (Scheme 2).20
Inspired by this report, we now report a comprehensive study
into using (S)-1-(4-methoxyphenyl)ethylamine (10) as a chiral
auxiliary for the diastereoselective three-component Strecker
synthesis of R-arylglycines. This has resulted in highly practical
conditions that employ inexpensive NaCN as a nucleophile
under aqueous conditions to afford diastereomerically pure
crystalline R-aminonitriles in good yield. Simple acidic hydrolysis
then results in removal of their chiral auxiliary fragments, with
concomitant hydrolysis of their nitrile functionalities, to afford
enantiopure R-arylglycines in good yield.
two-step process; first, lead tetraacetate was used to oxidatively
cleave the amino-alcohol fragment to its corresponding imine,
which was then hydrolyzed to afford the desired R-arylglycine
(Scheme 1b).15d
Kunz and co-workers found that 1-amino-tetra-O-pivaloyl-β-
D-galactopyranose (3) could control the addition of TMSCN to
preformed imines using zinc chloride as a Lewis acid catalyst.16
The diastereoselectivity of the reaction was found to be depen-
dent on the reaction solvent, due to the difference in complexa-
tion ability of zinc chloride in polar and apolar solvents.16b The
auxiliary could be removed by hydrolysis, with a single example of its
application for the formation of an R-arylglycine (Scheme 1c).16c
Davis et al. have used enantiomerically pure sulfinimines (4)
as chiral auxiliaries for the asymmetric Strecker reaction using
diethylaluminium cyanide (Et2AlCN) as a nucleophile.17 The
major diastereoisomer formed from the reaction could be iso-
lated by recrystallization and the auxiliary removed by hydrolysis to
form the R-arylglycine in good yield and high ee (Scheme 1d).17b
While the previous four examples of auxiliary-controlled
Strecker reactions employed preformed imines, Weinges et al.
have shown that (4S,5S)-5-amino-2,2-dimethyl-4-phenyl-1,3-
dioxane (5) can be used as an auxiliary in the three-component
Strecker reaction using sodium cyanide (NaCN) as a nucleophile.
’ RESULTS AND DISCUSSION
Our aim was to develop a highly practical three-component
asymmetric Strecker synthesis of R-arylglycines using a commer-
cially available chiral auxiliary and NaCN as an inexpensive
source of cyanide nucleophile (Scheme 3). In an adaptation of
literature procedures,13m,21 benzaldehyde (11a) was added to a
solution of (S)-1-(4-methoxyphenyl)ethylamine hydrochloride
(10) and NaCN in H2O/MeOH (1:1), and the resulting solution
1
stirred at room temperature for 16 h. After workup, H NMR
spectroscopic analysis of the crude reaction product revealed the
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Scheme 3. Three-Component Strecker Reaction to form
Chiral r-Aminonitriles Using (S)-1-(4-Methoxyphenyl)-
ethylamine (10) as a Chiral Auxiliary
Table 1. (S)-1-(4-Methoxyphenyl)ethylamine (10) Directed
Asymmetric Strecker Reactions
presence of a 3:1 diastereomeric ratio (dr) of R-aminonitriles
(R-S,S)-12a and (R-R,S)-13a, in a combined 88% isolated yield
(Table 1, entry 1).
The absolute configuration of the major diastereoisomer was
assigned as (R-S,S)-12a by comparison with spectroscopic data for
this compound,20 as well as the known preference for cyanide to
undergo preferential nucleophilic attack at the re-face of this class of
imine.13m Purification of the major diastereoisomer was achieved via
fractional recrystallization of the crude reaction product from a
solution of diethyl ether and saturated methanolic HCl to give the
major (R-S,S)-diastereoisomer 12a in >95% de and 62% yield.
This simple Strecker protocol was then applied to a range of
substituted benzaldehydes 11bꢀh that successfully gave their
corresponding (S,S)-R-aminonitriles 12bꢀh in >95:5 dr
(Table 1). It was found that the Strecker reactions of benzalde-
hydes (11bꢀf) resulted in formation of mixtures of diastereo-
meric R-aminonitriles whose major (R-S,S)-diastereoisomers
(12bꢀf) precipitated directly out of the reaction mixture in
>99:1 dr, thus enabling them to be collected via simple filtration.
The major R-aminonitriles from the reactions of 4-fluorobenzal-
dehyde (11g) and piperonal (11h) did not directly afford
crystalline precipitates. However, their major diastereoisomers
(S,S)-12g,h could be purified to >99:1 dr via fractional recrys-
tallization of their crude reaction products (77:23 and 80:20 dr)
from ether/methanolic HCl.
The configuration of p-tolyl-R-aminonitrile 12b was unequivo-
cally assigned as (R-S,S) by X-ray crystallographic analysis (see
Supporting Information). The gross structure revealed one-dimen-
sional chains that propagate along the a axis as a consequence of
intermolecular hydrogen-bonding between the N1-H of one mole-
cule and the nitrile nitrogen (N2) of a lattice neighbor. The
remaining R-aminonitriles (12cꢀh) were subsequently confirmed
as having (R-S,S) configurations by hydrolysis to their correspond-
ing R-arylglycines whose positive specific rotations were compared
with known literature values for (S)-R-arylglycines (vide infra).
We then looked to develop a convenient and scalable method
that would enable (R-S,S)-R-aminonitriles (12aꢀh) to be con-
verted into their corresponding R-arylglycines (14aꢀh). While
Singh has reported that treatment of (R-S,S)-R-aminonitrile 7
with CAN resulted in clean N-deprotection of its chiral auxiliary
fragment,20 we found that it was difficult to isolate pure
R-aminonitrile 8 free from residual cerium salts. A review of the
literature22 revealed that N-1-(4-methoxyphenyl)ethyl groups
could be removed under cationic conditions via treatment with
a Determined by 1H NMR spectroscopic analysis. b Obtained after
fractional recrystallization of the crude product from Et2O and saturated
methanolic HCl. c Yield and dr obtained after workup, prior to purifica-
tion via fractional recrystallization.
trifluoroacetic acid22a or HCOOH/Et3SiH.22c,g Consequently,
we reasoned that treatment of R-aminonitriles 12aꢀh under
aqueous acidic conditions might result in cleavage of their
auxiliary fragment with concomitant hydrolysis of their nitrile
groups, thus affording an R-arylglycine in a “one-pot” hydrolytic
process. It was found that heating (R-S,S)-phenyl-R-aminonitrile
12a in 6 M aqueous HCl at reflux for 4 h resulted in cleavage of its
N-1-(4-methoxyphenyl)ethyl fragment, accompanied by hydro-
lysis of its nitrile fragment, affording (S)-R-phenylglycine hydro-
chloride (14a) in 60% yield. The crude1H NMR spectra also
showed the presence of small amounts of (S)-1-(4-methoxyphe-
nyl)ethylamine hydrochloride 10 (∼15%), resulting from a
competing reaction pathway in which the R-aminonitrile
was hydrolyzed to its parent aldehyde and auxiliary. Any side
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Table 2. Hydrolysis of r-Aminonitriles (12aꢀh) into
R-Arylglycines (14aꢀh)
Scheme 4. Derivatization of (S)-Phenylalanine Methyl Ester
Hydrochloride (S)-15 (80% ee) Affords a 9:1 dr of Imino-
boronate Esters 17 and 18
It has been reported previously that direct acidic hydrolysis of
optically active R-aminonitriles can potentially result in partial
racemization of the R-center of R-arylglycines products.23 Con-
sequently, it was decided to unequivocally determine the en-
antiomeric excesses of the R-arylglycines 14aꢀh using our
recently published three-component chiral derivatization
procedure.24,25 This derivatization protocol involves treatment
of a chiral amine of unknown enantiopurity with 2-formylphe-
nylboronic acid (16) and enantiopure BINOL in CDCl3. This
results in formation of mixtures of diastereomeric iminoboronate
esters whose ratio is easily determined by integration of appro-
1
priate pairs of diastereomeric resonances in their H NMR
spectra. Because no kinetic resolution occurs in this process,
the observed dr corresponds directly to the enantiomeric ratio of
the parent amine. A representative example of the analysis of a
scalemic sample of phenylalanine methyl ester (S)-15 of 80% ee
is shown in Scheme 4.
While this derivatization protocol has been used successfully
to determine the enantiomeric excess of a wide range of chiral
amines,25 Urriolabeitia and co-workers reported that “When the
NMR Tony-James [sic] protocol is applied, racemization was
observed after the derivatization reaction. Similar results were
obtained when the commercial (R)-phenylglycinate methyl ester
hydrochloride was subjected to this NMR derivatization method.”26
In order to investigate this potential problem, we treated
commercially available (S)-R-phenylglycine methyl ester hydro-
chloride (98% ee) (S)-9a with 1.1 equiv of 2-formylphenylboro-
nic acid (16), (S)-BINOL, and cesium carbonate in CDCl3 for 10
min, then filtered and acquired its 1H NMR spectra. This
revealed the clean formation of (R-S,S)-iminoboronate ester
19 in a 99:1 dr, with no evidence of any racemization at its R-
stereocenter having occurred (Table 3, entry 1). However, we
did find that leaving this derivatization reaction for extended
periods of time (>1 h) resulted in epimerization of the R-
stereocenter of (R-S,S)-19, ultimately affording a 50:50 mixture
of (R-S,S)-iminoboronate ester 19 and (R-R,S)-iminoboronate
ester 20 after 24 h (Table 3, entries 2 and 3). In order to address
this epimerization problem, we decided to change the base from
partially soluble cesium carbonate to completely insoluble po-
tassium carbonate. This resulted in a clean derivatization reaction
a Determined by 1H NMR spectroscopic analysis of the iminoboronate
esters formed from derivatization using 2-formylphenylboronic acid
(16) and (S)-BINOL (vide infra).
products could be conveniently removed by suspending the
crude reaction mixture in chloroform and filtering the resultant
suspension to give (S)-R-phenylglycine hydrochloride (14a) in
60% yield as a white solid. The configuration of the R-phenyl-
glycine (14a) was confirmed by comparison of its specific
rotation with that of commercially available R-phenylglycine
(14a). These hydrolytic conditions were then applied to the
remaining R-aminonitriles (12bꢀh) (Table 2), providing their
corresponding R-arylglycines (14bꢀh) in reasonable yields
(52ꢀ81%) and ee’s (88ꢀ96%). The reduced yields observed
for hydrolysis of p-tolyl-R-aminonitrile (12b) and p-methoxy-
phenyl-R-aminonitrile (12d) were attributed to an increase in
the competing hydrolytic process that affords free auxiliary (10)
and the parent aldehyde.
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Table 3. Investigating the Epimerization of Iminoboronate
Complex 19
(R-S,S)-iminoboronate esters had been formed in >88% de in
each case. A representative 1H NMR spectrum that was obtained
for the derivatization of (S)-9a with (S)-BINOL is shown in
Figure 1b. This indicates that acidic hydrolysis of the R-amino-
nitriles (12aꢀh) to afford their corresponding R-arylglycines
(14aꢀh) proceeds without any significant racemization of their
R-stereocenters.
Finally, in order to demonstrate the applicability of our
methodology, we decided to optimize the asymmetric synthesis
of p-tolylglycine (14b) on a multigram scale. Therefore, the
Strecker reaction of p-tolualdehyde (11b) was repeated on a
15 mmol scale to afford its (R-S,S)-aminonitrile (12b) that
precipitated directly out of the reaction to enable its isolation
in 82% yield via simple filtration (Scheme 5). The (R-S,S)-R-
aminonitrile (12b) was immediately subjected to our deprotec-
tion/hydrolysis conditions by heating at reflux in 6 M HCl for
4 h. Pleasingly, the hydrolysis reaction resulted in essentially
quantitative formation of the desired (S)-R-p-tolylglycine (14b)
in 94% ee. This demonstrates that our three-component Strecker
procedure can be used to rapidly produce gram quantities of
enantiopure R-arylglycines in a time period of less than 24 h.
entry
base
timea
1H NMR acquisition time
dr (19:20)b
1
2
3
4
5
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
10 min
5 h
10 min
5 h
99:1
94:6
53:47
99:1
99:1
24 h
24 h
10 min
10 min
’ CONCLUSIONS
10 min
24 h
We have developed a practically simple three-component
Strecker reaction for the asymmetric synthesis of enantiopure
R-arylglycines. This protocol is based on the addition of aryl-
aldehydes to a solution of sodium cyanide and (S)-1-(4-methox-
yphenyl)ethylamine, which results in formation of highly crys-
talline (S,S)-R-aminonitriles that can are easily obtained in
diastereomerically pure form. Heating the resultant (S,S)-R-
aminonitriles in 6 M aqueous HCl at reflux results in cleavage
of their chiral auxiliary fragments and hydrolysis of their nitrile
groups to afford enantiopure (S)-R-arylglycines in good yield.
The enantiopurities of these (S)-R-arylglycines were determined
via derivatization of their corresponding methyl esters with
a Reaction time before filtering excess base. b Determined by 1H NMR
spectroscopic analysis.
that was complete after 10 min, which upon filtration gave a 1H
NMR spectra of (R-S,S)-iminoboronate ester 19 in a 99:1 dr
(Table 3, entry 4). Importantly, it was found that this filtered
solution of (R-S,S)-iminoboronate 19 in CDCl3 was configur-
ationally stable, giving an identical 99:1 dr after being left for 24 h
(Table 3, entry 5). This means that once the derivatization
mixture has been filtered its 1H NMR spectrum does not need to
be acquired immediately for an accurate dr to be obtained.
Therefore, we now recommend that potassium carbonate is used
as a base when the ee of amines that contain relatively acidic
stereocenters are determined using this three-component deri-
vatization protocol.
1
2-formylphenylboronic acid and (S)-BINOL, followed by H
NMR spectroscopic analysis of the resultant mixtures of diaster-
eomeric iminoboronate esters.
Having resolved any potential epimerization problems, this
derivatization protocol was then used to determine the ee of the
R-arylglycines (14aꢀh) produced in our Strecker reactions. The
R-arylglycines (14aꢀh) were first converted into their corre-
sponding methyl ester hydrochlorides by heating at reflux in
acidic methanol. Each R-arylglycine methyl ester was derivatized
via treatment with 2-formylphenylboronic acid (16), rac-BI-
NOL, and potassium carbonate in CDCl3 for 10 min. The excess
potassium carbonate was then filtered off, and 1H NMR spectro-
scopic analysis was performed to afford authentic spectra of
50:50 mixtures of their corresponding diastereomeric iminobor-
onate esters in each case. Examination of the 1H NMR spectra of
each derivatization reaction revealed the presence of at least one
pair of resolved diastereomeric resonances in each case, whose
integrals could be used to indirectly determine the enantiopurity
of their parent R-arylglycine (14aꢀh). A representative 1H NMR
spectrum that was obtained for the derivatization of (S)-9a with
rac-BINOL is shown in Figure 1a.
’ EXPERIMENTAL SECTION
General. Commercially available (S)-1-(4-methoxyphenyl)ethylamine
was converted to its hydrochloride salt (10) using 1 M HCl in Et2O. Best
resultswereobtainedwhenaldehydeswerepurified, eitherbyrecrystallization
or distillation, before use. 1H NMR spectra were recorded at either 300
or 400 MHz, and 13C{1H} NMR spectra were recorded at either 75 or
100 MHz. NMR peak assignments were confirmed using 2D 1H COSY
where necessary. Capillary melting points are reported uncorrected.
Optical rotations were recorded with a path length of 1 dm; concentra-
tions (c) are quoted in g/100 mL. Infrared spectra were recorded with
internal background calibration in the range 600ꢀ4000 cmꢀ1, as
solutions in chloroform (CHCl3), using thin films on NaCl plates
(film) or KBr discs (KBr) as stated. High resolution mass spectra were
recorded using electron impact (EI), chemical ionization (CI), or
electrospray (ES).
General Procedure for the Synthesis of (S,S)-R-Aryl-
R-[1-(4-methoxyphenyl)ethylamino]acetonitrile Hydro-
chlorides (12aꢀh). In an adaptation of literature procedures,13m,21
(S)-1-(4-methoxyphenyl)-ethylamine hydrochloride (S)-10 (563 mg,
3.00 mmol) and NaCN (154 mg, 3.15 mmol) were dissolved in H2O
(4 mL). MeOH (4 mL) and the corresponding aryl-aldehyde 11aꢀh
(3.00 mmol) were then added, and the mixture was stirred for 16 h. The
The enantiomeric excess of each R-arylglycine methyl ester
hydrochloride was then determined by repeating the derivatiza-
tion reaction using enantiopure (S)-BINOL. 1H NMR spectro-
scopic analysis of each derivatization reaction revealed that
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Figure 1. Representative derivatization protocol. (a) Derivatization of (S)-R-phenylglycine methyl ester hydrochloride (9a) with 2-formylphenyl-
boronic acid (16) and rac-BINOL results in formation of a 50:50 mixture of diastereomeric iminoboronate esters (R-S,S)-19 and (R-S,R)-20. (b)
Derivatization of synthesized R-phenylglycine methyl ester hydrochloride (9a) with (S)-BINOL reveals a 98:2 mixture of (R-S,S)-19:(R-R,S)-20,
corresponding to a 96% ee for (S)-R-phenylglycine (14a).
did not precipitate out of solution, the reaction mixture was extracted with
CH2Cl2 (3 ꢁ 10 mL). The combined CH2Cl2 extracts were dried
(MgSO4), filtered, and concentrated in vacuo. The crude mixture was
dissolved in Et2O, and the addition of saturated methanolic HCl gave a
white crystalline solid that was collected via filtration and washed with n-
hexane, which corresponded to the major (R-S,S)-aminonitrile hydrochlor-
ide 12aꢀh in >95% de.
Scheme 5. Application of the Strecker Protocol to the Mul-
tigram Scale Synthesis of (S)-R-p-Tolylglycine (14b)
(S,S)-R-Phenyl-R-[1-(4-methoxyphenyl)ethylamino]aceto-
nitrile Hydrochloride (R-S,S)-12a. The title compound was
synthesized according to the general procedure using benzaldehyde
11a (0.30 mL, 3.00 mmol). After workup and recrystallization from
Et2O and saturated methanolic HCl the aminonitrile hydrochloride 12a
(562 mg, 62%) was obtained as white needles: mp 127ꢀ128 °C; [R]D25
1
ꢀ95 (c 0.525, CHCl3), ꢀ54 (c 0.350, MeOH); H NMR (300 MHz;
CDCl3) δH 7.49ꢀ7.46 (2H, m, ArH), 7.42ꢀ7.34 (5H, m, ArH), 6.93
(2H, d, J = 8.7 Hz, ArH), 4.38 (1H, s, CHCN), 4.20 (1H, q, J = 6.5 Hz,
CHCH3), 3.82 (3H, s, CH3O), 1.41 (3H, d, J = 6.5 Hz, CHCH3);
13C{1H} NMR (75 MHz; CDCl3) δC 161.1, 134.9, 131.3, 130.8, 130.2,
129.6, 128.9, 115.4, 114.8, 59.3, 55.8, 50.7, 20.7; m/z (CI) 266 (2%, M ꢀ
HCl), 251 (25, M ꢀ HCl ꢀ Me), 240 (18, M ꢀ HCl ꢀ CN), 135 (100,
C8H9NO). Found: C, 67.1; H, 6.40; N, 9.18. C17H19ClN2O requires C,
67.43; H, 6.32; N, 9.25.
reaction was then diluted with H2O (10 mL), and the resulting solid was
collected via filtration and washed with n-hexane. If a single diastereoisomer
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(S,S)-R-p-Tolyl-R-[1-(4-methoxyphenyl)ethylamino]ac-
tonitrile Hydrochloride (R-S,S)-12b. The title compound was
synthesized according to the general procedure using p-tolualdehyde
11b (0.35 mL, 3.00 mmol). After workup and recrystallization from
Et2O and saturated methanolic HCl the aminonitrile hydrochloride 12b
(739 mg, 77%) was obtained as white needles: mp 118ꢀ119 °C; [R]D25
ꢀ100 (c 0.510, CHCl3), ꢀ28 (c 0.360, MeOH); 1H NMR (300 MHz;
CDCl3) δH 7.39ꢀ7.33 (4H, m, ArH), 7.20 (2H, d, J = 8.0 Hz, ArH), 6.92
(2H, d, J = 8.6 Hz, ArH), 4.34 (1H, s, CHCN), 4.19 (1H, q, J = 6.5 Hz,
CHCH3), 3.82(3H, s, CH3O), 2.35(3H, s, ArCH3), 1.40 (3H, d, J=6.5Hz,
CHCH>3); 13C{1H} NMR (75 MHz; CDCl3) δC 159.3, 138.9, 135.1,
132.5, 129.7, 128.2, 127.2, 119.3, 114.4, 56.3, 55.4, 52.1, 25.0, 21.3; IR
(film, cmꢀ1) νmax = 3304 (NH), 2228 (CN); m/z (EI) 265 (24%, M ꢀ
HCl ꢀ Me), 253 (45, M ꢀ HCl ꢀ HCN), 238 (64, M ꢀ HCl ꢀ HCN ꢀ
Me), 135 (100, C8H9NO). Found for the free base form: C, 77.1; H, 7.19;
N, 9.86. C18H20N2O requires C, 77.1; H, 7.19; N, 9.99.
CDCl3) δH 7.63ꢀ7.56 (2H, m, ArH), 7.42ꢀ7.35 (3H, m, ArH),
7.28ꢀ7.21 (1H, m, ArH), 6.93ꢀ6.90 (2H, m, ArH), 4.66 (1H, s,
CHCN), 4.18 (1H, q, J = 6.6 Hz, CHCH3), 3.83 (3H, s, CH3O), 1.74
(1H, brs, NH), 1.42 (3H, d, J = 6.6 Hz, CHCH3); 13C{1H} NMR (75
MHz; CDCl3) δC 159.7, 135.2, 134.5, 134.1, 131.0, 129.7, 128.9, 128.6,
123.7, 118.9, 114.4, 56.7, 55.7, 52.8, 24.9; νmax(CHCl3)/cmꢀ1 3333
(NH), 2228 (CN); m/z (CI) 346 (3%, Mþ), 344 (3%, Mþ), 331 (66,
M ꢀ Me), 329 (66, M ꢀ Me), 318 (69, M ꢀ CN), 304 (12, M ꢀ CN ꢀ
Me ꢀ H), 302 (12, M ꢀ CN ꢀ Me ꢀ H), 135 (100, C8H9NO). Found:
C, 59.2; H, 4.86; N, 8.10. C17H17BrN2O requires C, 59.14; H, 4.96;
N, 8.11.
(S,S)-R-(4-Fluorophenyl)-R-[1-(4-methoxyphenyl)ethyl-
amino]-acetonitrile Hydrochloride (R-S,S)-12g. The title com-
pound was synthesized according to the general procedure using
4-fluorobenzaldehyde 11g (0.32 mL, 3.00 mmol). After workup and
recrystallization from Et2O and saturated methanolic HCl the aminoni-
trile hydrochloride 12g (674 mg, 70%) was obtained as white needles:
mp 137ꢀ138 °C; [R]2D5 ꢀ53 (c 0.510, MeOH); 1H NMR (300 MHz;
(CD3)2SO) δH 7.66ꢀ7.58 (2H, m, ArH), 7.39 (2H, d, J = 8.6 Hz, ArH),
7.23ꢀ7.17 (2H, m, ArH), 6.87 (2H, d, J = 8.6 Hz, ArH), 5.19 (1H, s,
CHCN), 4.16 (1H, q, J = 6.5 Hz, CHCH3), 3.64 (3H, s, OCH3), 1.49
(3H, d, J = 6.5 Hz, CHCH3); 13C{1H} NMR (75 MHz; (CD3)2SO) δC
159.7, 132.1 (d, J = 9.0 Hz, CArHCArHCArF), 129.8, 129.4, 128.8,
124.3 (d, J = 207 Hz, CArF), 116.0 (d, J = 22.1 Hz, CArHCArF), 114.5,
114.2, 56.8, 55.2, 48.2, 20.3; m/z (CI) 284 (2%, M ꢀ HCl), 269 (21,
M ꢀ HCl ꢀ Me), 258 (29, M ꢀ HCl ꢀ CN), 135 (100, C8H9NO).
Found: C, 63.4 ; H, 5.74; N, 8.67. C17H18ClFN2O requires C, 63.65;
H, 5.66; N, 8.73.
(S,S)-R-(Benzo[d][1,3]dioxol-5-yl)-R-[1-(4-methoxyphenyl)-
ethylamino]-acetonitrile Hydrochloride (R-S,S)-12h. The title
compound was synthesized according to the general procedure using
piperonal 11h (0.45 g, 3.00 mmol). After workup and recrystallization
from Et2O and saturated methanolic HCl the aminonitrile hydro-
chloride 12h (558 mg, 54%) was obtained as a white solid: mp
116ꢀ119 °C; [R]2D2 ꢀ60 (c 0.55, CHCl3); 1H NMR (300 MHz;
CDCl3) δH 7.64 (2H, d, J = 8.7 Hz, ArH), 7.24ꢀ7.22 (1H, m, ArH),
7.01ꢀ6.79 (4H, m, ArH), 5.91 (2H, s, CH2), 4.57 (1H, s, CHCN), 4.41
(1H, q, J = 6.8 Hz, CHCH3), 3.84 (3H, s, OCH3), 1.66 (3H, d, J = 6.4
Hz, CHCH3); 13C{1H} NMR (75 MHz; CD3OD) δC 160.9, 150.1,
150.0, 148.3, 130.0, 129.8, 125.2, 124.6, 115.1, 114.9, 110.7, 108.8,
102.0, 58.9, 55.5, 50.3, 20.6; IR (film, cmꢀ1) νmax = 3032 (NH), 2049
(CN); HRMS m/z (ES) 311.1382, C18H19N2O3 [M þ H]þ requires
311.1396.
General Procedure for the Synthesis of (S)-R-Arylglycine
Hydrochlorides 14aꢀh. The corresponding aminonitrile hydrochloride
(12aꢀh) was treated with 6 M aqueous HCl (amount corresponding to a
0.1 M solution), and the mixture was heated at 90 °C for ca. 3ꢀ4 h. The
reaction mixture was allowed to cool to room temperature and
extracted with Et2O. The organic extract was discarded, and the
aqueous layer was concentrated in vacuo to dryness to give a white/
yellowish solid. The crude was suspended in CDCl3 (using a sonicator)
and filtered to give the corresponding (S)-R-arylglycine hydrochloride
(14aꢀh) as a white solid.
(S,S)-R-o-Tolyl-R-[1-(4-methoxyphenyl)ethylamino]aceto-
nitrile Hydrochloride (R-S,S)-12c. The title compound was synthe-
sized according to the general procedure using o-tolualdehyde 11c
(0.35 mL, 3.00 mmol). After filtration, the aminonitrile hydrochloride
12c (570 mg, 60%) was obtained as white plates: mp 129ꢀ132 °C; [R]D25
ꢀ
189 (c0.475, CHCl3),ꢀ109 (c0.525, MeOH); 1H NMR (400 MHz; CDCl3)
δH 7.57ꢀ7.55 (1H, m, ArH), 7.38 (2H, d, J = 8.7 Hz, ArH), 7.28ꢀ7.15
(3H, m, ArH), 6.92 (2H, d, J = 8.6 Hz, ArH), 4.39 (1H, s, CHCN), 4.20 (1H,
q, J= 6.4 Hz, CHCH3),3.83(3H,s,CH3O),2.14(3H,s,ArCH3), 1.40 (3H, d,
J = 6.4 Hz, CHCH3); 13C{1H} NMR (75 MHz; CDCl3) δC 159.7, 136.7,
134.9, 133.8, 131.5, 129.5, 128.8, 127.7, 127.0, 119.5, 114.5, 56.7, 55.7, 50.6,
24.7, 19.0; νmax(CHCl3)/cmꢀ1 3338 (NH), 2222 (CN); m/z (CI) 265
(12%, M ꢀ Me), 253 (22, M ꢀ HCN), 135.0 (100, C8H9NO). Found: C,
77.0; H, 7.03; N, 9.86. C18H20N2O requires C, 77.11; H, 7.19; N, 9.99.
(S,S)-R-(4-Methoxyphenyl)-R-[1-(4-methoxyphenyl)ethyl)-
amino]-acetonitrile Hydrochloride (R-S,S)-12d. The title com-
pound was synthesized according to the general procedure using p-
methoxybenzaldehyde 11d (0.37 mL, 3.00 mmol). After filtration, the
aminonitrile hydrochloride 12d (871 mg, 87%) was obtained as a white
solid, mp 109ꢀ111 °C; [R]D20 ꢀ27.4 (c 0.475, MeOH); 1H NMR (300
MHz; CDCl3) δH 7.40ꢀ7.35 (4H, m, ArH), 6.95ꢀ6.86 (4H, m, ArH),
4.32 (1H, s, CHCN), 4.18 (1H, q, J = 6.6 Hz, CHCH3), 3.82 (3H, s,
OCH3), 3.81 (3H, s, OCH3), 1.40 (3H, d, J = 6.6 Hz, CHCH3);
13C{1H} NMR (75 MHz, CDCl3) δC 160.1, 159.3, 135.1, 128.5, 128.2,
127.5, 119.3, 114.4, 56.3, 55.5, 55.4, 51.8, 24.9; IR (film, cmꢀ1) νmax
=
3306 (NH), 2227 (CN); HRMS m/z (ES) 297.1605, C18H21N2O2
[M þ H]þ requires 297.1603.
(S,S)-R-(4-Hydroxyphenyl)-R-[1-(4-methoxyphenyl)ethyl)-
amino]-acetonitrile hydrochloride, (R-S,S)-12e. The title
compound was synthesized according to the general procedure using
p-hydroxybenzaldehyde 11e (0.37 g, 3.00 mmol). After filtration, the
aminonitrile hydrochloride 12e (819 mg, 86%) was obtained as a white
solid, mp 132ꢀ134 °C; [R]D20 ꢀ40.7 (c 0.590, MeOH); 1H NMR (300
MHz; CDCl3) δH 7.37 (2H, app d, J = 8.7 Hz, ArH), 7.30 (2H, app d,
J = 8.4 Hz, ArH), 6.92 (2H, app d, J = 8.7 Hz, ArH), 6.81 (2H, app d,
J = 8.7 Hz, ArH), 4.30 (1H, s, CHCN), 4.16 (1H, q, J = 6.4 Hz, CHCH3),
3.82 (3H, s, OCH3), 1.40 (3H, d, J = 6.4 Hz, CHCH3); 13C{1H} NMR
(75 MHz, CDCl3) δC 159.3, 156.4, 135.0, 128.7, 128.2, 127.3, 119.3,
115.9, 114.4, 56.3, 55.5, 51.8, 24.9; IR (film, cmꢀ1) νmax = 3261 (NH),
2228 (CN); HRMS m/z (ES) 305.1255, C17H18N2NaO2 [M þ Na]þ
requires 305.1266.
(S)-R-Amino-R-phenylacetic Acid Hydrochloride (S)-14a.
The title compound was synthesized according to the general procedure
using aminonitrile (S,S)-12a (124 mg, 0.47 mmol) and 5 mL of 6 M
aqueous HCl. The title compound 14a was obtained as a white solid (53
mg, 60%);[R]2D0 þ152 (c 0.100, 1 M HCl); 1H NMR (400 MHz; D2O)
δH 7.47ꢀ7.42 (5H, m, ArH), 5.07 (1H, s, CHCO2H); 13C{1H} NMR
(100 MHz; D2O) δC 171.2, 131.9, 130.2, 129.7, 128.1, 56.9; m/z (CI)
152 (6%, M ꢀ HCl), 135 (39, M ꢀ HCl ꢀ NH3), 107 (100, M ꢀ HCl ꢀ
CO2H).
(S,S)-R-(2-Bromophenyl)-R-[1-(4-methoxyphenyl)ethyl-
amino]-acetonitrile Hydrochloride (R-S,S)-12f. The title com-
pound was synthesized according to the general procedure using
2-bromobenzaldehyde 11f (0.35 mL, 3.00 mmol). After filtration, the
aminonitrile hydrochloride 12f (662 mg, 58%) was obtained as white
plates: mp 117.0ꢀ118.5 °C; For a sample with ca. 90% de [R]2D5 ꢀ166
(c 0.525, CHCl3), ꢀ116 (c 0.490, MeOH); 1H NMR (300 MHz;
(S)-R-Amino-R-p-tolylacetic Acid Hydrochloride (S)-14b.
The title compound was synthesized according to the general procedure
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The Journal of Organic Chemistry
ARTICLE
using aminonitrile (S,S)-12b (150 mg, 0.53 mmol) and 5 mL of 6 M
aqueous HCl. The title compound 14b was obtained as a white solid (60
mg, 56%); [R]2D0 þ70 (c 0.100, H2O); 1H NMR (300 MHz; D2O) δH
7.29 (2H, d, J = 8.5 Hz, ArH), 7.26 (2H, d, J = 8.5 Hz, ArH), 5.02 (1H, s,
CHCO2H), 2.28 (3H, s, CH3); 13C{1H} NMR (75 MHz; D2O) δC
171.1, 140.8, 130.1, 128.8, 128.0, 56.6, 20.3; IR (film, cmꢀ1) νmax = 2976
(br, NH), 2880 (br, OH), 1727 (CdO); HRMS m/z (ES) 166.0870,
C9H12NO2 [M þ H]þ requires 166.0868.
solid (118 mg, 64%); [R]D20 þ48 (c 0.415, H2O); 1H NMR (300 MHz;
D2O) δH 7.01ꢀ6.94 (3H, m, ArH), 6.03 (2H, s, CH2), 5.07 (1H, s,
CHCO2H); 13C{1H} NMR (75 MHz; D2O) δC 171.6, 149.0, 148.4,
125.7, 123.0, 109.5, 108.4, 102.2, 57.0; IR (film, cmꢀ1) νmax = 2985 (br,
NH), 2915 (br, OH), 1734 (CdO); HRMS m/z (ES) 196.0610,
C9H10NO4 [M þ H]þ requires 196.0610.
General Procedure for the Determination of the Enantio-
meric Excess of the Synthesized (S)-R-Arylglycine Hydro-
chlorides. The R-arylglycines hydrochlorides 14aꢀh were converted
to their respective methyl ester hydrochloride derivatives in quantitative
yield by heating them at reflux at 85 °C in 3 M aqueous HCl in MeOH
for 12 h, followed by simple evaporation of the solvent. The R-amino
ester hydrochloride (1 equiv) and K2CO3 (1.1 equiv) were suspended in
a minimum amount of CDCl3. 2-Formylphenylboronic acid (16)
(1.1 equiv), (S)-(BINOL) (1.1 equiv), 4 Å molecular sieves, and CDCl3
were then added in order to produce a 0.1 M solution of the R-amino
ester hydrochloride. The solution was stirred for 10 min before being
filtered through a small pad of Celite and the solution analyzed by
1H NMR spectroscopy.
(S)-R-Amino-R-o-tolylacetic Acid Hydrochloride (S)-14c.
The title compound was synthesized according to the general procedure
using aminonitrile (S,S)-12c (300 mg, 1.07 mmol) and 11 mL of 6 M
aqueous HCl. The title compound 14c was obtained as a white solid
(173 mg, 80%); [R]2D5 þ90 (c 0.100, 5 M HCl); 1H NMR (300 MHz;
D2O) δH 7.41ꢀ7.20 (4H, m, ArH), 5.05 (1H, s, CHCO2H), 2.04 (3H, s,
CH3); 13C{1H} NMR (75 MHz; D2O) δC 170.8, 137.4, 131.5, 130.3,
129.8, 127.1, 126.8, 53.1, 18.8, m/z (CI) 166 (8%, M ꢀ Cl), 149.0
(26, M ꢀ Cl ꢀ NH3), 120 (100, M ꢀ HCl ꢀ CO2H).
(S)-R-Amino-R-(4-methoxyphenyl)acetic Acid Hydro-
chloride (S)-14d. The title compound was synthesized according to
the general procedure using aminonitrile (S,S)-12d (210 mg, 0.70
mmol) and 7 mL of 6 M aqueous HCl. The title compound 14d was
obtained as a white solid (79 mg, 52%); [R]2D2 þ41.7 (c 0.120, H2O); 1H
NMR (300 MHz; D2O) δH 7.38 (2H, app d, J = 8.9 Hz, ArH), 7.03 (2H,
app d, J = 8.9 Hz, ArH), 4.99 (1H, s, CHCO2H), 3.81 (3H, s, OCH3);
13C{1H} NMR (75 MHz, D2O) δC 160.4, 130.0, 124.8, 115.3, 56.7,
55.7; IR (film, cmꢀ1) νmax = 2969 (OH), 1733 (CdO); HRMS m/z
(ES) 182.0809, C9H12NO3 [M þ H]þ requires 182.0817.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra of R-
S
b
aminonitriles 12aꢀh and R-arylglycines 14aꢀh and CIF file for
(R-S,S)-12b. This material is available free of charge via the
Internet at http://pubs.acs.org. Crystallographic data for com-
pound (R-S,S)-12b have also been deposited with the Cambridge
Crystallographic Data Centre as supplementary publications CCDC
811794.
(S)-R-Amino-R-(4-hydroxyphenyl)acetic Acid Hydrochlor-
ide (S)-14e. The title compound was synthesized according to the
general procedure using aminonitrile (S,S)-12e (200 mg, 0.70 mmol)
and 7 mL of 6 M aqueous HCl. The title compound 14e was obtained as
a white solid (116 mg, 81%); [R]2D2 þ58.5 (c 0.205, H2O); H NMR
1
’ AUTHOR INFORMATION
(300 MHz; D2O) δH 7.31 (2H, app d, J = 8.6 Hz, ArH), 6.91 (2H, app d,
J = 8.6 Hz, ArH), 5.04 (1H, s, CHCO2H); 13C{1H} NMR (75 MHz,
Corresponding Author
*E-mail: S.D.Bull@bath.ac.uk; T.D.James@bath.ac.uk.
D2O) δC 171.7, 157.4, 130.2, 123.9, 116.6, 56.6; IR (film, cmꢀ1) νmax
=
3000 (OꢀH), 1728 (CdO); HRMS m/z (ES) 168.0643, C8H10NO3
[M þ H]þ requires 168.0661.
’ ACKNOWLEDGMENT
(S)-R-Amino-R-(2-bromophenyl)acetic Acid Hydrochlor-
ide (S)-14f. The title compound was synthesized according to the
general procedure using aminonitrile (S,S)-12f (246 mg, 0.71 mmol)
and 8 mL of 6 M aqueous HCl. The compound 14f was obtained as a
white solid (151 mg, 80%); [R]2D5 þ60 (c 0.515, 1 M HCl); 1H NMR
(300 MHz; D2O) δH 7.64 (1H, d, J = 7.7 Hz, ArH), 7.38ꢀ7.33 (2H, m,
ArH), 7.31ꢀ7.25 (1H, m, ArH), 5.45 (1H, s, CHCO2H); 13C{1H}
NMR (75 MHz; D2O) δC 169.7, 133.0, 131.2, 130.5, 129.0, 128.0,
123.1, 55.5; νmax(KBr)/cmꢀ1 3409 (OH), 1747 (CdO), 1405 (OH);
m/z (CI) 232 (29%, M ꢀ HCl), 230 (29%, M ꢀ HCl), 215 (14, M ꢀ
HCl ꢀ NH3), 213 (14, M ꢀ HCl ꢀ NH3), 186 (100, M ꢀ HCl ꢀ
CO2H), 184 (100, M ꢀ HCl ꢀ CO2H).
We would like to thank the EPSRC and the University of Bath
for funding.
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ARTICLE
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