Synthesis and characterization of some new c2 symmetric chiral bisamide ligands derived from chiral feist's acid

Article abstract of DOI:10.3390/molecules17055550

The hemilabile chiral C₂ symmetrical bidentate substituted amide ligands (1R,2R)-5^a-d and (1S,2S)-6^a-d were synthesized in quantitative yield from (1R,2R)-(+)-3- methylenecyclo-propane-1,2-dicarboxylic acid (1R,2R)-3 and (1S,2S)-(-)-3-methylenecyclopropane- 1,2-dicarboxylic acid (1S,2S)-3, in two steps, respectively. The chiral Feist's acids (1R,2R)-3 and (1S,2S)-3 were obtained in good isomeric purity by resolution of trans-(±)-3-methylene-cyclopropane-1,2-dicarboxylic acid from an 8:2 mixture of tert-butanol and water, using (R)-(+)-α-methylbenzyl amine as a chiral reagent. This process is reproducible on a large scale. All these new synthesized chiral ligands were characterized by ¹H-NMR, ¹³C-NMR, IR, and mass spectrometry, as well as elemental analysis and their specific rotations were measured. These new classes of C₂ symmetric chiral bisamide ligands could be of special interest in asymmetric transformations.

Full text of DOI:10.3390/molecules17055550

Molecules 2012, 17, 5550-5563; doi:10.3390/molecules17055550
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Characterization of Some New C2 Symmetric
Chiral Bisamide Ligands Derived from Chiral Feist’s Acid
Abdullah M. A. Al Majid *, Mohammad Shahidul Islam *, Zeid Abdullah Al-Othman,
Ahlam F. Al-Salhoob and Assem Barakat
Department of Chemistry, Faculty of Science, King Saud University, P.O. Box 2455, Riyadh 11451,
Saudi Arabia; E-Mails: zaothman@ksu.edu.sa (Z.A.A.-O.); rhofy29@hotmail.com (A.F.A.-S.);
ambarakat@ksu.edu.sa (A.B.)
* Authors to whom correspondence should be addressed; E-Mails: amajid@ksu.edu.sa (A.M.A.A.M.);
shahid.10amui@gmail.com (M.S.I.); Tel.: +9661-467-5889 (A.M.A.A.M.);
Fax: +9661-467-5992 (A.M.A.A.M.); Tel.: +9665-467-5884 (M.S.I.); Fax: +9661-467-5992 (M.S.I.).
Received: 7 February 2012; in revised form: 16 April 2012 / Accepted: 20 April 2012 /
Published: 9 May 2012
Abstract: The hemilabile chiral C2 symmetrical bidentate substituted amide ligands
(1R,2R)-5a-d and (1S,2S)-6a-d were synthesized in quantitative yield from (1R,2R)-(+)-3-
methylenecyclo-propane-1,2-dicarboxylic acid (1R,2R)-3 and (1S,2S)-(-)-3-methylene-
cyclopropane-1,2-dicarboxylic acid (1S,2S)-3, in two steps, respectively. The chiral Feist’s
acids (1R,2R)-3 and (1S,2S)-3 were obtained in good isomeric purity by resolution
of trans-(±)-3-methylene-cyclopropane-1,2-dicarboxylic acid from an 8:2 mixture of
tert-butanol and water, using (R)-(+)-α-methylbenzyl amine as a chiral reagent. This
process is reproducible on a large scale. All these new synthesized chiral ligands were
1
13
characterized by H-NMR, C-NMR, IR, and mass spectrometry, as well as elemental
analysis and their specific rotations were measured. These new classes of C2 symmetric
chiral bisamide ligands could be of special interest in asymmetric transformations.
Keywords: resolution of Feist’s acid; bisamide ligand; C2 symmetric
1. Introduction
Over the past few decades, C2 symmetric chiral amides and sulfonamides have proven to be
efficient ligands for several asymmetric transformations [1–4], due to their great potential of binding

Molecules 2012, 17
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with the metal alkoxides, especially with Ti(IV) alkoxides, through the nitrogen atom. Therefore
considerable efforts have been devoted to the synthesis of a variety of substituted C2 symmetric chiral
amide ligands [5–8]. Recently a series of new chiral sulfonamides with a rigid cyclohexyl backbone
were introduced by Wals and co-workers for the asymmetric addition of diethyl zinc to aldehydes [8].
In addition, all these C2 symmetric chiral amides and sulfonamides are capable of forming five- and
six-membered rings with metal chelates, in which the transition states only allow the approach of
incoming groups from the less hindered side by blocking the highly hindered face. Moreover,
asymmetric addition of organozinc to aldehydes is probably the most successful and still vigorously
pursued area in asymmetric C-C bond formation [9–13]. Despite of the enormous success of chiral
ligands in asymmetric reactions, a limited number of amides with 1,1'-biaryl backbones are reported
for the organozinc addition [14–22]. In addition, the rational design of new chiral ligands for
enantioselective conjugate alkylation has achieved limited success, presumably due to several factors
that have to be taken into consideration. In case of C2 symmetric chiral amide ligands, these factors
could be explained as follows: firstly, due to the presence of C2 symmetric axis in the chiral ligand, a
number of possible transition states, in particular chiral transformations could be minimized [23].
Secondly, in the amide functional group, the carbonyl group has a potential donor site -NH group and
therefore elucidation of their protonation behavior and related phenomena such as hydrogen bonding
and Lewis acid complexation has drawn a good deal of attention. An amide molecule may have a dual
role of both proton acceptor and donor, conferring a dual nature to the amide functionality [24].
Nevertheless, the size of the chelate ring has also proven to be important, since it controls the
orientation of the substituents around the metal center. Hence, the bulkiness of the substituent in the
amide ligands could be adjusted by changing the amide chain in order to achieve a better ligand
structure for a particular reaction simply by selecting the appropriate stereochemistry and bulkiness [23].
In addition, Ikeda reported that the presence of stereogenic centers on the backbone of the ligands,
introduces an extra element of complexity in the ligand structure, and special effect will arise when
such ligands are employed in asymmetric catalysis [25]. Therefore C2 symmetric chiral ligands have
been used in the past few decades for catalytic asymmetric processes with a high degree of
enantioselectivity [26–29], although chiral amides still remain an attractive choice for highly selective
catalytic reactions due to their ready availability and simple reaction conditions. Hence, the
development and application of C2 symmetric chiral amides are still interesting and limited.
In this article, we report the preparation of (±)-Feist’s acid as a chiral precursor in order to introduce
a cyclopropane framework into the C2 symmetric chiral ligands. For this purpose we need an effective
resolution of this (±)-Feist’s acid. There are many protocols in the literature for the resolution of
(±)-Feist’s acid. In the earliest, Doering and Roth described the resolution of Feist’s acid, using
L-(−)-quinine as the resolving reagent [30], whereas Al-Majid et al., used L-(−)-menthol as a resolving
reagent [31]. Recently, Godfrey et al. have used (R)-(+)-α-methylbenzyl amine as a chiral reagent [32].
Although a generally applicable method is still lacking, our attention, in this context, has focused on
the effective modification of (±)-Feist’s acid resolution, and the general method for the synthesis of
novel C2 symmetric chiral bisamide ligands with a rigid cyclopropane framework.

Molecules 2012, 17
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2. Results and Discussion
A series of new chiral bisamide ligands (1R,2R)-5a–d and (1S,2S)-6a–d (Figure 1) has been
synthesized from the highly enantiopure Feist’s acids (1R,2R)-3 and (1S,2S)-3, which were prepared
from trans-(±)-3-methylenecyclopropane-1,2-dicarboxylic acid (2) in very good yield (~92%) using
(R)-(+)-α-methylbenzyl amine as a chiral reagent. Since an optical active Feist’s acid is a
commercially available but highly expensive material, therefore it was prepared in house with an
overall yield of 19% over three steps, starting from a very cheap and readily available material; ethyl
acetoacetate, as described by Goss, Ingold and Thorpe [33], as shown in Scheme 1.
Figure 1. Substituted bis-amide ligands derived from Feist’s acids.
O
O
NHR
NHR1
NHR
NHR
----------------------------------------------------------------------------------------------------------------------
H2N
H2N
H2N
H2N
NHR1
O
O
a
b
c
d
(1R,2R)-3
(1S,2S)-3
(1R,2R)-5a-d and (1S,2S)-6a-d
Scheme1. Synthesis of trans-(±)-3-methylenecyclopropane-1,2-dicarboxylic acid (±)-2.
Reagents and conditions: (a) Dry HCl (g), 14 days, in a dark place; (b) Br2, CHCl3, 24 h, RT;
(c) 7 M KOH, 105 °C, 1 h.
In order to obtain enantiopure Feist’s acids (1R,2R)-3 and (1S,2S)-3 as a precursor, a resolution has
been carried out by the reaction between trans-(±)-3-methylenecyclopropane-1,2-dicarboxylic acid
(±)-2 and one molar equivalent of (R)-(+)-α-methylbenzyl amine in aqueous tert-butanol (8:2) to give a
mixture of diastereomeric ammonium salts of trans-(±)-3-methylenecyclopropane-1,2-dicarboxylic
acid, as presented in Scheme 2.

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Scheme 2. Synthesis of (R)-(+)-α-methylbenzammonium salt of trans-(±)-3-
methylenecyclopropane-1,2-dicarboxylic acids{(1R,2R,1'R)-(+)-3a and (1S,2S,1'R)-(+)-3b}.
On standing overnight at ambient temperature a solid precipitate of (R)-(+)-α-methyl-benzammonium
salt of (1R,2R)-(+)-3-methylenecyclopropane-1,2-dicarboxylic acid {(1R,2R,1'R)-(+)-3a} was obtained in
97.2% yield (1:1) and the (R)-(+)-α-methylbenzammonium salt of (1S,2S)-(−)-3-methylenecyclopropane-
1,2-dicarboxylic acid (1:1) (1S,2S,1'R)-(+)-3b(≈100%) was collected as mother liquor. The yields of
isolated compounds (1R,2R,1'R)-(+)-3a and (1S,2S,1'R)-(+)-3b were measured based on one of the
diastereomeric Feist’s acid salts. The melting point and specific rotation of compound (1R,2R,1'R)-(+)-
3a were found to be 220–222 °C and [α]observed + 0.55°, [α]20D + 110°, (c, 0.5%, H2O), [lit. [32], [α]23.5
D
+ 86.1°; (c, 0.57%, H2O)] accordingly. Further recrystalization of compound (1R,2R,1'R)-(+)-3a
from tert-butanol and water (8:2) was carried out to obtain pure crystals of the (R)-(+)-α-
methylbenzammonium salt of (+)-3-methylenecyclopropane-(1R,2R)-1,2-dicarboxylic acid (1R,2R,1'R)-
(+)-3a in approximately 92% yield (based on one of the diastereomeric Feist’s acid salts), m.p.
219–222 °C, [α]observed + 0.60°, [α]20 + 120°, (c, 0.50%, H2O), [lit. [32], [α]25 + 94.7° (c, 0.61%,
D
D
H2O)]. The melting point and specific rotation values of compound (1R,2R,1'R)-(+)-3a were in
accordance with those reported in the literature [32].
The hydrolysis of the salt (1R,2R,1'R)-(+)-3a by using 1 N H2SO4 in ethyl acetate yielded (1R,2R)-
(+)-3-methylenecyclopropane-1,2-dicarboxylic acid {(1R,2R)-3}, as an off white solid in 94% yield,
m.p 200–203 °C, [lit. [32], 203–2005 °C), [α]observed + 0.65, [α]20 + 130, (c, 0.5%, EtOH), lit. [32],
D
[α]20 + 176° (c, 0.70, EtOH)]. Hydrolysis of the mother liquor (1S,2S,1'R)-(+)-3b gave (1S,2S)-(−)-
546
3-methylenecyclopropane-1,2-dicarboxylic acid {(1S,2S)-3} as an off-white solid in 90% yield, m.p.
201 203 °C, (lit. [32], m.p. 199.2–199.7 °C), [α]observed + 1.25, [α]20D − 125, (c, 0.5%, EtOH), lit. [32],
[α]25 − 131.3°; c, 0.81%, EtOH)], as shown in Scheme 3. The melting point, specific rotation values
D
and the analytical data of compounds (1R,2R)-3 and (1S,2S)-3 were in agreement with those reported
in the literature [32].

Molecules 2012, 17
5554
Scheme 3. Hydrolysis of (R)-(+)-α-methylbenzammonium salt of trans-(±)-3-
methylenecyclopropane-1,2-dicarboxylic acids {(1R,2R,1'R)-(+)-3a and (1S,2S,1'R)-(+)-3b}.
C2 Symmetric chiral bisamide ligands (1R,2R)-5a–d and (1S,2S)-6a–d have been synthesized in
modest yield in two steps via the corresponding acid chloride intermediates, starting from the chiral
Feist’s acids (1R,2R)-3 and (1S,2S)-3, respectively, as described in Schemes 4 and 5.
Scheme 4. Synthesis of bis-amide ligands (1R,2R)-5a–d via acid chlorides.
Reagents and conditions: (i) 3 eq. (COCl)2, DMF (2 drops), CH2Cl2, RT, 2 h; (ii) RNH2 (2 eq.),
DIPA (5 eq.), CH2Cl2, 0 °C-RT, 24 h.
Scheme 5. Synthesis of bis-amide ligands (1S,2S)-6a–d via acid chlorides.
Reagents and conditions: (i) 3 eq. (COCl)2, DMF (2 drops), CH2Cl2, RT, 2 h; (ii) RNH2 (2 eq.),
DIPA (5 eq.), CH2Cl2, 0 °C-RT, 24 h.

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The syntheses of the acid chlorides (1R,2R)-4 and (1S,2S)-4 were carried out using two different
procedures A and B, although the better yields of the ligands (up to 85%) were achieved by using the
acid chloride obtained from procedure B, as described in the Experimental section. The formation of
the acid chloride intermediates (1R,2R)-4 and (1S,2S)-4 was confirmed by IR spectroscopy, where the
absence of a broad band around 3,452 cm–1 (due to OH stretching frequency) was observed, along with
the shifting of the C=O stretching frequencies from 1,710 to 1,800 cm–1, indicating the formation of
the acid chlorides. Furthermore, appearance of a sharp peak at 764 cm–1 was attributed to C–Cl
stretching frequency.
The chiral bisamide ligands (1R,2R)-5a and (1S,2S)-6a were synthesized by treating two
equivalents of tert-butyl amine with one equivalent of the freshly prepared acid chlorides (1R,2R)-4
and (1S,2S)-4, respectively, in dry CH2Cl2 under inert conditions, as shown in Schemes 4 and 5. The
structures of both the compounds (1R,2R)-5a and (1S,2S)-6a were mainly deduced from their 1H-NMR
spectra, where the presence of 18 protons at δ 1.24 and two protons at δ 7.87 as a singlet,
corresponding to the 2×C(CH3)3 and 2×CONH groups, respectively, could be observed. These two
ligands (1R,2R)-5a and (1S,2S)-6a were further confirmed by their IR spectra, where three
characteristic sharp peaks were observed at 3,318 and 3,321, 1,641 and 1,642 and 1,551 and 1,549 cm-1
due to N–H(sec) stretching, C=O stretching and C–N stretching frequencies, respectively. The specific
rotation values of the compounds (1R,2R)-5a and (1S,2S)-6a were found to be [α]20D + 150° (c, 0.30%,
10% MeOH/CHCl3) and [α]20D − 129 (c, 0.31%, 10% MeOH/CHCl3), respectively, in total agreement
with their configuration.
The ligands (1R,2R)-5b and (1S,2S)-6b with a sec-butyl amide side chain, were obtained in good
yield, in a similar fashion as described in the above paragraph (Schemes 4 and 5). Formation of these
1
compounds were confirmed by IR and H-NMR spectroscopy. The IR spectra of these two ligands,
showed sharp peaks at 3,273 and 3,269, 1,632 and 1,630 and 1,557 and 1,560 cm–1, which were
assigned to the N–H (sec) stretching, C=O stretching and C–N stretching vibrations, respectively.
1
In case of their H-NMR spectra, the presence of a triplet at δ 0.81, a doublet at δ 1.02 and another
doublet at δ 8.05, which were assigned to the protons of two sets of primary methyls, secondary
methyls and two sets of amide groups, respectively. The splitting of the NH proton is mainly due to the
presence of an adjacent tertiary proton in the sec-butyl chain. The calculated specific rotation of the
ligands (1R,2R)-5b and (1S,2S)-6b were found to be [α]20 + 129 (c, 0.31%, 10% MeOH/CHCl3) and
D
[α]20D − 112 (c, 0.31%, 10% MeOH/CHCl3), respectively, which matching well with their configuration.
The ligands with the isobutyl chain (1R,2R)-5c and (1S,2S)-6c were obtained in very good yield, as
described in the Experimental section (Schemes 4 and 5). The structures of these amide ligands were
1
elucidated from their IR and H-NMR spectra. In the IR spectra, three sharp peaks were observed for
both the ligands at 3,296 and 3,288, 1,632 and 1,634, and 1,558 and 1,559 cm–1, due to the stretching
frequencies of sec-N–H, C=O and C–N groups, respectively. In the 1H-NMR, observation of a doublet
at δ 0.84, and a triplet at δ 8.21, are indicative of the presence of four sets of primary methyls and two
sets of amide groups, accordingly. The presence of two methylene protons in the iso-butyl chain
adjacent to the NHCO, are responsible for the splitting of the NH proton signal into a triplet. The
configuration of these ligands were determined from their specific rotation values, which were found
to be [α]20 + 76 (c, 0.26%, 10% MeOH/CHCl3) and [α]20 − 133 (c, 0.30%, 10% MeOH/CHCl3),
D
D
respectively.

Molecules 2012, 17
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Finally, the ligands (1R,2R)-5d and (1S,2S)-6d with benzyl groups in amide side chain were
prepared in very satisfactory yield by reaction of benzylamine (2 eq.) with the intermediates (1R,2R)-4
1
and (1S,2S)-4, respectively. These ligands were also characterized from the IR and H-NMR spectra.
In the IR spectra of these two ligands, three characteristic sharp peaks at 3,289 and 3,297, 1,631 and
1,630 and 1,540 and 1,541 cm–1 were observed for the stretching frequencies of sec-N–H, C=O and
C–N, respectively. The 1H-NMR of these ligands revealed characteristic peaks at δ 7.25–7.32 and 8.78
as a multiplet and triplet, which were assigned to the corresponding aromatic and amide protons,
respectively. Again the splitting of the NH proton into a triplet was due to the presence of two benzylic
protons in the amide chain. The configurations of these ligands were determined from their specific
optical rotations. Thus the specific rotations for these two ligands were found to be [α]20 + 100
D
(c, 0.4%, 10% MeOH/CHCl3) and [α]20D − 166 (c, 0.31%, 10% MeOH/CHCl3), respectively.
In 1H-NMR spectra, for both types of ligands (1R,2R)-5a–d and (1S,2S)-6a–d, we found a shift of the NH
proton’s δ values downfield to δ 7.87, 8.05, 8.21, and 8.78, and this downfield shift is due to the decreasing
+I effect for the substituent groups in the amide chain in going from tert-butyl to a benzyl group.
3. Experimental
3.1. General
All the moisture and air sensitive reactions were carried out under an inert atmosphere using an
argon filled glove box and standard Schlenk-line techniques. All the chemicals were purchased from
Aldrich, Sigma-Aldrich and Fluka and were used as received without purification, unless otherwise
stated. TLC plates were used for monitoring the reactions. Flash chromatography was carried out with
silica gel (100–200 mesh). Pyridine, triethylamine and diisopropylamine were dried over sodium
hydroxide. Diethyl ether and tetrahydrofuran were distilled from sodium benzophenone ketyl. Hexane,
heptane and pentane were distilled by using sodium/triglyme benzophenone ketyl. Chloroform,
dichloromethane, benzene, toluene and dimethyformamide were dried using calcium hydride.
Deuterated solvents were dried over calcium hydride and deoxygenated prior to use. 1H and 13C-NMR
spectra were recorded on Jeol-400 spectrometer (1H 400 MHz, 13C 100 MHz): using deuterated CHCl3
or DMSO as solvent. The chemical shifts (δ in ppm) for 1H- and 13C-NMR were referenced internally
using residual non deuterated solvent resonance shift and reported to trimethylsilane (TMS). Coupling
constants (J) are taken in Hertz (Hz). Specific rotations were measured by using ATAGO-POLAX-2L.
Elemental analyses were performed on a Perkin Elmer 2400 Elemental Analyzer. IR spectra were
recorded on a Model FTIR-800 Infrared FT-IR Spectrometer using KBr pellets for solids or neat for
liquids. Mass spectrometric analysis was conducted by using ESI mode on AGILENT Technologies
6410-triple quad LC/MS instrument.
3.2. Resolution of trans-(±)-3-Methylenecyclopropane-1,2-dicarboxylic Acid [(±)-2]
Synthesis of the Ammonium Salts of trans-(±)-3-Methylenecyclopropane-1,2-dicarboxylic Acids
[(1R,2R,1'R)-(+)-3a &(1S,2S,1'R)-(−)-3b]. The trans-(±)-3-methylenecyclopropane-1,2-dicarboxylic
acid [±-(2), 20 g, 0.14 mol) was added to an 8:2 mixture of tert-butanol-water (160 mL) and the
suspension was heated to 90 °C on a steam bath until it had completely dissolved. The resulting

Molecules 2012, 17
5557
solution was then removed from the steam bath and (R)-(+)-α-methylbenzamine (17 g, 0.14 mol) was
added slowly over a period of 20 min. The reaction mixture was stirred for 10 min and left to stand for
24 h to give a mixture of (1R,2R,1'R)-(+)-3a and (1S,2S,1'R)-(+)-3b in 1:1 ratio.
Isolation of the (R)-(+)-α-Methylbenzammonium Salt of (+)-3-Methylenecyclopropane-(1R,2R)-(+)-
1,2-dicarboxylic Acid {(1R,2R,1'R)-(+)-3a}. After keeping the solution of (1R,2R,1'R)-(+)-3a and
(1S,2S,1'R)-(+)-3b at room temperature overnight, a white crystalline solid precipitated out, which was
collected by filtration and washed with a cold mixture of tert-butyl alcohol and water (9:1, 2 × 80 mL).
Finally the solid was dried to obtain the ammonium salt 3a. Yield 18 g (68.1 mmol, 97.2 %, based on one
of the diastereomeric Feist’s acid salts), m.p. 220–222 °C, [α]observed + 0.55°, [α]20D + 110° (c, 0.5%, H2O),
(lit. [32], [α]23.5D + 86.1°; c, 0.57%, H2O).
The crystalline material was recrystallized further from an 8:2 mixture of tert-butyl alcohol and
water (60 mL) to afford fine crystals of the (R)-(+)-α-methylbenzammonium salt of (1R,2R)-(+)-3-
methylenecyclopropane-1,2-dicarboxylic acid (1:1) {(1R,2R,1'R)-(+)-3a}; yield 17 g (64.32 mmol,
91.89%), based on the diastereomeric Feist’s acid salt), m.p. 219–222 °C, [α]observed + 0.60°, [α]20D + 120°
(c, 0.50%, H2O), (lit. [32], [α]25 + 94.7°; c, 0.61%, H2O). A small sample was further recrystallized,
D
but no change of specific rotation and melting point was observed. Elemental analyses were in
accordance with the reported literature [32].
Resolution of the (R)-(+)-α-Methylbenzammonium Salt of (1S,2S)-(−)-3-Methylene-cyclopropane-
1,2-dicarboxylic Acid (1:1) {(1S,2S,1'R)-(−)-3b} and Regeneration of (1S,2S)-(−)-3-
Methylenecyclopropane-1,2-dicarboxylic Acid {(1S,2S)-3}. The mother liquor obtained after the
isolation of solid (R)-(+)-α-methylbenzammonium salt of (1R,2R)-(+)-3-methylenecyclopropane-1,2-
dicarboxylic acid (1:1){(1R,2R,1'R)-(+)-3a}, was concentrated under reduced pressure to give pale
yellow coloured viscous solid (1S,2S,1'R)-(+)-3b(19.5 g, crude) which was dissolved in water
(200 mL) and washed with ethyl acetate (2 × 100 mL) in order to remove the organic impurities. The
aqueous phase was acidified with 1M H2SO4 and extracted with ethyl acetate (3 × 100 mL). The
combined organic phase was then washed with brine (100 mL) and dried over anhydrous Mg2SO4. The
organics were then concentrated under reduced pressure to afford (1S,2S)-(−)-3-methylenecyclopropane-
1,2-dicarboxylic acid {(1S,2S)-3}, as an off white solid. Yield 9.0 g (63.38 mmol, 90%, based on one
enantiomer). M.p. 201–203 °C, (lit. [32], m.p. 199.21–199.7 °C); [α]observed + 1.25, [α]20 − 125°
D
(c, 0.5%, EtOH), (lit. [32], [α]25D − 131.3°; c, 0.81%, EtOH); IR (cm-1): 3,500–2,500 (bs, OH str.),
1,700 (bs, C=O str.), 1,470 (s), 1,320 (s), 1,300 (s), 1,210 (s), 1,100 (s), 980 (s), 920 (s), 790 (s), 660
1
(m); H-NMR (DMSO-d6): δ 2.85 (s, 2H, CH), 5.9 (s, 2H, C=CH2), 12.9–13.2 (bs, 2H, COOH);
13C-NMR (DMSO-d6): δ 29.5 (CH), 110 (C=CH2), 133.5 (C=CH2), 174.0 (COOH); Anal. Calcd. for
C6H6O4: C, 50.71; H, 4.26. Found: C, 50.52; H, 4.33; LC/MS (EI+): m/z = 141.02 [M–H+].
(1R,2R)-(+)-3-Methylenecyclopropane-1,2-dicarboxylic
Acid
{(1R,2R)-3:
The
(R)-(+)-α-
methylbenzammonium salt of (1R,2R)-(+)-3-methylenecyclopropane-(+)-1,2-dicarb-oxylic acid (1:1)
{(1R,2R,1'R)-(+)-3a}(17 g, 64.71 mmol) was dissolved in a 1:1 mixture of ethyl acetate and water
(200 mL) and then acidified with 1 M H2SO4. The reaction mixture was stirred for 5 min then the
organic phases were separated out. The aqueous phase was further extracted with 10% methanol in ethyl

Molecules 2012, 17
5558
acetate (2 × 100 mL) and the combined organics were washed with brine (100 mL). Then the organics
were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford
(1R,2R)-(+)-3-methylenecyclopropane-1,2-dicarboxylic acid {(1R,2R)-3}, as an off white solid. Yield
8.5 g (59.85 mmol, 92.5%, based on one enantiomer). 200–203 °C, (lit. [32], 203–205 °C), [α]observed + 0.65°,
[α]20D + 130 (c, 0.5%, EtOH), (lit [32], [α]20546 + 176°; c, 0.70, EtOH); IR (cm–1): 3500–2500 (bs, OH
str.), 1700 (bs, CO str.), 1470 (s), 1320 (s), 1300 (s), 1210 (s), 1100 (s), 980 (s), 920 (s), 790 (s),
1
660 (m); H-NMR (DMSO-d6): δ 2.85 (s, 2H, CH), 5.9 (s, 2H, C=CH2), 12.9–13.2 (bs, 2H, COOH);
13C-NMR (DMSO-d6): δ 29.5 (CH), 110 (C=CH2), 133.5 (C=CH2), 174.0 (COOH); Anal. Calcd. for
C6H6O4: C, 50.71; H, 4.26. Found: C, 50.52; H, 4.33; LC/MS (EI+): m/z = 141.02 [M−H+].
3.3. General Procedure for the Preparation of Acid Chlorides (1R,2R)-4 and (1S,2S)-4 (GP1)
Procedure A: In a 100 mL round bottom flask equipped with a condenser and inert atmosphere,
Compound (1R,2R)-3 or (1S,2S)-3 (0.5 g, 3.52 mmol) was dissolved in benzene (20 mL) and 2 drops
of DMF were added. Thionyl chloride (3 g, 14.08 mmol) was added to the reaction mixture at room
temperature. The reaction mixture was heated to 60 °C for two hours, a clear wine red colour solution
formed. The benzene was then removed under reduced pressure to afford crude acid chlorides (1R,2R)-4
and (1S,2S)-4 with quantitative yield ~100%. IR (cm–1): 1,800 cm–1 (C=O str.), absence of OH str.
Frequency from 3,452 cm–1.
Procedure B: In a 100 mL round bottom flask equipped with a condenser and inert atmosphere,
Compound (1R,2R)-3 or (1S,2S)-3 (0.5 g, 3.52 mmol) was suspended in dry dichloromethane (20 mL)
and 2 drops of DMF were added. Then oxallyl chloride (1.32 g, 10.56 mmol) was added dropwise to
the reaction mixture at room temperature. The reaction mixture was stirred at ambient temperature for
1 h and it became the typical yellow colour of acid chloride solutions. The solvent was then removed
under reduced pressure to afford crude acid chlorides (1R,2R)-4 and (1S,2S)-4 in very good yield (0.7 g,
3.53 mmol, ~100%, crude). IR (cm–1): 1,800 cm–1 (C=O str.), absence of OH str. vibration at 3,452 cm–1.
3.4. General Procedure for the Synthesis of Amides (1R,2R)-5a–d and (1S,2S)-6a–d (GP2)
A solution of compound (1R,2R)-4 or (1S,2S)-4 (0.7 g, 3.52 mmol) in CH2Cl2 (10 mL), was added
slowly to the solution of amine a–d (2eq.) and diisopropyl amine (5 eq.) dissolved in CH2Cl2
(10 mL), at 0 to 5 °C. The reaction mixture was then allowed to stir at ambient temperature for 3 h.
TLC showed (10% MeOH/CH2Cl2) complete consumption of starting material. The reaction mixture
was then quenched with saturated solution of ammonium chloride (15 mL) and extracted with 10%
methanol in chloroform (5 × 100 mL). The combine organic layers were washed with brine (100 mL)
and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to
afford crude material which was washed with diethyl ether to afford pure amides (1R,2R)-5a–d and
(1S,2S)-6a–d.
(1R,2R)-N1,N2-Tert-butyl-3-methylenecyclopropane-1,2-dicarboxamide [(1R,2R)-5a]: Compound
(1R,2R)-5a was obtained as a white solid by treating acid chloride (1R,2R)-4 (3.52 mmol) with 2 eq. of
tert-butylamine according to GP2. Yield 730 mg (2.9 mmol, 82.2%); m.p. 235–238 °C, [α]observed + 0.45°,
[α]20 + 150°, (c, 0.30%, 10% MeOH/CHCl3); IR (cm–1): 3318 (s, sec N–H str.), 3073 (s), 2979 (s),
D

Molecules 2012, 17
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2961 (s), 1641 (s, C=O str.), 1551 (s, C–N str.), 1480 (s), 1360 (s), 1344 (s), 1249 (s), 1225 (s), 1108
1
(s), 890 (s), 652 (s); H-NMR (DMSO-d6): δ 1.24 (s, 18H, C(CH3)3), 2.68 (s, 2H, cyclopropyl CH),
13
5.37 (s, 2H, C=CH2), 7.87 (s, 2H, NH); C-NMR (DMSO-d6): δ 29.1 (C(CH3)3), 39.43 (C(CH3)3),
50.9 (cyclopropyl CH), 103.6 (C=CH2), 133.4 (C=CH2), 167.9 (NHC=O); Anal. Calcd. for
C14H24N2O2 (252.18); C, 66.63; H, 9.59; N, 11.10; Found: C, 66.52; H, 9.83; N, 10.72; LC/MS (EI+):
m/z = 253.1 [M+H+].
(1R,2R)-N1,N2-sec-Butyl-3-methylenecyclopropane-1,2-dicarboxamide [(1R,2R)-5b]: Compound
(1R,2R)-5b was obtained as an off white solid by treating acid chloride (1R,2R)-4 (3.52 mmol) with 2
eq. of sec-butylamine according to GP2. Yield 677 mg (2.68 mmol, 76%); m.p 235–238 °C,
[α]observed + 0.4, [α]20D + 129, (c, 0.31%, 10% MeOH/CHCl3); IR (cm–1): 3273 (s, sec N–H str.), 3080 (s),
2968 (s), 2929 (s), 1632 (s, C=O str.), 1558 (s, C-N str.), 1451 (s), 1361 (s),1219 (s), 1107 (s), 903 (s),
723, (s), 670 (s); 1H-NMR (DMSO-d6): δ 0.82 (t, 6H, J = 7.32 Hz, CH2CH3), 1.02 (d, 6H, J = 6.6 Hz,
CH(CH3)CH2), 1.37 (m, 4H, CH2CH3), 2.69 (s, 2H, cyclopropyl CH), 3.64 (m, 1H, CH(CH3)CH2),
13
5.40 (s, 2H, C=CH2), 8.06 (d, J = 7.72 Hz, 2H, NH); C-NMR (DMSO-d6): δ 11.0 (CH2CH3), 20.73
(CHCH3), 26.2 (CH2CH3), 29.5 (cyclopropyl CH), 46.6 (CHCH3), 103.9, (C=CH2), 133.16 (C=CH2),
167.8 (NHC=O); Anal. Calcd. for C14H24N2O2 (252.18); C, 66.63; H, 9.59; N, 11.10; Found: C, 65.99; H,
9.50; N, 10.11; LC/MS (EI+): m/z = 252.0 [M+].
(1R,2R)-N1,N2-Isobutyl-3-methylenecyclopropane-1,2-dicarboxamide
[(1R,2R)-5c]:
Compound
(1R,2R)-5c was obtained as an off white solid by treating acid chloride (1R,2R)-4 (3.52 mmol) with
2 eq. of iso-butylamine according to GP2. Yield 755 mg (3.00 mmol, 85%); m.p. 225–229 °C,
[α]observed + 0.2, [α]20 + 76, (c, 0.26%, 10% MeOH/CHCl3); IR (cm–1): 3296 (s, sec N–H str.), 3084
D
(s), 2952 (s), 2913 (s), 1632 (s, C=O str.), 1558 (s, C-N str.), 1330 (s), 1212 (s), 1107 (s), 893 (s), 671
(s); 1H-NMR (DMSO-d6): δ 0.84 (d, 6H, J = 6.6 Hz, CH(CH3)2), 1.66 (m, 1H, CH(CH3)2), 2.74 (s, 2H,
cyclopropyl CH), 2.89 (m, 2H, CH2CH(CH3)2), 5.41 (s, 2H, C=CH2), 8.21 (t, 2H, J = 5.36 Hz, NH);
13C-NMR (DMSO-d6): δ 20.1(CH(CH3)2), 25.6 (CH(CH3)2), 28.0 (cyclopropyl CH), 104.89 (C=CH2),
132.5 (C=CH2), 167.9 (NHC=O); Anal. Calcd. for C14H24N2O2 (252.18); C, 66.63; H, 9.59; N, 11.10;
Found: C, 66.50; H, 9.77; N, 10.69; LC/MS (ES+): m/z = 253.2 [M+H+].
(1R,2R)-N1,N2-Benzyl-3-methylenecyclopropane-1,2-dicarboxamide
[(1R,2R)-5d]:
Compound
(1R,2R)-5d was obtained as an off white solid by treating acid chloride (1R,2R)-4 (3.52 mmol) with
2 eq. of benzylamine according to GP2. Yield 970 mg (3.1 mmol, 86%); 231–235 °C, [α]observed + 0.4,
[α]20 + 100, (c, 0.4%, 10% MeOH/CHCl3); IR (cm–1): 3290 (s, sec-N–H str.), 1631 (s, C=O str.),
D
1
1540 (s, C–N str.), 1325 (s), 732 (s), 696 (s); H-NMR (DMSO-d6): δ 2.82 (s, 2H, cyclopropyl CH),
4.29 (d, 4H, J = 5.36 Hz, CH2Ph), 5.48 (s, 2H, C=CH2), 7.24–7.33 (m, 10H), 8.77 (t, 2H, J = 5.12 Hz,
NH); 13C-NMR (DMSO-d6): δ 26.3 (cyclopropyl CH), 43.0 ((cyclopropyl CH), 104.6 (C=CH2), 127.4
(C4 of aromatic), 127.9 (C2 of aromatic), 128.9 (C3 of aromatic), 132.6 (C=CH2), 139.7 (C1 of
aromatic ), 168.5 (NHC=O); Anal. Calcd. for C20H20N2O2 (320.15); C, 74.98; H, 6.29; N, 8.74; Found:
C, 74.83; H, 6.47; N, 8.52; LC/MS (EI+): m/z = 321.15 [M+H+].
(1S,2S)-N1,N2-tert-Butyl-3-methylenecyclopropane-1,2-dicarboxamide
[(1S,2S)-6a]:
Compound
(1S,2S)-6a was obtained as awhite solid by treating acid chloride (1S,2S)-4 (3.52 mmol) with 2 eq. of

Molecules 2012, 17
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tert-butylamine according to GP2. Yield 715 mg (2.83 mmol, 80.5%); m.p. 234–236 °C,
[α]observed − 0.40, [α]20D − 129, (c, 0.31%, 10% MeOH/CHCl3); IR (cm–1): 3321 (s, sec-N–H str.), 3071
(s), 2979 (s), 2960 (s), 1642 (s, C=O str.), 1549 (s, C–N str.), 1481 (s), 1362 (s), 1344 (s), 1249 (s),
1
1228 (s), 1108 (s), 890 (s), 654 (s); H-NMR (DMSO-d6): δ 1.24 (s, 18H, C(CH3)3), 2.68 (s, 2H,
13
cyclopropyl CH), 5.37 (s, 2H, C=CH2), 7.87 (s, 2H, NH); C-NMR (DMSO-d6): δ 29.09 (C(CH3)3),
39.4 (C(CH3)3), 50.9 (cyclopropyl CH), 103.6 (C=CH2), 133.38 (C=CH2), 167.9 (NHC=O); Anal.
Calcd. for C14H24N2O2 (252.18); C, 66.63; H, 9.59; N, 11.10; Found: C, 66.62; H, 9.85; N, 10.91;
LC/MS (EI+): m/z = 253.0 [M+H+].
(1S,2S)-N1,N2-sec-butyl-3-methylenecyclopropane-1,2-dicarboxamide
[(1S,2S)-6b]:
Compound
(1S,2S)-6b was obtained as a white solid by treating acid chloride (1S,2S)-4 (3.52 mmol) with 2 eq. of
sec-butylamine according to GP2. Yield 690 mg (2.73 mmol, 77.73%); m.p. 234–236 °C, [α]observed − 0.35,
[α]20 − 112, (c, 0.31%, 10% MeOH/CHCl3); IR (cm–1): 3269 (s, sec-N–H str.), 3081 (s), 2968 (s),
D
2930 (s), 1630 (s, C=O str.), 1560 (s, C–N str.), 1450 (s), 1361 (s),1219 (s), 1109 (s), 903 (s), 723, (s),
1
672 (s); H-NMR (DMSO-d6): δ 0.82 (t, 6H, J = 7.24 Hz, CH2CH3), 1.02 (d, 6H, J = 6.8 Hz,
CH(CH3)CH2), 1.37 (m, 4H, CH2CH3), 2.69 (s, 2H, cyclopropyl CH), 3.64 (m, 1H, CH(CH3)CH2),
5.40 (s, 2H, C=CH2), 8.06 (d, 2H, J = 7.76 Hz, NH); 13C-NMR (DMSO-d6): δ 10.96 (CH2CH3), 20.73
(CHCH3), 26.18 (CH2CH3), 29.45 (cyclopropyl CH), 46.57 (CHCH3), 103.88 (C=CH2), 133.16
(C=CH2), 167.78 (NHC=O); Anal. Calcd. for C14H24N2O2 (252.18); C, 66.63; H, 9.59; N, 11.10;
Found: C, 65.95; H, 9.51; N, 10.73; LC/MS (EI+): m/z = 252.2 [M+].
(1S,2S)-N1,N2-isobutyl-3-methylenecyclopropane-1,2-dicarboxamide [(1S,2S)-6c]: Compound (1S,2S)-6c
was obtained as a white solid by treating acid chloride (1S,2S)-4 (3.52 mmol) with 2 eq. of
iso-butylamine according to GP2. Yield 740 mg (2.93 mmol, 83.36%); 226–230 °C, [α]observed − 0.4,
[α]20 − 133, (c, 0.30%, 10% MeOH/CHCl3); IR (cm–1): 3288 (s, sec-N-H str.), 3085 (s), 2950 (s),
D
2917 (s), 1634 (s, C=O str.), 1559 (s, C-N str.), 1330 (s), 1211 (s), 1107 (s), 893 (s), 670 (s); 1H-NMR
(DMSO-d6): δ 0.84 (d, 6H, J = 6.68 Hz, CH(CH3)2), 1.66 (m, 1H, CH(CH3)2), 2.74 (s, 2H, cyclopropyl
13
CH), 2.89 (m, 2H, CH2CH(CH3)2), 5.41 (s, 2H, C=CH2), 8.21 (t, 2H, J = 5.24 Hz, NH); C-NMR
(DMSO-d6): δ 20.1 (CH(CH3)2), 25.6 (CH(CH3)2), 28.0 (cyclopropyl CH), 104.9 (C=CH2), 132.47
(C=CH2), 167.9 (NHC=O); Anal. Calcd. for C14H24N2O2 (252.18); C, 66.63; H, 9.59; N, 11.10; Found:
C, 66.55; H, 9.68; N, 10.93; LC/MS (EI+): m/z = 252.1 [M+].
(1S,2S)-N1,N2-benzyl-3-methylenecyclopropane-1,2-dicarboxamide [(1S,2S)-6d]: Compound (1S,2S)-6d
was obtained as an off white solid by treating acid chloride (1S,2S)-4 (3.52 mmol) with 2 eq. of
benzylamine according to GP2. Yield 944 mg (2.94 mmol, 83.76%); m.p. 232–234 °C, [α]observed − 0.5,
[α]20 − 166, (c, 0.31%, 10% MeOH/CHCl3); IR (cm–1): 3297 (s, sec-N–H str.), 1630 (s, C=O str.),
D
1
1541 (s, C–N str.), 1325 (s), 732 (s), 696 (s); H-NMR (DMSO-d6): δ 2.82 (s, 2H, cyclopropyl CH),
4.28 (d, 4H, J = 5.24 Hz, CH2Ph), 5.48 (s, 2H, C=CH2), 7.24–7.33 (m, 10H), 8.77 (t, 2H, J = 5.12 Hz,
13
NH); C-NMR (DMSO-d6): δ 26.30 (cyclopropyl CH), 43.01 (cyclopropyl CH), 104.47 (C=CH2),
127.4 (C4, aromatic), 127.84 (C2, aromatic), 128.91 (C3, aromatic), 132.60 (C=CH2), 139.73 (C1,
aromatic), 168.53 (NHC=O); Anal. Calcd. for C20H20N2O2 (320.15); C, 74.98; H, 6.29; N, 8.74;
Found: C, 74.74; H, 6.43; N, 8.87; LC/MS (EI+): m/z = 321.15 [M+H+].

Molecules 2012, 17
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4. Conclusions
In conclusion, the synthesis of the new class of C2 symmetric chiral bisamide ligands with high
specific rotation values were carried out. All these ligands were derived from trans-(±)-3-methylene-
cyclopropane-1,2-dicarboxylic acid (Feist’s acid), which served as the key precursor. In order to obtain
the chiral backbone of the ligands, we have resolved trans-(±)-3-methylenecyclopropane-1,2-
dicarboxylic acid in a new modified method, hence (1R,2R)-(+)-3-methylenecyclopropane-1,2-
dicarboxylic acid and (1S,2S)-(−)-3-methylenecyclopropane-1,2-dicarboxylic acid were obtained with
a high degree of enantioselectivity. The applications of these chiral ligands are under investigation and
the results will be reported in the nearest future. On the basis of the chiral Feist’s acid, we are working
to explore a large variety of novel classes of chiral C2 symmetrical bidentate, or tetradentate ligands,
with bulky environments.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/17/5/5550/s1
Acknowledgments
The authors extend their appreciation to the Deanship of Scientific Research at King Saud
University for funding the work through the research group project No. RGP-VPP-044.
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Sample Availability: Samples of the compounds (1R,2R)-3, (1S,2S)-3, 5a–d, 6a–d are available from
the authors.
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).