Isophthalic acid-derived dicarbothioamides as novel metal-free catalysts in hydrogen bond-promoted reactions

Article abstract of DOI:10.1080/00397910902838847

The synthesis of N,N'-diaryl-1,3-benzene-dicarbothioamides was accomplished in only two steps with good yields, and their ability to act as hydrogen-bond donors in Diels-Alder reactions was evaluated. These new organocatalysts were indeed able to promote the cycloaddition of cyclopentadiene to ,-unsaturated aldehydes. In the attempt to control the absolute stereochemistry of the reaction, chiral catalysts were also prepared by simple condensation of isophthalic acid and-amino acid derivatives. Molecular mechanics calculations were performed to elucidate the mode of action of these metal-free catalytic systems and to find a rationale for the achieved enantioselectivity.

Full text of DOI:10.1080/00397910902838847

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Isophthalic Acid–Derived
Dicarbothioamides as Novel
Metal-Free Catalysts in
Hydrogen Bond–Promoted
Reactions
Stefania Guizzetti a , Maurizio Benaglia a ,
Alessandra Puglisi a & Laura Raimondi a
a Department of Organic and Industrial Chemistry,
University of Milan, Milan, Italy
Version of record first published: 08 Sep 2009.
To cite this article: Stefania Guizzetti , Maurizio Benaglia , Alessandra Puglisi &
Laura Raimondi (2009): Isophthalic Acid–Derived Dicarbothioamides as Novel Metal-
Free Catalysts in Hydrogen Bond–Promoted Reactions, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:20,
3731-3742
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Synthetic Communications1, 39: 3731–3742, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902838847
Isophthalic Acid–Derived Dicarbothioamides
as Novel Metal-Free Catalysts in Hydrogen
Bond–Promoted Reactions
Stefania Guizzetti, Maurizio Benaglia,
Alessandra Puglisi, and Laura Raimondi
Department of Organic and Industrial Chemistry,
University of Milan, Milan, Italy
Abstract: The synthesis of N,N0-diaryl-1,3-benzene-dicarbothioamides was
accomplished in only two steps with good yields, and their ability to act as
hydrogen-bond donors in Diels–Alder reactions was evaluated. These new orga-
nocatalysts were indeed able to promote the cycloaddition of cyclopentadiene to
a,b-unsaturated aldehydes. In the attempt to control the absolute stereochemistry
of the reaction, chiral catalysts were also prepared by simple condensation of
isophthalic acid and a-amino acid derivatives. Molecular mechanics calculations
were performed to elucidate the mode of action of these metal-free catalytic
systems and to find a rationale for the achieved enantioselectivity.
Keywords: Carbothioamides, C–C bond formation, cycloaddition, hydrogen
bond, organocatalysis
INTRODUCTION
It has been recently recognized that the use of hydrogen bonding to
activate a properly functionalized substrate may be a viable alternative
to the traditional methodology that relies upon Lewis acid catalysis.[1]
Among different chiral compounds capable of donating one or more
Received December 16, 2008.
Address correspondence to Maurizio Benaglia, Dipartimento di Chimica
`
Organica e Industriale, Universita degli Studi di Milano, via Golgi 19, I-20133
Milan, Italy. E-mail: Maurizio.Benaglia@unimi.it
3731

3732
S. Guizzetti et al.
hydrogen bonds and therefore catalyzing stereoselective reactions,
phosphoric acids,[2] diols,[3] thiourea derivatives[4] and, less often,
carboxylic acids[5] have been widely used. In the last few years, the class
of thiourea catalysts was further expanded through the development of
bifunctional catalytic systems,[6] where the thiourea group is usually
coupled to a chiral Lewis base to realize a greater degree of stereocontrol
over the reaction. If it is clear that thiourea catalysts are an important
class of organocatalysts able to efficiently control the stereochemistry
in several chemical transformations, it is also true that the synthesis of
chiral compounds embedding the thiourea group is not always that
straightforward.
We decided to explore the catalytic ability of a new class of readily
available compounds that are able to act as hydrogen-bond donors in
C–C bond-formation reactions as alternatives to the well-established
thiourea derivatives.
RESULTS AND DISCUSSION
We focused our attention on molecules featuring two carbothioamide
groups, designed to properly orientate two acidic hydrogen atoms in such
a way as to bind a substrate bearing a functional group able to accept
hydrogen bonding, such as an a,b-unsaturated aldehyde.
In this context, derivatives of isophthalic acid of the general structure
shown in Fig. 1 seem especially attractive. In particular, we hoped that
both carbothioamidic hydrogen atoms could be involved in the
H-bonding of the aldehyde, thus providing activation of the latter. To
determine if our working hypothesis was correct, a conformational
analysis with forcefield methods (MM2ꢀ) was performed,[7] by running
molecular mechanics calculations on the complex of N,N0-dimethyl-
1,3-benzene-dicarbothioamide with crotonic aldehyde. Despite our hopes,
Figure 1. General structure of a new class of hydrogen-bond donors in
organocatalysis.

Dicarbothioamides as Metal-Free Catalysts
3733
Figure 2. Molecular mechanics calculations on the complex of N,N0-dimethyl-
1,3-benzene-dicarbothioamide with crotonic aldehyde.
only monocoordination of the aldehydic oxygen was supported by the
calculated data. (The minimum energy conformation of the complex is
shown in Fig. 2.) However, only hydrogen-bonded structures were
located: thus activation of the a,b-unsaturated compounds toward
nucleophylic additions and cycloadditions was likely to be more than a
working hypothesis.
At the beginning of our investigation, we decided to prepare achiral
molecules and to study their ability to promote reactions through
hydrogen-bonding activation of the substrate. The synthesis of these
compounds is straightforward and involves the condensation of
isophthalic acid with an aromatic amine to afford the expected
N,N0-diaryl-1,3-benzene-dicarboxamide, followed by the conversion to
bis-carbothioamide derivative by reaction with Lawesson’s reagent[8]
(Scheme 1).
The reaction of isophthaloyl chloride 1 with 4-methoxyaniline led to
compound 2 in 71% yield, which was converted by reaction with Lawesson’s
reagent in the bis-carbothioamide derivative 3 in 98% yield. Similarly, the
condensation of 1 with 3,5-bis-trifluoromethyl aniline to give bis-carboxy-
amide 4, in 97% yield followed by the transformation of carboxy-amide
groups into carbothioamides, afforded product 5 in 71% yield.
Compounds 3 and 5, bearing aryl groups of different electronic char-
acteristics, were employed to test the cycloaddition of cyclopentadiene
with crotonic aldehyde (Scheme 2). In a typical experiment, aldehyde

3734
S. Guizzetti et al.
Scheme 1. Synthesis of achiral catalysts 3 and 5.
(1 mol. eq.) was added to a stirred solution of the catalyst (0.1 mol. eq.)
in the proper solvent under an inert atmosphere; after 5 min, cyclopenta-
diene (3.5 mol. eq.) was added. The reaction mixture was allowed to stir
at room temperature for 72 h. The reaction mixture was evaporated
under reduced pressure and analyzed by NMR. The yield and diastereoi-
someric ratio were then confirmed on the isolated product, which was
purified by flash chromatography on a short silica-gel column with an
ethylacetate=hexane mixtures as eluant.
The results of the reaction performed in different solvents at room
temperature in the presence of compounds 3 or 5 are collected in
Table 1, together with the data obtained by running the cycloaddition
without catalyst.
Scheme 2. Diels–Alder reaction catalyzed by N,N0-diaryl or dialkyl-1,3-
benzene-dicarbothioamides.

Dicarbothioamides as Metal-Free Catalysts
3735
Table 1. Diels–Alder reaction of cyclopentadiene to crotonic
aldehyde catalyzed by compounds 3 and 5
Yielda
(%)
Exo=endo
ratiob
Entry
Solvent
Catalyst
1
2
3
4
5
6
7
8
9
DCM
DCM
DCM
THF
THF
THF
—
—
3
30
48
37
13
41
37
23
47
51
55=45
58=42
70=30
51=49
55=45
71=29
68=32
62=38
75=25
5
—
3
5
—
3
—
—
5
aDetermined by 1H NMR and confirmed after chromato-
graphic purification after 72 h at 25ꢁC.
bDetermined by 1H NMR and confirmed by HPLC analysis.
From the data of Table 1, it is evident that both compounds 3 and 5
are indeed able to activate the carbonyl compound toward the cycloaddi-
tion with cyclopentadiene through coordination mediated by hydrogen
bonding. The reaction of cyclopentadiene with cinnamaldehyde afforded
the products in lesser yields. Although the reaction without any catalyst
afforded the cycloadduct in very poor yields after 72 h at room tempera-
ture (entries 1, 4, and 7 of Table 1), in the presence of 3 or 5, the product
was isolated constantly in great yields independent of the solvent system.
For example, compound 3 promoted the Diels–Alder reaction in 48%,
41%, and 47% yields in dichloromethane (DCM), in tetrahydrofuran
(THF), and without solvent, respectively (entries 2, 5, and 8 of Table 1).
An analogous behavior also was shown by bis-carbothioamide 5 which
catalyzed the reaction in up to 51% yield with 75=25 endo=exo isomer
ratio at room temperature (entries 3, 6, and 9 of Table 1). The findings
seem to suggest an effective ability of molecules 3 and 5 to bind carbonyl
substrates and activate them in cycloaddition reactions, as was evidenced
by the molecular mechanics preliminary investigations.
Based on these promising results, we decided to prepare a chiral ver-
sion of such new catalytic systems in an attempt to control the absolute
stereochemistry of the reaction. At this preliminary stage of the investiga-
tion, simple a-amino acid derivatives were employed in the condensation
with isophthalic acid (Scheme 3).
The EDC-mediated condensation of isophthalic acid with (S)-phenyl
alanine methylester afforded the expected bis-carboxyamide derivative 7

3736
S. Guizzetti et al.
Scheme 3. Synthesis of chiral catalysts 7–10, 13, and 15.
in 85% yield, which was converted in the bis-carbothioamide derivative 8
in 98% yield by reaction with Lawesson’s reagent. A similar methodology
allowed us to synthesize compounds 9 and 10, in 77% and 83% overall
yields, by reaction with (S)-ter-leucine methylester and (S)-phenyl glycine
methylester, respectively.
These chiral compounds were employed in the cycloaddition between
crotonic aldehyde and cyclopentadiene, and the results of this early
exploration are shown in Table 2.
Bis-carbothioamide derivative 8 promoted the reaction clearly in
greater yield than bis-amide 7, further demonstrating that for this kind
of reaction the more acidic hydrogen atoms of the carbothioamide group
make such compounds better hydrogen-bond donors than amides and
therefore are more efficient catalysts (entries 1 and 2 of Table 2).[9]
Compounds 8, 9, and 10 showed similar chemical efficiency in
promoting the cycloaddition reaction in up to 55% yield and 75=25
endo=exo isomer ratio at room temperature (entries 2–4). However, the
catalysts were not able to exert any control in determining the absolute
stereochemistry of the product. Performing the reaction in different

Dicarbothioamides as Metal-Free Catalysts
3737
Table 2. Cycloaddition of cyclopentadiene to crotonic aldehyde
Temp.
(ꢁC)
Yielda
(%)
Endo=exo
ratiob
Ee endoc
(%)
Entry
Catalyst
1
2
3
4
5
6
7
8
9
7
8
25
25
25
25
25
0
ꢂ40
25
0
19
55
50
43
53
71
33
47
79
63=37
75=25
65=35
62=38
67=33
77=23
75=25
67=33
77=23
n.d.
<5
<5
<5
13
14
19
10
9
9
10
13
13
13
15
15
1
aDetermined by H NMR and confirmed after chromatographic
purification after 72 h without any solvent.
1
bDetermined by H NMR.
cDetermined by GC on chiral stationary phase (Agilent HP-chiral)
tmajor
¼ 59.1 min, tmin
¼ 59.6 min, tmajor
¼ 60.6 min, tmin
exo
exo
endo
¼ 62.2 min.
endo
solvents and at lower temperature did not improve the stereoselectivity of
the cycloaddition.
To improve the enantioselectivity of the process, we decided to use
chiral amino-alcohol derivatives to build new chiral catalysts bearing
two hydroxyl groups, which could help the carbothioamide groups in
coordinating in a more conformational rigid chiral environment in the
substrate to be activated (Scheme 3). Enantiomerically pure (1S,2R)-1,2-
diphenyl-2-amino-1-ethanol 11 was condensed to isophthalic acid via
EDC methodology to afford compound 12 in 44% yield; reaction with
Lawesson’s reagent allowed us to obtain the enantiomerically pure 13
in 91% yield. Analogously, compound 14 was prepared by condensation
between isophthalic acid and (1R,2S)-nor-ephedrine in 71% yield, which
was then transformed into the derivative 15 in 97% yield after chromato-
graphic purification. Both 13 and 15 were then used as organocatalysts in
the Diels–Alder reaction (Table 2).
Both compounds 13 and 15 showed good chemical efficiency at room
temperature (entries 5 and 8 of Table 2) and even better efficiency at 0ꢁC,
leading to the cycloadduct 6 in 71% and 79% yield, respectively (entries 6
and 9 of Table 2). The product was obtained with a good endo=exo isomer
ratio, up to 77=23 (entries 6 and 9), but once again with a low level of enan-
tioselectivity (best result: 19% ee for the endo isomer with catalyst 13; entry
6 of Table 2). A further decrease of the temperature did not bring any
improvement on the enantioselectivity of the reaction (entry 7, Table 2).

3738
S. Guizzetti et al.
Figure 3. Molecular mechanics calculations on the complexes of catalysts 13 with
crotonic aldehyde.
A tentative rationale for the disappointing stereochemical outcome
of the reaction was attempted by performing molecular mechanics calcu-
lations on the complexes of catalysts 13 and 15 with crotonic aldehyde.
See Figure 3. From complete conformational analysis of both complexes,
it appeared that in this case carbothioamidic hydrogens were not
involved in the interaction with the aldehyde, and hydrogen bonding with
one of the hydroxylic hydrogens was preferred by at least 2.6 kcal=mol (in
the adduct 13 þ crotonic aldehyde).
CONCLUSIONS
In conclusion, the synthesis of N,N0-diaryl-1,3-benzene-dicarbothioamides
was accomplished in only two steps with good yields, and their ability to
act as hydrogen-bond donors in Diels–Alder reactions was evaluated.
These new organocatalysts were indeed able to promote the cycloaddition
of cyclopentadiene to a,b-unsaturated aldehydes, in up to 79% yield and
77=23 endo=exo isomer ratio. In an attempt to control the absolute stereo-
chemistry of the reaction, chiral catalysts were also prepared by simple
condensation of isophthalic acid with enantiomerically pure a-amino ester
and a-amino alcohol derivatives, which showed a poor ability in deter-
mining the absolute stereochemistry of the reaction. Further work is in

Dicarbothioamides as Metal-Free Catalysts
3739
progress to improve the chemical and especially the stereochemical
efficiency of these novel metal-free catalysts.
EXPERIMENTAL
General
1H NMR spectra were recorded at 300 MHz in chloroform-d (CDCl3)
unless otherwise stated, and were referenced to tetramethylsilane
(TMS) at 0.00 ppm. 13C NMR spectra were recorded at 75 MHz and were
referenced to 77.0 ppm in CDCl3. Optical rotations were obtained on a
Perkin-Elmer 241 polarimeter at 589 nm. Infrared (IR) spectra were
obtained on a Jasco Fourier transform (FT)-IR 4100 type A instrument.
Gas chromotography (GC) for ee determination was performed on an
Agilent HP-chiral instrument under the conditions reported.
Reagents and solvents were used as purchased.
General Procedure for the Synthesis of Achiral Catalysts 3 and 5
Catalyst 3
Isophthalic acid (0.15 g, 0.9 mmol) was refluxed for 20 h in 2 mL of
thionyl chloride; then the solution was evaporated under vacuum. The
residue was dissolved in dry CHCl3 (2 mL) and added to a solution of
4-methoxyaniline (0.25 g, 2 mmol) and triethylamine (0.38 mL, 2.7 mmol)
in dry CHCl3 (10 mL). After 70 h of reaction at 40ꢁC, the solvent was
evaporated, and the crude reaction mixture was purified by flash chroma-
tography with a 99:1 DCM=methanol mixture as eluant to afford
compound 2 as a white solid in 71% yield, whcih was used in the next step
(0.24 g, 0.63 mmol). Lawesson’s reagent [2,4-bis(4-methoxyphenyl)-
1,3-dithia-2,4-diphosphetane-2,4-disulfide] was added (0.28 g, 0.69 mmol)
to a solution of compound 2 (0.17 g, 0.46 mmol) in dry toluene (7 mL); the
solution was allowed to stir under reflux for 20 h, concentrated, and pur-
ified by flash chromatography 95:5 DCM=methanol mixture as eluant to
afford compound 3 as yellow solid in 98% yield (0.18 g, 0.45 mmol). Com-
pound 3: IR (neat): n 1225, 1177 cmꢂ1. Mp 67–69ꢁC. 1H NMR (DMSO)
d 3.8 (s, 6 H, OMe); 7.00 (d, 4H, 9.0 Hz, HA of OMe–Ph); 7.51 (t, 1H,
J ¼ 8.0 Hz), 7.70 (d, 4H, 9.0 Hz, HB of OMe–Ph); 7.80 (d, 2H,
J ¼ 8.0 Hz), 8.21 (s, 1H), 11.80 (bs, 2H, NH). 13C NMR (CDCl3): d
37.2, 118.6, 120.1, 123.4, 127.1, 127.7, 129.1, 135.9, 141.9, 171.1, 196.1.
Elem. anal. found: C, 64.61; H, 4.91; N, 6.89. C22H20N2O2S2 requires:

3740
S. Guizzetti et al.
C, 64.68; H, 4.93; N, 6.86. Following the same procedure, compound 5
was synthesized.
Compound 5
1
IR (neat): n 1215, 1187 cmꢂ1. Mp 79–81ꢁC. H NMR (DMSO): d 7.55
(t, 1 H, J ¼ 12.0 Hz), 8.00 (d, 2H, J ¼ 12.0 Hz), 8.03 (s, 2H), 8.23
(s, 1H), 8.70 (s, 4H), 11.50 (bs, 2H, NH). 13C NMR (CDCl3): d 39.5,
119.3, 124.0, 124.8, 128.1, 129.7, 130.1, 141.4, 142.0, 198.1. Elem. anal.
found: C, 46.39; H,1.91; N, 4.55. C24H12F12N2S2 requires: C, 46.46; H,
1.95; N, 4.51.
General Procedure for the Synthesis of Chiral Catalysts 7–10, 13, and 15
Representative Synthetic Sequence for the Preparation of Catalyst 8
Under a nitrogen atmosphere, a solution of 1-(3-dimethylaminopropyl)-
3-ethylcarbodiimide, EDC (0.21 g, 1.1 mmol), and 1-hydroxybenzo-
triazole (HOBT) (0.14 g, 1.1 mmol) in chloroform (5 mL) was added
to a mixture of (S)-phenyl alanine methylester hydrochloride (0.21 g,
1.0 mmol) and isophtalic acid (0.08 g, 0.5 mmol) in chloroform (5 mL)
at 0ꢁC. After the reaction mixture was allowed to stir for 20 h at 25ꢁC,
it was poured into a 1 N HCl solution (10 mL). The phases were sepa-
rated, and the organic phase was washed with a saturated NaHCO3
solution and a saturated NaCl solution. The organic phase was dried over
Na2SO4, filtered, and concentrated under vacuum to afford the crude
product 7, which was used without any further purification (0.21 g,
0.42 mmol, 85% yield).
To a solution of compound 7 (0.1 g, 0.2 mmol) in dry toluene
(5 mL), Lawesson’s reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,
4-diphosphetane-2,4-disulfide] was added (0.08 g, 0.2 mmol); the solution
was allowed to stir under reflux for 20 h. Then it was concentrated and
purified by flash chromatography with a 20:80 AcOEt–hexane mixture
as eluant to afford compound 8 as yellow solid (0.1 g, 0.19 mmol). IR
(neat): n 3369, 1738, 1633, 1590, 1509, 1205 cmꢂ1. ½aꢃD23 260.9 (c 0.69,
1
DCM). Mp 81–83ꢁC. H NMR (CDCl3): d 3.31 (dd, 2H, J ¼ 5.0 Hz,
14.0 Hz, HA of CH2Ph), 3.60 (dd, 2H, J ¼ 6.0 Hz, 14.0 Hz, HB of CH2Ph),
3.85 (s, 6H, MeO), 5.61 (m, 2H, CH–N), 7.18 (4H, aromatic
protons), 7.35 (8 H, aromatic protons), 7.85 (2 H, aromatic protons),
8.08 (2H, NH), 13C NMR (CDCl3): d 36.2, 52.6, 59.1, 123.6, 125.1,
127.4, 128.1, 128.7, 129.2, 135.3, 141.4, 171.1, 197.4. Elem. anal.

Dicarbothioamides as Metal-Free Catalysts
3741
found: C, 64.64; H, 5.45; N, 5.36. C28H28N2O4S2 requires: C, 64.59; H,
5.42; N, 5.38.
Following the same procedure, catalysts 13 and 15 were also
prepared.
Compound 13
IR (neat): n 3519, 1204, 1122 cmꢂ1. ½aꢃD23 60.1 (c 0.11, CHCl3). Mp
288–289ꢁC. 1H NMR (CDCl3): d 3.9 (bs, 2 H, OH), 5.0 (dd, 2H,
J ¼ 6.0 Hz, 8 Hz, CH–N), 5.9 (d, 2 H, J ¼ 8.0 Hz, CH–O), 7.0 (bs, 2H,
NH), 7.18–7.30 (m, 21H, aromatic protons of phenyl rings þ1H of
central phenyl ring), 7.57 (t, 1H, J ¼ 5.0 Hz), 8.00 (d, 2H, J 5.0 Hz).
13C NMR (CDCl3): d 71.7, 81.6, 125.9, 126.6, 126.9, 127.5, 127.9,
128.2, 128.5, 128.9, 131.7, 132.0, 133.6, 141.7, 169.7. Elem. anal.
found: C, 73.41; H, 5.47; N, 4.79. C36H32N2O2S2 requires: C, 73.44; H,
5.48; N, 4.76.
Compound 15
1
IR (neat): n 3052, 1265, 1193 cmꢂ1. ½aꢃD23 ꢂ142.9 (c 0.12, CHCl3). H
NMR (CDCl3): d 1.55 (d, 6H, J ¼ 4.0 Hz, methyl groups), 3.8 (bs, 2H,
OH), 4.70 (d, 2H, J ¼ 6.0 Hz, CH–N), 4.85 (d, 2 H, J ¼ 6.0 Hz, CH–O),
7.18–7.30 (m, 21 H, aromatic protons of phenyl rings þ1H of central phe-
nyl ring), 7.47 (t, 1 H, J ¼ 4.0 Hz), 8.05 (d, 2 H, J ¼ 4.0 Hz), 8.30 (bs, 2H,
NH). 13C NMR (CDCl3): d 20.1, 61.9, 81.0, 126.3, 127.5, 127.9, 128.4,
128.9, 131.2, 133.6, 141.1, 165.4. Elem. anal. found: C, 67.31; H, 6.11;
N, 5.99. C26H28N2O2S2 requires: C, 67.21; H, 6.07; N, 6.03.
Conformational Analysis of Complexes Between Bis-carbothioamides
and Crotonic Aldehyde
The conformational analyses were performed on the complexes with the
MonteCarlo pseudo-systematic algorithm[10] as implemented in Macro-
Model 7.2 package.[7] As variables, all free torsional angles were selected,
while aldehyde was allowed translation and rotation with respect to the
catalyst. Duplicate conformations were eliminated, and convergence of
the search was considered as achieved when all low-energy conformations
(within 3 kcal=mol) were repeatedly sampled. Allinger’s forcefield as imple-
mented in MacroModel 7.2 package was used for all calculations because
of its proven reliability in the treatment of small organic molecules.

3742
S. Guizzetti et al.
ACKNOWLEDGMENTS
`
This work was supported by Ministero Istruzione, Universita e Ricerca
(MIUR) (Rome) within the national project ‘‘Nuovi metodi catalitici
stereoselettivi e sintesi stereoselettiva di molecole funzionali.’’
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