Click mechanochemistry: Quantitative synthesis of "ready to use" chiral organocatalysts by efficient two-fold thiourea coupling to vicinal diamines

Article abstract of DOI:10.1002/chem.201200632

Mechanochemical methods of neat grinding and liquid-assisted grinding have been applied to the synthesis of mono- and bis(thiourea)s by using the click coupling of aromatic and aliphatic diamines with aromatic isothiocyanates. The ability to modify the re

Full text of DOI:10.1002/chem.201200632

DOI: 10.1002/chem.201200632
Click Mechanochemistry: Quantitative Synthesis of “Ready to Use” Chiral
Organocatalysts by Efficient Two-Fold Thiourea Coupling to Vicinal
Diamines
[a]
[a]
[a]
[b]
ˇ
Vjekoslav Strukil, Marina D. Igrc, Mirjana Eckert-Maksic´,* and Tomislav Frisˇcˇic´*
Abstract: Mechanochemical methods
of neat grinding and liquid-assisted
grinding have been applied to the syn-
reactions, we also show that the de-
scribed mechanochemical reaction pro-
cedures can be readily scaled up to at
least the one-gram scale. In that way,
mechanochemical synthesis provides
a facile method to fully transform val-
uable enantiomerically pure reagents
into useful products that can immedi-
ately be applied in their designed pur-
pose. This was demonstrated by using
some of the mechanochemically pre-
pared reagents as organocatalysts in
a model Morita–Baylis–Hillman reac-
tion and as cyanide ion sensors in or-
ganic solvents. The use of electronically
and sterically hindered ortho-phenyle-
nediamine revealed that mechano-
chemical reaction conditions can be
readily optimized to form either the 1:1
or the 1:2 click-coupling product, dem-
onstrating that reaction stoichiometry
can be more efficiently controlled
under these conditions than in solu-
tion-based syntheses. In this way, it was
shown that excellent stoichiometric
control by mechanochemistry, previ-
ously established for mechanochemical
syntheses of cocrystals and coordina-
tion polymers, can also be achieved in
the context of covalent-bond forma-
tion.
thesis of mono- and bisACTHUNTGRNEUNG(thiourea)s by
using the click coupling of aromatic
and aliphatic diamines with aromatic
isothiocyanates. The ability to modify
the reaction conditions allowed the op-
timization of each reaction, leading to
the quantitative formation of chiral bis-
ACHTUNGTRENNUNG(thiourea)s with known uses as organo-
catalysts or anion sensors. Quantitative
reaction yields, combined with the fact
that mechanochemical reaction condi-
tions avoid the use of bulk solvents, en-
abled solution-based purification meth-
ods (such as chromatography or recrys-
tallization) to be completely avoided.
Importantly, by using selected model
Keywords: click chemistry · green
chemistry
· mechanochemistry ·
milling · reaction efficiency · sol-
vent-free reactions
Introduction
ceed in a straightforward and clean fashion. In such cases, it
is possible to obtain the desired product in high purity and
quantitative yield. Milling mechanochemistry is environmen-
tally benign[10] as chemical transformations can be very ef-
fectively performed either under completely solvent-free
conditions, or facilitated and directed by a catalytic amount
of a liquid phase (liquid-assisted grinding, LAG, also known
as solvent-drop grinding).[11] Recent critical studies have es-
tablished mechanochemistry to be the environmentally
friendly tool of organic synthesis that combines high reac-
tion efficiency with minimal input of energy and solvent.
Mechanosynthesis has improved a variety of carbon–carbon
bond-forming reactions, including Suzuki–Miyaura, Heck,
and Sonogashira couplings, aldol reactions, cycloadditions,
and heterocycle synthesis.[10b,12–16]
Mechanochemical[1] grinding or milling is rapidly becoming
a method of choice in different areas of chemical and mate-
rials synthesis. To date, the applications of mechanochemical
milling have included the crystal engineering of organic
solids with pharmaceutical,[2] luminescent,[3] and photo- or
thermoactive properties,[4] studies of biomolecular recogni-
tion,[5] the synthesis of supramolecular, coordination, and co-
valent cages,[6] interlocked systems,[7] coordination polymers,
and metal–organic frameworks,[8] asymmetric catalysis, and
deracemization.[9] There can be many benefits of mechano-
chemical milling in chemical synthesis if the reactions pro-
ˇ
´
[a] Dr. V. Strukil, Dipl.-Ing. M. D. Igrc, Dr. M. Eckert-Maksic
We recognized the laboratory-scale transformations of
chiral reagents to be an important, but unexplored field that
could benefit from the efficiency of mechanochemical mill-
ing. In particular, we now address the laboratory-scale syn-
thesis of modern organocatalysts, which often requires rare
reagents the availability of which in a typical laboratory en-
vironment is limited by their cost, and the conversion of
which necessitates the highest synthetic efficiency. We dem-
onstrate the use of LAG mechanosynthesis to synthesize bi-
functional chiral thiourea catalysts in >99% isolated yield.
Division of Organic Chemistry and Biochemistry
ˇ
´
Ruder Boskovic Institute
¯
ˇ
Bijenicka cesta 54, HR-10002 Zagreb (Croatia)
E-mail: mmaksic@emma.irb.hr
ˇˇ ´
[b] Dr. T. Friscic
Department of Chemistry, McGill University
801 Sherbrooke St., H3A 2K6 Montrꢀal, Quꢀbec (Canada)
Fax : (+1)514-398-3757
E-mail: tomislav.friscic@mcgill.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200632.
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FULL PAPER
These bis
(thiourea)s have been used as catalysts in many
nochemical thiourea synthesis to more complex molecules,
as well as optimizing the reaction yields to provide products
in high purity. These products could be immediately used
for the intended applications without resorting to conven-
tional laboratory purification techniques (e.g., chromatogra-
phy, flash chromatography, recrystallization) that are both
wasteful of solvent[21] and severely limit the isolated product
yield in laboratory syntheses.[23]
We now demonstrate that the application of LAG in an
automated mill enables the expansion of the mechanochemi-
cal click coupling of organic amines and isothiocyanates to
sterically and electronically hindered amines and diamines
important reactions, notably the Morita–Baylis–Hillman re-
action, the acetalization of aldehydes and ketones, and the
Friedel–Crafts alkylation.[17] As well as their use as organo-
catalysts, thioureas have found applications as anion sensors
and transporters.[18]
As a model reaction, we used the coupling of organic iso-
thiocyanates and amines, a known click reaction in solu-
tion.[19] The application of milling to conduct click reactions
was very recently reported by Stolle and co-workers, who
performed the popular coupling of organic azides and acety-
lenes in this manner. Their work provided excellent yields,
albeit in the presence of inert additives to counter the
shock-sensitive nature of organic azides.[20] We find thiourea
coupling to be particularly suitable to mechanochemistry be-
cause it avoids shock-sensitive reagents and, therefore, does
not require sample dilution. For this study, we were encour-
aged by the literature precedent by Kaupp et al.[21a] on the
synthesis of N-methyl-N’-aryl thioureas by milling methyl-
to provide well-known achiral (compounds
1 and 2,
Scheme 1) and chiral catalysts (compounds 3–6, Scheme 1).
These products are mechanochemically obtained in quanti-
tative[24] isolated yields, making them immediately applica-
ble for organocatalytic or anion-binding studies. Whereas
most of our initial study is conducted with only the amounts
of expensive reagents that would typically be available in
a research laboratory, we also demonstrate the applicability
of the synthesis on a one-gram scale without loss of isolated
yield. We also show a superior ability of milling synthesis
relative to synthesis in solution to control reaction stoichi-
ometry. In particular, we show the selective synthesis of the
ACHTUNGTRENNUNG
co-workers, who conducted the mechanosynthesis of simple
aromatic thioureas by using a mortar and pestle.[21b] The
high yields that were obtained through such a simple meth-
odology led us to speculate that
an automated milling approach,
in which reaction parameters
can be readily controlled and
optimized, would allow these
syntheses to be carried out in
a fast and reproducible fashion.
The introduction of the LAG
methodology, which is conduct-
ed in a mechanical mill and uti-
lizes substoichiometric amounts
of a liquid phase to enhance
and direct mechanochemical re-
actions, provides an opportunity
to modify the mechanochemical
reaction environment in a simi-
lar way to changing the solvent
in traditional organic synthesis.
Thus, in addition to the reaction
time, milling frequency, and
impact force (controlled in ball
milling by varying the number
and size of milling balls), LAG
provides an opportunity to im-
prove and control reactivity
either by switching between dif-
ferent liquid phases, or by vary-
ing h,[22] that is, the ratio of the
added liquid phase (in mL) to
the weight of the reactant mix-
ture (in mg). We expected that
LAG would enable us to
Scheme 1. a) Achiral and b) chiral organocatalysts and c) symmetrical and nonsymmetrical thioureas prepared
expand the scope of the mecha- by mechanochemical neat grinding or LAG.
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T. Friscic, M. Eckert-Maksic et al.
non-symmetrical mono- and symmetrical bisACTHNURTGNEU(GN thiourea)s 7
and 8, respectively, simply by milling the reactants in the
correct stoichiometric ratio (Scheme 1).
Results and Discussion
Monothiourea targets derived from aniline derivatives: The
first targets in our study were symmetrical N,N’-bis
ACHTUNGTRENN[UNG 3,5-bis-
ACHTUNGTRENNUNG
[3,5-bis(trifluoromethyl)phenyl]-N’-[4-chlorophenyl]thiourea
(2). The LAG reaction of 3,5-bis(trifluoromethyl)phenyl iso-
thiocyanate with 3,5-bis(trifluoromethyl)aniline in a 1:1
ratio by using methanol (MeOH) as the grinding liquid,
quantitatively[24] yielded 1 (Table 1). The complete forma-
Table 1. Optimized mechanochemical syntheses of thiourea-based orga-
nocatalysts by neat grinding (NG) and LAG by using MeOH in a ball
mill. Literature yields are given in brackets.
Product
Reactant state
Method[b]
Yield[c]
[%]
of aggregation[a]
1
2
3
4
5
6
7
8
9
10
11
12
13
1
1
2
liquid/liquid
liquid/liquid
liquid/solid
liquid/solid
liquid/solid
liquid/solid
liquid/solid
solid/solid
LAG[d]
LAG (1 g scale)
LAG
>99 (84)[17b]
Figure 1. FTIR spectra of the reactant isothiocyanate (top) and the (un)-
symmetrical thiourea catalysts 1 (middle) and 2 (bottom) immediately
after milling. The absence of the isothiocyanate absorption band between
2000 and 2200 cmÀ1 is notable, indicating the complete conversion of the
isothiocyanate reactant.
98[e]
>99
A
NG/LAG
NG (1 g scale)
NG/LAG
NG/LAG
NG/LAG
NG/LAG
LAG[f]
>99 (94)[17a]
ACHTUNGTRENNUNG
98[e]
N
>99
N
>99 (81)[29]
>99 (89)[18b]
>99
ACHTUNGTRENNUNG
T
solid/solid
nate reactant was readily verified by the absence of the
characteristic isothiocyanate stretching band in the spectrum
of the mechanochemical product (Figure 1).
(R)-6
liquid/solid
liquid/solid
liquid/solid
liquid/solid
>99 (85)[17f]
99[h]
7
8
8
NG[d]
LAG[g]
>99
LAG (1 g scale)
99[i]
BisACHTNUTRGNEUNG(thiourea) targets derived from ortho-phenylenediamine
[a] Isothiocyanate/(di)amine at standard temperature and pressure.
[b] 20 min of ball milling by using one 12 mm diameter stainless-steel
ball. [c] Based on 1H NMR spectroscopy and HPLC. [d] 30 min grinding.
[e] 180 min grinding, isolated yield. [f] 60 min grinding. [g] 180 min grind-
ing. [h] 10 mol% excess of ortho-phenylenediamine was used, isolated
yield after chromatography. [i] 9 h grinding, isolated yield.
and 1,1’-binaphtyl-2,2’-diamine: Stoichiometric control in co-
valent mechanosynthesis: Following the successful synthesis
of diarylmonothioureas 1 and 2, we explored the formation
of bis
ACHTUNGTREN(NGNU thiourea)s based on symmetrical ortho-phenylenedi-
AHCTUNGTREGaNNUN mine and asymmetrical (R)-1,1’-binaphtyl-2,2’-diamine. The
click coupling reaction of these diamines with isothiocya-
nates is expected to be particularly hindered by steric fac-
tors. Whereas the binaphthyl-based target (R)-6 is attractive
because of its established use as an asymmetric organocata-
lyst, we were also tempted to explore the mechanochemical
reaction of ortho-phenylenediamine with phenylisothiocya-
nate. In particular, the inverted mechanochemical reaction
by grinding of benzene-1,2-bis(isothiocyanate) with aniline
has previously been explored,[23a] and resulted in the forma-
tion of an unstable isothiocyanate-substituted monothiourea
intermediate that underwent an intramolecular cyclization
to form a benzimidazole thione (Scheme 2a).
tion of 1 and the absence of starting materials in the mecha-
nochemically prepared sample was confirmed spectroscopi-
1
cally by using H and 13C NMR and Fourier-transform infra-
red (FTIR) spectroscopy (Figure 1).
Recording the FTIR spectrum of the solid immediately
after the reaction ensured that the observed quantitative
transformations are not an artifact of sample preparation
for NMR or HPLC analysis. Quantitative conversion of the
reactant isothiocyanate was readily noted by the disappear-
ance of the characteristic isothiocyanate stretching band be-
tween 2000 and 2200 cmÀ1. Furthermore, reflections in the
powder X-ray diffraction (PXRD) pattern of mechanochem-
ically prepared 1 coincided with those expected for the pre-
viously reported crystal structure.[17b,25]
We speculated that by using a 1,2-diamine instead of
a 1,2-bis(isothiocyanate) as the reaction locus we could
avoid the intramolecular cyclization and enable the synthesis
Similarly, the nonsymmetrical organocatalyst 2[26] was pre-
pared by a mechanochemical LAG coupling of 3,5-bis(tri-
fluoromethyl)phenyl isothiocyanate with 4-chloroaniline in
>99% yield (Table 1). Again, the absence of the isothiocya-
of the nonchiral sterically congested bisACTHNGUTERNNUG
(thiourea) 8[18c]
through the stable intermediate 7 (Scheme 2b). Indeed,
milling of ortho-phenylenediamine and phenyl isothiocya-
nate in a 1:2 ratio gave the bisACTHNUTRGNEUGN(thiourea) 8 in quantitative
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Click Mechanochemistry
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Scheme 2. a) Mechanochemical coupling of a vicinal isothiocyanate with an aniline via a reactive monothiourea intermediate; b) intermolecular mecha-
nochemical coupling of a vicinal diamine and an aromatic isothiocyanate via a stable monothiourea intermediate 7; and c) mechanochemical coupling of
1,1’-binaphtyl-2,2’-diamine and 3,5-bis(trifluoromethyl)phenyl isothiocyanate via a stable monothiourea compound (R)-9.
yield within 3 h after exploring different mechanochemical
reaction conditions (grinding liquid, time). Although the
quantitative disappearance of the isothiocyanate reactant
was verified through FTIR spectroscopy of the reaction mix-
ture immediately after grinding (Figure 2), the 1H NMR
spectra (Figure 3) revealed that the product was pure com-
pound 8.
1
However, H NMR spectroscopy (Figure 3) also revealed
that with mechanochemical milling times of less than an
hour the reaction mixture contained a significant amount of
the intermediate amino-substituted monothiourea 7 (Fig-
ure 3d). Consequently, we decided to explore whether mon-
othiourea 7 could be selectively synthesized in a mechano-
chemical process. Indeed, milling of ortho-phenylenediamine
with phenyl isothiocyanate in a 1:1 ratio led to clean forma-
tion of monothiourea 7 in >95% yield (Figure 4), as estab-
lished by HPLC. The yield of 7 could be further improved
by using a slight excess (10 mol%) of the diamine reactant,
leading to an overall isolated yield of 99% following milling
and brief washing with ethyl acetate to remove the excess
diamine.
The ability to synthesize and isolate both 7 and 8 in excel-
lent yields without using a large excess of the starting mate-
rials is in stark contrast with solution-based syntheses. Spe-
cifically, we have conducted the reaction of ortho-phenyle-
nediamine and phenylisothiocyanate in ratios of 1:1 and 1:2
Figure 2. Optimization of the LAG synthesis (12 mm ball, methanol, h=
by using conventional solution-based techniques. The 1:1 re-
0.25 mLmgÀ1) of the ortho-phenylenediamine bis
ACTHNUTRGNEUNG(thiourea) 8 monitored
action yielded a solid product, the weight of which amount-
ed to 81% of the weight of the starting materials. Analysis
by 1H NMR spectroscopy revealed that the product was
by FTIR spectroscopy after a) 30, b) 90, and c) 180 min. The isothiocya-
nate absorption band between 2000 and 2200 cmÀ1 is still present after
30 min grinding.
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T. Friscic, M. Eckert-Maksic et al.
Figure 4. Optimization of the reaction conditions in the mechanosynthesis
of the ortho-phenylenediamine monothiourea 7 monitored by 1H NMR
spectroscopy (samples were taken directly from the reaction jar and dis-
solved in [D6]DMSO). a) NG, 30 min, 2ꢂ6 mm balls; b) NG, 30 min,
8 mm ball; c) NG, 30 min, 12 mm ball, 10 mol% excess of ortho-phenyle-
nediamine; and d) a solution-based synthesis in dichloromethane at room
temperature. Compound 7 corresponds to the monothiourea, 8 to the bis-
AHCTUNGTREG(NNNU thiourea), and PDA to unreacted ortho-phenylenediamine.
try was previously observed in the contexts of hydrogen-
and halogen-bonded cocrystals, as well as coordination poly-
mers, the syntheses of 7 and 8 indicates that a similar level
of control is also possible for covalent-bond-forming reac-
tions, at least in cases in which the second reaction step is
significantly more sterically hindered than the first.
Similar observations were made in the mechanosynthesis
of the binaphthyl-based bisACHTNUTRGNE(NUG thiourea) 6, the (R)-enantiomer
Figure 3. Optimization of the reaction conditions in the mechanosynthesis
of the ortho-phenylenediamine bis
(thiourea) 8 monitored by 1H NMR
of which was recently used in the asymmetric catalysis of
the Henry reaction,[17f] and the (S)-enantiomer of which has
been reported as an organocatalyst in the Friedel–Crafts al-
kylation.[17e] Neat grinding of (R)-1,1’-binaphtyl-2,2’-diamine
and 3,5-bis(trifluoromethyl)phenyl isothiocyanate in a 1:2
ratio for 10 min resulted in a mixture of the starting materi-
als, the non-symmetrical monothiourea (R)-9, and the de-
AHCTUNGTRENNUNG
spectroscopy (samples were taken directly from the reaction jar and dis-
solved in [D6]DMSO). a) ortho-Phenylenediamine; b) phenyl isothiocya-
nate; c) a solution-based synthesis in dichloromethane at room tempera-
ture; d) NG, 30 min, 12 mm ball; e) LAG (methanol, h=0.25 mLmgÀ1),
90 min, 12 mm ball; f) LAG (methanol, h=0.40 mLmgÀ1), 90 min, 12 mm
ball; g) LAG (methanol, h=0.25 mLmgÀ1), 180 min, 12 mm ball; and
h) LAG (methanol, h=0.33 mLmgÀ1), 180 min, 12 mm ball. Compound 7
sired bisACTHNUTRGENUG(N thiourea) (R)-6 (Scheme 2c and Figure S29 in the
corresponds to the monothiourea and 8 to the bisACHTNUTRGNE(UNG thiourea).
Supporting Information). However, LAG by using MeOH
as the grinding liquid (h=0.25 mLmgÀ1)[22] drastically im-
proved the conversion to the final product leaving behind
only a small amount of monothiourea intermediate (R)-9
(ꢀ5–6 mol%). As one of the reactants is a liquid, this im-
provement in mechanochemical reactivity by LAG cannot
be ascribed solely to improved molecular diffusion, but is
more likely a result of the modification in the chemical envi-
ronment. A similar effect of the grinding liquid in a mecha-
nochemical system that already involves a liquid reactant
has previously been reported for the synthesis of three-com-
ponent cocrystals.[11a]
a 29:1 mixture of monothiourea 7 and bisACHTNUTRGNEUNG(thiourea) 8, re-
spectively (Figure 4d). The 1:2 reaction yielded a solid prod-
uct, the weight of which was 60% of the total starting mate-
1
rial weight. H NMR analysis revealed that the product was
a mixture of 7 and 8 in a ratio of 7:1, respectively (Fig-
ure 3c).
The comparison of solution and mechanochemical experi-
ments strongly indicates the superior ability of mechano-
chemistry to control the stoichiometric composition of the
product. Although excellent control of product stoichiome-
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For the quantitative synthesis of (R)-6, however, we ex-
plored a variety of further reaction conditions and estab-
lished that (R)-6 was obtained in >99% purity (based on
HPLC) after 60 min of LAG (MeOH as the grinding liquid,
h=0.4 mLmgÀ1). In contrast to the reactions involving
ortho-phenylenediamine, the intermediate urea (R)-9 was
not obtained in high purity by conducting the mechano-
chemical reaction in a 1:1 ratio. A significant amount of bis-
proved rate of product formation in comparison with reac-
tions involving aniline derivatives is consistent with a signifi-
cantly more activated electron pair on the amine moieties.
The facile reaction between 3,5-bis(trifluoromethyl)phenyl
isothiocyanate and 1,2-diaminocyclohexane was also ob-
1
served in solution, as demonstrated by the H NMR spec-
trum of a mixture of the diamine and the isothiocyanate in
[D6]DMSO (see Figure S28 in the Supporting Information).
Consequently, to confirm that the high reaction yields are
truly the result of mechanochemical grinding, rather than an
artifact of solution-based preparation of samples for HPLC
or NMR analysis, we analyzed each mechanochemical prod-
uct by FTIR immediately after grinding. The disappearance
of the isothiocyanate stretching band at 2200 cmÀ1 indicated
the full conversion of the reactants. The analysis of the me-
chanochemical products by PXRD revealed significant dif-
ferences in sample crystallinity depending on the mechano-
chemical method. In particular, the product obtained by
neat grinding for 20 min exhibited a PXRD pattern with
broad features, indicating poor product crystallinity and/or
highly amorphous content. Crystallinity was improved, how-
ever, in cases in which the mechanochemical synthesis was
conducted by LAG with MeOH. Such outcomes are consis-
tent with previous analyses of amorphous/crystalline content
in molecular cocrystals obtained by neat or liquid-assisted
grinding methods.[27] The mechanochemical synthesis of the
ACHTUNGTRENNUNG(thiourea) (R)-6 was always present, which we ascribe to
a more activated isothiocyanate reactant and the reduced
steric hindrance on the 1,1’-binaphtyl core.
Chiral bis
ACHTUNGTRENNUNG
nal diamines: Our next targets were the chiral bisAHCTUNGTRENNUNG
organocatalysts 3–5 (Scheme 1b), in which the two thiourea
moieties reside on an asymmetrical (1R,2R)- or (1S,2S)-1,2-
diaminocyclohexane (3 and 5) or (1R,2R)-1,2-diphenylethy-
lene (4) backbone. Neat grinding of a 2:1 mixture of 3,5-
bis(trifluoromethyl)phenyl isothiocyanate and (1R,2R)- or
(1S,2S)-diaminocyclohexane for 20 min afforded enantio-
merically pure ACHTUNGTRENNUNG ACHTUGNTREN(NUGN 1S,2S)-3, respectively, in
(1R,2R)-3[17a] and
quantitative yield, as shown by FTIR analysis (Figure 5) im-
mediately after milling and by HPLC (Table 1). The im-
organocatalyst ACTHNUTRGNEUNG(1R,2R)-3 was also readily scaled up to 1 g
amounts without a noticeable loss in the isolated yield
(Table 1).
The mechanochemical coupling of 3,5-bis(trifluorome-
thyl)phenyl isothiocyanate with (1R,2R)-1,2-diphenyl-1,2-di-
aminoethane by neat grinding or LAG quantitatively gave
the catalyst ACTHNUTRGNEUNG
(1R,2R)-4.[17a,28] (Table 1). The complete disap-
pearance of the isothiocyanate reactant was confirmed by
FTIR spectroscopy. Again, PXRD indicated that the neat
grinding product is poorly crystalline, whereas LAG afford-
ed a crystalline material. Differential scanning calorimetry
(DSC) analysis of the neat grinding product revealed an
exothermic event at 1068C, followed by endothermic events
above 1858C. The exothermic event is consistent with the
transition from an amorphous to a crystalline phase, where-
as the endothermic peaks are assigned to melting or decom-
position of the compound.[17a,28] Such conjecture is supported
by subsequent PXRD measurements that show significant
improvement in the crystallinity of the sample after the
1068C exotherm, as well as by the DSC analysis of the LAG
product, which displayed only the endotherms at 1858C (see
the Supporting Information).
Our next targets were the bis(para-nitrophenyl) deriva-
tives ACHTNUTRGENNUG(1R,2R)-5 and ACHTUTGNREN(NUNG 1S,2S)-5. Racemic compound 5 has
been used as a colorimetric sensor for cyanide ions in
DMSO.[18b] Both neat grinding and LAG reactions of
(1R,2R)- or (1S,2S)-1,2-diaminocyclohexane with para-nitro-
phenyl isothiocyanate in a ratio of 1:2 yielded the desired
ACHUTNGREN(NUG 1R,2R)-5 and ACHUTNGTRENN(GUN 1S,2S)-5, respectively, in high purity and
quantitative yield, surpassing earlier solution-based synthe-
ses, as demonstrated by FTIR analysis immediately after
Figure 5. From top-to-bottom: an overlay of the FTIR spectra of chiral
bisACHTUNGTRENNUNG(thiourea) catalysts immediately after milling: (1R,2R)-3, (1S,2S)-3,
(1R,2R)-4, (1R,2R)-5, and (1S,2S)-5. The absence of the isothiocyanate
absorption band between 2000 and 2200 cmÀ1 is notable in all cases.
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Table 2. General and crystallographic information for crystal structure analysis of
compound ACHTUNGTRENNUNG(1R,2R)-3·2ACHTUNGTRENNUNG(iPrOH).
(N···O separations: 2.95 and 2.92 ꢃ), and are also
À
attached to a second set of iPrOH molecules by O
formula
Mr
crystal system monoclinic
space group
a[ꢃ]
C30H36N4O2S2
776.8
Z
2
H···O hydrogen bonds (O···O separation: 2.76 ꢃ).
The second set of iPrOH molecules also links to the
neighboring thiourea groups by not very common
1calc [gcmÀ3
l [ꢃ]
]
1.431
0.71073
0.243
0.0826
P21
m [mmÀ1
]
R, for all 5358 reflections
À
O H···S interactions (O···S separation: 3.36 ꢃ).
14.321(2)
8.904(2)
14.418(2)
101.323(3)
1802.7(5)
b [ꢃ]
c [ꢃ]
wR2, for 4479 reflections with Iꢁ2s(I) 0.1617
Molecules of
A
S
1.050
À0.69, 0.68
À
N H···S contacts (N···S separations: 3.39 and
3.35 ꢃ) that exhibit a bent geometry characteristic
of thioureas in the solid state, with the angle be-
tween the planes of the hydrogen-bond donor and
acceptor thiourea moieties being 698.[29]
b [8]
1min,max [eꢃÀ3
]
V [ꢃ3]
1
grinding, as well as subsequent HPLC analysis and H NMR
spectroscopy.
Immediate applicability of mechanochemically-prepared bis-
ACHTUNGTREN(NUNG thiourea)s and reaction scale-up: To verify the applicability
Crystal-structure analysis: For structure confirmation,
A
of the mechanochemically prepared organocatalysts, we
zation from isopropanol (iPrOH). Single-crystal X-ray dif-
tested the as-prepared achiral compound 1 and chiral com-
fraction (Table 2) revealed that the single crystals were an
pound ACTHNGUTER(NNUG 1R,2R)-3 for nonstereoselective and asymmetric
iPrOH solvate of the ACTHNUTRGNE(NUG 1R,2R)-3 organocatalyst (Figure 6).
The solvated crystal consist of hydrogen-bonded tapes in
which a set of iPrOH molecules are associated with thiourea
À
moieties through bifurcated N H···O hydrogen bonds
Scheme 3. Thiourea-catalyzed Morita–Baylis–Hillman reaction.
versions of a Morita–Baylis–Hillman reaction, respectively
(Scheme 3).[17a,g,h] Following the literature procedure, benzal-
dehyde and 2-cyclohexene-1-one were used as the reactants
and 1,4-diazabicyclo
Yields of 58% in the case of the nonstereoselective reaction
and 70% in the (1R,2R)-3 catalyzed asymmetric Morita–
[2.2.2]octane was used as the base.[17a]
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Baylis–Hillman reaction were obtained (Table 3), which are
comparable to the previously reported results.
Table 3. Catalytic performance of 1 and ACTHNUGTRNEUNG(1R,2R)-3 in the Morita–Baylis–
Hillman reaction of benzaldehyde and 2-cyclohexene-1-one. Literature
values in brackets.[17a]
Catalyst
Method for catalyst
synthesis
Yield[a] ee[b]
[%]
[%]
1
2
3
1
A
LAG
58 (60)
–
24
neat grinding or LAG 70
A
68 (72) 25 (33)[d]
[a] Isolated yields after column chromatography. [b] Determined by
chiral HPLC analysis (Chiralcel OJ 250ꢂ4.6 mm stationary phase).
[c] Stirring in THF, then recrystallization from hexane/EtOAc.[17a] [d] Dif-
ference from literature value can be explained by a four-fold reduction in
scale.
To fully verify that the mechanochemical method of prep-
aration does not affect the catalytic performance of the cata-
lyst, we also prepared ACHTUNRGTNE(NUG 1R,2R)-3 through the reported solu-
tion-based procedure involving the thiourea coupling in
THF and recrystallization from a mixture of hexane and
EtOAc.[17a] The catalytic activity of the solution-prepared
catalyst was identical to that of our mechanochemically syn-
thesized material. However, 1H NMR spectra of the solu-
tion-synthesized catalyst revealed that it was a 1:1 EtOAc
Figure 6. Crystal structure of (1R,2R)-3·2
ACHTUNGERTN(NUNG iPrOH): a) one molecule of
A
a
(1R,2R)-3 and iPrOH, with hydrocarbon hydrogen atoms and the disor-
der of trifluoromethyl groups not shown.
8470
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 8464 – 8473

Click Mechanochemistry
FULL PAPER
Figure 7. Comparison of 1H NMR spectra of bis
ACTHUNTGRNENUG(thiourea) ACHTUNGTRENN(UGN 1R,2R)-3
prepared by a) neat grinding and b) a solution-based reaction in THF
and recrystallized from hexane/ethyl acetate. Recrystallization affords
the 1:1 ethyl acetate solvate according to NMR analysis (EtOAc peaks
are labeled with *).
solvate of ACHTUNGTRENNUNG(1R,2R)-3 (Figure 7), which was also corroborat-
ed by thermal analysis (thermogravimetric analysis (TGA)
and DSC). The surprising stability of the ethyl acetate sol-
vate was proven by the difficulty in removing it from the so-
lution-made organocatalyst: complete removal of the sol-
vent was accomplished only after drying the solid under
high vacuum (p=10À4 mbar) for three hours. As established
by TGA (see the Supporting Information), the EtOAc sol-
vates of ACHTUNGTRENNUNG(1R,2R)-3 and ACHUTNGTREN(NGUN 1S,2S)-3 retained 75–90% of the
solvent of crystallization even after standing for two months
in open air. Consequently, besides enhancing the reaction
speed and efficiency, mechanosynthesis circumvented the
previously unrecognized formation of a highly stable catalyst
solvate in the solution-based synthesis.[30]
To further verify the immediate applicability of our me-
chanochemically obtained bis
organocatalysis, we explored the efficiency of the as-pre-
pared (1R,2R)-5, (1S,2S)-5, and their racemic 1:1 mixture
as colorimetric indicators for cyanide ions (Figure 8), as pre-
viously reported for the racemic form of 5.[18b,31] The results
reveal the sensitivity of mechanochemically prepared enan-
tiomeric 5 to CNÀ is comparable to that reported for the
racemate (concentration range 10À5 to 10À4 moldmÀ3).
Although the presented mechanochemical syntheses of
ACHTUNGTNER(NUNG thiourea)s in areas other than
Figure 8. UV/Vis absorption spectrophotometric titration of a) ACHTUNGTRENNUNG(1R,2R)-
G
ACHTUNGTRENNUNG
5, b) ACTHNUGRTENUNG(1S,2S)-5, and c) a 1:1 mixture of the enantiomers (c=2.0ꢂ
10À5 moldmÀ3 solution in DMSO) with tetrabutylammonium cyanide.
Arrows indicate the changes in the absorbances at 360 and 475 nm upon
addition of cyanide ions (from 0 to 10 equivalents).
mono- and bis
G
uct workup render the presented mechanosyntheses very
suitable for the efficient conversion of valuable reagents in
a typical chemical laboratory, illustrated here for the quanti-
tative transformations of enantiomerically pure diamines.
Preliminary tests indicate that mechanochemically prepared
thioureas are as effective catalysts and anion sensors as
those synthesized by traditional methods, and that mechano-
chemistry avoids the unwanted formation of solvated prod-
ucts that could serendipitously result from solution-based
synthesis. Our results also demonstrate that mechanosynthe-
that would be expected in a typical research laboratory, we
also explored the synthesis of 1, 3, and 8 on a one-gram
scale. The results (Table 1) show that excellent isolated
yields are retained upon scaling up of the reaction with reac-
tion times of between three and nine hours.
We have shown that mechanochemical milling allows the
click synthesis of known achiral and chiral thiourea catalysts
in excellent yields on up to a one gram reaction scale. Short
reaction times, quantitative yields, and the absence of prod-
sis can provide excellent yields of bisACTHNGUTERNNU(G thiourea)s based on
reactants hindered by stereochemical and electronic effects.
In this way, mechanochemistry is superior to established so-
lution-based methods and we are now exploring the high-
Chem. Eur. J. 2012, 18, 8464 – 8473
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8471

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All chemicals were purchased from commercial sources (Sigma Aldrich
or Alfa Aesar) and were used as received (except 4-nitrophenyl isothio-
cyanate, which was purified by column chromatography). The experi-
ments were carried out in a Retsch MM400 mill at a frequency of 30 Hz
by using a 10 cm3 stainless steel grinding jar and a single stainless steel
ball with a 12 mm diameter. Dry methanol was used as the liquid phase
in all liquid-assisted grinding (LAG) experiments.
1H and 13C NMR spectra were recorded on Bruker Avance (300 and
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1
ing Information, along with individual results of H and 13C NMR, FTIR,
HPLC, PXRD, DSC, and UV/Vis measurements. CCDC-862352 (-
ACHTUNGTRENNUNG(1R,2R)-3·2iPrOH) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
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Acknowledgements
We acknowledge the financial support of the Unity Through Knowledge
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with n-tetrabutylammonium cyanide as the anion source (see the
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Received: February 25, 2012
Published online: May 30, 2012
Chem. Eur. J. 2012, 18, 8464 – 8473
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8473