Synthesis and analytical resolution of chiral pyrazoles derived from (5R)-dihydrocarvone

Article abstract of DOI:10.1039/b812123k

In the course of the development of chiral hydrotris(pyrazolyl)borate ligands for unidirectional molecular machines, we have investigated the preparation of original chiral pyrazoles using (5R)-dihydrocarvone as starting material. Of the two synthetic rou

Full text of DOI:10.1039/b812123k

View Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/njc | New Journal of Chemistry
Synthesis and analytical resolution of chiral pyrazoles derived
from (5R)-dihydrocarvonew
Henri-Pierre Jacquot de Rouville,ab Guillaume Vives,ab Eva Tur,c Jeanne Crassous*c
ab
´ ¨
and Gwenael Rapenne*
Received (in Montpellier, France) 15th July 2008, Accepted 21st August 2008
First published as an Advance Article on the web 24th October 2008
DOI: 10.1039/b812123k
In the course of the development of chiral hydrotris(pyrazolyl)borate ligands for unidirectional
molecular machines, we have investigated the preparation of original chiral pyrazoles using
(5R)-dihydrocarvone as starting material. Of the two synthetic routes examined and described in
this article, the most efficient one involved the formation of the pyrazole ring in a last step. This
method appeared very efficient and granted access to a pyrazole functionalized with an ester
group for subsequent deposition of the corresponding tris(pyrazolyl)borate on insulating oxide
surfaces. Analytical HPLC confirmed the presence of a mixture of four diastereoisomers.
Introduction
The hydrotris(pyrazolyl)borate ligands discovered by
Trofimenko in the late sixties1 have been used increasingly in
bio-inorganic, organometallic and coordination chemistry.2
Modification of the functional groups connected to the pyr-
azolyl moiety in order to control or modify the steric and
electronic environment surrounding the metal centre gave rise
to extended studies. However, only a few chiral analogues
have been studied.3 Chiral pyrazoles are interesting precursors
for the preparation of C3-symmetrical hydrotris(pyrazolyl)borate
ligands which may be used for instance in asymmetric
catalysis.4 Such tripodal ligands have also a potential interest
in the design of molecular machines developed recently in our
group to prepare organometallic molecular turnstiles5 or as a
Fig. 1 Prototype of a molecular motor with a symmetric tripodal ligand.
The ruthenium center is coordinated to a hydrotris(indazolyl)borate
building block in the synthesis of a family of surface-mounted
electrically-driven molecular motors6 (Fig. 1) where the hydro-
tris(indazolyl)borate tripodal ligand7 has been used.
ligand and to
ligand.
a penta(4-(ethynylferrocenyl)phenyl)cyclopentadienyl
In order to conceive a unidirectional rotation in a molecular
machine, which is still a challenge nowadays, a strong dis-
symmetrization of the two directions of rotation is required. In
agreement with the second principle of thermodynamics,
chirality alone is not sufficient to achieve this goal.8 However,
the combination of chirality and an external energy source9
could be a very efficient way to highly dissymmetrize the
system and obtain such a controlled unidirectional motion.10
Since single molecular rotary motors require a unidirectional
rotation, the use of a chiral hydrotris(pyrazolyl)borate stator
is therefore of major interest to favour one direction of motion
over the opposite one, as already seen in synthetic molecular
motors11 or in biological motors such as ATP synthase.12
In this context, we studied the synthesis of enantiopure
chiral pyrazoles for the preparation of C3-symmetrical hydro-
tris(pyrazolyl)borate ligands. For this purpose, we focussed on
pyrazoles derived from (5R)-dihydrocarvone 1, commercially
available as a (2R,5R) and (2S,5R) diastereomeric mixture
from the chiral pool. Its olefin moiety was converted into an
ester function for the future immobilization of the molecular
motor onto insulating oxide surfaces. We present here the
synthesis of chiral pyrazoles following two different routes as
well as their analytical resolution.
a
´
CNRS; CEMES (Centre d’Elaboration des Materiaux et d’Etudes
Structurales), BP 94347, 29 rue J. Marvig, F-31055 Toulouse,
France. E-mail: rapenne@cemes.fr
Results and discussion
b Universite´ de Toulouse, UPS, 118 route de Narbonne, 31062
Toulouse, France
Sciences chimiques de Rennes, UMR CNRS 6226, Universite de
Molecular modelling
c
´
Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France.
E-mail: jeanne.crassous@univ-rennes1.fr
w Dedicated to Prof. Jean-Pierre Sauvage on the occasion of his 65th
birthday.
Molecular modelling was performed on the ruthenium com-
plex with Cerius2 (Fig. 2, right) in order to check that the
target tris(pyrazolyl)borate coordinated to the ruthenium
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
New J. Chem., 2009, 33, 293–299 | 293

View Online
Fig. 2 Chemical structure (left) and molecular modelling (right, bottom view) of a the ruthenium complex integrating a chiral hydrotris(pyrazolyl)-
borate ligand. The modeling has been performed on the full molecule but to obtain a clear representation, the ester and the ethynylferrocenyl
fragments have been omitted. The modelling clearly show the induced helicity of the molecule in the minimum energy conformation (Universal Force
Field, Cerius2 software13).
center (Fig. 2, left) would indeed induce the desired helicity
once coordinated.13 The chirality of the tripodal ligand, and
particularly the methyl groups at the 4-position of the ring,
strongly interact with the cyclopentadienyl ligand, which is the
key to induce a strong dissymmetry in the system. The use of
(5R)-dihydrocarvone as starting material seems particularly
appropriate to bring chirality through the helicity of the
C6-fused ring and will simultaneously allow to build the
pyrazole heterocycle through its carbonyl function.
Two strategies are usually followed to build a pyrazole ring,
both starting from an enolisable ketone (Scheme 1). The first
one is based on a Claisen formylation with ethyl methanoate.
In the following step, the b-ketoaldehyde formed is reacted
with hydrazine to yield the pyrazole ring.14 The second
strategy introduces the enamine function, precursor of the
pyrazole ring, by reaction with DMF–dimethylacetal.15 After
Scheme 2 Retrosynthetic analysis of the required ester pyrazole (2).
purification, the intermediate is cyclized by reaction with
First route
hydrazine yielding the pyrazole ring. It must be noted that
Pyrazole 4 (Scheme 3) was prepared in two steps from
these strategies are compatible with a large variety of chiral
(5R)-dihydrocarvone (1) by a Claisen condensation followed
substrates.
by a cyclization reaction with hydrazine which resulted in a
mixture of (4R,7S) and (4S,7S) diastereomers.16 The Claisen
From a retrosynthetic point of view, the preparation of the
hydrotris(pyrazolyl)borate ligand requires the synthesis of the
formylation was performed by reaction of 1 with sodium
optically pure ester pyrazole (2). The latter can be prepared
ethanolate forming the corresponding enolate. The latter was
following two different routes (Scheme 2), which mainly differ
then involved in an acyl nucleophilic substitution on ethyl
by the stage at which the pyrazole ring is constructed, i.e. in
methanoate. The literature describes14 the hereafter obtained
the first step or in the last step.
b-ketoaldehyde (3) as a poorly stable compound. It should be
used immediately without any further purification.
The pyrazole cycle was formed subsequently via a cyclisa-
tion with hydrazine. Pyrazole 4 was obtained with a global
yield of 61% starting from 1. It must be noted that compound
Scheme 1 The two most common synthetic strategies to prepare
pyrazoles (R and R0 are alkyl or aryl groups).
Scheme 3 Synthesis of the pyrazole ring followed by hydroboration–
oxidation of the exocyclic double bond.
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
294 | New J. Chem., 2009, 33, 293–299

View Online
Scheme 4 Sequential oxidation and functionalization of 5 to yield the
ester-functionalized pyrazole (2).
4 is not so stable. A slow reduction of the isopropenyl group
into an isopropyl group has been observed upon long storage
period. The characteristic isopropyl group has been easily
1
identified by H NMR and confirmed by mass spectrometry
performed on the mixture of stereoisomers.
Scheme
5 Alternative route to prepare the ester-functionalized
The conversion of the alkene into the least substituted
alcohol was achieved by hydroboration followed by the clas-
sical oxidation of the borane formed.17 Compound 4 was
reacted with BH3 in THF followed by the addition of sodium
hydroxide and hydrogen peroxide to give alcohol 5 with a 55%
yield. The reaction was performed in the presence of the
2-methylbut-2-ene in order to favour the regioselectivity of
the addition18 by coordination of the alkene on the boron
centre, which induces a steric hindrance.
pyrazole (2).
strategy requires the functionalization of the exocyclic double
bond. The hydroboration reaction performed on (5R)-dihydro-
carvone (1), as shown on Scheme 5, gave the desired hydroxy-
ketone (8a). Despite the use of 2-methylbut-2-ene in order to
minimize the reduction of the carbonyl group,18 the reduced
by-product 8b was also obtained, possibly due to the high
energy of the boron–oxygen bond, the formation of which
could constitute the driving force of the side reaction.
However, it is not necessary to separate 8a from 8b because
the next oxidation step using Jones’ reagent (CrO3, H2SO4)
performed on the mixture of 8a and 8b yields as the unique
product the carboxylic acid (9). Once 9 is obtained, the
formylation reaction is realized using three equivalents of
sodium because of the presence of an acidic proton in 9. It is
interesting to notice that the same reaction performed on the
methyl ester derivative of 9 gave the corresponding ethyl ester
without any formylation product. Therefore, the carboxylic
acid 10 can be esterified in the presence of chlorotrimethyl-
silane in methanol.23 After column chromatography, 11 was
obtained with a global yield of 20% from dihydrocarvone 1
(four steps). The last step of this alternative strategy consisted
in the synthesis of the pyrazole ring by reaction of 11 with
hydrazine. The desired pyrazole ester 2 was then obtained in a
64% yield.
The next step consisted in the conversion of the alcohol
function into the corresponding ester. A first attempt to
directly oxidize the hydroxy group was performed using the
Sarett reagent system (CrO3 and pyridine in the presence of
acetic anhydride and tert-butanol).19 Unfortunately these
conditions yielded a decomposition of the pyrazole ring as
shown by 1H NMR with the absence of aromatic proton which
would be expected for the pyrazole ring. An alternative route
using milder conditions (TEMPO/NaOCl/NaClO2)20 was
attempted unsuccessfully. Therefore, we envisaged a multistep
oxidation procedure as represented in Scheme 4.21
Alcohol 5 was first oxidized into an aldehyde under the mild
Swern conditions22 which preserved the pyrazole ring. Alde-
hyde 6 was obtained quantitatively and reacted with acetone
cyanohydrin in the presence of a catalytic amount of triethyl-
amine. After the quantitative conversion of the aldehyde,
the crude cyanohydrin 7 was again oxidized under Swern
conditions. After addition of triethylamine, the intermediate
was quenched with methanol. The corresponding ester (2) was
formed with a global yield of 19% from 5 (i.e. 66% average
yield by step).
Following this second strategy, it has been possible to
double the overall yield (from 6 to 13%) of the desired
pyrazole ester (2) but also to facilitate the purification steps.
Since it is not realistic to prepare the tripodal ligand on a
mixture of four diastereoisomers, a resolution of the mixture is
required before performing the reaction with KBH4 to yield
the optically pure tripodal ligands. If not, the reaction would
give a useless mixture of 20 stereoisomers after addition of
three pyrazoles on the boron center.
Nevertheless, this synthetic strategy showed two drawbacks.
Pyrazoles display strong interactions with silica and therefore
their purification on column chromatography is difficult on a
large scale and is accompanied by an important loss of
material on the column as shown by the poor yields. In
addition, during the second oxidation step using the Swern
conditions, the aldehyde and the ester are difficult to separate.
To overcome these obstacles, an alternative route was devel-
oped, the key point of this second strategy being the pyrazole
ring formation as a last step of the alternative route.
Analytical resolution
To resolve such a mixture, we investigated chromatographic
methods. As shown on Fig. 3, analytical resolution of the
mixture was achieved using HPLC separation with an apolar
column as the stationary phase (vide infra for experimental
details) and granted access to the proportion of each of the
four diastereoisomers.
Alternative route
We subsequently investigated another synthetic route invol-
ving the formation of the pyrazole ring in the last step. This
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
New J. Chem., 2009, 33, 293–299 | 295

View Online
was dried over CaH2. (6R)-3-methyl-2-oxo-6-(prop-1-en-2-yl)-
cyclohexanecarbaldehyde (3) was prepared according to a
literature procedure.14 (4S)-Isopropylidenemethyl-4,5,6,7-tetra-
hydro-2(1)H-indazole (4) was prepared as a mixture of two
diastereoisomers in two steps according to a literature pro-
cedure.14 The Jones reagent solution (8 N) was prepared by
dissolving 26.72 g of CrO3 in 23 mL of concentrated H2SO4 and
diluted with water up to 100 mL. All reactions were carried out
using standard Schlenk techniques under an argon atmosphere.
Flash column chromatography was carried out on silica gel
230–400 mesh from SDS.
NMR Spectra were recorded on Bruker Avance 300 or
Avance 500 spectrometers and full assignments were made
using COSY, ROESY, HMBC and HMQC methods. Chemi-
cal shifts are defined with respect to TMS = 0 ppm for 1H and
13C NMR spectra and were measured relative to residual
solvent peaks. The following abbreviations have been used
to describe the signals: s for singlet; d for doublet; t for triplet;
q for quadruplet; m: for multiplet. The numbering scheme is
given in Schemes 3 and 4. FAB and DCI mass spectrometry
were performed using a Nermag R10-10. The analytical HPLC
experiments were performed on a unit composed of Mass
Lynx system manager, Waters 2545 pump, Waters 2767
injector, Waters 2996 UV PDA-detector, and Waters 3100
MS detector. The column used was a Sunfire C18 (150 mm ꢁ
4.6 mm 5 mm) from Waters SA (Saint Quentin en Yvelines,
France). The eluent was a 1:1 mixture of H2O and MeOH and
Fig. 3 HPLC chromatogram (Sunfire column C18, 150 mm ꢁ
4.6 mm ꢁ 5 mm, eluent: H2O–MeOH 1:1, rate 1 mL minꢂ1) of the
analytic resolution of the ester-functionalized pyrazole (2) showing the
four diastereoisomers and their respective percentages.
The respective amounts are close but different from the
statistical distribution, with percentages between 22 and 30%
compared to the statistical value of 25%. In the course of the
synthesis, the formation of the third chiral center during the
hydroboration step could occur with an asymmetric induction.
Up to now, extension of this methodology to the prepara-
tive scale did not allow us to obtain pure diastereoisomers, the
separation between the four different peaks being too small to
yield sufficient amounts of pure material. The major problem
seems once again to be the behaviour of pyrazole derivatives
on various columns.
the elution rate was 1 mL minꢂ1
.
Synthesis
Conclusion
(4S)-4-Isopropylidene-7-methyl-4,5,6,7-tetrahydro-1(2)H-
indazole (4). To a sodium suspension (1.5 g, 65 mmol, 2 eq.) in
distilled diethylether (250 mL) were added (5R)-dihydro-
carvone (5.4 mL, 32.8 mmol, 1 eq.) and ethyl methanoate
(4 mL, 49 mmol, 1.5 eq.). After one hour, absolute ethanol
(1.5 mL) was added to the mixture. The solution was stirred
overnight. Additional absolute ethanol (1 mL) was added
followed 2 hours later by water (30 mL). The b-ketoaldehyde
formed was extracted with ether. The organic layer was washed
with water, and the aqueous layers were acidified to pH = 1 by
a 33% HCl solution. After a second extraction with ether, the
organic layer was dried over magnesium sulfate. Concentration
in vacuum gave the crude material which was purified by
column chromatography (SiO2, CH2Cl2). The (6R)-3-methyl-
2-oxo-6-(prop-1-en-2-yl)cyclohexanecarbaldehyde (3) was
obtained pure as an orange oil. The same day, hydrazine
monohydrate (3.24 mL, 67 mmol, 2.5 eq.) was added to a
solution of the b-ketoaldehyde in methanol (20 mL). The
mixture was refluxed overnight. After concentration in
vacuum, the product was extracted with dichloromethane
and washed with a saturated NaCl solution. After evapora-
tion, the crude product was purified by column chromato-
graphy (SiO2, CH2Cl2/AcOEt 8:2 then CH2Cl2/MeOH 9:1). 4
was obtained as a yellow oil with a yield of 61%. MS
(DCI/NH3): 177 ([M+H]+, 100%, calc. 177); HR-MS
(DCI/CH4): calculated [M+H]+: 177.1392 (C11H17N2),
found: 177.1365; 1H NMR (300 MHz, CD2Cl2) d 12.54
(s, 1H, NH), 7.34 (s, 0.5H, Ha), 7.33 (s, 0.5H, Ha), 5.3–4.8
In conclusion, the racemic synthesis of chiral pyrazoles has
been performed using (5R)-dihydrocarvone from the chiral
pool as starting material. The first strategy involving the
functionalization of a pre-formed pyrazole ring is limited by
the difficulties of purification on a large scale and the poor
yield of the conversion of the alcohol function into an ester
group, in the last step. The second strategy enabled to obtain
cleanly the pyrazole functionalized with an ester anchoring
group for subsequent deposition of the target tris(pyrazolyl)-
borate ruthenium complex on insulating oxide surfaces. Ana-
lytic HPLC confirmed the presence of a mixture of four
diastereoisomers, with percentages close to the statistical dis-
tribution. Work is now underway to develop an asymmetric
synthesis of one stereoisomer, focussing on performing the
hydroboration step in the presence of a chiral inductor.
Experimental
Materials and methods
All commercially available chemicals were of reagent grade
and were used without further purification. (5R)-2-methyl-5-
(prop-1-en-2-yl)cyclohexanone (known as (5R)-dihydrocarvone, 1)
and 2-methylbut-2-ene were purchased from Aldrich. Ethyl
methanoate and chlorotrimethylsilane were purchased from
Acros. Triethylamine was dried over KOH, diethyl ether and
THF over sodium with benzophenone and dichloromethane
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
296 | New J. Chem., 2009, 33, 293–299

View Online
(m, 2H, Hb), 3.4 (m, 1H, Hd), 3.0–2.9 (m, 1H, Hc), 2.2–1.4
(m, 10H, Hf-g-h-i); 13C NMR (75 MHz, CD2Cl2) d 164.3; 148.8;
109.0; 46.1; 39.3; 36.3; 32.8; 31.2; 20.6; 16.6.
distilled THF (125 mL), a solution of BH3 (1 M in THF,
134.5 mL, 134.5 mmol, 2.5 eq.) was added under an argon
atmosphere at 0 1C. After 2 h, a (5R)-dihydrocarvone solution
(8.83 mL, 53.8 mmol, 1 eq.) in THF (50 mL) was added. The
mixture was stirred overnight at room temperature. Absolute
ethanol (6 mL), followed by a 15% NaOH solution (50 mL)
and a 30% aqueous H2O2 solution (50 mL) were successively
added dropwise at 0 1C. The mixture was stirred overnight.
After concentration in vacuum, the aqueous layer was
acidified with concentrated HCl and the product extracted
with ether, and washed with a saturated NaCl solution. The
mixture of alcohols 8a and 8b was obtained as a colorless oil
used without further purification. The oil was dissolved in
acetone (125 mL) and cooled at 0 1C. After addition of Celite
(50 g), 15 mL of the Jones reagent solution (8 N) was added
dropwise until a brown color remained. After 10 minutes,
isopropanol (5 mL) was added. After separation, the aqueous
layer was extracted with ether, and washed with water. The
organic layers were dried over magnesium sulfate and con-
centrated in vacuum. 9 was obtained as a yellow oil in 88%
yield. MS (DCI/NH3): 202 ([M+NH4]+, 100%, calc. 202); 1H
NMR (300 MHz, CD2Cl2) d 2.50–1.80 (m, 6H), 1.65 (q, 1H,
J = 7.4 Hz), 1.32 (tq, 1H, J = 12.9 Hz J = 3.1 Hz), 1.17 (td,
3H, J = 6.7 Hz J = 1.9 Hz), 1.06 (dd, 1H, J = 6.9 Hz J =
2.7 Hz), 0.98 (d, 3H, J = 6.4 Hz); 13C NMR (75 MHz, CDCl3)
d (ppm) 212.0; 211.9; 181.8; 181.6; 180.6; 76.0; 75.9; 70.7; 45.6;
44.6; 44.5; 44.2; 42.2; 42.1; 39.8; 39.7; 39.4; 36.5; 36.3; 36.2;
36.2; 34.4; 34.3; 33.5; 32.8; 32.7; 30.3; 30.0; 29.6; 28.4; 27.7;
26.8; 25.9; 25.8; 18.0; 17.9; 17.3; 14.1; 13.3; 13.2.
(4S)-(1-methyl-2-hydroxyethyl)-7-methyl-4,5,6,7-tetrahydro-
1(2)H-indazole (5). To a solution of 2-methylbut-2-ene (9 mL,
85 mmol, 15 eq.) in freshly distilled THF (40 mL), a solution of
BH3 (1 M in THF, 212.5 mL, 212.5 mmol, 2.5 eq.) was added
under argon at 0 1C. After 2 hours, a solution of 4 (1 g,
5.15 mmol, 1 eq.) in THF (30 mL) was added. The solution
was stirred overnight at room temperature. Absolute ethanol
(25 mL) followed by an aqueous NaOH solution (4 M, 10 mL)
and 30% aqueous H2O2 (10 mL) were successively added
dropwise at 0 1C. The solution was stirred overnight. After
evaporation of the solvent, the product was extracted with
dichloromethane and washed with a saturated NaCl solution.
After concentration in vacuum, the crude mixture was purified
by column chromatography (SiO2, AcOEt/CH2Cl2 8:2). 5 was
obtained as a white solid in 54% yield. MS (DCI/NH3): 195
([M+H]+, 100%, calc. 195); HR-MS (DCI/CH4): calculated
[M+H]+: 195.1497 (C11H19N2O), found: 195.1476; 1H NMR
(300 MHz, CD2Cl2) d 7.32–7.30 (m, 1H, Ha), 3.67–3.56
(m, 2H, Hb), 2.92–2.87 (m, 1H, Hc), 2.79–2.71 (m, 1H, Hd),
2.00–1.33 (m, 3H, He-f-g), 1.28–1.23 (m, 3H, Hh), 0.99–0.78
(m, 3H, Hi); 13C NMR (75 MHz, CDCl3) d (ppm) 130.9; 77.5;
77.4; 77.2; 76.9; 68.0; 66.3; 66.1; 53.8; 53.7, 53.7; 53.6; 53.5;
53.4; 53.3; 53.0; 52.7; 39.8; 39.1; 34.2; 33.2; 30.3; 29.6; 29.3;
28.9; 27.2; 27.1; 23.7; 21.3; 20.6; 20.4; 14.8; 13.0.
(2S)-(7-Methyl-4,5,6,7-tetrahydro-2H-indazol-4-yl)propanal
(6). To an oxalyl chloride solution (0.18 mL, 2.15 mmol, 1.1 eq.)
in dichloromethane (4.8 mL), a mixture of DMSO (0.33 mL,
4.68 mmol, 2.4 eq.) in dichloromethane (1 mL) was added
dropwise under an argon atmosphere at ꢂ60 1C. After 10 min
of stirring, a solution of 5 (0.378 g, 1.95 mmol, 1 eq.) in
dichloromethane (15 mL) was added at ꢂ60 1C via a second
addition funnel. The mixture was stirred at ꢂ60 1C during
15 min. After addition of triethylamine (1.4 mL, 9.87 mmol,
5 eq.), the mixture was allowed to warm to room temperature.
Water (6 mL) was then added and the solution was stirred for
10 min. The aqueous layer was extracted with dichloro-
methane and the organic layers were dried over magnesium
sulfate. After concentration, the crude product was purified by
column chromatography (SiO2, CH2Cl2/AcOEt 7:3). 6 was
obtained pure as a yellow oil in a quantitative yield. MS
(DCI/NH3): 193 ([M+H]+, 100%, calc. 193); HR-MS
(DCI/CH4): calculated [M+H]+: 193.1341 (C11H17N2O),
found: 193.1324; 1H NMR (300 MHz, CD2Cl2) d 9.80–9.70
(m, 1H, Hb), 7.30–7.20 (m, 1H, Ha), 3.27–3.07 (m, 1H),
3.00–2.51 (m, 2H), 2.00–1.85 (m, 1H), 1.80–1.50 (m, 2H),
1.50–1.30 (m, 1H), 1.30–1.15 (m, 3H, Hh), 1.10–1.00 (m, 3H,
Hi); 13C NMR (75 MHz, CDCl3) d (ppm) 205.3; 205.2; 204.9;
131.8; 131.2; 127.7; 54.3; 53.9; 53.8; 53.8; 53.7; 53.6; 53.4; 53.4;
53.3; 53.1; 52.8; 50.6; 50.5; 50.4; 50.3; 33.5; 33.0; 32.6; 32.4;
32.3; 32.2; 32.0; 31.9; 29.6; 29.3; 28.8; 28.7; 28.3; 28.1; 27.3;
27.2; 27.1; 25.4; 24.6; 22.6; 20.4; 20.3; 19.9; 19.8; 19.6; 19.4;
19.3; 10.7; 10.1; 9.4; 9.2.
2-((1R)-2-Formyl-4-methyl-3-oxocyclohexyl)propanoic acid
(10). To a suspension of sodium (0.561 g, 24.4 mmol, 3 eq.)
in distilled THF, was added (2R)-(4-methyl-3-oxocyclohexyl)-
propanoic acid (9) (1.5 g, 8.14 mmol, 1 eq.) and ethyl
methanoate (1.3 mL, 16.3 mmol, 2 eq.). After 1 h, absolute
ethanol (0.5 mL) was also added to the mixture. The solution
was stirred overnight at room temperature. Absolute ethanol
(0.3 mL) was added again, followed 2 hours later by water
(10 mL). After concentration in vacuum, the product was
extracted with ether and washed with water. 10 was obtained
as a yellow oil in 47% yield. MS (DCI/NH3): 212 ([M]ꢂ,
100%, calc. 212); HR-MS (DCI/CH4): calculated [M+H]+:
1
213.1127 (C11H17O4), found: 213.1095; H NMR: (300 MHz,
CD2Cl2) d 8.65–8.50 (m, 1H, Ha), 2.50–2.30 (m, 1H), 2.20–2.00
(m, 2H), 1.95–1.75 (m, 1H), 1.75–1.50 (m, 2H), 1.30–1.05
(m, 3H), 1.05-0.90 (m, 3H); 13C NMR (75 MHz, CDCl3)
d (ppm) 206.8; 206.7; 175.7; 175.6; 173.2; 173.1; 101.6; 53.9;
53.8; 51.7; 51.6; 41.8; 41.7; 41.5; 41.3; 37.1; 36.9; 36.1; 35.5;
25.4; 24.8; 14.3; 14.2; 13.3; 12.7.
Methyl 2-((1R)-2-formyl-4-methyl-3-oxocyclohexyl)propanoate
(11). To a solution of 10 (0.7 g, 3.3 mmol, 1 eq.) in freshly
distilled methanol (66 mL), was added chlorotrimethylsilane
(1 mL, 7.75 mmol, 2.35 eq.). After stirring overnight at room
temperature, the solvent was evaporated in vacuum. The
crude product was purified by column chromatography
(SiO2, CH2Cl2/AcOEt 8:2). 11 was obtained as a white solid
in 49% yield. MS (DCI/NH3): 244 ([M+NH4]+, 70%, calc.
244); HR-MS LSIL: calculated [M+H]+: 227.1283
(2R)-(4-Methyl-3-oxocyclohexyl)propanoic acid (9). To a
2-methylbut-2-ene solution (28.55 mL, 269.9 mmol, 5 eq.) in
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
New J. Chem., 2009, 33, 293–299 | 297

View Online
1
(C12H19O4), found: 227.1301; H NMR (300 MHz, CD2Cl2)
15.20–15.00 (m, 1H, Ha), 8.64–8.38 (m, 1H, enol),
for providing the HPLC apparatus. Dr Isabelle M. Dixon is
d
warmly acknowledged for her corrections and comments on
this manuscript.
3.68–3.58 (m, 2H), 2.50–2.20 (m, 2H), 2.15–1.92 (m, 2H),
1.88–1.72 (m, 2H), 1.70–1.60 (m, 1H), 1.40–1.20 (m, 1H),
1.12–1.08 (m, 3H), 1.00–0.91 (m, 3H).
References
Methyl (2S)-(7-methyl-4,5,6,7-tetrahydro-2H-indazol-4-yl)-
propanoate (2)
1 (a) S. Trofimenko, J. Am. Chem. Soc., 1966, 88, 1842;
(b) S. Trofimenko, J. Am. Chem. Soc., 1967, 89, 6288.
First strategy: From 6. To a solution of 6 (106 mg, 5.5 mmol,
1 eq.) in dichloromethane (10 mL), triethylamine (15 mL,
0.11 mmol, 0.2 eq.) and acetone cyanohydrin (0.1 mL,
0.11 mmol, 2 eq.) were added under an argon atmosphere.
After stirring overnight at room temperature, the solvent was
evaporated. The cyanohydrin obtained (7) was used without
further purification. DMSO (185 mL, 2.61 mmol, 4 eq.) was
added dropwise at ꢂ78 1C to an oxalyl chloride solution
(67 mL, 0.78 mmol, 1.2 eq.) in dichloromethane (1.7 mL).
After 15 min, a solution of the freshly formed cyanohydrin 7 in
dichloromethane (2 mL) was added. After an additional hour
at ꢂ78 1C, triethylamine was added (0.5 mL, 3.52 mmol, 5.4 eq.).
The mixture was stirred 10 min at ꢂ78 1C, and then
15 min at ꢂ25 1C. After addition of methanol (0.9 mL), the
mixture was stirred overnight at room temperature. The
mixture was poured in water (30 mL), and the aqueous layer
was extracted with chloroform. The organic layers were dried
over magnesium sulfate, concentrated in vacuum and the
crude product purified by column chromatography (SiO2,
CH2Cl2/AcOEt 8:2). 2 was obtained as a yellow oil in an
overall 19% yield from 5.
2 (a) S. Trofimenko, Scorpionates: The Coordination Chemistry of
Polypyrazolylborate Ligands, Imperial College Press, London,
1999; (b) S. Trofimenko, Chem. Rev., 1993, 93, 943;
(c) C. Pettinari and C. Santini, in Comprehensive Coordination
Chemistry II, ed. A. B. P. Lever, Elsevier, Amsterdam, 2003,
vol. 1, p. 159; (d) D. L. Reger, Coord. Chem. Rev., 1996, 147,
571; (e) M. Etienne, Coord. Chem. Rev., 1996, 156, 201;
(f) P. K. Byers, A. J. Canty and R. T. Honeyman, Adv. Organomet.
Chem., 1992, 34, 1.
3 (a) D. D. LeCloux and W. B. Tolman, J. Am. Chem. Soc., 1993, 115,
1153; (b) D. D. LeCloux, C. J. Tokar, M. Osawa, R. P. Houser,
M. C. Keyes and W. B. Tolman, Organometallics, 1994, 13, 2855;
(c) M. C. Keyes, V. G. Young and W. B. Tolman, Organometallics,
1996, 15, 4133; (d) M. C. Keyes, B. M. Chamberlain,
S. A. Caltagirone, J. A. Halfen and W. B. Tolman, Organometallics,
1998, 17, 1984; (e) J. A. Katzenellenbogen, Org. Lett., 2000, 2, 2833.
4 For reviews on coordination chemistry of pyrazole derivatives, see:
(a) G. L. Monica and G. A. Ardizzoia, Prog. Inorg. Chem., 1997,
46, 151; (b) S. Trofimenko, Prog. Inorg. Chem., 1986, 34, 115;
(c) H. Vahrenkamp, Acc. Chem. Res., 1999, 32, 589.
5 (a) A. Carella, J. Jaud, G. Rapenne and J.-P. Launay, Chem.
Commun., 2003, 2434; (b) A. Carella, J.-P. Launay, R. Poteau and
G. Rapenne, Chem. Eur. J., 2008, 14, 8147.
6 (a) A. Carella, G. Rapenne and J.-P. Launay, New J. Chem., 2005,
29, 288; (b) G. Vives, A. Carella, J.-P. Launay and G. Rapenne,
Chem. Commun., 2006, 2283; (c) G. Vives, S. Sistach, A. Carella,
J.-P. Launay and G. Rapenne, New J. Chem., 2006, 30, 1429;
(d) G. Vives and G. Rapenne, Tetrahedron Lett., 2006, 47, 8741;
(e) G. Vives, A. Gonzalez, J. Jaud, J.-P. Launay and G. Rapenne,
Chem. Eur. J., 2007, 13, 5622; (f) G. Vives, A. Carella, J.-P. Launay
and G. Rapenne, Coord. Chem. Rev., 2008, 252, 1451;
(g) H. P. Jacquot de Rouville, G. Vives and G. Rapenne, Pure
Appl. Chem., 2008, 80, 659.
Second strategy: Formation of the pyrazole ring from 11.
Hydrazine monohydrate (86 mL, 1.77 mmol, 2.5 eq.) was
added to a solution of 11 (161 mg, 0.711 mmol, 1 eq.) in
methanol (6.5 mL). The mixture was refluxed overnight. After
concentration in vacuum, the product was extracted with
dichloromethane and washed with a saturated NaCl solution.
After evaporation, the crude product was purified by column
chromatography (SiO2, CH2Cl2/AcOEt 1:1). 2 was obtained as
a yellow oil in 64% yield. MS (DCI/NH3): 223 ([M+H]+,
100%, calc. 223); HR-MS LSI: calculated [M+H]+: 223.1447
(C12H19N2O2), found: 223.1488 ([M+H]+); 1H NMR
(300 MHz, CD2Cl2) d 7.25 (4 s, 1H, Ha), 3.67 (3 s, 3H, Hb),
3.10–2.50 (m, 3H, Hcꢂdꢂe), 2.10–1.79 (m, 2H, Hf), 1.79–1.30
(m, 2H, Hg), 1.27 (3 d, 3H, Hh), 1.01 (4 d, 3H, Hi); 13C NMR
(75 MHz, CD2Cl2) d 176.7; 176.5; 176.4; 117.0; 116.8; 115.5;
51.5; 51.4; 44.3; 44.9; 43.8; 43.3; 35.7; 35.2; 34.8; 34.5; 31.7;
31.6; 28.9; 28.6; 28.5; 27.8; 27.6; 25.2; 23.1; 20.4; 20.3; 19.8;
19.7; 15.0; 14.1; 13.2; 12.8.
7 (a) A. L. Rheingold, B. S. Haggerty, G. P. A. Yap and
S. Trofimenko, Inorg. Chem., 1997, 36, 5097; (b) A. Carella,
G. Vives, T. Cox, J. Jaud, G. Rapenne and J. P. Launay, Eur. J.
Inorg. Chem., 2006, 980.
8 (a) B. L. Feringa, Acc. Chem. Res., 2001, 34, 504; (b) C. P. Mandl
and B. Konig, Angew. Chem., Int. Ed., 2004, 43, 1622;
¨
(c) J. C. Chambron, C. Dietrich-Buchecker, G. Rapenne and
J.-P. Sauvage, Chirality, 1998, 10, 125.
9 It must be noted that pushing a molecule on a surface with the
STM tip necessarily induces a unidirectional rotation, as has been
shown in the following: (a) F. Chiaravalloti, L. Gross,
K. H. Rieder, S. Stojkovic, A. Gourdon, C. Joachim and
F. Moresco, Nat. Mater., 2007, 6, 30; (b) G. Rapenne and
G. Jimenez-Bueno, Tetrahedron, 2007, 63, 7018; (c) L. Grill,
K. H. Rieder, F. Moresco, G. Jimenez-Bueno, C. Wang,
G. Rapenne and C. Joachim, Surf. Sci., 2005, 584, 153;
(d) Y. Shirai, A. J. Osgood, Y. Zhao, Y. Yao, L. Saudan,
H. Yang, C. Yu-Hung, L. B. Alemany, T. Sasaki, J.-F. Morin,
J. M. Guerrero, K. F. Kelly and J. M. Tour, J. Am. Chem. Soc.,
2006, 128, 4854; (e) Y. Shirai, A. J. Osgood, Y. Zhao, K. F. Kelly
and J. M. Tour, Nano Lett., 2005, 5, 2330.
Acknowledgements
This work was supported by the CNRS, the University Paul
Sabatier (Toulouse) and the European Community. H.-P. J. de
R. thanks the French Ministry of National Education for a
PhD Fellowship. G. V. thanks the French Ministry of
10 Other kinds of dissymmetrization of the system are possible such as
correctly placing an electrode onto the surface where the molecule
is grafted, see: A. Carella, C. Coudret, G. Guirado, G. Rapenne,
G. Vives and J.-P. Launay, Dalton Trans., 2007, 177.
11 (a) T. R. Kelly, H. De Silva and R. A. Silva, Nature, 1999, 401, 150;
(b) N. Koumura, R. W. J. Zijistra, R. A. Van Delden, N. Harada
and B. L. Feringa, Nature, 1999, 401, 152; (c) D. Horinek and
J. Michl, J. Am. Chem. Soc., 2003, 125, 11900; (d) H. Jian and
J. M. Tour, J. Org. Chem., 2003, 68, 5091; (e) T. R. Kelly,
R. A. Silva, H. De Silva, S. Jasmin and Y. Zhao, J. Am. Chem.
Soc., 2000, 122, 6935; (f) D. A. Leigh, J. K. Y. Wong, F. Dehez and
National Education and the Ecole Normale Superieure of
´
Lyon for a PhD Fellowship. Prof. J.-P. Launay is thanked
for fruitful discussions. We also would like to thank Mrs
Chantal Zedde for the HPLC analysis and the Institute for
Advanced Technologies in Life Sciences of Toulouse (ITAV)
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
298 | New J. Chem., 2009, 33, 293–299

View Online
F. Zerbetto, Nature, 2003, 424, 174; (g) K. Tashiro, K. Konishi and
T. Aida, J. Am. Chem. Soc., 2000, 122, 7921; (h) M. K. J. Ter Wiel,
R. A. Van Delden, A. Meetsma and B. L. Feringa, J. Am. Chem.
Soc., 2003, 125, 15076; (i) M. Ikeda, M. Takeuchi, S. Shinkai,
F. Tani, Y. Naruta, S. Sakamoto and K. Yamaguchi, Chem. Eur.
J., 2002, 8, 5541; (j) T. Akutagawa, K. Shitagami, S. Nishihara,
S. Takeda, T. Hasegawa, T. Nakamura, Y. Hosokoshi, K. Inoue,
S. Ikeuchi, Y. Miyazaki and K. Saito, J. Am. Chem. Soc., 2005,
127, 4397; (k) G. S. Kottas, L. I. Clarke, D. Horinek and J. Michl,
Chem. Rev., 2005, 105, 1281; (l) E. R. Kay, D. A. Leigh and
F. Zerbetto, Angew. Chem., Int. Ed., 2007, 46, 72.
M. D. Santa Marıa, D. Sanz and J. Elguero, Prog. NMR Spectrosc.,
´
2006, 49, 169; (c) M. Moreno-Manas, R. M. Sebastian,
A. Vallribera, J. F. Piniella, A. Alvarez-Larena, M. L. Jimeno
and J. Elguero, New J. Chem., 2001, 25, 329; (d) E. Tur, G. Vives,
G. Rapenne, J. Crassous, N. Vanthuyne, C. Roussel, T. Lombardi,
T. Freedman and L. Nafie, Tetrahedron: Asymmetry, 2007, 18,
1911.
17 E. Turos, J. E. Audia and S. J. Danishefsky, J. Am. Chem. Soc.,
1989, 111, 8231.
18 G. W. Kabalka, S. Yu and N. S. Li, Tetrahedron Lett., 1997, 38,
5455.
12 J. F. Walker, Angew. Chem., Int. Ed., 1998, 37, 2308–2319.
13 Accelrys, Cerius2 4.6, San Diego, 2001.
19 E. J. Corey and B. Samuelsson, J. Org. Chem., 1984, 49,
4735.
14 R. Faure, A. Frideling, J.-P. Galy, I. Alkorta and J. Elguero,
Heterocycles, 2002, 57, 307.
15 G. M. Davies, J. C. Jeffery and M. D. Ward, New J. Chem., 2003,
27, 1550.
16 (a) R. Faure, A. Friedeling, J. P. Galy, I. Alkorta and J. Elguero,
20 F. J. Aladro, F. M. Guerra, F. J. Moreno-Dorado,
J. M. Bustamante, Z. D. Jorge and G. M. Massanet, Tetrahedron
Lett., 2000, 41, 3209.
21 R. P. Polniaszek and R. V. Stevens, J. Org. Chem., 1986, 51, 3023.
22 K. Omura and D. Swern, Tetrahedron, 1978, 34, 1651.
23 M. A. Brook and T. H. Chan, Synthesis, 1983, 201.
Heterocycles, 2002, 57, 307; (b) R. M. Claramunt, C. Lopeza,
´
ꢀc
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2009
New J. Chem., 2009, 33, 293–299 | 299