Synthesis and properties of chiral pyrazolidines derived from (+)-pulegone

Article abstract of DOI:10.1002/chem.201000219

Several enantiomerically pure N(2)-substituted octahydroindazoles were prepared as bicyclic pyrazolidine derivatives of (+)-pulegone. Condensation of pulegone with hydrazine delivered a hexahydroindazole intermediate, which underwent N(2)-substitution wit

Full text of DOI:10.1002/chem.201000219

FULL PAPER
DOI: 10.1002/chem.201000219
Synthesis and Properties of Chiral Pyrazolidines Derived from ACTHNUGRTNEUNG(+)-Pulegone
Florian Jakob,[a] Eberhardt Herdtweck,[b] and Thorsten Bach*[a]
Abstract: Several enantiomerically
thiobenzoyl and some N(2)-carbamoyl
derivatives as well as a N(1)-substitut-
ed octahydroindazole were synthesized.
The compounds showed medium activi-
ty as iminium ion catalysts promoting
quantitatively the Michael addition of
nitroethane to cinnamaldehyde in up
to 82% ee for the resulting syn-diaste-
reoisomer and 78% ee for the anti-dia-
pure N(2)-substituted octahydroinda-
zoles were prepared as bicyclic pyrazo-
lidine derivatives of (+)-pulegone.
Condensation of pulegone with hydra-
zine delivered a hexahydroindazole in-
termediate, which underwent N(2)-sub-
stitution with various electrophiles
(alkyl halides, acyl chlorides, phenyl
isocyanate). The resulting N(2)-substi-
tuted hexahydroindazoles could be re-
duced with LiBEt3H in THF to the
target compounds. In addition, a N(2)-
stereoisomer. Unexpectedly, the N(2)-
acyloctahydroindazoles were readily
oxidized under aerobic conditions.
Moreover, it was shown that an oxida-
tion of methyl phenyl sulfide to the
corresponding sulfoxide is promoted by
an N(2)-acyloctahydroindazole in deu-
terochloroform as solvent. It is pro-
posed that the oxidation of N(2)-acyl-
Keywords: heterocycles · Michael
addition · organocatalysis · oxida-
tion · terpenoids
AHCTUNGTRENNoGUN ctahydroindazoles proceeds by in situ
generation of hydrogen peroxide,
which in turn can act as an oxidant.
Introduction
hydes.[2] Since this discovery various modified chiral amines
have been synthesized and evaluated for iminium ion cataly-
sis.[1] Mechanistic studies have been conducted in an attempt
to elucidate all aspects pertinent to the activity and selectivi-
ty of the iminium ion forming catalysts.[3]
Iminium ion catalysis has emerged in recent years as one of
the most useful activation modes in organocatalysis. Com-
monly used organocatalysts include a broad variety of cyclic
secondary amines, which are capable of iminium ion forma-
tion with a,b-unsaturated aldehydes.[1] Due to the enhanced
electrophilicity of the iminium ion—as compared to the al-
dehyde—catalytic cycles are possible, in which addition
products at the double bond are formed. If an appropriate
stereogenic element is present in the amine, an enantioselec-
tive reaction course is possible. Imidazolidinones derived
from a-amino acids have been shown in a seminal contribu-
tion by MacMillan et al. to be useful catalysts for enantiose-
lective cycloaddition reactions to a,b-unsaturated alde-
Pyrazolidines of the general structure A can be consid-
ered as azanalogues of pyrrolidine-based organocatalysts
(Figure 1). They allow the evaluation of the so-called a-het-
eroatom effect or a-effect, according to which an enhanced
nucleophilicity is to be expected from these secondary
amines as compared to pyrrolidines.[4] In addition, the sub-
stituent R at the nitrogen atom, which is in close proximity
to the iminium ion forming nitrogen atom N(1) can carry an
additional stereogenic element.
Work by Ogilvie et al.[5] has been devoted to the synthesis
of pyrazolidinones B as cyclic hydrazides, which are easily
[a] Dipl.-Chem. F. Jakob, Prof. Dr. T. Bach
Lehrstuhl fꢀr Organische Chemie 1, Technische Universitꢁt Mꢀnchen
Lichtenbergstrasse 4, 85747 Garching (Germany)
Fax : (+49)89-289-13315
E-mail: thorsten.bach@ch.tum.de
[b] Dr. E. Herdtweck
Lehrstuhl fꢀr Anorganische Chemie
Technische Universitꢁt Mꢀnchen
Lichtenbergstrasse 4, 85747 Garching (Germany)
Figure 1. General structure of a chiral pyrazolidine A, of the chiral pyra-
zolidinones B earlier described by Ogilvie et al.,[5,7] and of the N(2)-sub-
stituted pyrazolidines C (octahydroindazoles), which are discussed in this
report.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000219.
Chem. Eur. J. 2010, 16, 7537 – 7546
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7537

accessible from camphor sulfonic acid.[6] The catalysts have
been successfully used in enantioselective Diels–Alder and
nitrone cycloaddition reactions. The mechanism of the
Diels–Alder reaction was studied in detail.[7] Enantioselec-
tivities achieved with the catalysts vary but can reach up to
96% ee. For R being achiral the benzyl substituent showed
the best performance. A further increase in selectivity can
be achieved if the R substituent is chiral (R=1-phenyleth-
yl). Other groups have employed different cyclic hydrazides
for related reactions.[8] A recent study by Tomkinson et al.
has been concerned with a comparison of 2-alkyoxycarbon-
yl-substituted piperazines and pyrazolidines as iminium ion
catalysts.[9]
formed as a 85/15 mixture of diastereoisomers, while prod-
uct 2b formed from ortho-isopropylphenyl hydrazine was
isolated as a single diastereoisomer.
Scheme 1. Acid-promoted condensation of (+)-pulegone (1) and aromat-
ic hydrazines to hexahydroindazoles 2.
Our interest in catalysts of type A was initially sparked by
the idea to establish a chirality axis at the nitrogen substitu-
ent N(2) in general structure C, which would be perfectly lo-
cated to induce enantioselectivity at the adjacent iminium
ion. A similar concept has been previously employed in the
construction of a chiral thiazolium-based organocatalyst
from (+)-pulegone.[10] Rotational barriers around the re-
The relative configuration was assigned in all hexahy-
droindazoles based on the assumption that the methyl group
at C(6) resides in an equatorial position and provides suffi-
cient bias for the six-membered ring to adopt a chair-like
conformation. In such an arrangement the hydrogen atom at
3
C(3a) must be axially positioned if it displays a large JHH
ꢀ
spective N C bond, however, seemed to be too low to guar-
coupling constant to the axial proton at C(4). This was
indeed the case for the major diastereoisomer with JHH
3
antee the required configurational stability even if influ-
enced by an adjacent stereogenic center at C(3). Intrigued
by the restricted bicyclic structure of compounds C we de-
cided to attempt their synthesis and evaluate their proper-
ties. It turned out that they do have catalytic potential in
enantioselective iminium ion catalysis. In addition and much
to our surprise the compounds proved to be capable of re-
ducing atmospheric oxygen to hydrogen peroxide.
varying between 11.9 and 12.8 Hz. The coupling constant to
the equatorial proton at C(4) varied between 5.5 and 6.3 Hz.
The same protons at C(3a) of the minor diastereoisomer led
to incompletely resolved multiplets, from which coupling
constants could not be obtained.
Unfortunately, the imine carbon atom C(7a) of products 2
turned out to be not sufficiently electrophilic to be attacked
by conventional nucleophiles. A reduction of hexahydroin-
dazoles 2 to the respective octahydroindazoles could not be
achieved with a variety of reducing reagents (NaBH3CN,
LiBEt3H, NaBH4, LiAlH4, Bu3SnH, Et3SiH, H2) under dif-
ferent reaction conditions nor was it possible to conduct nu-
cleophilic addition reactions again employing an array of
different reagents (MeMgCl, MeLi, AllylMgCl, AllylSiCl3,
NCSiMe3).
In this account we disclose our results regarding the prep-
aration of compounds C. The structure of the resulting prod-
ucts is discussed based on X-ray crystallographic and NMR
analysis. The Michael addition of nitroethane to cinnamal-
dehyde is presented as a test reaction to probe the potential
of compounds C in enantioselective catalysis. Eventually,
the above-mentioned reducing properties are disclosed in
detail.
In order to vary the N-substituent of the pulegone-derived
hexahydroindazoles, intermediate 3 was accessed by the
known condensation reaction of (+)-pulegone (1) and hy-
drazine monohydrate (Scheme 2).[16] Carbamoylation (to 4),
alkylation (to 5) and acylation (to 6) were readily achieved
via the crude condensation product 3. Urea 4 was obtained
as a diastereomeric mixture (d.r. 90:10) with phenylisocya-
nate as the electrophile while the reaction of intermediate 3
with alkylating reagents MeI and BnBr furnished pyrazo-
lines 5a (d.r. 87:13) and 5b (d.r. 89:11). Studies related to
the reactivity of hexahydroindazoles 5 towards nucleophiles
mirrored the observations made with the N(2)-aryl-substi-
tuted hexahydroindazoles 2. A reduction to the correspond-
ing octahydroindazoles could not be achieved. The acylated
products 6, which were obtained by the reaction of inter-
mediate 3 with acetic anhydride or acid chlorides, however,
were suited for a reduction with LiBEt3H and delivered the
octahydroindazoles 7. The relative configuration of the
product results from cyclic stereocontrol, with the major dia-
stereoisomer of substrate 6 exhibiting a (3aS,6R)-configura-
Results and Discussion
Synthesis of pyrazolidines from (+)-pulegone: Direct access
to enantiomerically pure pyrazolidines has become possible
in recent years by a variety of methods, which include the
Zr-catalyzed [3+2]-cycloaddition of hydrazones to olefins,[11]
the Pd-catalyzed cyclization of 3,4-allenylhydrazines,[12] and
the [3+2]-cycloaddition of diazoalkanes to electron-defi-
cient olefins.[13,14] The latter reactions proceed via pyrazo-
lines, which are further reduced with NaBH3CN or
LiBEt3H. As a potential access to compounds of type C a
direct condensation of (+)-pulegone (1) with hydrazines ap-
peared feasible. Precedence for the formation of pyrazolines
from hydrazines and a,b-unsaturated carbonyl compounds
exists.[15] After trifluoroacetic acid (TFA) was identified as a
suitable promoter for the condensation reaction the N(2)-
aryl substituted hexahydroindazoles 2 were readily obtained
(Scheme 1). The product 2a of phenyl hydrazine was
7538
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7537 – 7546

Chiral Pyrazolidines
FULL PAPER
ering the N-substituted ureas 8 (d.r. 90:10). Reduction of
these compounds with LiBEt3H was feasible and produced
the octahydroindazoles 9a and 9b in moderate yields. Re-
duction of the Boc-protected substrate 8c delivered the de-
sired formal reduction product of hexahydroindazoles 4 via
reduction and Boc cleavage. Significant amounts of triazol-
dione 10 were also obtained as a result of nucleophilic nitro-
gen attack at the carbonyl group of the carbamate
(Scheme 3).
Scheme 2. Access to various N(2)-substituted hexahydroindazoles 4–6
from the known intermediate 3 and reduction of the N(2)-acyl deriva-
tives 6 to octahydroindazoles 7.
tion. The newly formed stereogenic center at C(7a) is also
(S)-configurated (see below).
Octahydroindazoles 7 were isolated as single diastereoiso-
mers after reduction, while the intermediate hexahydroinda-
zole diastereoisomers were not separated. In Table 1 the
yields for the individual steps of acylation and reduction are
summarized. The diastereomeric ratio (d.r.) of the inter-
mediately formed hexahydroindazoles 6 is given. The rela-
tively low yield in the reduction step is partially due to the
fact that it refers to the single
Scheme 3. N-Alkylation and N-acylation of the secondary carbamate 4 to
hexahydroindazoles 8, which were further reduced with lithium triethyl-
borohydride.
diastereoisomer 7, which was
isolated, while no effort was
made to isolate and character-
Table 1. Preparation of diastereomerically pure N(2)-acyloctahydroindazoles 7 by acylation of intermediate 3
with RCOX and subsequent reduction of intermediate hexahydroindazoles 6 with LiBEt3H (Scheme 2).
Entry
R
X
6
Yield[a]
[%]
d.r.
7
Yield[b]
[%]
ize other
diastereoisomers.
Other reducing agents were
tried but delivered less satisfac-
tory results. Contrary to the ob-
servation made on unsubstitut-
ed pyrazolines,[17] reduction at-
tempts with NaCNBH3, NaBH4,
LiAlH4 and BH3 remained un-
successful. The use of hydrogen
in the presence of palladium
(Pd/C) led to deacylation. De-
acylation was also the major
side reaction observed with
LiBEt3H and the chosen reac-
tion temperature of 08C repre-
sents the best compromise be-
tween a sufficiently fast reac-
tion rate and a chemoselective
conversion.
1
2
OAc
Cl
6a
6b
76
52
84:16
78:22
7a
7b
41
61
3
4
Cl
Cl
6c
6d
58
48
77:23
78:22
7c
66
22
7d[c]
5
6
Cl
Cl
6e
6 f
39
28
78:22
78:22
7e
7 f
23
40
The direct reduction of hexa-
hydroindazole 4 was not possi-
ble. However, N-alkylation and
N-tert-butyloxycarbonylation
(Boc=tert-butoxycarbonyl)
7
Cl
6g
21
78:22
7g
32
[a] Yield of isolated product 6 (diastereomeric mixture) after chromatographic purification. [b] Yield of diaste-
reomerically pure product 7 after chromatographic purification. [c] The product is hydro-de-fluorinated in
could be readily achieved deliv- para-position.
Chem. Eur. J. 2010, 16, 7537 – 7546
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7539

T. Bach et al.
The regioisomer of compound 7b, that is, the N(1)-ben-
zoylated octahydroindazole 13 (Scheme 4), was accessible
via thioamide 12. Treatment of N(2)-benzoylhexahydroinda-
zole 6b (d.r. 78:22) with Lawesson reagent[18] delivered thio-
amide 11 (d.r. 78:22), which was reduced with LiBEt3H to
octahydroindazole 12. The diastereomerically pure com-
pound was N(1)-benzoylated with benzoyl chloride. The
thioACHTUNGTRENNUNGbenzoyl group at N(2) was reduced to a benzyl group,
which could be removed by hydrogen transfer hydrogenoly-
sis.
Figure 2. A molecule of compound 7a in the crystal.
tons, one methyl group resonating at 0.90 ppm, the other at
1.45 ppm. In addition, 1H-NOESY contacts between these
methyl groups and the ortho-protons of the phenyl group
were recorded strongly supporting an s-cis-thioamide con-
formation for this compound.
Scheme 4. Synthesis of the N(1)-benzoylated octahydroindazole 13 from
N(2)-benzoylated hexahydroindazole 6b via thioamide 12.
With octahydroindazoles 7a–g, 9a–c, 12, and 13 a total of
twelve compounds were prepared and could be tested for
their catalytic properties. Prior to that, the three-dimension-
al structure of this new class of compounds was briefly in-
vestigated.
Figure 3. 1H NMR chemical shift data of the gem-dimethyl substituents at
C(3) and significant 1H-NOESY contacts in octahydroindazoles 7b, 9c,
and 12.
Configuration and conformation of octahydroindazoles:
Suitable crystals for single crystal X-ray analysis could be
obtained from a solution of N(2)-acetyloctahydroindazole
7a in diethyl ether by diffusion with pentane. The structure
confirmed the expected (3aS,6R,7aS)-configuration of the
octahydroindazole skeleton and the previously mentioned
chair-like conformation of the cyclohexane ring. In addition,
it revealed a s-trans-conformation at the amide bond, with
the carbonyl oxygen atom and the nitrogen atom N(1) being
almost perfectly antiperiplanar to each other (Figure 2).
The conformational preference for a s-trans-amide bond
in N(2)-acyloctahydroindazoles was further corroborated by
1H NOESY spectra of N(2)-benzoylderivative 7b, which re-
vealed a strong contact between the hydrogen atom at N(1)
and the ortho-protons of the phenyl ring (Figure 3). The re-
moteness of the anisotropic phenyl group from the geminal
dimethyl substituents at C(3) was further undermined by the
almost identical chemical shift of the methyl protons. The
1H NMR properties of urea 9c were similar to those of
Michael addition of nitroethane to cinnamaldehyde: The ad-
dition of nitroethane to cinnamaldehyde (14, Scheme 5) has
been previously studied as a test reaction for proposed imi-
nium ion catalysts. Pioneering studies were conducted by
Arvidsson et al., who investigated in detail a possible imini-
um ion catalysis for the Michael addition of nitroalkanes to
a,b-unsaturated aldehydes.[19] They developed an imidazole-
containing imidazolidinone catalyst, which showed good ac-
tivity and high enantioselectivity. The catalyst (20 mol%)
delivered the respective addition products (syn/anti 50:50)
in 91% yield if the addition to cinnamaldehyde was run in
neat nitroethane (4 equiv) at ambient temperature for 47 h.
The enantiomeric excess under these conditions was 82% ee
for the syn-product and 80% ee for the anti-product. 2-Di-
phenyl(trimethylsilyloxy)methylpyrrolidine was found to be
a very active catalyst under the same conditions giving 91%
conversion in 15 h but with moderate enantioselectivity for
the syn-diastereoisomer (45% ee) and poor enantioselectivi-
ty for the anti-diastereoisomer (5% ee). Later, it was claim-
ed that the enantioselectivity with this catalyst can be signif-
1
amides 7. A H-NOESY contact between the two NH pro-
tons suggests a s-trans-orientation in the predominantly
populated conformer. Again, the methyl protons at C(3) are
almost isochronous. In stark contrast, thioamide 12 exhibit-
1
ed completely different H NMR shift values for these pro-
7540
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7537 – 7546

Chiral Pyrazolidines
FULL PAPER
icantly increased in the same reaction by changing the sol-
vent and by addition of additives.[20]
diastereoisomer did not vary significantly. The low enantio-
selectivities recorded for octahydroindazoles 9c (entry 10)
and 13 (entry 12) were in favor of the enantiomer, which
was disfavored with the other catalysts.
The assignment of the absolute configuration of the enan-
tiomers was deduced from previous work. The (S,S)-enantio-
mer of anti-15 was shown by Maruoka et al. in their studies
on the enantioselective silyl nitronate addition to cinnamal-
dehyde[21] to be levorotatory in CHCl3 as the solvent. The
(R,S)-enantiomer of syn-15 was shown by Wang et al. to be
also levorotatory in CHCl3.[20a] The major products anti-15
and syn-15 obtained in our study with N(2)-acyl substituted
octahydroindazoles 7 were dextrorotatory in CHCl3 indicat-
ing that they have the (R,R)- and (S,R)-configuration
(Scheme 6). Under optimized conditions employing catalyst
7b, products 15 were isolated from cinnamaldehyde (14)
and four equivalents of nitroethane at 608C in 97% yield.
Scheme 5. Michael addition of nitroethane to cinnamaldehyde (14) lead-
ing to the two diastereomeric addition products anti-15 and syn-15.
The reactions we conducted were run in neat nitroethane
as the solvent. It was found that the conversion at room
temperature was slow, which made us increase the reaction
temperature to 508C. Under these conditions the catalysts
could be nicely compared to each other (Scheme 5, Table 2).
There was a slight preference for the anti-product in all
runs.
Table 2. Michael addition of nitroethane to cinnamaldehyde (14) to
products 15 catalyzed by octahydroindazoles (20 mol%) 7, 9, 12, and 13
(Scheme 5).
Entry
Cat.
Conv.[a]
[%]
d.r.
(anti/syn)
ee [%][b]
(anti-15)
ee [%][b]
ACHTUNGTRENN(UNG syn-15)
G
U
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7 f
7g
9a
9b
9c
12
13
10
16
32
<3
4
52:48
52:48
52:48
n.d.
52:48
52:48
57:43
60:40
60:40
50:50
50:50
63:37
n.d.[c]
76
72
4
19
78
67
48
51
28
76
65
36
26
82
51
50
50
0
4
27
39
22
12
10
51
Scheme 6. Enantioselective preparation of Michael addition products
anti-15 and syn-15 and presumed structure of the iminium ion intermedi-
ate 16 formed from aldehyde 14 and octahydroinazole 7b.
9
10
11
12
ꢀ11
8
9
ꢀ12
ꢀ5
[a] The conversion was determined by 1H NMR after a reaction time of
three days. [b] The ee was calculated from the enantiomeric ratio, which
was determined by chiral GC analysis. [c] Not determined.
In order to explain the absolute product configuration we
invoke the iminium ion 16 as intermediate. The concave
shape of this molecule favors an approach from the top face,
which is the Re face if the iminium ion adopts the depicted
(Z)-configuration around the C=N double bond. Condensa-
tion of aldehyde 14 requires a turn of the amide bond at
N(2) from the preferred s-trans-conformation (see above) to
the s-cis conformation. With bulky substituents (entries 4–6,
Table 2), this rotation appears to be energetically so costly
that iminium ion formation is retarded. Electron-donating
substituents at the carbonyl group lower the rotational barri-
er around the amide bond and may therefore facilitate imi-
nium ion formation. The yellow color of the intermediate
iminium ion, which is observed immediately after addition
of conventional secondary amines, such as pyrrolidine, to al-
dehyde 14, does not occur with the octahydroindazoles
listed in table 2. Only after an extended period of time a
coloration of the reaction mixture was notable hinting at a
slow formation of the iminium ion. The simple diastereose-
lectivity is low because the approaching nitronate nucleo-
phile has no preferred orientation. In line with this assump-
There is a significant reactivity difference for the various
N-acyloctahydroindazoles 7. Apparently, an electron-donat-
ing effect of the substituent R is beneficial for the reactivity
(entries 3 and 8), while sterically encumbered substituents
without a strong donor are unproductive (entries 4–6). The
highest catalytic activity was recorded for the N(2)-carba-
moyl substituted octahydroindazole 9a (entry 8) and for the
N(1)-benzoyl-substituted octahydroindazole 13 (entry 12).
With regard to enantioselectivity, the highest enantiomer-
ic excesses were recorded for the N(2)-aroyl substituted oc-
tahydroindazoles 7b, 7c, 7 f, and 7g (entries 2, 3, 6, and 7).
It was hoped that catalyst 7g would combine the very good
enantioselectivity of the naphthoyl-substituted catalyst 7 f
and the relatively high reactivity of the para-methoxyben-
ACHTUNGTRENNUNGzoyl substituted catalyst 7c, but unfortunately it delivered a
lower enantioselectivity than 7 f (entries 6 and 7). In gener-
al, enantioselectivities determined for both syn- and anti-
Chem. Eur. J. 2010, 16, 7537 – 7546
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7541

T. Bach et al.
tion, the absolute configuration in b-position to the carbonyl
group is always identical (R) while the relative configuration
at the g-position is variable (R or S).
temperature, thioanisole oxidation was complete after nine
days and 71% of racemic sulfoxide 18 were obtained
(Scheme 8). In addition, reduction product 6a was isolated
in 96% yield. Based on these results it is likely that in situ
generated hydrogen peroxide is responsible of the oxidation
reaction.
Reduction of oxygen to hydrogen peroxide: The crystal
structure of compound 7a revealed the presence of a mole-
cule of hydrogen peroxide (H2O2) in the unit cell (see Ex-
perimental Section and Supporting Information). In addi-
tion, the oxidation product 6a of octahydroindazole 7a was
obtained as an oily material from the recrystallization at-
tempts. While the air sensitivity of pyrazolidines has been
earlier mentioned by others,[13,14,22] we are not aware that
this process was further studied. We assumed that pyrazoli-
dine 7a is capable of reducing oxygen under atmospheric
pressure to hydrogen peroxide (Scheme 7) and would there-
fore be a source of water-free hydrogen peroxide in organic
solvents. Commercially available hydrogen peroxide is nor-
mally delivered as an aqueous solution, which is obtained
predominantly by the well-established anthraquinone pro-
cess,[23] in which 2-alkyl-substituted anthrahydroquinones
serve as reducing agents at 30–608C and at ambient oxygen
pressure. Further methods for the generation of hydrogen
peroxide have been described.[24]
Scheme 8. Aerobic oxidation of sulfide 17 to sulfoxide 18 mediated by
octahydroindazole 7a.
Conclusion
In summary, chiral N(2)-substituted octahydroindazoles can
be easily prepared starting from (+)-pulegone. They repre-
sent chiral, cyclic hydrazides, which, however, show only
limited effectivity in iminium ion catalysis. While enantiose-
lectivities of up to 82% ee could be achieved in the Michael
addition of nitroethane to cinnamaldehyde, a complete con-
version was only possible at elevated temperature and after
extended reaction times. This result is in line with similar
observations made with simple achiral pyrazolidines, which
proved to be ineffective catalysts for the Diels–Alder reac-
tion of cinnamaldehyde.[9] A possible ring expansion to six-
membered rings, that is, to piperazines, seems a possible
way to achieve higher activity. The oxidation of octahydroin-
dazoles occurs at room temperature under aerobic condi-
tions. It was shown that the sulfoxidation of a sulfide is pos-
sible with air and octahydroindazole 7a as a promoter under
conditions conventionally used for a sulfoxidation by hydro-
gen peroxide. The reducing properties of octahydroindazoles
might be useful for enantioselective reduction reactions.
Scheme 7. Oxidation of octahydroindazole 7a to hexahydroindazole 6a
with concomitant formation of hydrogen peroxide.
Thioanisole (17) was chosen as a test substrate to substan-
tiate the notion that in situ generated hydrogen peroxide
was capable of oxidizing organic compounds in an organic
solvent. It is known that thioanisole can be oxidized by hy-
drogen peroxide to the respective sulfoxide 18 at elevated
temperature or upon addition of additives.[25] Indeed, follow-
ing a known procedure,[25f] product 18 was obtained in 69%
yield upon treatment of compound 17 with aqueous hydro-
gen peroxide at 608C. If run in an organic solvent (CDCl3)
the reaction slowed down significantly and remained incom-
plete even after four days delivering the respective product
in 24% yield. A similar yield was obtained if one equivalent
of thioanisole was stirred a 608C under air in the presence
of one equivalent of octahydroindazole 7a.
Experimental Section
General: All reactions involving water-sensitive chemicals were carried
out in flame-dried glassware with magnetic stirring under argon. Tetrahy-
drofuran (THF) and diethyl ether (Et2O) were distilled from sodium im-
mediately prior to use. Dichloromethane and triethylamine were distilled
from calcium hydride. All other chemicals were either commercially
available or prepared according to the cited references. TLC: Merck
glass sheets (0.25 mm silica gel 60, F254), eluent given in brackets. Detec-
tion by UV or coloration with cerium ammonium molybdate [CAM]. 1H
and 13C NMR spectra were recorded at ambient temperature. Chemical
shifts are reported relative to tetramethylsilane as internal standard. Ap-
parent multiplets which occur as a result of the accidental equality of
coupling constants of magnetically nonequivalent protons are marked as
virtual (virt.). Flash chromatography was performed on silica gel 60
(Merck, 230–400 mesh) (ca. 50–100 g for 1 g of material to be separated)
with the indicated eluent. Common solvents for chromatography [pen-
tane, ethyl acetate (EtOAc), diethyl ether (Et2O), dichloromethane] were
distilled prior to use. The preparation and analytical data of compounds
2b, 5b, 6b–g, 7b–g, 8b and 12 are reported in the Supporting Informa-
To further increase the activity of hydrogen peroxide
hexaACHTUNGTRENNUNGfluoroisopropanol (HFIP) has been recommended as
solvent. Rapid oxidation reactions of sulfides have been ob-
served in this solvent in a short period of time.[26] We
showed that oxygen is not capable of oxidizing sulfides in
this solvent by appropriate test experiments. However, upon
addition of one equivalent HFIP to CDCl3 and upon stirring
this solution with one equivalent of 7a in air at ambient
7542
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7537 – 7546

Chiral Pyrazolidines
FULL PAPER
tion. 13C NMR spectra of all new compounds are also presented in the
Supporting Information.
87:13). Rf =0.35 (pentane/Et2O=7:3) [CAM]; 1H NMR (360 MHz,
CDCl3): d = 0.93 (s, 3H), 0.98 (d, 3J=6.5 Hz, 3H), 1.03–1.09 (m, 1H),
1.17 (s, 3H), 1.35 (virt. qd, 2J ffi 3J=12.4, 3J=3.2 Hz, 1H), 1.46–1.61 (m,
1H), 1.65–1.80 (m, 3H), 2.34 (dd, 3J=12.4, 5.7 Hz, 1H), 2.56 (ddd, 2J=
14.4, 3J=4.3, 4J=1.8 Hz, 1H), 2.68 ppm (s, 3H); 13C NMR (90.6 MHz,
CDCl3): d = 17.1 (q), 22.2 (q), 24.8 (t), 25.1 (q), 33.5 (d), 33.5 (t), 34.6
(q), 36.3 (t), 56.0 (d), 66.0 (s), 155.2 ppm (s); IR (ATR): n˜ = 2950 (s),
2928 (s), 2867 (m), 1676 (s), 1455 (m), 1414 (m), 1379 (m), 1363 (m), 941
(w), 782 (w), 749 cmꢀ1 (w); MS (EI, 70 eV): m/z (%): 180 (20) [M+], 165
(100), 123 (4), 109 (24), 56 (3); HRMS (EI): m/z: calcd for C11H20N2:
180.1626 [M+]; found: 180.1629.
ACHTUNGTRENNUNG(3aS,6R)-(2-Phenyl-3,3,6-trimethyl)-3,3a,4,5,6,7-hexahydroindazole (2a):
(+)-Pulegone (538 mL, 502 mg, 3.30 mmol, 92%) was dissolved in THF
(12 mL). Phenylhydrazine (331 mL, 364 mg, 3.37 mmol, 1.02 equiv) and
trifluoroacetic acid (260 mL, 400 mg, 3.37 mmol, 1.02 equiv) were succes-
sively added and the mixture was stirred for 16 h at 458C. Water (50 mL)
and diethyl ether (50 mL) were added. The layers were separated and
the aqueous layer was extracted with diethyl ether (3ꢃ50 mL). The com-
bined organic layers were dried over Na2SO4, filtered and concentrated.
The crude product was purified by flash chromatography (pentane/Et2O
15:1) to give 2a (562 mg, 1.98 mmol, 67%) as a yellow solid. Rf =0.26
AHCTUNGTERG(NNUN 3aS,6R)-(2-Acetyl-3,3,6-trimethyl)-3,3a,4,5,6,7-hexahydroindazole (6a):
1
(pentane/Et2O 8:1) [CAM]; m.p. 588C; H NMR (360 MHz, CDCl3): d =
(+)-Pulegone (2.00 mL, 1.90 g, 11.5 mmol, 92%) was dissolved in toluene
(20 mL). Hydrazine monohydrate (0.56 mL, 0.58 g, 11.5 mmol) and meth-
anesulfonic acid (34.7 mL, 51.4 mg, 0.57 mmol, 0.05 equiv) were succes-
sively added at 808C. The reaction mixture was heated under reflux for
20 h in an argon atmosphere, while water was continuously removed
using a Dean–Stark apparatus. The solvent was removed under reduced
pressure at ambient temperature. The residue was cooled to 08C, treated
with acetic anhydride (5.94 mL, 6.40 g, 46.0 mmol, 4.00 equiv) and the re-
sulting mixture stirred for 10 h while allow to warm up to ambient tem-
perature. Sat. aqueous NaHCO3 (50 mL) was added and the aqueous
layer extracted with CH2Cl2 (3ꢃ50 mL). The combined organic layers
were dried over Na2SO4, filtered and concentrated. The crude product
was purified by flash chromatography (pentane/Et2O=2:1) to give 6a
(1.82 g, 8.74 mmol, 76%) as a pale yellow oil (d.r. 84:16). Rf =0.34 (pen-
tane/Et2O 2:1) [CAM]; 1H NMR (360 MHz, CDCl3): d = 1.05 (d, 3J=
6.5 Hz, 3H), 1.12–1.18 (m, 1H), 1.36–1.40 (m, 1H), 1.42 (s, 3H), 1.57 (s,
3H), 1.59–1.69 (m, 1H), 1.79–1.91 (m, 3H), 2.25 (s, 3H), 2.56 (dd, 3J=
12.8, 5.8 Hz, 1H), 2.64 ppm (dd, 2J=14.0, 3J=4.1 Hz, 1H); 13C NMR
(90.6 MHz, CDCl3): d = 20.3 (q), 22.1 (q), 23.0 (q), 26.6 (t), 27.5 (q),
33.1 (t), 33.6 (d), 36.1 (t), 57.6 (d), 64.6 (s), 160.9 (s), 169.7 pm (s); IR
(ATR): n˜ = 2950 (m), 2939 (m), 1655 (s), 1637 (m), 1573 (m), 1440 (m),
1413 (s), 1361 (m), 1326 (m), 932 cmꢀ1 (m); MS (EI, 70 eV): m/z (%):
208 (20) [M+], 193 (7), 166 (13), 151 (100), 109 (6), 95 (12), 43 (11);
HRMS (EI): m/z: calcd for C12H20N2O: 208.15756 [M+]; found:
208.15759.
1.05 (d, 3J=6.5 Hz, 3H), 1.07 (s, 3H), 1.10–1.17 (m, 1H), 1.42 (s, 3H),
1.43–1.48 (m, 1H), 1.60–1.69 (m, 1H), 1.77–1.89 (m, 3H), 2.60 (dd, 3J=
11.9, 5.5 Hz, 1H), 2.75 (ddd, 2J=14.4, 3J=4.3, 4J=1.5 Hz, 1H), 6.92–6.98
(m, 1H), 7.21–7.29 ppm (m, 4H); 13C NMR (90.6 MHz, CDCl3): d =20.1
(q), 22.4 (q), 25.6 (t), 27.8 (q), 33.5 (t), 33.6 (d), 36.2 (t), 57.3 (d), 67.6 (s),
119.1 (d), 121.4 (d), 128.5 (d), 146.0 (s), 155.2 ppm (s); IR (ATR): n˜ =
2946 (m), 2922 (m), 2863 (m), 1593 (s), 1492 (vs), 1385 (m), 1322 (m),
1275 (m), 1037 (w), 737 cmꢀ1 (m); MS (EI, 70 eV): m/z (%): 242 (18)
[M+], 227 (100), 171 (6), 77 (6); HRMS (EI): m/z: calcd for C16H22N2:
242.1783 [M+]; found: 242.1783.
ACHTUNGTRENNUNG(3aS,6R)-3,3,6-Trimethyl-3,3a,4,5,6,7-hexahydroindazole-2-carboxylic acid
anilide (4): (+)-Pulegone (2.00 mL, 1.90 g, 11.5 mmol, 92%) was dis-
solved in toluene (20 mL). Hydrazine monohydrate (0.56 mL, 0.58 g,
11.5 mmol) and methanesulfonic acid (34.7 mL, 51.4 mg, 0.57 mmol,
0.05 equiv) were successively added at 808C. The reaction mixture was
heated under reflux for 20 h in an argon atmosphere, while water was
continuously removed using a Dean–Stark apparatus. The solvent was re-
moved under reduced pressure at ambient temperature and the residue
was dissolved in CH2Cl2 (7 mL). The solution was cooled to 08C, treated
with NEt3 (1.61 mL, 1.16 g, 11.5 mmol), and phenylisocyanate (1.25 mL,
1.37 g, 11.5 mmol) and stirred for 10 h while warming to room tempera-
ture. Saturated aqueous NaHCO3 solution (30 mL) and CH2Cl2 (40 mL)
were added. The layers were separated and the aqueous layer was ex-
tracted with CH2Cl2 (3ꢃ40 mL). The combined organic layers were dried
over Na2SO4, filtered and concentrated. The crude product was purified
by flash chromatography (pentane/Et2O 3:1) to give 4 (2.13 g, 7.48 mmol,
65%) as a pale red solid (d.r. 90:10). Rf =0.32 (pentane/Et2O 3:1)
(3aS,6R,7aS)-(2-Acetyl-3,3,6-trimethyl)-octahydroindazole (7a): Hexahy-
droindazole 6a (208 mg, 1.00 mmol) was dissolved in dry THF (20 mL)
and cooled to 08C. 1 m LiEt3BH (2.25 mL, 2.25 mmol, 2.25 equiv) was
added slowly and the solution was stirred for 100 min at 08C. The reac-
tion was then hydrolyzed with 2m aqueous NaOH (15 mL). The layers
were separated and the aqueous layer was extracted with CH2Cl2 (3ꢃ
15 mL). The combined organic layers were dried over Na2SO4, filtered
and concentrated under reduced pressure. The oily residue was purified
by flash chromatography on silica gel (pentane/EtOAc 1:1) yielding the
corresponding diastereomerically pure 7a (86.1 mg, 0.41 mmol, 41%) as
a colorless solid. Although 7a can be manipulated in the air, it is unstable
and slowly oxidizes to the corresponding 6a. In order to prevent its oxi-
dation, it has to be stored under argon. Rf =0.54 (pentane/Et2O 1:2)
[CAM]; m.p. 1298C; 1H NMR (360 MHz, CDCl3): d
=
1.06 (d, 3J=
6.5 Hz, 3H), 1.14–1.20 (m, 1H), 1.41–1.47 (m, 1H), 1.43 (s, 3H), 1.58–
1.66 (m, 1H), 1.60 (s, 3H), 1.82–1.90 (m, 3H), 2.59 (dd, 3J=12.7 Hz,
5.8 Hz, 1H), 2.65 (ddd, 2J=14.1 Hz, 3J=4.5 Hz, 4J=1.6 Hz, 1H), 6.97–
7.02 (m, 1H), 7.24–7.28 (m, 2H), 7.45–7.50 (m, 2H), 7.99 ppm (brs, 1H);
13C NMR (90.6 MHz, CDCl3): d = 20.6 (q), 22.2 (q), 26.4 (t), 27.9 (q),
33.2 (t), 33.7 (d), 36.0 (t), 57.7 (d), 64.3 (s), 118.9 (d), 122.4 (d), 128.8 (d),
139.1 (s), 152.2 (s), 157.7 ppm (s); IR (ATR): n˜ = 3310 (m), 2961 (m),
2948 (m), 2931 (m), 1660 (s), 1590 (m), 1524 (s), 1550 (m), 1442 (s), 1396
(m), 1319 (m), 1230 (m), 1055 (m), 752 cmꢀ1 (m); MS (EI, 70 eV): m/z
(%): 285 (23) [M+], 166 (25), 151 (100), 109 (3), 95 (11), 69 (3), 41 (6);
HRMS (EI): m/z: calcd for C17H23N3O: 285.1841 [M+]; found: 285.1842.
[CAM]; m.p. 1098C; [a]D20
=
ꢀ57.4 (c=0.59 in CHCl3); 1H NMR
(360 MHz, CDCl3): d = 0.83–0.88 (m, 1H), 0.89 (d, 3J=6.3 Hz, 3H),
1.27–1.33 (m, 2H), 1.38–1.42 (m, 1H), 1.45 (s, 3H), 1.48 (s, 3H), 1.69–
1.73 (m, 2H), 1.75–1.82 (m, 1H), 1.95–2.02 (m, 1H), 2.10 (s, 3H), 3.40–
3.48 (m, 1H), 4.35 ppm (brs, 1H); 13C NMR (90.6 MHz, CDCl3): d =
21.9 (q), 22.3 (q), 23.0 (t), 23.8 (q), 25.9 (q), 27.0 (d), 33.1 (t), 33.3 (d),
50.6 (d), 55.6 (d), 66.1 (s), 169.6 ppm (s); IR (ATR): n˜ = 3223 (s), 2922
(s), 1628 (s), 1617 (s), 1481 (m), 1414 (s), 1377 (m), 1362 (m), 1128 (m),
972 cmꢀ1 (m); MS (EI, 70 eV): m/z (%): 210 (21) [M+], 167 (100), 153
(12), 95 (22), 43 (12); HRMS (EI): m/z: calcd for C12H22N2O: 210.1732
[M+]; found: 210.1731.
ACHTUNGTRENNUNG(3aS,6R)-(2,3,3,6-Tetramethyl)-3,3a,4,5,6,7-hexahydroindazole (5a): (+)-
Pulegone (2.00 mL, 1.90 g, 11.5 mmol, 92%) was dissolved in toluene
(20 mL). Hydrazine monohydrate (0.56 mL, 0.58 g, 11.5 mmol) and meth-
anesulfonic acid (34.7 mL, 51.4 mg, 0.57 mmol, 0.05 equiv) were succes-
sively added at 808C. The reaction mixture was heated under reflux for
20 h in an argon atmosphere, while water was continuously removed
using a Dean–Stark apparatus. The solvent was removed under reduced
pressure at ambient temperature and the residue dissolved in CH2Cl2
(4 mL). The solution was cooled to 08C, treated with NEt3 (1.61 mL,
1.16 g, 11.5 mmol), methyl iodide (0.72 mL, 1.63 g, 11.5 mmol) and stirred
for 10 h while warming to room temperature. Aqueous 6m NH3 solution
(30 mL) and CH2Cl2 (20 mL) were added. The layers were separated and
the aqueous layer was extracted with CH2Cl2 (3ꢃ40 mL). The combined
organic layers were dried over Na2SO4, filtered and concentrated. The
crude product was purified by flash chromatography (pentane/Et2O 9:1)
to give hexahydroindazole 5a (0.62 g, 3.45 mmol, 30%) as a red oil (d.r.
Single-crystal X-ray structure determination of compound 7a: Crystal
data and details of the structure determination (see also Supporting In-
formation): formula: C12H22N2O·ACHTUNGRTNEUNG(H2O2) ; Mr =244.33; crystal color and
shape: colorless plate, crystal dimensions=0.14ꢃ0.46ꢃ0.51 mm; crystal
system: orthorhombic; space group P212121 (no.: 19); a=6.3417(2), b=
11.1846(3), c=19.1812(5) ꢄ; V=1360.51(7) ꢄ3
;
Z=4;
mACHTUNGTRENNUNG(CuKa)=
0.692 mmꢀ1; 1calcd =1.193 gcmꢀ3; V range=4.58–66.598; data collected:
Chem. Eur. J. 2010, 16, 7537 – 7546
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7543

T. Bach et al.
17033; independent data [Io >2s(Io)/all data/Rint]: 2318/2356/0.022; data/
restraints/parameters: 2356/0/250; R1 [Io >2s(Io)/all data]: 0.0246/0.0250;
wR2 [Io >2s(Io)/all data]: 0.0648/0.0652; GOF=1.060; D1max/min = 0.12/
(d), 35.8 (t), 58.6 (d), 70.0 (s), 127.0 (d), 127.2 (d), 128.2 (d), 145.6 (s),
164.1 (s), 194.6 ppm (s); IR (ATR): n˜ = 2951 (m), 2926 (m), 1644 (m),
1454 (m), 1438 (s), 1269 (m), 1090 (m), 749 (m), 693 cmꢀ1 (m); MS (EI,
70 eV): m/z (%): 286 (100) [M+], 271 (10), 215 (24), 203 (25), 176 (20),
150 (16), 121 (96), 105 (30), 77 (27), 41 (19); HRMS (EI): m/z: calcd for
C17H22N2S: 286.1504 [M+]; found: 286.1511.
ꢀ0.12 eꢄꢀ3
.
CCDC 759340 (7a) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif
(3aS,6R,7aS)-(1-Benzoyl-3,3,6-trimethyl)-octahydroindazole (13): Octa-
hydroindazole 12 (0.45 g, 1.6 mmol) was dissolved in dry THF (50 mL),
Et3N (0.39 mL, 0.47 g, 4.7 mmol, 3.0 equiv) and benzoyl chloride
(0.54 mL, 0.66 g, 4.7 mmol, 3.0 equiv) were successively added at 08C.
The mixture was then heated to 508C and stirred at this temperature for
20 h. Upon cooling to room temperature water (15 mL) was added. The
layers were separated and the aqueous layer was extracted with CH2Cl2
(3ꢃ20 mL). The combined organic layers were dried over Na2SO4, fil-
tered and concentrated under reduced pressure. The oily residue was pu-
rified by flash chromatography (pentane/Et2O/CH2Cl2 70:27:3) to give a
yellow solid (0.59 g, Rf =0.20 [pentane/Et2O 7:3]), which was directly re-
duced with activated Raney-Ni (0.20 g, 2.3 mmol) in dry EtOH (10 mL)
at 508C for 2 h. The suspension was then filtered through a pad of Celite
under argon and the Celite was rinsed with CH2Cl2 (30 mL). After evap-
oration of the solvents, the oily residue was purified by flash chromatog-
raphy (pentane/Et2O/CH2Cl2 66:30:4) to give a yellow solid (0.21 g, Rf =
0.27 [pentane/Et2O 2:1]), which was then dissolved in formic acid (5 mL).
Pd/C (40 mg, 0.36 mmol, 10%) was added and the mixture was stirred for
2 h at ambient temperature. The suspension was filtered and the filtrate
was concentrated under reduced pressure. After purification by flash
chromatography (pentane/Et2O/CH2Cl2 50:47:3) 13 was obtained as a col-
orless solid (114 mg, 27%). Rf =0.34 (pentane/Et2O 1:1) [CAM]; m.p.
ACHTUNGTRENNUNG(3aS,6R)-3,3,6-Trimethyl-3,3a,4,5,6,7-hexahydroindazole-2-carboxylic
acid N-methyl-anilide (8a): Hexahydroindazole 4 (285 mg, 1.00 mmol)
was dissolved in dry CH3CN (10 mL) and treated with NaH (41.7 mg,
1.05 mmol, 60%, 1.05 equiv) at 08C for 30 min. Methyl iodide (68.5 mL,
156 mg, 1.10 mmol, 1.10 equiv) was added dropwise and the mixture was
stirred for 20 h at ambient temperature. The reaction was then hydro-
lyzed with saturated aqueous NH4Cl solution (20 mL) and the aqueous
layer was extracted with CH2Cl2 (3ꢃ20 mL). The combined organic
layers were dried over Na2SO4, filtered and concentrated under reduced
pressure. The oily residue was purified by flash chromatography on silica
gel (pentane/Et2O 2:1) yielding hexahydroindazole 8a (247 mg,
0.83 mmol, 83%) as a yellow oil. Rf =0.29 (pentane/Et2O 1:1) [CAM];
1H NMR (360 MHz, CDCl3): d [ppm]=0.90 (d, 3J=6.5 Hz, 3H), 0.98–
1.04 (m, 1H), 1.22–1.32 (m, 2H), 1.44 (s, 3H), 1.47–1.53 (m, 1H), 1.55 (s,
3H), 1.71–1.81 (m, 2H), 2.19 (ddd, 2J=14.0, 3J=4.5, 4J=1.7 Hz, 1H),
2.59 (dd, 3J=12.5, 5.6 Hz, 1H), 3.28 (s, 3H), 7.01–7.07 (m, 3H), 7.20–
7.27 ppm (m, 2H); 13C NMR (90.6 MHz, CDCl3): d =20.1 (q), 22.1 (q),
26.5 (t), 27.0 (q), 33.2 (t), 33.9 (d), 35.9 (t), 38.9 (q), 56.7 (d), 65.0 (s),
123.8 (d), 124.1 (d), 128.8 (d), 147.7 (s), 156.1 (s), 157.0 ppm (s); IR
(ATR): n˜ = 2951 (m), 2925 (m), 2865 (m), 1647 (s), 1596 (m), 1428 (s),
1397 (s), 1327 (m), 1101 (m), 740 (m), 695 cmꢀ1 (m); MS (EI, 70 eV): m/z
(%): 299 (53) [M+], 284 (40), 134 (100), 106 (29), 77 (18), 69 (13), 41 (7);
HRMS (EI): m/z: calcd for C18H25N3O: 299.1998 [M+]; found: 299.1995.
1
1808C; [a]2D0 = 187.3 (c=0.45 in CHCl3); H NMR (360 MHz, CDCl3): d
3
= 0.87–0.93 (m, 1H), 0.91 (d, J=6.0 Hz, 3H), 0.99 (s, 3H), 1.04 (s, 3H),
1.08.1.15 (m, 1H), 1.25–1.36 (m, 2H), 1.62–1.81 (m, 2H), 1.90–1.96 (m,
1H), 2.45–2.53 (m, 1H), 4.37 (brs, 1H), 4.40–4.48 (m, 1H), 7.35–7.42 (m,
3H), 7.59–7.65 ppm (m, 2H); 13C NMR (90.6 MHz, CDCl3): d = 20.0
(q), 22.1 (q), 24.9 (q), 25.4 (t), 27.9 (d), 32.7 (t), 35.6 (t), 46.5 (d), 58.1
(d), 61.8 (s), 127.6 (d), 128.5 (d), 130.0 (d), 136.8 (s), 174.0 ppm (s); IR
(ATR): n˜ = 3261 (w), 2958 (w), 1614 (s), 1576 (m), 1449 (m), 1392 (m),
1375 (m), 1368 (m), 1354 (m), 1338 (m), 711 (s), 690 cmꢀ1 (s); MS (EI,
70 eV): m/z (%): 272 (30) [M+], 257 (10), 167 (100), 105 (60), 77 (20), 58
(30); HRMS (EI): m/z: calcd for C17H24N2O: 272.1889 [M+]; found:
272.1890.
ACHTUNGTRENNUNG
4
1.00 mmol) was dissolved in dry THF (10 mL) and treated with NaH
(41.7 mg, 1.05 mmol, 60%, 1.05 equiv) at 08C for 30 min. Boc2O (1.09 g,
5.00 mmol, 5.00 equiv) was added, the mixture was heated under reflux
for 20 h. Upon cooling to room temperature the reaction was quenched
by the addition of water (40 mL) and the aqueous layer was extracted
with CH2Cl2 (3ꢃ40 mL). The combined organic layers were dried over
Na2SO4, filtered and concentrated under reduced pressure. The oily resi-
due was purified by flash chromatography on silica gel (pentane/Et2O
3:1) to give 8c (204 mg, 0.53 mmol, 53%) as a pale yellow solid. Rf =0.21
(pentane/Et2O 3:1) [CAM]; m.p. 1098C; 1H NMR (360 MHz, CDCl3): d
= 1.05 (d, 3J=6.5 Hz, 3H), 1.12–1.18 (m, 1H), 1.46 (s, 12H), 1.54–1.64
(m, 2H), 1.60 (s, 3H), 1.78–1.94 (m, 3H), 2.62–2.69 (m, 2H), 7.17–7.22
(m, 1H), 7.30–7.35 ppm (m, 4H); 13C NMR (90.6 MHz, CDCl3): d = 20.0
(q), 22.2 (q), 26.9 (t), 27.0 (q), 28.2 (q), 33.1 (t), 33.6 (d), 36.0 (t), 57.7
(d), 64.6 (s), 81.4 (s), 126.0 (d), 126.2 (d), 128.8 (d), 138.9 (s), 151.4 (s),
152.3 (s), 160.4 ppm (s); IR (ATR): n˜ = 2976 (w), 2927 (w), 1722 (s),
1671 (s), 1418 (s), 1333 (m), 1310 (m), 1232 (m), 1156 (s), 1015 (w),
740 cmꢀ1 (m); MS (EI, 70 eV): m/z (%): 385 (26) [M+], 285 (20), 166
(45), 151 (100), 105 (8), 57 (39), 41 (12); HRMS (EI): m/z: calcd for
C22H31N3O3: 385.2365 [M+]; found: 385.2363.
4-Nitro-3-phenylpentanal (15): Iminium ion catalysis: Cinnamaldehyde
(63 mL, 66 mg, 0.50 mmol) was dissolved in nitroethane (0.14 mL, 0.15 g,
2.0 mmol, 4.0 equiv) followed by the addition of catalyst 7. The mixture
was stirred at the indicated temperature and for the indicated period of
time in an argon atmosphere. After evaporation of residual nitroethane
under reduced pressure and purification of the residue by flash chroma-
tography (pentane/Et2O 3:2) diastereomers anti-15 and syn-15 were ob-
tained as colorless oils. anti-15: Rf =0.47 (pentane/Et2O 1:1) [CAM];
[a]2D0 = 8.9 (c=0.69 in CHCl3, 68% ee); ee values were determined by
GC (HP, 2,3-dimethyl-6-TBDMS-b-cyclodextrin), 33.6 and 34.1 min (60
! 1408C [58Cminꢀ1]); 1H NMR (360 MHz, CDCl3): d = 1.53 (d, 3J=
6.8 Hz, 3H), 2.95–3.03 (m, 2H), 3.82 (td, 3J=8.2, 3J=6.8 Hz, 1H), 4.87
(quin, 3J=6.8 Hz, 1H), 7.16–7.19 (m, 2H), 7.27–7.35 (m, 3H), 9.68 ppm
3
(t, J=1.1 Hz, 1H); 13C NMR (90.6 MHz, CDCl3): d = 16.7 (q), 43.5 (d),
ACHTUNGTRENNUNG(3aS,6R)-(2-Benzthioyl-3,3,6-trimethyl)-3,3a,4,5,6,7-hexahydroindazole
44.8 (t), 86.3 (d), 127.9 (d), 128.0 (d), 128.8 (d), 137.3 (s), 198.9 ppm (s).
(11): Hexahydroindazole 6b (405 mg, 1.50 mmol) was dissolved in 1,4-di-
oxane (4 mL). Lawessonꢅs reagent (424 mg, 1.05 mmol, 0.70 equiv) was
added and the mixture was stirred for 16 h at 1008C. Water (50 mL) and
Et2O (75 mL) were added at ambient temperature. The layers were sepa-
rated and the aqueous layer was extracted with Et2O (2ꢃ75 mL). The
combined organic layers were dried over Na2SO4, filtered and concentrat-
ed under reduced pressure. After purification by flash chromatography
(pentane/Et2O 4:1) 11 (322 mg, 1.13 mmol, 75%) was obtained as a
yellow solid. Rf =0.35 (pentane/Et2O 7:3) [CAM]; m.p. 1278C; 1H NMR
(360 MHz, CDCl3): d = 1.02 (d, 3J=6.5 Hz, 3H), 1.12–1.18 (m, 1H),
1.46–1.64 (m, 2H), 1.74–1.80 (m, 1H), 1.82 (s, 3H), 1.86–1.95 (m, 2H),
1.98 (s, 3H), 2.48 (ddd, 2J=14.2, 3J=4.2, 4J=1.9 Hz, 1H), 2.75 (dd, 3J=
12.7, 6.1 Hz, 1H), 7.26–7.29 (m, 3H), 7.34–7.37 ppm (m, 2H); 13C NMR
(90.6 MHz, CDCl3): d = 19.5 (q), 22.1 (q), 26.7 (t), 26.9 (q), 32.9 (t), 33.6
syn-15: Rf =0.42 (pentane/Et2O 1:1) [CAM]; ee values were determined
by GC (HP, 2,3-dimethyl-6-TBDMS-b-cyclodextrin), 30.9 and 31.2 min
(60 ! 1408C [58Cminꢀ1]); 1H NMR (360 MHz, CDCl3): d = 1.34 (d,
3J=6.7 Hz, 3H), 2.75 (ddd, 2J=17.4, 3J=4.3 Hz, 3J=0.9 Hz, 1H), 2.97
(ddd, 2J=17.4, 3J=9.8, 3J=1.9 Hz, 1H), 3.75 (td, 3J=9.8, 3J=4.3 Hz,
1H), 4.78 (dq, 3J=9.8, 3J=6.7 Hz, 1H), 7.18–7.22 (m, 2H), 7.29–7.38 (m,
3H), 9.56 ppm (dd, 3J=1.9, 3J=0.9 Hz, 1H); 13C NMR (90.6 MHz,
CDCl3): d = 17.7 (q), 44.2 (d), 46.4 (t), 87.1 (d), 128.1 (d), 128.2 (d),
129.2 (d), 137.5 (s), 198.6 ppm (s).
Methyl phenyl sulfoxide (18): Aerobic oxidation of sulfide 17 to 18 medi-
ated by 7a: Sulfide 17 (62 mL, 59 mg, 0.5 mmol) was dissolved in CDCl3
(0.5 mL) and treated with octahydroindazole 7a (104 mg, 0.5 mmol,
1.0 equiv) and hexafluoroisopropanol (53 mL, 84 mg, 0.5 mmol,
7544
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7537 – 7546

Chiral Pyrazolidines
FULL PAPER
1.0 equiv). The mixture was stirred under an atmosphere of oxygen for
14 d at ambient temperature. The solvent was removed under reduced
pressure and the oily residue purified by flash chromatography (EtOAc)
yielding 18 (50 mg, 0.36 mmol, 71%) as a colorless oil, which was in ana-
lytical data identical to the previously described compound.[28] Chiral
HPLC analysis (Daicel Chiralcel AS-H, isopropanol/hexane=7:3) re-
vealed the product to be completely racemic.
[13] a) M. R. Mish, F. M. Guerra, E. M. Carreira, J. Am. Chem. Soc.
1997, 119, 8379–8380; b) F. M. Guerra, M. R. Mish, E. M. Carreira,
Org. Lett. 2000, 2, 4265–4267.
[14] J. Barluenga, F. Fernꢇndez-Marꢈ, A. L. Viado, E. Aguilar, B. Olano,
S. Garcꢈa-Granda, C. Moya-Rubiera, Chem. Eur. J. 1999, 5, 883–
896.
[15] a) T. Curtius, F. Wirsing, J. Prakt. Chem. 1894, 50, 531–554; b) L. C.
Raiford, W. J. Peterson, J. Org. Chem. 1937, 1, 544; c) S. V. Tsuker-
man, A. I. Bugai, V. M. Nikitchenko, V. F. Lavrushin, Chem. Hetero-
cycl. Compd. Engl. Transl. 1970, 6, 370–373; d) B. V. Ioffe, N. B.
Burmanova, Chem. Heterocycl. Compd. Engl. Transl. 1971, 7, 1152–
1155; e) U. Bauer, B. J. Egner, I. Nilsson, M. Berghult, Tetrahedron
Lett. 2000, 41, 2713–2717; f) M. P. Sibi, R. Zhang, S. Manyem, J.
Am. Chem. Soc. 2003, 125, 9306–9307; g) M.-H. Shih, Synthesis
2004, 26–32; h) A. Lꢆvai, ARKIVOK 2005, 9, 344–352.
Acknowledgements
The help of Michaela Breier (undergraduate research participant) is
gratefully acknowledged.
[16] a) S. A. Busse, H. L. Gurewitsch, Chem. Ber. 1930, 63, 2209–2211;
b) E. D. Andrews, W. E. Harvey, J. Chem. Soc. 1964, 4636–4637;
c) B. Ramamoorthy, G. S. K. Rao, Tetrahedron Lett. 1967, 8, 5145–
5152.
[17] M. D. Curtis, N. C. Hayes, P. A. Matson, J. Org. Chem. 2006, 71,
5035–5038.
[18] a) H. Z. Lecher, R. A. Greenwood, K. C. Whitehouse, T. H. Chao, J.
Am. Chem. Soc. 1956, 78, 5018–5022; b) B. S. Pedersen, S. Scheibye,
N. H. Nilsson, S.-O. Lawesson, Bull. Soc. Chim. Belg. 1978, 87, 223;
c) S. Scheibye, J. Kristensen, S.-O. Lawesson, Tetrahedron 1979, 35,
1339–1343; d) M. Jesberger, T. P. Davis, L. Barm, Synthesis 2003,
1929–1958; e) T. ꢉztꢀrk, E. Ertas, O. Mert, Chem. Rev. 2007, 107,
5210–5278.
[1] Reviews: a) G. Lelais, D. W. C. MacMillan, Aldrichimica Acta 2006,
39, 79–87; b) A. Erkkilꢁ, I. Majander, P. M. Pihko, Chem. Rev. 2007,
107, 5416–5470; c) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli,
Angew. Chem. 2008, 120, 6232–6265; Angew. Chem. Int. Ed. 2008,
47, 6138–6171.
[2] K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am. Chem. Soc.
2000, 122, 4243–4244.
[3] a) G. J. S. Evans, K. White, J. A. Platts, N. C. O. Tomkinson, Org.
Biomol. Chem. 2006, 4, 2616–2627; b) G. Evans, T. J. K. Gibbs, R. L.
Jenkins, S. J. Coles, M. B. Hursthouse, J. A. Platts, N. C. O. Tomkin-
son, Angew. Chem. 2008, 120, 2862–2865; Angew. Chem. Int. Ed.
2008, 47, 2820–2823; c) S. Lakhdar, T. Tokuyasu, H. Mayr, Angew.
Chem. 2008, 120, 8851–8854; Angew. Chem. Int. Ed. 2008, 47, 8723–
8726; d) D. Seebach, U. Groscaronelj, D. M. Badine, W. B. Schweiz-
er, A. K. Beck, Helv. Chim. Acta 2008, 91, 1999–2034; e) J. B. Brazi-
er, G. Evans, T. J. K. Gibbs, S. J. Coles, M. B. Hursthouse, J. A.
Platts, N. C. O. Tomkinson, Org. Lett. 2008, 10, 133–136; f) U. Gro-
selj, D. Seebach, D. M. Badine, W. B. Schweizer, A. K. Beck, I.
Krossing, P. Klose, Y. Hayashi, T. Uchimaru, Helv. Chim. Acta 2009,
92, 1225–1259.
[4] a) W. P. Jencks, J. Carriuolo, J. Am. Chem. Soc. 1960, 82, 1778–1786;
b) J. O. Edwards, R. G. Pearson, J. Am. Chem. Soc. 1962, 84, 16–24;
c) V. Gold, Pure Appl. Chem. 1979, 51, 1731; d) J. L. Cavill, J.-U.
Peters, N. C. O. Tomkinson, Chem. Commun. 2003, 728–729; e) E.
Buncel, I.-H. Um, Tetrahedron 2004, 60, 7801–7825; f) J. L. Cavill,
R. L. Elliott, G. Evans, I. L. Jones, J. A. Platts, A. M. Ruda, N. C. O.
Tomkinson, Tetrahedron 2006, 62, 410–421; g) Y. Ren, H. Yamata-
ka, J. Org. Chem. 2007, 72, 5660–5667.
[19] L. Hojabri, A. Hartikka, F. M. Moghaddam, P. I. Arvidsson, Adv.
Synth. Catal. 2007, 349, 740–748.
[20] a) L. Zu, H. Xie, H. Li, J. Wang, W. Wang, Adv. Synth. Catal. 2007,
349, 2660–2664; b) Y. Wang, P. Li, X. Liang, T. Y. Zhang, J. Ye,
Chem. Commun. 2008, 1232–1234.
[21] T. Ooi, K. Doda, K. Maruoka, J. Am. Chem. Soc. 2003, 125, 9022–
9023.
[22] a) M. Ternon, F. Outurquin, C. Paulmier, Tetrahedron 2001, 57,
10259–10270; b) Y. Ju, R. S. Varma, Tetrahedron Lett. 2005, 46,
6011–6014; c) Y. Ju, R. S. Varma, J. Org. Chem. 2006, 71, 135–141;
d) N. C. Giampietro, J. P. Wolfe, J. Am. Chem. Soc. 2008, 130,
12907–12911; e) E. Frank, Z. Mucsi, I. Zupko, B. la Rethy, G.
Falkay, G. Schneider, J. Wolfling, J. Am. Chem. Soc. 2009, 131,
3894–3904.
[23] a) H.-J. Riedl, G. Pfleiderer, DE 671318, 1939; b) H.-J. Riedl, G.
Pfleiderer, US 2158535, 1939; c) G. Pfleiderer, H. J. Riedl, US
2369912, 1945; d) G. Pfleiderer, H. J. Riedl, W. Deuschel, DE
801840, 1951; e) J. M. Campos-Martin, G. Blanco-Brieva, J. L. G.
Fierro, Angew. Chem. 2006, 118, 7116–7139; Angew. Chem. Int. Ed.
2006, 45, 6962–6984.
[5] a) M. Lemay, W. W. Ogilvie, Org. Lett. 2005, 7, 4141–4144; b) M.
Lemay, L. Aumand, W. W. Ogilvie, Adv. Synth. Catal. 2007, 349,
441–447; c) M. Lemay, J. Trant, W. W. Ogilvie, Tetrahedron 2007, 63,
11644–11655.
[24] a) C. R. Harris (E. I. Du Pont de Nemours and Company), US
2479111, 1949; b) F. F. Rust (N. V. de Bataafsche Petroleum Maat-
schappij), DE 935303, 1955; c) V. R. Choudhary, A. G. Gaikwad,
S. D. Sansare, Angew. Chem. 2008, 120, 1826–1829; Angew. Chem.
Int. Ed. 2001, 40, 1776–1779; d) G. Centi, R. Dittmeyer, S. Pera-
thoner, M. Reif, Catal. Today 2003, 79–80, 139–149; e) T. S. Sheriff,
P. Carr, B. Piggott, Inorg. Chim. Acta 2003, 348, 115–122; f) G.
Blanco-Brieva, E. Cano-Serrano, J. M. Campos-Martin, J. L. G.
Fierro, Chem. Commun. 2004, 1184–1185; g) K.-H. Tong, K.-Y.
Wong, T. H. Chan, Tetrahedron 2005, 61, 6009–6014; h) P. de Fruto-
s Escrig, A. L. Garriga Meco, A. Padilla Polo, Ind. Eng. Chem. Res.
2008, 47, 8025–8031; i) I. Yamanaka, T. Murayama, Angew. Chem.
2008, 120, 1926–1928; Angew. Chem. Int. Ed. 2008, 47, 1900–1902.
[25] a) D. E. Richardson, H. Yao, K. M. Frank, D. A. Bennett, J. Am.
Chem. Soc. 2000, 122, 1729–1739; b) K. Sato, M. Hyodo, M. Aoki,
X.-Q. Zheng, R. Noyori, Tetrahedron 2001, 57, 2469–2476; c) J.
Brinksma, R. La Crois, B. L. Feringa, M. I. Donnoli, C. Rosini, Tet-
rahedron Lett. 2001, 42, 4049–4052; d) G. Kar, A. K. Saikia, U.
Bora, S. K. Dehury, M. K. Chaudhuri, Tetrahedron Lett. 2003, 44,
4503–4505; e) J. Kasai, Y. Nakagawa, S. Uchida, K. Yamaguchi, N.
[6] K.-S. Yang, K. Chen, Org. Lett. 2000, 2, 729–731.
[7] M. Lemay, W. W. Ogilvie, J. Org. Chem. 2006, 71, 4663–4666.
[8] a) H. He, B.-J. Pei, H.-H. Chou, T. Tian, W.-H. Chan, A. W. M. Lee,
Org. Lett. 2008, 10, 2421–2424; Y. Langlois, A. Petit, P. Rꢆmy, M.-C.
Scherrmann, C. Kouklovsky, Tetrahedron Lett. 2008, 49, 5576–5579;
b) L.-Y. Chen, H. He, B.-J. Pei, W.-H. Chan, A. Lee, W. M. Albert,
Synthesis 2009, 1573–1577; c) T. Tian, B.-J. Pei, Q.-H. Li, H. He, L.-
Y. Chen, X. Zhou, W.-H. Chan, A. Lee, Synlett 2009, 2115–2118;
d) I. Suzuki, A. Hirata, K. Takeda, Heterocycles 2009, 79, 851–863.
[9] J. B. Brazier, J. L. Cavill, R. L. Elliott, G. Evans, T. J. K. Gibbs, I. L.
Jones, J. A. Platts, N. C. O. Tomkinson, Tetrahedron 2009, 65, 9961–
9966.
[10] J. Pesch, K. Harms, T. Bach, Eur. J. Org. Chem. 2004, 2025–2035.
[11] a) S. Kobayashi, H. Shimizu, Y. Yamashita, H. Ishitani, J. Kobayashi,
J. Am. Chem. Soc. 2002, 124, 13678–13679; b) Y. Yamashita, S. Ko-
bayashi, J. Am. Chem. Soc. 2004, 126, 11279–11282.
[12] a) S. Ma, N. Jiao, Z. Zheng, Z. Ma, Z. Lu, L. Ye, Y. Deng, G. Chen,
Org. Lett. 2004, 6, 2193–2196; b) Q. Yang, X. Jiang, S. Ma, Chem.
Eur. J. 2007, 13, 9310–9316; c) W. Shu, Q. Yang, G. Jia, S. Ma, Tetra-
hedron 2008, 64, 11159–11166.
Chem. Eur. J. 2010, 16, 7537 – 7546
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7545

T. Bach et al.
Mizuno, Chem. Eur. J. 2006, 12, 4176–4184; f) F. Shi, M. K. Tse,
H. M. Kaiser, M. Beller, Adv. Synth. Catal. 2007, 349, 2425–2430.
[26] a) K. S. Ravikumar, Y. M. Zhang, J.-P. Bꢆguꢆ, D. Bonnet-Delpon,
Eur. J. Org. Chem. 1998, 2937–2940; b) K. Neimann, R. Neumann,
Org. Lett. 2000, 2, 2861–2863.
zoles with concurrent sulfoxidation to a racemic product) are in
agreement with its intermediacy.
[28] V. J. Traynelis, Y. Yoshikawa, S.-M. Tarka, J. R. Livingston, J. Org.
Chem. 1973, 38, 3986–3990.
[27] One reviewer has correctly pointed out that the evidence for an in
situ production of hydrogen peroxide is not substantial. Still, all ob-
servations (H2O2 in the crystal, aerobic oxidation of octahydroinda-
Received: January 26, 2010
Revised: March 5, 2010
Published online: May 21, 2010
7546
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7537 – 7546