Catalytic asymmetric 6π-electrocyclization: Accessing highly substituted optically active 2-pyrazolines via diastereoselective alkylations

Article abstract of DOI:10.1055/s-0029-1218792

The chiral phosphoric acid catalyzed asymmetric electrocyclization of α,β-unsaturated hydrazones has been studied. This reaction is one of the first catalytic asymmetric 6π-electrocyclizations reported, and enables the synthesis of 2-pyrazolines in high y

Full text of DOI:10.1055/s-0029-1218792

PAPER
2171
Catalytic Asymmetric 6p-Electrocyclization: Accessing Highly Substituted
Optically Active 2-Pyrazolines via Diastereoselective Alkylations
H
ighly Substit
t
uted O
e
ptically
A
c
f
tive 2-Py
f
razoline
e
s
n Müller, Benjamin List*
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax +49(208)3062999; E-mail: list@mpi-muelheim.mpg.de
Received 29 April 2010
Dedicated to Professor R. Huisgen with admiration
ic relationship between this process and the 6p-electrocy-
clization of the pentadienyl anion (Scheme 1).
Interestingly, it turns out that our reasoning was not en-
tirely new and that Huisgen had discussed this analogy 20
Abstract: The chiral phosphoric acid catalyzed asymmetric elec-
trocyclization of a,b-unsaturated hydrazones has been studied. This
reaction is one of the first catalytic asymmetric 6p-electrocycliza-
tions reported, and enables the synthesis of 2-pyrazolines in high
yields and enantiomeric ratios. The obtained products are not only years earlier.10
interesting because of their pharmaceutical properties, but can be
manipulated in highly diastereoselective fashion, as shown for alky-
lation reactions. Thus, the combination of catalytic asymmetric 6p-
electrocyclization followed by diastereoselective alkylation can
iso-
electronic
H
Me
HN
H
Me
R
N
N
NH
R
R
provide interesting synthetic building blocks in optically active
form.
R
Scheme 1 Isoelectronic 6p-electrocyclizations
Key words: electrocyclic reactions, enantioselective organocataly-
sis, heterocycles, diastereoselectivity, 2-pyrazolines
In light of its cationic nature, we wondered whether or not
it was possible to control the stereochemical outcome of
this reaction with a chiral counteranion. Although exam-
ples of Fischer’s pyrazoline synthesis employing substoi-
chiometric amounts of acid are rare, we hypothesized that
chiral phosphoric acids could possibly mediate the desired
transformation.11 Indeed, these catalysts turned out to
smoothly promote the cycloisomerization of benzylidene-
acetone-derived phenylhydrazone 1a to give pyrazoline
2a in good yields and promising enantioselectivities. Af-
ter intensive screenings, we identified the BINOL-derived
phosphoric acid 3 (10 mol%), bearing 9-anthracenyl sub-
stituents in the 3,3¢-positions, as the optimal catalyst. Dur-
ing further optimization of solvent, concentration, and
temperature, we developed a fairly general method for the
catalytic asymmetric 6p-electrocyclization of a,b-unsat-
urated hydrazones giving the desired products in high
yields and optical purity (Table 1).
Electrocyclizations, cycloadditions, and sigmatropic rear-
rangements are the most prominent classes of pericyclic
reactions. Due to their synthetic utility, these reactions
have become very popular in synthetic organic chemistry
and the development of catalytic asymmetric versions has
been a logical consequence. Compared to cycloadditions1
and sigmatropic rearrangements,2 which are now well es-
tablished in asymmetric catalysis, electrocyclizations re-
main largely unexplored in this respect. The first reports
of catalytic asymmetric electrocyclization reactions date
back to 2003, when the groups of Trauner and Aggarwal
reported enantioselective Nazarov-4p-electrocyclizations
catalyzed by chiral Lewis acids.3 While other groups in
the following years have also addressed the same prob-
lem,4 corresponding catalytic asymmetric 6p-electrocy-
clizations have remained elusive.5 Only recently, our
group6 and the group of Smith7 independently reported the
first catalytic asymmetric 6p-electrocyclizations. While
Smith and co-workers employed asymmetric phase trans-
fer catalysis to the cyclization of ortho-substituted benz-
aldimines, we were focusing on the 6p-electrocyclization
of a,b-unsaturated hydrazones.8
When carrying out the reaction in the presence of 3 (10
mol%) at 30 °C in chlorobenzene, 3-methyl-1,5-diphenyl-
2-pyrazoline (2a) was obtained with 92% yield and 88:12
enantiomeric ratio (Table 1, entry 1). Different substitu-
ents on the aromatic ring in the 5-position, either of elec-
tron-withdrawing (entries 2–5) or electron-donating
nature (entry 6), were well tolerated, giving the desired
products with up to 98:2 enantiomeric ratio (entry 5). Fur-
thermore, pyrazoline 2g, the 3-methyl-analogue of the
COX2-inhibitor (S)-(–)-E-6244,12 was obtained with sim-
ilarly good yield and enantiomeric excess.
Stimulated by a related project in our group, we became
interested in the rearrangement of a,b-unsaturated hydra-
zones into the corresponding 2-pyrazolines. This reaction
was originally discovered by E. Fischer9 and is known to
be acid catalyzed. Considering a protonated hydrazonium
ion as the reactive species, we recognized the isoelectron-
We also developed a direct method for the synthesis of op-
tically active 2-pyrazolines starting from a,b-unsaturated
ketones 4 and phenylhydrazine (5; Scheme 2). When a
mixture of 4 and 5 was stirred in chlorobenzene at 50 °C
in the presence of 4 Å molecular sieves, the corresponding
SYNTHESIS 2010, No. 13, pp 2171–2178
x
x.
x
x
.
2
0
1
0
Advanced online publication: 20.05.2010
DOI: 10.1055/s-0029-1218792; Art ID: C02910SS
© Georg Thieme Verlag Stuttgart · New York

2172
S. Müller, B. List
PAPER
Table 1 Substrate Scope of the Catalytic Asymmetric 6p-Electrocyclization of a,b-Unsaturated Arylhydrazonesa
O
O
P
OH
O
R2
3 (10 mol%)
H
N
N
N
R1
N
R2
chlorobenzene
0.1 M, 20–50 °C, 60–109 h
R1
2a–g
1a–g
Entry
Product
2a
R1
Ph
R2
Yield (%)b
erc
1
2
3
4
5
6
7
Ph
92
95
95
88
99
85
88
88:12
95:5
96:4
96:4
98:2
93:7
88:12
2b
4-BrC6H4
3-BrC6H4
4-F3CC6H4
3-O2NC6H4
Ph
2c
Ph
2d
Ph
2e
Ph
2f
3,4-(OCH2O)-C6H3
4-MeSO2C6H4
Ph
2g
4-FC6H4
a Unless otherwise stated, the reactions were performed under an Ar atmosphere with hydrazones 1a–g (0.10 mmol) and phosphoric acid 3 (10
mol%) in chlorobenzene (1.0 mL).
b Isolated yield.
c Determined by HPLC analysis on chiral stationary phase (the absolute configuration of 2c was determined by X-ray structure analysis.6
phenylhydrazones were formed readily. After simple re- ly active form, triggered our interest in possible further
moval of the drying agent by filtration and addition of the transformations. In particular, the substructure of a
catalyst, these intermediates underwent the cyclization masked 1,3-diamine and the presence of five potentially
well, as in the previous case. Thus, pyrazoline 2h was ob- acidic protons, which allows modifications of the pyrazo-
tained in 89% yield and 95:5 er. Furthermore, this proto- line core as well as the side chain in the 3-position,
col now also allowed the use of aliphatic enones. prompted us to investigate the follow-up chemistry of our
Previously, the corresponding aliphatic hydrazones had products more closely.
been more difficult to obtain in pure form compared to
their aromatic counterparts. Although these substrates re-
When we treated a racemic sample of 2a at –78 °C with
lithium diisopropylamide followed by the addition of io-
quired higher catalyst loadings (20 mol%) and only low
domethane, to our surprise, we found that rather than the
yields and enantioselectivities were obtained when phos-
3-methyl group, the C-4-methylene unit inside the pyrazo-
line ring was alkylated under these conditions
phoric acid 3 was used as the catalyst, the corresponding
N-triflyl-phosphoramide (20 mol%), albeit giving lower
(Scheme 3). Remarkably, the methylated product 6a was
enantioselectivities in the case of aromatic substrates,
1
obtained as a single diastereoisomer (according to H
turned out to improve both yields (40%) and optical purity
(75:25 er). These results clearly demonstrate the potential
of our new reaction to develop into a broadly applicable
synthetic methodology.
MS 4 Å
chlorobenzene
50 °C, 4 h
then
Ph
O
H
N
N
+
N
Besides a broad interest in pyrazolines due to their mani-
fold biological activities,13 the use of pyrazolines as syn-
thetic building blocks is of high importance and interest
due to the high diastereoselectivities usually observed in
derivatization reactions.14 To the best of our knowledge,
no derivatizations of the 3-methyl-1,5-diarylpyrazolines
obtained herein (except their oxidation to give the corre-
sponding pyrazoles) have been reported so far. This fact,
and the new opportunity to obtain pyrazolines 2 in optical-
Ph
NH2
R1
3 (10–20 mol%)
chlorobenzene, 0.1 M
R1
4
5
2h (R = 3-I-C6H4)
89%, er = 95:5
2i (R = n-C5H11
18%, er = 35:65
(40%, er = 75:25)
)
Scheme 2 Phosphoric acid 3 catalyzed synthesis of optically active
2-pyrazolines from enones 4 and phenylhydrazine (5)
Synthesis 2010, No. 13, 2171–2178 © Thieme Stuttgart · New York

PAPER
Highly Substituted Optically Active 2-Pyrazolines
2173
1
NMR analysis). Based on the H NMR analysis and by
comparison with literature data,15 we were able to assign
our new product as trans-3,4-dimethyl-1,5-diphenyl-
pyrazoline (6a). We also obtained a byproduct that dif-
fered from 6a by the presence of an additional methyl
group and was identified as pyrazoline 7a, resulting from
the double methylation of 2a. It is noteworthy, that hetero-
cycle 7a was also obtained as a single diastereoisomer
(according to 1H NMR analysis).
1. LDA (2.4 equiv)
2. MeI (2.6 equiv)
N
N
N
N
THF, –78 °C
(rac)-2a
7a 89%
Scheme 4 Double alkylation of 2a
We also submitted an enantiomerically enriched sample
of 2a to the methylation conditions. Although deprotona-
tion of the pyrazoline at C-4 could cause racemization by
reversible intramolecular elimination, we were pleased to
find that the enantiomeric ratio of 2a dropped only slight-
ly and the desired product 6a was obtained with 64% yield
(Scheme 5).
1. LDA
2. MeI
Ph
Ph
Ph
N
N
N
N
N N
+
Ph
Ph
Ph
THF, –78 °C
(rac)-2a
6a
7a
Scheme 3 Methylation of product 2a
We found that 2a is readily alkylated by a variety of alky-
lating agents and that products 6 were obtained in satisfac-
tory yields with perfect diastereocontrol (Table 2).
1. LDA
2. MeI
N
N
N
N
THF, –78 °C
The scope of alkylating agents includes primary alkyl ha-
lides, allyl halides, benzyl halides, chloromethoxymethyl-
ether, and even secondary alkyl halides, although in the
latter case 6e was obtained in a slightly reduced yield.
2a
6a 64%
er = 88:12
er = 85:15
Scheme 5 Methylation of optically active 2-pyrazoline 2a
Table 2 Highly Diastereoselective Alkylations of Pyrazoline 2a
The enantioselective cycloisomerization of a,b-unsaturat-
ed hydrazones thus turned out to be a powerful tool to ac-
cess optically active 2-pyrazolines, which are not only
interesting due to their pharmaceutical properties, but can
undergo further highly diastereoselective transformations
and as such serve as potentially useful synthetic building
blocks.
LDA
N
N
N
N
X
+
R
THF, –78 °C
R
(rac)-2a
6a–e
X = Cl, Br, I
Mechanistically, we assume the electrocyclization occurs
as shown in Scheme 6. Hydrazone 1a was obtained as a
single isomer and X-ray structure analysis unambiguously
proved that the compound had an E-configured carbon–
nitrogen double bond.6 To attain the reactive (Z)-s-cis-
conformation, rotation around the carbon–carbon single
bond, as well as isomerization of the carbon–nitrogen
double bond has to occur. While the s-trans- to s-cis-
isomerization should readily proceed at room temperature
in solution, the carbon–nitrogen double bond isomeriza-
tion requires acid catalysis or elevated temperatures. In-
deed, we were able to show through HPLC analysis that a
solution of 1a in chlorobenzene contains exclusively the
E-isomer, whereas after addition of the catalyst a second
species, most likely the Z-isomer, is formed, which disap-
pears again in the course of the reaction while the product
is formed. After this isomerization process, the hydrazo-
nium ion – the cation of the chiral hydrogen-bonding-
assisted ion pair – can undergo the 6p-electrocyclization.
3-Pyrazoline 8 obtained after the cyclization subsequently
isomerizes to give the thermodynamically favored 2-pyra-
zoline 2a and releases the catalyst 3.
Entry
Product
6a
R
X
I
Yield (%)
1
2
3
4
5
Me
allyl
Bn
66
61
60
60
43
6b
Br
Br
Cl
I
6c
6d
CH2OCH3
i-Pr
6e
Since the only significant byproducts of the alkylation re-
actions were the doubly alkylated products 7, this obser-
vation prompted us to modify the reaction conditions such
that 7a could be obtained as the major product. Indeed,
when we used 2.4 equivalents of lithium diisopropyl-
amide and an excess of iodomethane, the two carbon–
carbon bond-forming reactions, namely the diastereo-
selective methylation of the pyrazoline core and the side
chain homologization, could be performed in one step.
Accordingly, 7a was obtained in 89% yield, again as a sin-
gle diastereoisomer (Scheme 4).
Synthesis 2010, No. 13, 2171–2178 © Thieme Stuttgart · New York

2174
S. Müller, B. List
PAPER
cerning
a
possible torquoselectivity of the
2a
1a
O
*
electrocyclization. In fact, depending on the mechanism,
one could expect to obtain the 1,5-cis-configured product
for the electrocyclization for steric reasons, whereas the
nucleophilic addition should favor the corresponding
trans-product. But, due to the configurational lability of
the N-stereocenter, the outcome of the reaction is the same
for both. However, the isoelectronicity mentioned above,
and the fact that a nucleophilic addition would involve a
5-endo-trig cyclization, which is a disfavored process ac-
cording to Baldwin’s rules, point towards the electrocy-
clic mechanism. The true mechanism may well turn out to
be something between these two descriptions and theoret-
ical studies are clearly needed to gain clarity.
HO
P
O
O
O
P
O
O
H
N
3
O
H
Ph
H
Ph
N
H
Ph
N
N
(E)-s-trans
Ph
O
O
8
P
O
O
[6π]
O
O
P
O
Ph
O
N
H
O
H
N
*
O
P
O
H
N
Ph
O
In summary, we have demonstrated that the catalytic
asymmetric 6p-electrocyclization of a,b-unsaturated hy-
drazones is a powerful tool for the synthesis of 2-pyrazo-
lines in high yields and enantioselectivites. Furthermore, it
was shown that the 2-pyrazolines obtained undergo highly
diastereoselective alkylation reactions with a broad vari-
ety of different alkylating reagents. These transformations
allow both the modification of the pyrazoline core and the
side chain in the 3-position and thus enable the creation of
molecular diversity from readily available, optically ac-
tive starting materials. The exploration of other types of
diastereoselective transformations such as aldol- or
Mannich-type reactions is the subject of future research.
Ph
(Z)-s-trans
N
(Z)-s-cis
H
Ph
Scheme 6 Plausible catalytic cycle
Although the need for the carbon–nitrogen double bond
isomerization prior to the cyclization, as well as the for-
mation of the thermodynamically favored 2-pyrazoline
after the carbon–nitrogen bond-forming step are clear, one
might argue about the key step of this mechanistic propos-
al: the 6p-electrocyclization. Can the ring-closure not also
be described by a different mechanism? Huisgen already
raised this question in 1980 and came up with a simple an-
swer: ‘Cannot the formation of pyrazolines also be classi-
fied as a nucleophilic addition of the NH2 group […] to Unless otherwise stated, all reagents were purchased from commer-
cial suppliers and used without further purification. Phenylhydra-
zine was distilled prior to use. All solvents employed were distilled
from appropriate drying agents prior to use. Column chromatogra-
phy was performed on Merck silica gel 60 (particle size 0.040–
the electrophilic a,b-unsaturated imine? This is an alter-
native description of one and the same process, differing
only in the choice of words and not in its meaning from
that given above. Like the electrocyclization of [the cyclo-
pentadienyl anion], that of [an a,b-unsaturated hydra-
zone] requires the two 90° rotations about the axes of the
terminal bonds’.10 But are these reaction modes really
identical? In principle, we could imagine different transi-
tion states for both scenarios (Figure 1). In the case of a
pericyclic 6p-electrocyclization, both ends of the conju-
gated p-electron system fulfill a rotation in disrotatory
fashion, whereas in the case of the nucleophilic attack the
nitrogen lone pair would interact with the LUMO of the
conjugated carbon–carbon double bond in a Michael ad-
dition like mechanism.
0.063 mm). 1H and 13C NMR spectra were recorded using a Bruker
AV-400 or AV-500 spectrometer at ambient temperature. Chemical
shifts (d) are reported in ppm relative to tetramethylsilane (TMS),
using the solvent resonance as internal standard. The following ab-
breviations were used to designate chemical shift multiplicities:
s = singlet, d = doublet, t = triplet, m = multiplet, br = broad, cou-
pling constants are given in hertz (Hz). Mass spectra were recorded
using a Finnigan MAT 8200 at 70 eV in the EI mode. High-resolu-
tion mass spectra were determined using a Bruker APEX III FTMS
(7 T magnet). Optical purity (er, ee) were measured by HPLC anal-
ysis on a chiral stationary phase, exact conditions are reported for
each compound separately.
Preparation of Hydrazones 1a–g
Prepared from the corresponding enones and phenylhydrazines or
their hydrochlorides following modified literature procedures.16
H
H
H
H
N
N
N
N
Cyclization of Hydrazones; General Procedure A
H
H
Hydrazone 1a–g (0.10 mmol) and catalyst 3 (7.0 mg, 0.01 mmol)
were placed in a reaction vial under Ar and dissolved in anhydrous
chlorobenzene (1 mL). The mixture was stirred at 30 °C (unless oth-
erwise stated) until the starting material was completely consumed
(reaction monitored by TLC). After cooling to ambient temperature,
the mixture was directly submitted to flash chromatography on sil-
ica gel to obtain pure 2a–g.
pericyclic
6π-electrocyclization
intramolecular
Michael addition
(5-endo-trig)
Figure 1 Two possible mechanistic scenarios
From the perspective of the synthetic chemist, the result is
the same for both cases, because the structure of the sub-
strates and products do not allow any conclusions con-
(S)-3-Methyl-1,5-diphenyl-4,5-dihydro-1H-pyrazole (2a)
Following general procedure A, the product 2a was obtained after
column chromatography (hexane–EtOAc, 9:1).
Synthesis 2010, No. 13, 2171–2178 © Thieme Stuttgart · New York

PAPER
Highly Substituted Optically Active 2-Pyrazolines
2175
Yield: 21.7 mg (92%); white solid.
(S)-3-Methyl-1-phenyl-5-[4-(trifluoromethyl)phenyl]-4,5-dihy-
dro-1H-pyrazole (2d)
Following general procedure A (reaction time: 9 d), the product 2d
was obtained after column chromatography (hexane–EtOAc, 6:1).
1H NMR (CDCl3, 500 MHz): d = 7.35–7.30 (m, 4 H), 7.27 (m, 1 H),
7.14 (dd, J = 7.9, 7.3 Hz, 2 H), 6.92 (d, J = 7.9 Hz, 2 H), 6.74 (t,
J = 7.3 Hz, 1 H), 5.01 (dd, J = 11.9, 8.1 Hz, 1 H), 3.42 (dd,
J = 17.5, 11.9 Hz, 1 H), 2.73 (dd, J = 17.5, 8.1 Hz, 1 H), 2.07 (s,
3 H).
13C NMR (CDCl3, 100 MHz): d = 148.7, 146.2, 143.1, 129.2, 129.0,
127.5, 126.0, 118.8, 113.2, 64.9, 48.0, 16.1.
Yield: 26.9 mg (88%); white solid.
1H NMR (CDCl3, 500 MHz): d = 7.60 (d, J = 8.1 Hz, 2 H), 7.43 (d,
J = 8.1 Hz, 2 H), 7.16 (dd, J = 8.4, 7.3 Hz, 2 H), 6.89 (d, J = 8.4 Hz,
2 H), 6.77 (t, J = 7.3 Hz, 1 H), 5.07 (dd, J = 12.0, 8.0 Hz, 1 H), 3.45
(dd, J = 17.5, 12.0 Hz, 1 H), 2.70 (dd, J = 17.5, 8.0 Hz, 1 H), 2.08
(s, 3 H).
13C NMR (CDCl3, 125 MHz): d = 148.6, 147.1, 145.9, 130.0, 129.8,
129.1, 126.5, 126.2, 119.2, 113.2, 64.5, 47.7, 16.0.
MS (EI, 70 eV): m/z (%) = 236 (100) [M]+, 159 (67) [M – C6H5]+.
HRMS (EI-MS): m/z calcd for C16H16N2: 236.131348; found:
236.131539.
The enantiomeric ratio was determined by HPLC analysis using a
Daicel Chiralcel OD-H column: n-heptane–i-PrOH, 90:10; flow
rate: 0.5 mL/min; l = 254 nm: major enantiomer tR = 10.68 min,
minor enantiomer tR = 13.68 min.
MS (EI, 70 eV): m/z (%) = 304 (100) [M]+, 159 (64) [M –
C6H4CF3]+.
+
HRMS (ESI-MS): m/z calcd for C17H16N2F3 : 305.126011; found:
305.126003.
(S)-5-(4-Bromophenyl)-3-methyl-1-phenyl-4,5-dihydro-1H-
pyrazole (2b)
Following general procedure A, the product 2b was obtained after
The enantiomeric ratio was determined by HPLC analysis using a
Daicel Chiralcel OD-H column: n-heptane–i-PrOH, 90:10; flow
rate: 0.5 mL/min; l = 254 nm: major enantiomer tR = 9.62 min, mi-
nor enantiomer tR = 13.18 min.
column chromatography (hexane–EtOAc, 6:1).
Yield: 30.0 mg (95%); yellowish solid.
(S)-3-Methyl-5-(3-nitrophenyl)-1-phenyl-4,5-dihydro-1H-pyra-
zole (2e)
Following general procedure A (reaction temperature: 40 °C), the
product 2e was obtained after column chromatography (hexane–
EtOAc, 4:1).
1H NMR (CD2Cl2, 500 MHz): d = 7.47 (d, J = 8.4 Hz, 2 H), 7.19 (d,
J = 8.4 Hz, 2 H), 7.11 (dd, J = 8.1, 7.3 Hz, 2 H), 6.86 (d, J = 8.1 Hz,
2 H), 6.72 (t, J = 7.3 Hz, 1 H), 4.99 (dd, J = 12.0, 7.9 Hz, 1 H), 3.43
(dd, J = 17.4, 12.0 Hz, 1 H), 2.67 (dd, J = 17.4, 7.9 Hz, 1 H), 2.05
(s, 3 H).
Yield: 28.0 mg (99%); orange oil.
13C NMR (CD2Cl2, 125 MHz): d = 149.0, 146.3, 142.7, 132.4,
129.2, 128.2, 121.3, 118.9, 113.3, 64.4, 47.9, 15.9.
1H NMR (CDCl3, 500 MHz): d = 8.20 (dd, J = 1.7, 1.7 Hz, 1 H),
8.13 (dd, J = 8.1, 1.7 Hz, 1 H), 7.65 (d, J = 7.7 Hz, 1 H), 7.51 (dd,
J = 8.1, 7.7 Hz, 1 H), 7.16 (dd, J = 7.9, 7.3 Hz, 2 H), 6.88 (d, J = 7.9
Hz, 2 H), 6.78 (t, J = 7.3 Hz, 1 H), 5.12 (dd, J = 12.0, 8.0 Hz, 1 H),
3.49 (dd, J = 17.5, 12.0 Hz, 1 H), 2.72 (dd, J = 17.5, 8.0 Hz, 1 H),
2.09 (s, 3 H).
MS (EI, 70 eV): m/z (%) = 316/314 (69/74) [M]+, 159 (68) [M –
C6H4Br]+, 91 (100).
HRMS (EI-MS): m/z calcd for C16H15N2Br: 314.041875; found:
314.041608.
13C NMR (CDCl3, 125 MHz): d = 149.0, 148.6, 145.7, 145.4, 132.3,
The enantiomeric ratio was determined by HPLC analysis using a
Daicel Chiralcel OD-H column: n-heptane–i-PrOH, 90:10; flow
rate: 0.5 mL/min; l = 254 nm: major enantiomer tR = 10.83 min,
minor enantiomer tR = 13.31 min.
130.4, 129.2, 122.8, 121.3, 119.5, 113.3, 64.3, 47.8, 16.0.
MS (EI, 70 eV): m/z (%) = 281 (100) [M]+, 159 (67) [M –
C6H4NO2]+.
(S)-5-(3-Bromophenyl)-3-methyl-1-phenyl-4,5-dihydro-1H-
pyrazole (2c)
HRMS (EI-MS): m/z calcd for C16H15N3O2: 281.116424; found:
281.116163.
Following general procedure A, the product 2c was obtained after
column chromatography (hexane–EtOAc, 9:1).
The enantiomeric ratio was determined by HPLC analysis using a
Daicel Chiralcel OD-H column: n-heptane–i-PrOH, 90:10; flow
rate: 0.5 mL/min; l = 254 nm: major enantiomer tR = 27.20 min,
minor enantiomer tR = 31.92 min.
Yield: 30.0 mg (95%); yellowish solid.
1H NMR (CD2Cl2, 500 MHz): d = 7.48 (br s, 1 H), 7.42–7.40 (m,
1 H), 7.26–7.21 (m, 2 H), 7.13 (dd, J = 8.2, 7.3 Hz, 2 H), 6.88 (d,
J = 8.2 Hz, 2 H), 6.73 (t, J = 7.3 Hz, 1 H), 4.98 (dd, J = 12.0, 7.9 Hz,
1 H), 3.43 (dd, J = 17.6, 12.0 Hz, 1 H), 2.69 (dd, J = 17.6, 7.9 Hz,
1 H), 2.05 (s, 3 H).
13C NMR (CD2Cl2, 125 MHz): d = 149.0, 146.3, 146.1, 131.0,
130.8, 129.3, 129.2, 125.1, 123.3, 119.0, 113.3, 64.5, 48.0, 15.9.
(S)-5-(Benzo[d][1,3]dioxol-5-yl)-3-methyl-1-phenyl-4,5-dihy-
dro-1H-pyrazole (2f)
Following general procedure A (reaction temperature: 20 °C), the
product 2f was obtained after column chromatography (hexane–
EtOAc, 6:1).
Yield: 23.9 mg (85%); white solid.
MS (EI, 70 eV): m/z (%) = 316/314 (56/58) [M]+, 159 (100) [M –
1H NMR (CDCl3, 500 MHz): d = 7.15 (dd, J = 8.5, 7.4 Hz, 2 H),
6.94 (d, J = 8.5 Hz, 2 H), 6.79–6.73 (m, 4 H), 5.94–5.92 (m, 2 H),
4.92 (dd, J = 11.9, 8.1 Hz, 1 H), 3.67 (dd, J = 17.5, 11.9 Hz, 1 H),
2.69 (dd, J = 17.5, 8.1 Hz, 1 H), 2.06 (s, 3 H).
C6H4Br]+.
HRMS (ESI-MS): m/z calcd for C16H15N2NaBr+: 337.031089;
found: 337.031150.
13C NMR (CDCl3, 125 MHz): d = 148.6, 148.4, 147.0, 146.1, 137.2,
The enantiomeric ratio was determined by HPLC analysis using a
Daicel Chiralcel OD-H column: n-heptane–i-PrOH, 90:10; flow
rate: 0.5 mL/min; l = 254 nm: major enantiomer tR = 10.90 min,
minor enantiomer tR = 14.52 min.
129.0, 119.2, 118.8, 113.2, 108.7, 106.4, 101.2, 64.7, 48.0, 16.1.
MS (EI, 70 eV): m/z (%) = 280 (100) [M]+, 159 (38) [M – C7H5O2]+.
HRMS (EI-MS): m/z calcd for C17H16N2O2: 280.121178; found:
280.120995.
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S. Müller, B. List
PAPER
The enantiomeric ratio was determined by HPLC analysis using a
Daicel Chiralcel OD-H column: n-heptane–i-PrOH, 95:05; flow
rate: 0.5 mL/min; l = 254 nm: major enantiomer tR = 21.34 min,
minor enantiomer tR = 22.84 min.
(R)-3-Methyl-5-pentyl-1-phenyl-4,5-dihydro-1H-pyrazole (2i)
Following general procedure B (reaction temperature: 50 °C, N-tri-
flyl-phosphoramide of 3 was used as catalyst), the product 2i was
obtained after column chromatography (hexane–EtOAc, 30:1).
Yield: 9.1 mg (40%); colorless oil.
(S)-1-(4-Fluorophenyl)-3-methyl-5-[4-(methylsulfonyl)phenyl]-
4,5-dihydro-1H-pyrazole (2g)
Following general procedure A (reaction temperature: 50 °C), the
product 2g was obtained after column chromatography (hexane–
EtOAc, 1:1).
1H NMR (CD2Cl2, 500 MHz): d = 7.20 (dd, J = 7.7, 7.6 Hz, 2 H),
6.96 (d, J = 8.3 Hz, 2 H), 6.73 (t, J = 7.2 Hz, 1 H), 4.10–4.06 (m,
1 H), 3.03 (dd, J = 17.3, 11.0 Hz, 1 H), 2.54 (dd, J = 17.3, 5.6 Hz,
1 H), 2.02 (s, 3 H), 1.81–1.74 (m, 1 H), 1.47–1.40 (m, 1 H), 1.31 (br
m, 6 H), 0.89 (t, J = 6.1 Hz, 3 H).
13C NMR (CD2Cl2, 100 MHz): d = 149.8, 146.2, 129.3, 118.2,
113.1, 60.3, 42.9, 33.1, 32.1, 25.2, 23.0, 16.1, 14.1.
Yield: 29.3 mg (88%); yellow solid.
1H NMR (CD2Cl2, 500 MHz): d = 7.89 (d, J = 8.0 Hz, 2 H), 7.52 (d,
J = 8.0 Hz, 2 H), 6.87–6.80 (m, 4 H), 5.03 (dd, J = 11.8, 8.7 Hz,
1 H), 3.47 (dd, J = 17.5, 11.8 Hz, 1 H), 3.03 (s, 3 H), 2.70 (dd,
J = 17.5, 8.5 Hz, 1 H), 2.05 (s, 3 H).
MS (EI, 70 eV): m/z (%) = 230 (23) [M]+, 159 (100) [M – C5H11]+.
HRMS (ESI-MS): m/z calcd for C15H22N2Na+: 253.167519; found:
13C NMR (CDCl3, 125 MHz): d = 158.0, 156.1, 149.5, 149.4, 143.1,
140.3, 128.5, 127.5, 115.7, 115.5, 114.6, 114.6, 65.3, 48.1, 44.7,
15.8.
253.167351.
The enantiomeric ratio was determined by HPLC analysis using a
Daicel Chiralcel OD-H column: n-heptane–i-PrOH, 95:5; flow rate:
0.5 mL/min; l = 254 nm: major enantiomer tR = 10.69 min, minor
enantiomer tR = 12.82 min.
MS (EI, 70 eV): m/z (%) = 332 (100) [M]+, 177 (49) [M –
C7H7O2S]+.
HRMS (ESI-MS): m/z calcd for C17H17N2O2FSNa+: 355.088698;
found: 355.088461.
(4R,5S)-3,4-Dimethyl-1,5-diphenyl-4,5-dihydro-1H-pyrazole
(6a)
The enantiomeric ratio was determined by HPLC analysis using a
Daicel Chiralcel OD-3 column: n-heptane–i-PrOH, 70:30; flow
rate: 0.5 mL/min; l = 254 nm: minor enantiomer tR = 15.67 min,
major enantiomer tR = 16.69 min.
A solution of (S)-2a (100 mg, 0.423 mmol, er = 88:12) in THF (1
mL) was added dropwise to a solution of LDA [freshly prepared
from n-BuLi (300 mL, 0.75 mmol, 2.5 M in hexanes) and diisopro-
pylamine (100 mL, 0.712 mmol) in THF (4 mL)] at –78 °C. The re-
sulting red solution was stirred at –78 °C for 1 h before MeI (40 mL,
0.635 mmol) was added. After stirring at –78 °C for 3 h, the mixture
was quenched by addition of brine (2 mL) and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried over
MgSO4 and, after evaporation of the solvent, the residue was puri-
fied by column chromatography on silica gel (hexane–EtOAc, 50:1)
to give 6a.
Reaction of a,b-Unsaturated Ketones 4 and Phenylhydrazine
(5); General Procedure B
The enones 4 (0.105 mmol in case of aromatic enones, 0.110 mmol
in case of aliphatic enones) and molecular sieves 4 Å (30 mg) were
placed in a reaction vial under argon and suspended in a stock solu-
tion of phenylhydrazine (5; 0.2 M in chlorobenzene, 0.5 mL). After
stirring for 4 h at 50 °C, the cold mixture was filtered into a reaction
vial containing 3 (10 mol% in case of aromatic enones, 20 mol% in
case of aliphatic enones). The filtrate was washed with additional
chlorobenzene (0.5 mL) and the resulting mixture was stirred at the
given temperature until complete conversion (reaction monitored
by TLC). After cooling to ambient temperature, the mixture was di-
rectly submitted to flash chromatography on silica gel to obtain the
pure pyrazolines.
Yield: 67.7 mg (64%); white solid.
1H NMR (CD2Cl2, 500 MHz): d = 7.39–7.34 (m, 4 H), 7.31–7.28
(m, 1 H), 7.13–7.09 (m, 2 H), 6.91 (dd, J = 8.7, 0.9 Hz, 2 H), 6.72
(t, J = 7.3 Hz, 1 H), 4.43 (d, J = 8.9 Hz, 1 H), 2.91 (m, 1 H), 2.03 (d,
J = 1.0 Hz, 3 H), 1.32 (d, J = 7.2 Hz, 3 H).
13C NMR (CD2Cl2, 125 MHz): d = 153.0, 146.9, 143.1, 129.4,
129.0, 127.8, 126.2, 119.0, 113.7, 73.3, 55.2, 16.6, 13.9.
MS (EI, 70 eV): m/z (%) = 250 (100) [M]+, 235 (13) [M – CH3]+,
173 (53).
HRMS (ESI-MS): m/z calcd for C17H18N2Na+: 273.136220; found:
273.136182.
(S)-5-(3-Iodophenyl)-3-methyl-1-phenyl-4,5-dihydro-1H-pyra-
zole (2h)
Following general procedure B (reaction temperature: 40 °C), the
product 2h was obtained after column chromatography (hexane–
EtOAc, 9:1).
The enantiomeric ratio was determined by HPLC analysis using a
Daicel Chiralcel OD-H column: n-heptane–i-PrOH, 90:10; flow
rate: 0.5 mL/min; l = 254 nm: major enantiomer tR = 9.31 min, mi-
nor enantiomer tR = 10.02 min.
Yield: 32.3 mg (89%); yellow solid.
1H NMR (CDCl3, 500 MHz): d = 7.68 (s, 1 H), 7.60 (d, J = 7.8 Hz,
1 H), 7.27 (d, J = 7.8 Hz, 1 H), 7.16 (dd, J = 8.1, 7.6 Hz, 2 H), 7.06
(dd, J = 7.8, 7.8 Hz, 1 H), 6.90 (d, J = 8.1 Hz, 2 H), 6.77 (t,
J = 7.3 Hz, 1 H), 4.92 (dd, J = 11.9, 8.2 Hz, 1 H), 3.41 (dd,
J = 17.6, 11.9 Hz, 1 H), 2.70 (dd, J = 17.6, 8.2 Hz, 1 H), 2.07 (s,
3 H).
13C NMR (CDCl3, 100 MHz): d = 148.6, 146.1, 145.7, 136.7, 135.0,
131.0, 129.1, 125.3, 119.1, 113.3, 95.1, 64.4, 47.9, 16.0.
MS (EI, 70 eV): m/z (%) = 362 (100) [M]+, 159 (68) [M – C6H4I]+.
HRMS (ESI-MS): m/z calcd for C16H15N2INa+: 385.017217; found:
trans-4-Allyl-3-methyl-1,5-diphenyl-4,5-dihydro-1H-pyrazole
(6b)
Following the procedure described for the synthesis of 6a with al-
lylbromide as the alkylating agent, the title compound was obtained
after column chromatography on silica gel (hexane–EtOAc, 50:1).
Yield: 70.9 mg (61%); white solid.
1H NMR (CD2Cl2, 500 MHz): d = 7.36–7.33 (m, 2 H), 7.28–7.27
(m, 3 H), 7.12 (dd, J = 8.1, 7.2 Hz, 2 H), 6.89 (d, J = 8.1 Hz, 2 H),
6.70 (t, J = 7.2 Hz, 1 H), 5.79–5.74 (m, 1 H), 5.25–5.19 (m, 2 H),
4.72 (d, J = 6.6 Hz, 1 H), 3.02–2.99 (m, 1 H), 2.57–2.52 (m, 1 H),
2.42–2.36 (m, 1 H), 2.06 (s, 3 H).
385.017255.
The enantiomeric ratio was determined by HPLC analysis using a
Daicel Chiralcel OD-H column: n-heptane–i-PrOH, 90:10; flow
rate: 0.5 mL/min; l = 254 nm: major enantiomer tR = 11.23 min,
minor enantiomer tR = 14.39 min.
Synthesis 2010, No. 13, 2171–2178 © Thieme Stuttgart · New York

PAPER
Highly Substituted Optically Active 2-Pyrazolines
2177
13C NMR (CD2Cl2, 125 MHz): d = 150.5, 145.9, 143.0, 134.9,
129.3, 129.1, 127.7, 126.3, 118.5, 118.4, 113.0, 68.9, 59.7, 35.8,
14.5.
1 H), 4.78 (d, J = 5.2 Hz, 1 H), 2.91–2.89 (m, 1 H), 2.16–2.10 (m,
1 H), 2.06 (d, J = 0.8 Hz, 3 H), 1.11 (d, J = 6.9 Hz, 3 H), 0.84 (d,
J = 6.9 Hz, 3 H).
MS (EI, 70 eV): m/z (%) = 276 (40) [M]+, 235 (100) [M –
13C NMR (CD2Cl2, 100 MHz): d = 150.3, 145.3, 144.1, 129.3,
129.2, 127.5, 126.2, 118.1, 112.5, 66.8, 64.9, 28.6, 20.3, 17.2, 14.9.
CH2CHCH2]+.
HRMS (ESI-MS): m/z calcd for C19H20N2Na+: 299.151865; found:
MS (EI, 70 eV): m/z (%) = 278 (47) [M]+, 235 (100) [M – i-Pr]+.
299.151789.
HRMS (ESI-MS): m/z calcd for C19H22N2Na+: 301.167514; found:
301.167422.
trans-4-Benzyl-3-methyl-1,5-diphenyl-4,5-dihydro-1H-pyra-
zole (6c)
trans-3-Ethyl-4-methyl-1,5-diphenyl-4,5-dihydro-1H-pyrazole
(7a)
A solution of 2a (100 mg, 0.423 mmol) in THF (1 mL) was added
dropwise to a solution of LDA [freshly prepared from n-BuLi (200
mL, 0.50 mmol, 2.5 M in hexanes) and diisopropylamine (72 mL,
0.50 mmol) in THF (1 mL)] at –78 °C. The resulting red solution
was stirred at –78 °C for 1 h before a solution of benzylbromide
(100 mL, 0.846 mmol) in THF (1 mL) was added over a period of 30
min. After stirring at –78 °C for 8 h, the mixture was quenched by
addition of brine (2 mL) and extracted with CH2Cl2 (3 × 20 mL).
The combined organic layers were dried over MgSO4 and, after
evaporation of the solvent, the residue was purified by column chro-
matography on silica gel (hexane–EtOAc, 50:1) to give 6c.
A solution of 2a (100 mg, 0.423 mmol) in THF (1 mL) was added
dropwise to solution of LDA [freshly prepared from n-BuLi (415
mL, 1.04 mmol, 2.5 M in hexanes) and diisopropylamine (143 mL,
1.02 mmol) in THF (4 mL)] at –78 °C. The resulting red solution
was stirred at –78 °C for 1 h before MeI (35 mL, 0.55 mmol) was
added. After stirring at –78 °C for 2 h, a second portion of MeI (35
mL, 0.55 mmol) was added. After stirring for an additional 5 h at
–78 °C, the mixture was quenched by addition of brine (2 mL) and
extracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were dried over MgSO4 and, after evaporation of the solvent, the
residue was purified by column chromatography on silica gel (hex-
ane–EtOAc, 50:1) to give 7a.
Yield: 83.4 mg (60%); yellow oil.
1H NMR (CD2Cl2, 500 MHz): d = 7.38–7.35 (m, 2 H), 7.32–7.29
(m, 1 H), 7.23 (d, J = 7.1 Hz, 2 H), 7.20–7.17 (m, 3 H), 7.13–7.09
(m, 2 H), 6.85 (d, J = 8.0 Hz, 2 H), 6.82–6.80 (m, 2 H), 6.69 (t,
J = 7.3 Hz, 1 H), 4.75 (d, J = 5.2 Hz, 1 H), 3.23–3.19 (m, 2 H), 2.74
(dd, J = 14.9, 11.4 Hz, 1 H), 2.08 (s, 3 H).
13C NMR (CD2Cl2, 125 MHz): d = 150.5, 145.6, 142.6, 138.6,
129.7, 129.1, 129.1, 129.0, 127.5, 127.1, 126.0, 118.3, 112.7, 68.7,
61.9, 38.2, 14.7.
Yield: 99.4 mg (89%); colorless oil.
1H NMR (CD2Cl2, 500 MHz): d = 7.37–7.33 (m, 4 H), 7.30–7.27
(m, 1 H), 7.10 (dd, J = 8.0, 7.3 Hz, 2 H), 6.91 (d, J = 8.0 Hz, 2 H),
6.71 (t, J = 7.3 Hz, 1 H), 4.42 (d, J = 8.7 Hz, 1 H), 2.98–2.92 (m,
1 H), 2.49–2.40 (m, 1 H), 2.34–2.26 (m, 1 H), 1.30 (d, J = 7.2 Hz,
3 H), 1.21 (t, J = 7.2 Hz, 3 H).
13C NMR (CD2Cl2, 125 MHz): d = 157.3, 147.0, 143.1, 129.3,
129.0, 127.8, 126.2, 118.9, 113.7, 73.3, 54.0, 21.8, 16.7, 11.1.
MS (EI, 70 eV): m/z (%) = 326 (35) [M]+, 235 (100) [M – Bn]+.
HRMS (ESI-MS): m/z calcd for C23H22N2Na+: 349.167520; found:
MS (EI, 70 eV): m/z (%) = 264 (100) [M]+, 249 (17) [M – CH3]+,
349.167337.
187 (45).
HRMS (ESI-MS): m/z calcd for C18H20N2Na+: 287.151864; found:
287.151826.
trans-4-(Methoxymethyl)-3-methyl-1,5-diphenyl-4,5-dihydro-
1H-pyrazole (6d)
The procedure for the synthesis of 6c was followed. After complete
addition of the chloromethyl methyl ether solution, the mixture was
stirred for 2 h at –78 °C and then worked up as described to give 6d
after column chromatography on silica gel (hexane–EtOAc, 20:1).
Acknowledgment
The authors acknowledge generous funding from the Max-Planck-
Society, the DFG (SPP 1179, Organocatalysis), and the Fonds der
Chemischen Industrie (Award to B.L. and Fellowship to S.M.).
Yield: 71.4 mg (60%); white solid.
1H NMR (CD2Cl2, 500 MHz): d = 7.37–7.31 (m, 4 H), 7.29–7.26
(m, 1 H), 7.11 (dd, J = 8.0, 7.3 Hz, 2 H), 6.88 (d, J = 8.0 Hz, 2 H),
6.70 (t, J = 7.3 Hz, 1 H), 4.82 (d, J = 8.0 Hz, 1 H), 3.58 (d,
J = 5.1 Hz, 2 H), 3.38 (s, 3 H), 3.08–3.06 (m, 1 H), 2.04 (s, 3 H).
13C NMR (CD2Cl2, 125 MHz): d = 149.1, 146.3, 143.2, 129.3,
129.1, 127.8, 126.3, 118.8, 113.3, 71.3, 67.9, 61.0, 59.3, 14.5.
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Synthesis 2010, No. 13, 2171–2178 © Thieme Stuttgart · New York