Cinchona alkaloid-catalyzed enantioselective amination of α,β-Unsaturated ketones: An asymmetric approach to Δ2-pyrazolines

Article abstract of DOI:10.1002/adsc.201100447

Δ²-Pyrazolines are of significant medicinal and synthetic interest due to their therapeutic properties and utility in the synthesis of 1,3-diamines, yet few asymmetric methods exist to prepare them. An unprecedented and highly enantioselective organocatalytic synthesis of 2-pyrazolines was achieved through an asymmetric conjugate addition catalyzed by 9-epi-amino Cinchona alkaloids followed by deprotection-cyclization, which furnished chiral 2-pyrazolines in 46-78% yield and 59-91% ee. This bifunctional catalytic methodology thus provides easy access to a considerable range of optically active 3,5-dialkyl 2-pyrazolines. Copyright

Full text of DOI:10.1002/adsc.201100447

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DOI: 10.1002/adsc.201100447
Cinchona Alkaloid-Catalyzed Enantioselective Amination of
a,b-Unsaturated Ketones: An Asymmetric Approach to
D2-Pyrazolines
Nathaniel R. Campbell,a Bingfeng Sun,a Ravi P. Singh,a and Li Denga,*
a
Department of Chemistry, Brandeis University, 415 South St., Waltham, MA 02454-9110, USA
Fax : (+1)-781-736-2516; e-mail: deng@brandeis.edu
Received: May 31, 2011; Revised: July 21, 2011; Published online: November 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100447.
Abstract: D2-Pyrazolines are of significant medici-
nal and synthetic interest due to their therapeutic
properties and utility in the synthesis of 1,3-di-
To date, however, only a few examples have been
reported for the asymmetric synthesis of chiral 2-pyr-
azolines, and optically pure 2-pyrazolines are com-
monly obtained by resolution of their racemic coun-
terparts.[12] In 2000, the first asymmetric catalytic syn-
thesis of 2-pyrazolines through the 1,3-dipolar cyclo-
addition of acrylamides was reported utilizing a chiral
Lewis acid catalyst.[13] In 2005 an indirect strategy to
synthesize chiral 2-pyrazoline 3 (Figure 1) was report-
ed where chirality was introduced by enantioselective
organocatalytic thia-Michael addition to enones.
However, 2-pyrazolines obtained by further transfor-
mation of the thia-adduct showed low ees, and were
found to readily undergo racemization.[14] Alternative-
ly, organometallic approaches which cover asymmet-
ric [3+2]cycloadditions of 1,3-dipoles such as diazo-
esters,[15] nitrile imine dipole precussors[16] to a,b-
ACHTUNGTRENNUNGamines, yet few asymmetric methods exist to pre-
pare them. An unprecedented and highly enantiose-
lective organocatalytic synthesis of 2-pyrazolines
was achieved through an asymmetric conjugate ad-
dition catalyzed by 9-epi-amino Cinchona alkaloids
followed by deprotection-cyclization, which fur-
nished chiral 2-pyrazolines in 46–78% yield and 59–
91% ee. This bifunctional catalytic methodology
thus provides easy access to a considerable range of
optically active 3,5-dialkyl 2-pyrazolines.
Keywords: asymmetric catalysis; Cinchona alka-
loids; conjugate addition reaction; cyclization;
enones; D2-pyrazolines
D2-Pyrazolines and their derivatives have been report-
ed to possess antimicrobial,[1] immunosuppressive,[2]
anticancer,[3] antidepressant,[4] and central nervous
system effects.[5] More recently, compounds with a 2-
pyrazoline (4,5-dihydropyrazole) backbone have been
targeted as potent CB1 receptor antagonists
(Figure 1), which have exhibited antiobesity activity
(Ibipinabant 1[6]). Also 2-pyrazolines have demon-
strated potential activity in several biological
screens,[7] e.g., optimized 2-pyrazoline 2 has shown ex-
cellent activity (IC50 =26 nM) against kinesin spindle
protein; inhibitors of this protein constitute a unique
strategy in cancer treatment.[8] Apart from their me-
dicinal significance, 2-pyrazolines have also been
shown as useful intermediates in the synthesis of vari-
ous amines including pyrazolidines,[9] azaprolines,[10]
and 1,3-diamines.[11]
Figure 1. 2-Pyrazolines with valuable biological activities.
Adv. Synth. Catal. 2011, 353, 3123 – 3128
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3123

Nathaniel R. Campbell et al.
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Scheme 1. Synthetic route to 3,5-disubstituted pyrazolines 6 and 9-amino-Cinchona alkaloid catalysts 7-Q and 7-QD.
enones provide trisubstituted 3,5-dialkyl-2-pyrazolines zine with benzyl carbamate (Cbz) provided both the
4 in high ee and yield. More recently List and Mꢁller required regioselectivity and allowed the use of mild
disclosed the use of chiral phosphoric acid catalysis to deprotection through hydrogenolysis. Benzyl substitu-
obtain 2-pyrazolines 5 in high enantioselectivity and tion at the other hydrazine nitrogen made possible
yield through a 6p electrocyclization,[17] however, di- the cleavage of this group under hydrogenolysis con-
ACHTUNGTRENNUNG
For the promotion of the conjugate addition of an
Building upon this work, Briꢂre and co-workers em- amine nucleophile via iminium catalysis, selection of
ployed a Cinchona alkaloid-derived phase-transfer an appropriate acid co-catalyst is crucial for achieving
catalyst to arrive at 3,5-diarylpyrazolines with good ee optimal reaction rate and enantioselectivity. Accord-
and yield.[18]
ingly, a screening of several acids of varying acidity
However, the substrate scope was restricted to aryl- and steric properties was performed (Table 1) utilizing
substituted a,b-unsaturated enones making it of limit- 9a as a model substrate. As expected, there was no re-
ed use. Thus, development of an asymmetric method action observed after 15 h without any acid co-catalyst
which can use the alkyl-substituted a,b-unsaturated
enones to provide the chiral 3,5-dialkylpyrazolines in
useful yield and enantioselectivity will afford a com-
Table 1. Acid co-catalyst screening.[a]
plementary way to bridge this gap and allow direct
access to important classes of pyrazoline heterocycles
(Scheme 1).[9a]
First reported in 1968,[19] 9-epi-amino-Cinchona al-
kaloids (7, Scheme 1) were found to serve as highly
enantioselective organic catalysts during the last sev-
eral years. To date, they have demonstrated high
enantioselectivity in the promotion of a series of
asymmetric conjugate additions of carbon,[20] sulfur,[21]
nitrogen,[22] and oxygen[23] nucleophiles to a,b-unsatu-
rated carbonyl compounds, as well as of other nucleo-
philic additions[24] and Diels–Alder reactions.[25] Fol-
lowing our recent success in the development of 7-cat-
alyzed aminations[22b] and peroxidations[23d] of aliphat-
ic a,b-enones, we became interested in developing the
efficient enantioselective conjugate addition of hydra-
zide nucleophile 8 to aliphatic a,b-enones 9 followed
by a deprotection-cyclization of the 1,4-adduct 10 as a
Entry Acid
Equiv. vs. Conversion ee 10a
7-Q
[%][b]
[%]
1
2
3
4
5
6
7
8
–
–
3
3
3
3
3
3
3
2
1
0
3
3
33
15
12
3
12
9
–
85
37
7
CH3CO2H
ClCH2CO2H
Cl2CHCO2H
CF3CO2H
Ph2CHCO2H
Ph3CCO2H
PhCO2H
racemic
76
86
90
91
–
catalytic asymmetric access to 2-pyrazolines
(Scheme 1).
6
9
PhCO2H
10
PhCO2H
2
We began our studies by selecting the appropriate
hydrazide 8, which was critical for the desired trans-
formation, as the observed instability of 10 required
mild deprotection conditions. Protecting the hydra-
[a]
[b]
8 (0.05 mmol) and 9a (0.1 mmol).
For comparative purposes only, determined by relative
integration of 8 and 10a on GC.
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Cinchona Alkaloid-Catalyzed Enantioselective Amination of a,b-Unsaturated Ketones
(entry 1, Table 1). Acetic acid (entry 2), and several poor solubility of 8 in toluene in mind, several mix-
halogenated derivatives (entries 3–5) revealed a trend tures with chloroform (entries 8–10) were investigat-
of decreasing ee with increasing acidity; however, ac- ed, all of which improved solubility; however, with
ceptable levels of conversion could not be obtained in decreased conversion. A mixed solvent of toluene and
conjunction with high ee. Two sterically hindered ether (entry 11) maintained both excellent ee and
acetic acid derivatives (entries 6 and 7) were investi- good substrate solubility; however, the rate was
gated next, both of which afforded 76% and 86% ee, slower in toluene. Finally, a mixture of toluene and
though not at a useful level when coupled with an ac- 1,2-dichloroethane (entry 12) provided improved sub-
ceptable reaction rate. Finally, benzoic acid (entry 8) strate solubility along with a slight improvement in ee
was used, giving an optimal combination of enantiose- compared to pure toluene, while sacrificing a negligi-
lectivity and reaction rate. Lowering the equivalents ble level of conversion.
of benzoic acid versus catalyst (entries 9 and 10) de-
With optimized reaction conditions for the asym-
creased the reaction rate without decreasing selectivi- metric conjugate addition, we decided to explore the
ty, indicating that 3 equivalents of benzoic acid gave deprotection-cyclization step. It was observed that
the best combination of ee and conversion.
due to the oxidative decomposition of N1-benzylated
We next screened the effect of solvent on the reac- 2-pyrazolines (cyclized product) the enantioselectivity
tion (Table 2). Toluene, although a poor solvent for was lower in comparision to aza-Michael adduct 10a.
dissolving hydrazide 8, proved to be one of the best We chose to stabilize 2-pyrazolines 6 by adding an
for the asymmetric conjugate addition (entry 1). electron-withdrawing acetyl group to the 1-position
Halogenated solvents, while fully dissolving all sub- during cyclization. When subjected to deprotection-
strates, resulted in only moderate ee and conversion cyclization after acetyl substitution, the model sub-
(entries 2–4). Ethers, which also allowed full dissolu- strate 9a furnished 2-pyrazoline 6a in 72% yield in
tion, gave generally moderate to high ee; however, two steps with no loss of ee compared to 10a (Table 3,
conversions were significantly lower than with toluene entry 1 vs. Table 2, entry 12).
(entries 5–7). Following these results, and with the
We then investigated the scope of the reaction with
regard to a,b-unsaturated enones 9 (Table 3). We
found that a variety of alkyl substituents (R1 and R2)
with or without a functional group could be tolerated.
Substrates with a methyl group as R1, and R2 either
as ethyl (9a, entries 1 and 2) or methyl group (9b, en-
tries 3 and 4) afforded good yield and selectivity,
though enone 9b showed slightly lower levels of ee
than 9a. Fixing R1 as a methyl group, a variety of
straight-chain aliphatic substrates were successfully
applied in high ee. In addition to R1 as n-propyl (9c,
entries 5 and 6) and n-pentyl (9d, entries 7 and 8), the
substrate scope included R1 groups with a terminal
chloride (9e, entries 9 and 10), and a SEM-protected
alcohol (9f, entries 11 and 12), indicating compatibili-
ty with the use of protecting groups. Additionally, the
methodology could be extended to enone 9g, with
straight-chain alkyl substituents at both R1 and R2
(entries 13 and 14). Furthermore, the enantiomer of
6a was obtained in 83% ee by using catalyst 7-QD
(Table 3, entry 2). This deprotection protocol could be
applied to intermediates 10 to obtain 3,5-disubstituted
2-pyrazolines 6 in synthetically useful ees and yields
(Table 3). For all substrates, we observed similar iso-
lated yields with both 7-Q- and 7-QD-catalyzed reac-
tions; however, the ee of the product obtained with
the 7-QD pseudoenantiomer was consistently lower
by 4 to 23% compared with that of the 7-Q-catalyzed
product. Importantly, in all cases either enantiomer
could still be obtained in useful overall yield and
enantiomeric excess.
Table 2. Solvent screening for the addition of 8 to 9a.[a]
Entry
Solvent
Conv.
[%][b]
ee
10a
[%]
1
2
3
4
5
6
7
toluene
CHCl3
1,2-dichloroethane
CH2Cl2
THF
51
13
22
13
8
21
24
40
33
35
31
47
88
76
77
82
82
88
91
87
89
89
91
90
TBME
Et2O
8[c]
9[c]
10[c]
11
12[c]
toluene/CHCl3 (7/3)
mesitylene/CHCl3 (7/3)
Et2O/CHCl3 (7/3)
toluene/Et2O (1/1)
tolene/1,2-DCE
[a]
Reaction conditions: 8 (0.05 mmol) and 9a (0.1 mmol),
and solvent (0.18 mL).
For comparative purposes only, determined by relative
integration of 8 and 10a on GC.
Solvent (0.2 mL).
[b]
[c]
In the presence of an acid co-catalyst, the 9-amino-
Cinchona alkaloid 7 was postulated to activate the
Adv. Synth. Catal. 2011, 353, 3123 – 3128
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Nathaniel R. Campbell et al.
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Table 3. Substrate scope for the addition of 8 to enones 9a–f.[a]
Entry
R1/R2
9–6
7
Yield 6 [%] (2 steps)
ee 6 [%]
1
2
3
4
5
6
7
8
Me/Et
Me/Et
9a–6a
9a–6a
9b–6b
9b–6b
9c–6c
9c–6c
9d–6d
9d–6d
9e–6e
9e–6e
9f–6f
9f–6f
9g–6g
9g–6g
7-Q
7-QD
7-Q
7-QD
7-Q
7-QD
7-Q
7-QD
7-Q
7-QD
7-Q
7-QD
7-Q
72
60
57
46
78
74
58
63
50
63
64
66
66
72
90
83
82
59
90
81
82
76
91
75
91
76
90
86
Me/Me
Me/Me
n-Pr/Me
n-Pr/Me
n-Pen/Me
n-Pen/Me
9
Cl
Cl
ACHTUNGTRENNUNG
A
10
11
12
13
14
SEMO
SEMO
n-Pr/n-Bu
n-Pr/n-Bu
ACHTUNGTRENNUNG
A
7-QD
[a]
Reaction conditions (a): 8 (0.1 mmol) 9 (0.2 mmol), 7 (15 mol%), PhCO2H (45 mol%), and solvent (0.35 mL); (b): AcCl
(0.2 mmol), Pd/C (20 mg), and THF (2.0 mL).
a,b-unsaturated enone 9 via iminium catalysis while nature of 9-amino-Cinchona alkaloid catalysts. Mode
interacting with the hydrazide 8 through hydrogen A involves hydrogen bonding of the ammonium salt
bonding in the stereo-defining step. Due to the pres- to substrate 8. Although this mode decreases the nu-
ence of benzoic acid in the reaction mixture, the cata- cleophilicity of 8 electronically, it promotes catalysis
lyst could exist as both the ammonium salt and the through bringing both reactants close to each other,[26]
free amine. Thus, two modes of nucleophile activation facilitating the reaction while imparting stereocontrol.
by the catalyst-substrate iminium salt could be pro- Three hydrogen bonding interactions are possible, in-
posed (Scheme 2), both based on the bifunctional volving the catalyst interacting with the carbonyl
oxygen of the carbamate (mode A1), or with the nu-
cleophilic nitrogen (mode A2). Additionally, the free
amine catalyst can act as a base, activating nucleo-
phile 8 via hydrogen bonding to the nucleophilic ni-
trogen (mode B). As has been postulated previous-
ly,[27] there exists the potential for nitrogen nucleo-
philes to compete with catalysts under iminium catal-
ysis conditions through the formation of a nucleophile
iminium salt; however, in this case no such back-
ground reaction was observed, indicating that the con-
jugate addition was promoted exclusively by the cata-
lyst 7.
In conclusion, we have developed an efficient enan-
tioselective organocatalytic approach, which provides
an unprecedented asymmetric access to 3,5-dialkyl-2-
pyrazolines 6 in useful yield and enantioselectivity.
This methodology was tolerant of a variety of aliphat-
ic a,b-unsaturated enones, using an easily accessible
nitrogen nucleophile and catalyst. Additionally, both
enantiomers of the chiral pyrazolines could be ac-
cessed by using the readily available bifunctional Cin-
Scheme 2. Proposed modes of substrate activation by cata-
lyst 7, and potential substrate-activated mode of background
catalysis.
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Cinchona Alkaloid-Catalyzed Enantioselective Amination of a,b-Unsaturated Ketones
dullah, M. A. Bakht, J. Majeed, Eur. J. Med. Chem.
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and quinidine (7-QD). Such a methodology should
provide a useful asymmetric route to a variety of pre-
viously inaccessible asymmetric 3,5-dialkyl-2-pyrazo-
lines and their derivatives.
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Experimental Section
General Procedure for the Enantioselcective
Synthesis of D2-Pyrazolines
Catalyst 7-Q (4.9 mg, 15 mmol) or 7-QD (4.9 mg, 15 mmol),
benzoic acid (5.5 mg, 45 mmol), and 8 (25.6 mg, 0.1 mmol)
were dissolved in toluene/1,2-dichloroethane (7/3, 0.35 mL)
in an ultrasonic bath for 5 min. The reaction vial was placed
in a À258C freezer for 20 min, at which point 9 (0.2 mmol)
was added. After standing at À258C for 4 days, the reaction
mixture was purified by flash chromatography to give a mix-
ture of 10 and 6 (inseparable mixture). This mixture was
concentrated under vacuum and used for the formation of 6.
To an oven-dried Schlenk flask under N2 were added Pd/
C (20 mg, 0.2 mmol, dry support) and 10 in THF (2.0 mL).
The flask was cooled to À788C, exchanged with H2, and
AcCl (14 mL, 0.2 mmol) was added. The bath was changed
to À188C (dry ice in saturated aqueous NaCl) and allowed
to warm slowly to room temperature until the full consump-
tion of 10 was observed by TLC (2–4 h). The reaction was
stopped by passing the suspension through a Celiteꢃ plug
with CHCl3. Solvent was removed under vacuum, the resi-
due was dissolved in CH2Cl2 (2 mL) and treated with excess
aqueous NaHCO3. The aqueous layer was extracted with
CH2Cl2 (2ꢄ1 mL), the combined organic layers were dried
over anhydrous Na2SO4, and concentrated under vacuum.
The basified residue was purified by flash chromatography
to give 6a–g as pale yellow oils.
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Acknowledgements
We are grateful for financial support from the National Insti-
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