Organocatalytic one-pot asymmetric synthesis of 4 H,5 H-pyrano[2,3-c] pyrazoles

Article abstract of DOI:10.1021/ol301983f

An efficient one pot asymmetric synthesis of tetrahydropyrano[2,3-c] pyrazoles has been developed. This class of biologically active heterocycles can be obtained via a secondary amine catalyzed asymmetric Michael/Wittig/oxa- Michael reaction sequence. Remarkably, the title compounds were accessible in good to very good yields and very good to excellent enantioselectivities after a single purification step.

Full text of DOI:10.1021/ol301983f

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4254–4257
Organocatalytic One-Pot
Asymmetric Synthesis of
4H,5H‑Pyrano[2,3‑c]pyrazoles
,†
†
†
†
ꢀ
€
Dieter Enders,* Andre Grossmann, Bianca Gieraths, Muharrem Duzdemir, and
Carina Merkens‡
Institute of Organic Chemistry and Institute of Inorganic Chemistry, RWTH Aachen
University, Landoltweg 1, 52074 Aachen, Germany
enders@rwth-aachen.de
Received July 17, 2012
ABSTRACT
An efficient one pot asymmetric synthesis of tetrahydropyrano[2,3-c]pyrazoles has been developed. This class of biologically active heterocycles
can be obtained via a secondary amine catalyzed asymmetric Michael/Wittig/oxa-Michael reaction sequence. Remarkably, the title compounds
were accessible in good to very good yields and very good to excellent enantioselectivities after a single purification step.
Pyrazoles are one of the most important classes of
bioactive heterocycles gaining increased interest from
pharmaceutical, chemical, and agricultural industries over
the past decade.1 Among various possible pyrazole deri-
vatives, pyrazolones have played an outstanding role for
more than one century. As a matter of fact, in 1884 Knorr
and Filehne developed phenazone (1), which is the very
first fully synthetic antipyretic and analgesic,2 sometimes
also referred to as the “mother” of all modern painkillers,3
while its successor metamizole (2) is the strongest anti-
pyretic in modern medicine (Figure 1). Currently, many
pyrazole and pyrazolone derivatives are known with a
broad range of bioactive properties such as anti-inflam-
matory, antipyretic, analgetic, antiviral, antibacterial,
antifungal, etc. Furthermore, they are used in food and
chemical industries as optical bleach, food colorants, and
ligands for transition metals.1
After the first synthesis of a pyrazole derivative in 18834
and one year later of pyrazolone,5 much effort was focused
toward developing new preparation methods for these
heterocycles, usually via condensation of dicarbonyl com-
pounds with hydrazines or [3þ2]-cycloadditions, and their
subsequent derivatization.6
Due to tautomerism, 5-hydroxy-1,2-diazoles can act
either as a carbonyl compound or as an aromatic hetero-
cycle. In solution the pyrazolone form predominates lead-
ing to carbonyl reactivity while an appreciable amount
of the aromatic pyrazole-5-ol is only present in the case
of a special substitution pattern.7 Several alkylations of
(4) Knorr, L. Ber. Dtsch. Chem. Ges. 1883, 16, 2597–2599.
(5) Knorr, L. Ber. Dtsch. Chem. Ges. 1884, 17, 2032–2049.
(6) (a) Elguero, J. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, U.K., 1984; Vol. 5, p 167.
(b) Elguero, J. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, U. K., 1996; Vol. 3,
p1. (c)Yet, L. InComprehensive Heterocyclic Chemistry III;Katritzky, A. R.,
Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier: Oxford, U.K.,
2008; Vol. 4, p 1.
† Institute of Organic Chemistry.
‡ Institute of Inorganic Chemistry.
(1) For recent reviews on pyrazoles, see: (a) Varvounis, G. Adv.
(7) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley VCH:
2010; pp 493ꢀ501.
Heterocycl. Chem. 2009, 98, 143–224. (b) Schmidt, A.; Dreger, A. Curr.
(8) For recent examples, see: (a) Altieri, E.; Cordaro, M.; Grassi, G.;
Risitano, F.; Scala, A. Synlett 2010, 2106–2108. (b) Wang, A.-Q.; Jin,
T.-S.; Cheng, Z.-L.; Li, T.-S. Asian J. Chem. 2010, 22, 1973–1976.
(c) Alba, A.-N. R.; Calbet, T.; Font-Bardıa, M.; Moyano, A.; Rios, R.
Eur. J. Org. Chem. 2011, 2053–2056.
ꢀ
ꢀ
Org. Chem. 2011, 15, 1423–1463. (c) Fustero, S.; Sanchez-Rosello, M.;
ꢀ
Barrio, P.; Simon-Fuentes, A. Chem. Rev. 2011, 111, 6984–7034.
(2) Brune, K. Acute Pain 1997, 1, 33–40.
(3) Tainter, M. L. Ann. N.Y. Acad. Sci. 1948, 51, 3–11.
r
10.1021/ol301983f
Published on Web 08/01/2012
2012 American Chemical Society

Table 1. Optimization of the Reaction Conditionsa
Figure 1. Bioactive pyrazolones and tetrahydropyrano[2,3-c]-
pyrazoles.
cat.
additive
(mol %)
yieldb
(%)
entry (mol %)
solvent
erc
1
8a (2.5)
8b (2.5)
8c (2.5)
8d (2.5)
10 (2.5)
11 (2.5)
8b (2.5)
8b (2.5)
8b (2.5)
8b (2.5)
8b (2.5)
8b (2.5)
8b (20)
CHCl3
CHCl3
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
76
88
22
88
97
45
82
94
80
71
88
n.r.
95
80:20
83:17
76:24
70:30
55:45
67:33
83:17
83:17
77:23
77:23
77:23
ꢀ
pyrazolones R to the carbonyl group have been reported,8
but only a few were performed in an enantioselective
manner.9 Herein the pyrazolones acted as typical enolates;
no aromatization was observed, and therefore after the
first alkylation in the R-position a second alkylation could
take place. In contrast, FriedelꢀCrafts-type alkylations
of pyrazole-5-ols are possible when the aromatic form is
stabilized by an electron-withdrawing group (e.g., a tri-
fluoromethyl group in the 3-position or carbonyl group in
the 4-position),10 but to the best of our knowledge, there
are no reports of performing this reaction in an enantiose-
lective fashion.
2
3
CHCl3
4
CHCl3
5
CHCl3
6
CHCl3
7
CH2Cl2
Toluene
CHCl3
8
9
AcOH (10)
BZA (10)
pNO2-BZA (10)
TsOH (10)
ꢀ
10
11
12
13d
CHCl3
CHCl3
CHCl3
Toluene/
MeOH (10:1)
89:11
a Reaction conditions: 6a (1.0 mmol), 7a (1.0 mmol), solvent (4.0
mL), 24 h, rt, under air. b Yields of 9a were determined via 1H NMR
spectroscopy using 4,40-di-tert-butylbiphenyl (DTBP) as internal stan-
dard; sum of isomers. c Enantiomeric ratios were determined by HPLC
analysis on a chiral stationary phase after converting 9a to 13k. d At ꢀ78 °C.
pTsOH = p-toluenesulfonic acid. BZA = benzoic acid.
Hence we would like to close this gap and report the first
asymmetric synthesis of tetrahydropyrano[2,3-c]pyrazoles
in one pot via a Michael/acetalization cascade followed by
a ring-opening/Wittig/oxa-Michael domino reaction. The
core structure of the corresponding products is present in
several bioactive molecules11 (Figure 1, compounds 3ꢀ5).
We started our investigations by optimizing the reaction
conditions of the Michael/acetalization cascade reaction
utilizing 3-trifluoromethylpyrazolone 7a and crotonalde-
hyde (6a) in the presence of diphenyl TMS-prolinol 8a
(Table 1). Indeed the reaction proceeded smoothly in
chloroform affording the acetal 9a in 76% yield. Unfortu-
nately, rapid equilibrium between the two diastereomers
(dr 71:29) and the open chained form of 9a12 and its
instability at higher temperature prevented the determina-
tion of the enantiomeric ratio of 9a by HPLC or gas
chromatography. Hence, 9a was treated with a Wittig
reagent 12 leading to configurationally stable tetrahy-
dropyrano[2,3-c]pyrazoles 13 via a spontaneous ring-
opening/Wittig/oxa-Michael domino reaction (scheme in
Table 2). Best results were achieved in toluene or chlori-
nated solvents at rt yielding compounds 13 in 85ꢀ86%
yields and moderate diastereoselectivities (dr 71:29).13
After having established this protocol we continued the
optimization of the conditions of the Michael/acetaliza-
tion cascade reaction applying different catalysts. The
MacMillan imidazolidinone 10 showed the best product
(9) (a) Liao, Y.-H.; Chen, W.-B.; Wu, Z.-J.; Du, X.-L.; Cun, L.-F.;
Zhang, X.-M.; Yuan, W.-C. Adv. Synth. Catal. 2010, 352, 827–832. (b)
ꢀ
Companyo, X.; Zea, A.; Alba, A.-N. R.; Mazzanti, A.; Moyano, A.;
Rios, R. Chem. Commun. 2010, 46, 6953–6955. (c) Wang, Z.; Yang, Z.;
Chen, D.; Liu, X.; Lin, L.; Feng, X. Angew. Chem. 2011, 123, 5030–5034.
Angew. Chem., Int. Ed. 2011, 50, 4928–4932. (d) Yang, Z.; Wang, Z.; Bai,
S.; Liu, X.; Lin, L.; Feng, X. Org. Lett. 2011, 13, 596–599. (e) Alba, A.-N.
R.; Zea, A.; Valero, G.; Calbet, T.; Font-Bardıa, M.; Mazzanti, A.;
Moyano, A.; Rios, R. Eur. J. Org. Chem. 2011, 1318–1325. (f) Zea, A.;
Alba, A.-N. R.; Mazzanti, A.; Moyano, A.; Rios, R. Org. Biomol. Chem.
2011, 9, 6519–6523.
(10) For selected examples, see: (a) Wong, F. F.; Huang, Y.-Y.
Tetrahedron 2011, 67, 3863–3867. (b) Abaszadeh, M.; Sheibani, H.;
Saidi, K. Aust. J. Chem. 2010, 63, 92–95. (c) Guo, C.; Holzer, W.
Molbank 2009, M605. (d) Castognolo, D.; De Logu, A.; Radi, M.;
Bechi, B.; Manetti, F.; Magnani, M.; Meleddu, R.; Chisu, L.; Botta, M.
Bioorg. Med. Chem. 2008, 16, 8587–8591. (e) Yao, C.-S.; Yu, C.-X.; Tu,
S.-J.; Shi, D.-Q.; Wang, X.-S.; Zhu, Y.-Q.; Yang, H.-Z. J. Fluorine
Chem. 2007, 128, 105–109. (f) Bol’But, A. V.; Dorokhov, V. I.; Sukach,
V. A.; Tolmachev, A. A.; Vovk, M. V. Russ. J. Org. Chem. 2003, 39,
1860–1862. (g) Ceulemans, E.; Voets, M.; Emmers, S.; Uytterhoeven, K.;
Meervelt, L. V.; Dehaen, W. Tetrahedron 2002, 58, 531–544.
(11) (a) Stegelmeier, H.; Brandes, W. Bayer AG, U.S. Patent
4,515,801, May 7, 1985. (b) Mochizuki, M.; Imaeda, T. Takeda Pharma-
ceutical Company Limited, Int. Patent WO/2010/140339, Dec. 9, 2010. (c)
Van Herk, T.; Brusee, J.; van den Nieuwendijk, A. M. C. H.; van der Klein,
P. A. M.; IJzerman, A. P.; Stannek, C.; Burmeister, A.; Lorenzen, A. J. Med.
Chem. 2003, 46, 3945–3951.
(12) The ratio between the closed and open chained form of 9a was
88:12 as determined by 1H NMR spectroscopy.
(13) For details on the optimization of the ring opening/Wittig/oxa-
Michael cascade, see Supporting Information.
Org. Lett., Vol. 14, No. 16, 2012
4255

time, and costs and sometimes have a higher efficiency
than the corresponding stepwise protocols.16 With both
steps toward the configurationally stable cascade product
13 optimized, we compared the results from the one-pot
process and the stepwise protocol. Indeed, the first proved
to be superior in yield (87% vs 83%; over two steps)
and asymmetric induction (er 96:4 vs 89:11; major
diastereomer) for compound 13k. Therefore, the substrate
scope was studied on the total asymmetric one-pot
Michael/Wittig/oxa-Michael reaction sequence (Table 2).
Different aldehydes and pyrazolones were applied yielding
the desired one-pot products in good to very good yields
and enantioselectivities with moderate diastereoselectiv-
ities. Aromatic aldehydes performed similar to aliphatic
ones in terms of yield but with significantly lower enantio-
meric excesses (Table 2, entry 13a vs 13f). Furthermore,
branched aldehydes (Table 2, 13e) and functional groups
such as an ester or protected alcohol in the form of a silyl
ether were tolerated (Table 2, 13h and 13i). Worth men-
tioning is that er values up to 98:2 were reached. Finally,
more electron-rich 3-trifluoromethylpyrazolones bearing a
phenyl moiety at the nitrogen atom were used without any
loss in yield or selectivities (Table 2, 13b). The configura-
tion of the major diastereomer was trans, as was deter-
mined via NOESY experiments on compounds 13e and
13f. In addition, X-ray crystallographic analysis of com-
pound 13j confirmed the (4R,6S)-configuration (Figure 2).
Subsequently, we studied the influence of different
phosphoranes on the reaction (Table 3). Electron-rich or
-neutral Wittig reagents showed similar results leading to
tetrahydropyrano[2,3-c]pyrazoles 13 in very good yields
and enantioselectivities (Table 3, 13a and 13k). In contrast,
less reactive phosphoranes bearing slightly electron-defi-
cient substituents gave only moderate yields and good
stereoinduction (Table 3, 13l). Since the Wittig reagent
cannot influence the stereogenic center generating step
directly, there is likely a slow racemization and decom-
position process present.17 Hence, the faster the Wittig
reagent can remove the intermediate acetal 9 from the
reaction mixture by the formation of pyrazole derivative
13, the higher the enantioselectivity and yield are. Finally,
after changing group R3 on the Wittig reagent from a
ketone to an ester, cyclization was no longer observed
leading to open-chained pyrazole-5-ol derivative 13m0.
Interestingly, the corresponding pyrazolone tautomer
was not observed, while the product was isolated in very
good yields.
Table 2. Scopeof Aldehyde and 3-Trifluoromethyl Pyrazolonea,b
yieldc
(%)
erd
erd
13
R1
R2
drd
(trans)
(cis)
a
b
c
d
e
f
Me
Me
Et
Me
Ph
86
85
73
77
70
88
81
74
84
75
72:28
71:29
77:23
79:21
64:36e
64:36
86:14
74:26
84:16
83:17e
96:4
94:6
97:3
98:2
97:3
88:12
97:3
98:2
96:4
98:2
96:4
93:7
98:2
99:1
98:2
n.d.
99:1
99:1
n.d.
93:7
Me
Me
Me
Me
Me
Me
Me
Ph
nPr
iPr
Ph
Bn
g
h
i
CH2OTIPS
CH2OBz
Bn
j
a Reaction conditions: 6 (1.0 mmol), 7 (1.0 mmol), toluene/MeOH
(4.0 mL), 24 h at ꢀ78 °C, then 12 (0.95 mmol), CHCl3 (4.0 mL), 24 h at
ꢀ78 to rt, under air. b R3 was 3-(MeO)C6H4 for 13aꢀi and 4-BrC6H4 for
13j. c Yields of isolated diastereomeric mixture of 13. d Diastereomeric
and enantiomeric ratios were determined via HPLC analysis on a chiral
1
stationary phase. e Diastereomeric ratio was determined via H NMR
spectroscopy. n.d. = not determined.
yield from all tested catalysts but with low asymmetric
induction (Table 1, entry 5). A sterically more demanding
catalyst 11 increased the enantiomeric ratio of the pro-
ducts, but the yields dropped significantly (Table 1, entry 6).
Better results were achieved with prolinol derivatives
8aꢀ8d (Table 1, entries 1ꢀ4) with secondary amine 8b
performing the best and affording the desired product in
88% yield with a moderate enantiomeric ratio (83:17).
Subsequently, a range of solvents and additives were
tested. In all polar solvents the reaction was not clean
giving only low yields (32ꢀ44%) while maintaining mod-
erate enantiomeric ratios (er 66:34ꢀ76:24).14 Similarly,
the use of protic acids as additives in most cases did reduce
both the yield and the enantiomeric ratios (Table 1,
entries 9ꢀ12).15 In contrast, toluene or dichloromethane
improved both yields and enantioselectivities (Table 1,
entries 7ꢀ8). Finally, by decreasing the temperature to
ꢀ78 °C, increasing the catalyst loading to 20 mol %, and
adding some methanol to toluene for better pyrazolone
solubility we achieved excellent yields and good enantios-
electivity in this reaction (Table 1, entry 13).
The proposed mechanism of the reported cascade reac-
tion is shown in Scheme 1. The reaction starts with the
formation of the iminium intermediate I by condensation
of the catalyst 8b with the aldehyde 6. The pyrazolone 7
Recently, one-pot reactions have received a lot of atten-
tion since they reduce the number of purification steps,
(14) For details on solvent screening, see Supporting Information.
(15) It is widely accepted that protic additives increase the reaction
rate of secondary amine catalyzed reactions by providing a faster iminium
ion formation. For a recent review, see:Jensen, K. L.; Dickmeiss, G.;
Jiang, H.; Albrecht, L.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45,
248–264.
(16) For a recent review on one-pot processes, see: Albrecht, Ł.;
Jiang, H.; Jørgensen, K. A. Angew. Chem. 2011, 123, 8642–8660. Angew.
Chem., Int. Ed. 2011, 50, 8492–8509.
(17) The slow decomposition of the intermediate acetal was proven
by stirring an isolated and purified sample of 9a, which initially had an er
of 88:12, with (R)-8a as the catalyst in toluene/methanol 10:1 at rt. After
24 h the er dropped to 75:25 while more than 50% of the startingmaterial
decomposed. For details, see Supporting Information.
(18) CCDC-890616 contains the supplementary crystallographic
data for the compound 13j reported in this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
4256
Org. Lett., Vol. 14, No. 16, 2012

Scheme 1. Proposed Mechanism of the One-Pot Reaction
Sequence
Figure 2. ORTEP plot of 13j determined by X-ray analysis.18
Table 3. Influence of the Wittig Reagenta
intermediate 130. Finally, spontaneous intramolecular oxa-
Michael addition closes the ring to the final product 13.
In summary, we have developed a new efficient asym-
metric synthesis of tetrahydropyrano[2,3-c]pyrazoles.
This class of biologically important compounds was
accessible via a one-pot, asymmetric Michael/Wittig/
oxa-Michael reaction sequence in very good yields and
enantioselectivities. Noteworthy, the pyrazole derivative 9
formed as an intermediate is the formal product of a, thus
far, unknown asymmetric FriedelꢀCrafts-type alkylation
of pyrazole-5-ols.
yieldb
(%)
erc
erc
13
R
drc
(major)
(minor)
13a
13k
13l
3-(MeO)C6H4
Ph
86
87
69
85
72:28
72:28
72:28
ꢀ
96:4
96:4
94:6
n.d.
96:4
98:2
94:6
n.d.
4-BrC6H4
OEt
13m0
a Reaction conditions: see Table 2. b Yields of isolated diastereomeric
mixture of 13 or of pure 130. c Diastereomeric and enantiomeric ratios
were determined via HPLC analysis on a chiral stationary phase.
Acknowledgment. We thank the German Research
Foundation for support (scholarship for A.G. and C.M.,
International Research Training Group “Selectivity in
Chemo- and Biocatalysis” - SeleCa). The donation of
chemicals by the former Degussa AG and BASF SE is
gratefully acknowledged.
attacks the intermediate I from the backside generating
the heteroaromatic structure II.19 Subsequently, the cata-
lyst 8b is liberated by hydrolysis of II generating the
intermediate 9 after hemiacetalization. Since compound
9 is in equilibrium with its open chained form 90 the
Wittig olefination occurs leading to the R,β-unsaturated
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) We conclude that the aromatization occurs directly after or
during the alkylation since in all isolated structures bearing a substituent
in the 4-position such as 9 or 130 the aromatic form was preferred. In
contrast, the aromatic tautomer of pyrazolone 7 was not observed under
our reaction conditions as was verified in a control experiment.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
4257