6722
S. Degorce et al. / Tetrahedron Letters 52 (2011) 6719–6722
symmetrical 3,5-bis(arylamino)pyrazoles to ensure the protocol
proceeded efficiently. Retrospectively and rather fortuitously, we
decided to test the ‘limitations’ of process with phenyl and 3-fluor-
ophenylisothiocyanates. Indeed, application of the methodology
reported1,2 worked affording very poor yields of propane bis(aryl-
thioamide) precursors 16 and 18. However, cyclisation with hydra-
zine2 proceeded in excellent yield to afford the symmetrical
bis(arylaminopyrazoles) or BAPyrs 17 and 19 (Scheme 3).
During the preparation of 17 and 19, we noticed the relative sig-
nificant difference between the retention times (2.98 min vs
3.30 min, respectively) of both final products using a standard
LCMS gradient12 and even silica gel thin-layer chromatography.
Therefore, we postulated that we could aim for a diversity-orien-
tated synthesis approach with the knowledge that all three BAPyrs
would be useful for enriching our compound collection and that we
designed our library to have one hydrophilic aniline moiety and
one lipophilic moiety so we anticipated the separation to be even
more significant.
ducing another diversity point to the process by varying the cyclis-
ing binucleophile.
Acknowledgments
The authors would like to acknowledge Mr. Auélien Adam, Mr.
Lionel Graux, Dr Jean-Jacques Lohman, Mr. Michel Vautier, Mr. Fab-
rice Renaud, and Mr. Christian Delvare for custom isothiocyanate
synthesis and analytical support for this exploration.
Supplementary data
Supplementary data (full experimental procedures and sup-
porting LCMS and 1H NMR characterisation data) associated with
this article can be found, in the online version, at doi:10.1016/
References and notes
In order to test the approach, we carried out a modified one-pot
version of the reported protocol with 0.5 equiv of both phenyliso-
thiocyanate and 0.5 equiv of 3-fluorophenylisothiocyanate. To our
satisfaction, the reaction proceeded as expected affording a quasi-
statistical mixture of BAPyrs (17, 19, and 21) in acceptable yields
that was easily separated using our standard preparative LCMS
gradient (Scheme 3).
1. (a) FR1410275, 1965, p 9.; (b) Barnikow, G.; Kath, V.; Richter, D. J. Prakt. Chem.
1965, 30, 63–66.
2. (a) Barnikow, G.; Kunzek, H.; Richter, D. Justus Liebigs Ann. Chem. 1966, 695, 49–
54; (b) Hartke, K.; Mueller, H. G. Arch. Pharm. 1988, 321, 863–871.
3. (a) Heyde, C.; Zug, I.; Hartmann, H. Eur. J. Org. Chem. 2000, 19, 3273–3278; (b)
Reuveni, H.; Levitzki, A.; Steiner, L.; Sasson, R.; Ben-David, I.; Weissberg, A. PCT
Int. Appl. 2008, WO2008068751, p 92.
The actual mechanism of the reaction has not yet been dis-
cussed in any detail1,2 but we assume that the reaction happens
through double nucleophilic addition of sodium acetylacetonate
on to the first and second isothiocyanate affording 22. From this
point and experimental evidence,14 we estimate that the reaction
proceeds through a double retro-Claisen reaction affording the
propane bis(arylthioamide) intermediate 25 with the loss of
2 equiv of ethyl acetate. Finally, quite simply hydrazine affords
the desired 3,5-bis(arylamino)pyrazole (29) through nucelophilic
attack at both thiocarbonyl moieties eliminating 2 equiv of H2S
(Scheme 4).
While we were satisfied by the simplicity and applicability of
the operations to library synthesis, we were rather disappointed
by the isolated yields, even if they were obtained after a single
injection using mass-triggered preparative LCMS. After a signifi-
cant amount of optimisation, we made four key changes to the ori-
ginal protocol to assure a library process capable of tolerating a
large degree of structural diversity.13 Firstly, we purchased sodium
acetylacetonate to ensure that there was no remaining sodium eth-
anolate which could consume the isothiocyanate to afford the sta-
ble ethyl thiocarbamate impurities. Secondly, we found changing
the solvent from ethanol to 2-methoxyethanol was critical in
obtaining reproducible results reducing competing retro-Claisen
prior to the addition of the second isothiocyanate.14 Thirdly, we
found that conducting the first step at room temperature for 48 h
was advantageous resulting in practically no mono-acetyl impuri-
ties.14 Finally, we found that the first step to synthesise the pro-
pane bis(arylthioamides) was very sensitive to air and to obtain
the optimum transformations, the reaction mixture must be
sparged with argon and agitated under a blanket of argon. These
four key changes permitted the preparation of over 200 novel BAP-
yrs in less than 1 month.
4. Laing, V. E.; Brookings, D. C.; Carbery, R. J.; Gascon S.; Jose M.; Hutchings, M. C.;
Langham, B. J.; Lowe, M. A. PCT Int. Appl. 2008, WO2008020206, p 123.
5. For recent review articles consult: (a) Surry, D. S.; Buchwald, S. L. Chem. Sci.
2011, 2, 27–50; (b) Klinkenberg, J. L.; Hartwig, J. F. Angew. Chem., Int. Ed. 2011,
50, 86–95. and references cited therein.
6. (a) Delaunay, T.; Genix, P.; Es-Sayed, M.; Vors, J.-P.; Monteiro, N.; Balme, G. Org.
Lett. 2010, 12, 3328–3331; (b) Delaunay, T.; Es-Sayed, M.; Vors, J.-P.; Monteiro,
N.; Balme, G. Eur. J. Org. Chem. 2011, 20–21, 3837–3848.
7. Toto, P.; Chenault, J.; El Hakmaoui, A.; Akssira, M.; Guillaumet, G. Synth.
Commun. 2008, 38, 674–683.
8. Morimoto, K.; Sato, T.; Yamamoto, S.; Takeuchi, H. J. Heterocycl Chem. 1997, 34,
537–540.
9. According to a search carried out on the 16th September 2011 using Sci-
FinderTM, there were no direct references for transition-metal catalysed
(hetero)aryl aminations of C-3 or C-5-halogen substituted pyrazoles without
protection and just one reference with a SO2N(CH3)2 protecting group reported
in Yasuma, T.; Sasaki, S.; Ujikawa, O.; Miyamoto, Y.; Gwaltney, S. L.; Cao, S. X.;
Jennings, A. PCT Int. Appl. 2008, WO2008156757, p 341.
10. Park, S.-J.; Lee, J.-C.; Lee, K.-I. Bull. Korean Chem. Soc. 2007, 28, 1203–1205.
11. Di Braccio, M.; Grossi, G.; Ceruti, M.; Rocco, F.; Loddo, R.; Sanna, G.; Busonera,
B.; Murreddu, M.; Marongiu, M. E. Farmaco 2005, 60, 113–125.
12. (a) Standard analytical LCMS of the crude reactions were carried out using a
Waters 2690 photodiode array detector system using the following conditions:
Column, C-18 Waters X-Bridge 4.8 Â 50 mm; Solvent A, water 0.2% ammonium
carbonate; Solvent B, CH3CN; flow rate, 2.5 mL/min; run time, 4.5 min;
gradient, from 0 to 100% solvent B; mass detector, micro mass ZMD; (b)
Preparative LCMS was carried out using Waters 600 Pumps linked to a Waters
2700 Sample Manager and a Waters micromass ZMD mass detector. Column
C18 Waters X-Bridge 30 Â 150 mm,
5 l. Eluant: 40 mL/mn 10 to 100%
Acetonitrile-Buffer Ammonium Carbonate 2 g/L over 14 mn.
13. General process: To a stirred suspension/solution of aryl isothiocyanate 1
(0.5 equiv) and aryl isothiocyanate 2 (0.5 equiv) in 2-methoxyethanol (1.5 mL/
1 mmol) pre-saturated with argon, was added sodium acetylacetonate hydrate
(1.0 equiv) in one portion and the resulting solution/suspension was stirred for
48 h at room temperature giving
a clear solution. Hydrazine hydrate
(1.1 equiv) was added in one portion and the resulting solution was stirred
at 85 °C for 2 h. The reaction mixture was purified by mass-triggered
preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5
microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/min) and
decreasingly polar mixtures of water (containing 0.2% ammonium carbonate)
and acetonitrile as eluent. The fractions containing the desired compounds
were evaporated to dryness to afford separately the most hydrophilic BAPyr A
(5–15%), the desired BAPyr B (22–61%) and the least hydrophilic BAPyr C (4–
15%) in that order, usually as solids.
In conclusion, we have developed a novel combinatorial proto-
col to access a poorly-studied heterocyclic template using a simple,
atom-efficient one-pot two-step procedure which allows for the
isolation of three novel BAPyrs from one single purification. The
yields are reproducible and the process is very tolerant of steric
hindrance and electronic factors (Table 1). We are in the process
of enlarging the substrate scope to alkyl isothiocyanates and intro-
14. During our investigations, mono-acetyl impurities arising through retro-
Claisen of 21 before addition of the second isothiocyanate (particularly
present when EtOH was used as the solvent) did not react further during the
reaction before adding hydrazine which led to contamination of the final
desired 3,5-bis(arylamino)pyrazole libraries with close-running 3-arylamino-
5-methylpyrazole impurities.