Org.biomol.chem. 2011, 9 (19), 6506

Chemistry
Cite this: Org. Biomol. Chem., 2011, 9, 6506
COMMUNICATION
Base-free two-step synthesis of 1,3-diketones and b-ketoesters from
a-diazocarbonyl compounds, trialkylboranes, and aromatic aldehydes†‡
Miguel A. Sanchez-Carmona, David A. Contreras-Cruz and Luis D. Miranda*
Received 27th January 2011, Accepted 29th July 2011
DOI: 10.1039/c1ob05150d
We describe a convergent, base-free two-step synthesis of
1,3-diketones and b-ketoesters from a-diazocarbonyl com-
pounds, trialkylboranes, and aromatic aldehydes in a three-
component process. The synthetic potential of this protocol
was underscored by the synthesis of several symmetrical 1,3,5-
triaryl-4-alkyl and 1,3,4,5-tetraryl substituted pyrazoles in a
three-step sequence.
substituent of the borane 2 to the diazocarbonyl compound 1,
Pyrazoles, which are five-membered aromatic heterocyclic com- which was then trapped by the aldehyde.8 Electrophiles such as
pounds, are synthetic targets of considerable importance in both dimethylethylenammonium iodide,9 NBS and NCS10 and nitriles
the pharmaceutical and agrochemical industries.1 The pyrazole
could also be used as trapping agents of 3.11 It is noteworthy that a-
nucleus is frequently present in natural products and synthetic diazocarbonyl compounds are usually easily prepared from readily molecules, some of which display a range of pharmacological accessible precursors generally under relatively mild conditions.12
activities, including inhibition of antitumor cyclin-dependent The acylation of diazomethane with an acid chloride (Arndt– kinase,2 monoamine oxidase-B, and inflammation, and also are
Eistert synthesis of diazo ketones)12a–c and also with a carboxylic
potential atypical antipsychotics.2 Some noteworthy commercially
acid,12d remains the single most important methodology to obtain
successful pyrazole containing compounds are Viagra,3 used
acyclic a-diazo ketones. In addition, the diazo group transfer for the treatment of erectile dysfunction; Celebrex, used as a technique introduced by Regitz and coworkers,12e,f is useful for
potent anti-inflammatory agent;4 and Acomplia,5 used for the
the preparation of cyclic and acyclic a-diazocarbonyl containing Downloaded by John Rylands University Library on 25 September 2011 Published on 29 July 2011 on http://pubs.rsc.org | doi:10.1039/C1OB05150D treatment of obesity. Undoubtedly, the most general method for preparing pyrazoles is the condensation of hydrazines and 1,3- Although the Hooz reaction allows efficient construction of two dicarbonyl compounds.6 Nevertheless, the scope of this synthesis
C–C bonds under metal-free conditions (Scheme 1), its application is limited by the availability of the 1,3-dicarbonyl compounds. The in synthetic organic chemistry has remained largely unexplored.
usual methodology for generating these building blocks typically We reasoned that this process might be a versatile source of 1,3- involves acylation of an enolate with an acid chloride. This dicarbonyl compounds (6), by simply oxidizing the corresponding
process usually requires the use of strongly basic conditions and aldol adduct 5 (Table 1). This report describes the use of the
low temperatures.7 Furthermore, the generation of 2-alkyl-1,3-
Hooz reaction/oxidation sequence as the source of the various diketones, which are used for the preparation of polysubstituted 1,3-dicarbonyl compounds, and the subsequent use thereof for pyrazoles, also requires the use of a strong base, and dialkylation the preparation of various polysubstituted pyrazoles.
often is a competing reaction. Interestingly, 40 years ago, Hooz First, to optimize the reaction conditions, we studied the and coworkers8 reported that the aldols 5 could be efficiently
condensation of a-diazoacetophenone 1a12d (Table 1, entry 1),
prepared in a three component reaction involving a trialkylborane the commercially available triethylborane, and benzaldehyde.
2, a diazocarbonyl compound 1, and an aldehyde 4 (Scheme 1).
However, when a 1 M solution of Et B in hexane was utilized, Mechanistically, the formation of 5 was interpreted as proceeding
a low yield of the desired aldol 5a was obtained (Table 1, entry 1).
via the boron enolate 3, resulting from the transfer of an alkyl
In contrast, when a solution of 1a in a THF solution was added
dropwise to a solution of the aldehyde and Et B in THF, at room
temperature, a moderate yield of 5a was obtained (Table 1, entry
Instituto de Qu´ımica, Universidad Nacional Aut´onoma de M´exico, Circuito 2). Under these optimized conditions, the use of p-OMe-, p-tolyl Exterior, Ciudad Universitaria, Coyoac´an M´exico, D. F. 04510, M´exico.
E-mail: [email protected]; Tel: +52 5556224440 a-diazoacetophenone and p-Me, and p-methoxybenzaldehyde † We thank CONACYT (82643) for financial support and Dr Joseph M.
in combination with Et B resulted in excellent yields of the Muchowski for many helpful discussions. We also thank R. Pati ˜no, J.
corresponding aldols 5c–d (Table 1, entries 3–4). Similarly, n-
P´erez, L. Velasco, H. Rios, E. Huerta, A. Pe ˜na, and I. Chavez for technical Pr B13 afforded good yields of the expected aldol 5e. Furthermore,
‡ Electronic supplementary information (ESI) available. See DOI: we confirmed that a phenyl group could be introduced into the enol derivative by simply using the corresponding Ph B.13 It is worth
6506 | Org. Biomol. Chem., 2011, 9, 6506–6508
This journal is The Royal Society of Chemistry 2011 8a (60)a
1a, 2a, 4a
1b, 2a, 4a
1b, 2a, 4b
1c, 2a, 4c
OMe 5d (98)
1c, 2b, 4c
OMe n-Pr OMe 5e (75)
1b, 2c, 4b
Conditions: i) Method A: For 7a, 1,3-diketone (1 eq.), hydrazine (1.4
Conditions: i) diazoketone (1 eq.), aldehyde (1 eq.), trialkylborane (3 eq.), eq.), CAN (3 mol%), MeCN, reflux, 3 h. Method B: For 7b·HCl (3 eq.)
THF, r. t. 1 h. ii) PCC, CH2Cl2, molecular sieves 4 A DMF/THF (3 : 1) 120 ◦C.a As a 1 : 1 mixture of regioisomers.
noting that this sort of transformation typically entails the use of component Hooz reaction. Unfortunately, attempts to carry out transition metal-catalyzed conditions.
the same reaction protocol using aliphatic aldehydes failed to Next, we focused our efforts on finding efficient oxidation conditions for transforming the aldols 5a–f into the corresponding
With the diketones 6a–f (Table 1) in hand, we next explored their
diketones 6a–f. After testing several conditions, we found that
reactions with phenylhydrazine and p-methoxyphenylhydrazine treating the corresponding aldol (5a–f) with an excess of PCC, in
hydrochloride (Table 3). In reactions with the free hydrazines 7a–b
the presence of molecular sieves, afforded the diketones 6a–f in
(Table 3), we employed ceric ammonium nitrate (CAN), which moderate yields. In order to avoid the generation of regioisomeric was recently reported to improve yields in this transformation.14
pyrazole mixtures, symmetrical diketones were prepared, in all but The reaction with the unsymmetrical diketone 6b produced the
one case (6b, Table 1, entry 2).
expected 1 : 1 (determined by 1H NMR) mixture of regioisomeric We then explored the utility of this approach for the preparation pyrazoles 8a, (Table 3, entry 1). However, when symmetrical
of b-ketoesters. Straightforwardly, the reaction of the commer- diketones 6a,c–f were employed, several symmetrical tetrasub-
Downloaded by John Rylands University Library on 25 September 2011 cially available ethyl diazoacetate with benzaldehydes 4a–c and
Published on 29 July 2011 on http://pubs.rsc.org | doi:10.1039/C1OB05150D stituted pyrazoles 8a–f were obtained in moderate to excellent
boranes 2a–c afforded the corresponding aldols 5g–j, which were
yields (Table 3, entries 2–7). It is worth noting that the 1,2,3,4- transformed into the expected b-ketoesters 6g–j in moderate yields
tetraaryl pyrazoles 8f–g (Table 3, entries 6 and 7) were efficiently
(Table 2). Both triphenylborane and triethylborane both gave constructed in three steps from readily available starting materials moderate to good product yields in this variation of the three- in a convergent, base-free, synthetic sequence that did not requireexpensive Pd-catalyst-mediated protocols. Interestingly, the 1,3,5- triaryl-4-alkyl substituted pyrazoles, exemplified by propylpyra-
zole triol (PPT) 9 (Scheme 2), are selective estrogen receptor
modulator compounds (SERMs), which display a broad spectrum
of agonist and antagonist actions at different target tissues.15,16 In
this context, the data collected in Table 3 demonstrate that several
structurally diverse 1,3,5-triaryl-4-alkyl substituted pyrazoles (i.e.,
8b–e) can be readily available using the protocol reported in
the present letter. Indeed, PPT was obtained in good yield
Conditions: i) diazoketone (1 eq.), aldehyde (1 eq.), trialkylborane (3 eq.),THF, r. t. 1 h. ii) PCC, CH Synthesis of propylpyrazole triol (PPT), a selective estrogen This journal is The Royal Society of Chemistry 2011 Org. Biomol. Chem., 2011, 9, 6506–6508 | 6507
after demethylation of 8e with BBr , as reported previously
3 P. Dunn, Org. Process Res. Dev., 2005, 9, 88.
(Scheme 2).16
4 T. D. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Carter, P. W. Collins, S. Docter, M. J. Graneto, L. F. Lee, J. W. Malecha, J. M. Miyashiro, R.
The N-unsubstituted 2,4-diaryl-3-ethyl pyrazoles 10a and 10b
S. Rogers, D. J. Rogier, S. S. Yu, G. D. Anderson, E. G. Burton, J. N.
were also prepared when diketones 6b and 6c were reacted with
Cogburn, S. A. Gregory, C. M. Koboldt, W. E. Perkins, K. Seibert, A.
tosylhydrazine in refluxing acetonitrile (Scheme 3).17
W. Veenhuizen, Y. Y. Zhang and P. C. Isakson, J. Med. Chem., 1997,
40, 1347.
5 M. Rinaldi-Carmona, F. Barth, M. H´eaulme, D. Shire, B. Calandra, C. Congy, S. Martinez, J. Maruani, G. N´eliat, D. Caput, P. Ferrara, P.
Soubri´e, J. C. Breli´ere and G. Le Fur, FEBS Lett., 1994, 350, 240.
6 (a) L. Knorr, Ber., 1883, 16, 2587; (b) M. V. Patel, R. Bell, S.
Majest, R. Henry and T. Kolasa, J. Org. Chem., 2004, 69, 7058; (c) S.
Peruncheralathan, T. A. Khan, H. Ila and H. Junjappa, J. Org. Chem.,
2005, 70, 10030.
Synthesis of 2,4-diaryl-3-ethyl pyrazole.
7 (a) T. T. Dang, C. Fischer, H. G ¨orls and P. Langer, Tetrahedron, 2008, 64, 2207; (b) Z. Turgut and N. ¨
Ocal, Russ. J. Org. Chem., 2002, 38,
602; (c) S. R. Stauffer, Y. Huang, C. J. Coletta, R. Tedesco and J. A.
Katzenellenbogen, Bioorg. Med. Chem., 2001, 9, 141.
Conclusions
8 (a) J. Hooz and S. Linke, J. Am. Chem. Soc., 1968, 90, 5936–37; (b) J.
Hooz and D. M. Gunn, Tetrahedron Lett., 1969, 3455–56; (c) J. Hooz In conclusion, we have described a highly convergent, two-step and G. F. Morrison, Can. J. Chem., 1970, 48, 868–70; (d) J. Hooz,
J. Oudenes, J. L. Roberts and A. Benderly, J. Org. Chem., 1987, 52,
synthesis of 1,3-diketones and b-ketoesters from a-diazocarbonyl compounds, trialkylboranes, and aldehydes in a three-component 9 J. Hooz and J. Bridson, J. Am. Chem. Soc., 1973, 95, 602–603.
process. The synthetic potential of this protocol was underscored 10 J. Hooz and J. Bridson, Can. J. Chem., 1972, 50, 2387–2390.
by the synthesis of several symmetrical 1,3,5-triaryl-4-alkyl and 11 J. Hooz and J. Oudenes, Synth. Commun., 1982, 12, 189–194.
12 (a) F. Anrdt, B. Eistert and W. Part de, Ber. Dtsch. Chem. Ges., 1927,
1,2,3,4-tetraryl substituted pyrazoles in a three-step protocol. This 60B, 1364; (b) F. Amdt and J. Amende, Ber. Dtsch. Chem. Ges., 1928,
protocol precludes the use of strong bases and expensive Pd- 61B, 1122; (c) F. Arndt, B. Eistert and J. Amende, Ber. Dtsch. Chem.
catalysis-mediated conditions. Furthermore, it offers a modular Ges., 1928, 61B, 1949; (d) E. Cuevas-Ya ˜nez, M. A. Garc´ıa, M. A. de
la Mora, J. M. Muchowski and R. Cruz-Almanza, Tetrahedron Lett.,
approach for easily introducing different substituents by simply 2003, 44, 4815–4817; (e) M. Regitz, Angew. Chem., Int. Ed. Engl., 1967,
varying the substituents in the starting materials.
6, 733; (f) M. Regitz, Synthesis, 1972, 351.
13 H. C. Brown and U. S. Racherla, J. Org. Chem., 1986, 51, 427–432.
Notes and references
14 R. Flowers, J. Devery, P. Mohanta and B. Casey, Synlett, 2009, 1490.
15 B. E. Fink, D. S. Mortensen, S. R. Stauffer, Z. D. Aron and J. A.
1 I. Shinkai, In: Comprehensive Heterocyclic Chemistry II, Vol. 3; I.
Katzenellenbogen, Chem. Biol., 1999, 6, 205–219.
Shinkai, Ed., Pergamon: Oxford UK, 1996, 1–75.
16 S. R. Stauffer, C. J. Coletta, R. Tedesco, G. Nishigushi, K. E. Carlson, 2 R. Lin, G. Chiu, Y. Yu, P. J. Connolly, S. Li, Y. Lu, M. Adams, A. R.
J. Sun, B. S. Katzenellenbogen and J. A. Katzenellenbogen, J. Med. Fuentes-Pesquera, S. L. Emanuel and L. M. Greenberger, Bioorg. Med. Chem., 2000, 43, 4934–4947.
Chem. Lett., 2007, 17, 4557–4561.
17 A. Padwa, J. Org. Chem., 1965, 30, 1274–1275.
Downloaded by John Rylands University Library on 25 September 2011 Published on 29 July 2011 on http://pubs.rsc.org | doi:10.1039/C1OB05150D 6508 | Org. Biomol. Chem., 2011, 9, 6506–6508
This journal is The Royal Society of Chemistry 2011

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