Base-free two-step synthesis of 1,3-diketones and β-ketoesters from α-diazocarbonyl compounds, trialkylboranes, and aromatic aldehydes

Article abstract of DOI:10.1039/c1ob05150d

We describe a convergent, base-free two-step synthesis of 1,3-diketones and β-ketoesters from α-diazocarbonyl compounds, trialkylboranes, and aromatic aldehydes in a three-component process. The synthetic potential of this protocol was underscored by the

Full text of DOI:10.1039/c1ob05150d

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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-
Scheme 1 Hooz three-component reaction.
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,
which was then trapped by the aldehyde.8 Electrophiles such as
dimethylethylenammonium iodide,9 NBS and NCS10 and nitriles
could also be used as trapping agents of 3.11 It is noteworthy that a-
diazocarbonyl compounds are usually easily prepared from readily
accessible precursors generally under relatively mild conditions.12
The acylation of diazomethane with an acid chloride (Arndt–
Eistert synthesis of diazo ketones)12a–c and also with a carboxylic
acid,12d remains the single most important methodology to obtain
acyclic a-diazo ketones. In addition, the diazo group transfer
technique introduced by Regitz and coworkers,12e,f is useful for
the preparation of cyclic and acyclic a-diazocarbonyl containing
systems.
Although the Hooz reaction allows efficient construction of two
C–C bonds under metal-free conditions (Scheme 1), its application
in synthetic organic chemistry has remained largely unexplored.
We reasoned that this process might be a versatile source of 1,3-
dicarbonyl compounds (6), by simply oxidizing the corresponding
aldol adduct 5 (Table 1). This report describes the use of the
Hooz reaction/oxidation sequence as the source of the various
1,3-dicarbonyl compounds, and the subsequent use thereof for
the preparation of various polysubstituted pyrazoles.
First, to optimize the reaction conditions, we studied the
condensation of a-diazoacetophenone 1a12d (Table 1, entry 1),
the commercially available triethylborane, and benzaldehyde.
However, when a 1 M solution of Et3B in hexane was utilized,
a low yield of the desired aldol 5a was obtained (Table 1, entry 1).
In contrast, when a solution of 1a in a THF solution was added
dropwise to a solution of the aldehyde and Et3B in THF, at room
temperature, a moderate yield of 5a was obtained (Table 1, entry
2). Under these optimized conditions, the use of p-OMe-, p-tolyl
a-diazoacetophenone and p-Me, and p-methoxybenzaldehyde
in combination with Et3B resulted in excellent yields of the
corresponding aldols 5c–d (Table 1, entries 3–4). Similarly, n-
Pr3B13 afforded good yields of the expected aldol 5e. Furthermore,
we confirmed that a phenyl group could be introduced into the enol
derivative by simply using the corresponding Ph3B.13 It is worth
Pyrazoles, which are five-membered aromatic heterocyclic com-
pounds, are synthetic targets of considerable importance in both
the pharmaceutical and agrochemical industries.1 The pyrazole
nucleus is frequently present in natural products and synthetic
molecules, some of which display a range of pharmacological
activities, including inhibition of antitumor cyclin-dependent
kinase,2 monoamine oxidase-B, and inflammation, and also are
potential atypical antipsychotics.2 Some noteworthy commercially
successful pyrazole containing compounds are Viagra,3 used
for the treatment of erectile dysfunction; Celebrex, used as a
potent anti-inflammatory agent;4 and Acomplia,5 used for the
treatment of obesity. Undoubtedly, the most general method for
preparing pyrazoles is the condensation of hydrazines and 1,3-
dicarbonyl compounds.6 Nevertheless, the scope of this synthesis
is limited by the availability of the 1,3-dicarbonyl compounds. The
usual methodology for generating these building blocks typically
involves acylation of an enolate with an acid chloride. This
process usually requires the use of strongly basic conditions and
low temperatures.7 Furthermore, the generation of 2-alkyl-1,3-
diketones, which are used for the preparation of polysubstituted
pyrazoles, also requires the use of a strong base, and dialkylation
often is a competing reaction. Interestingly, 40 years ago, Hooz
and coworkers8 reported that the aldols 5 could be efficiently
prepared in a three component reaction involving a trialkylborane
2, a diazocarbonyl compound 1, and an aldehyde 4 (Scheme 1).
Mechanistically, the formation of 5 was interpreted as proceeding
via the boron enolate 3, resulting from the transfer of an alkyl
Instituto de Qu´ımica, Universidad Nacional Auto´noma de Me´xico, Circuito
Exterior, Ciudad Universitaria, Coyoaca´n Me´xico, D. F. 04510, Me´xico.
E-mail: lmiranda@servidor.unam.mx; Tel: +52 5556224440
† We thank CONACYT (82643) for financial support and Dr Joseph M.
Muchowski for many helpful discussions. We also thank R. Patin˜o, J.
Pe´rez, L. Velasco, H. Rios, E. Huerta, A. Pen˜a, and I. Chavez for technical
support.
‡ Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05150d
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Table 1 Synthesis of 1,3-diketones
Table 3 Synthesis of tetrasubstituted pyrazoles
entry Substrates
R1
R2
R3
R4
Pyrazole, yield (%)
entry substrates R1
R2 R3
Aldol, yield (%) Diketone, yield (%)
1
2
3
4
5
6
7
6b
6a
6c
6d
6e
6f
7b
7b
H
H
Et
Et
Et
Me
H
Me
OMe
OMe 8a (60)a
OMe 8b (98)
1
2
3
4
5
6
1a, 2a, 4a
1b, 2a, 4a
1b, 2a, 4b Me Et Me 5c (96)
1c, 2a, 4c OMe Et OMe 5d (98)
1c, 2b, 4c OMe n-Pr OMe 5e (75)
1b, 2c, 4b Me Ph Me 5f (72)
H
H
Et
H
5a (41)
6a (58)
6b (73)
6c (60)
6d (56)
6e (63)
6f (65)
7a Me
H
H
8c (54)
8d (49)
Et Me 5b (56)
7a OMe Et
7b OMe n-Pr OMe OMe 8e (74)
7a Me
7b Me
Ph
Ph
Me
Me
H
8f (90)
6f
OMe 8g (64)
Conditions: i) Method A: For 7a, 1,3-diketone (1 eq.), hydrazine (1.4
eq.), CAN (3 mol%), MeCN, reflux, 3 h. Method B: For 7b·HCl (3 eq.)
DMF/THF (3 : 1) 120 ◦C.a As a 1 : 1 mixture of regioisomers.
Conditions: i) diazoketone (1 eq.), aldehyde (1 eq.), trialkylborane (3 eq.),
˚
THF, r. t. 1 h. ii) PCC, CH2Cl2, molecular sieves 4 A, r. t. 4 h.
noting that this sort of transformation typically entails the use of
transition metal-catalyzed conditions.
component Hooz reaction. Unfortunately, attempts to carry out
the same reaction protocol using aliphatic aldehydes failed to
obtain the expected aldols.
Next, we focused our efforts on finding efficient oxidation
conditions for transforming the aldols 5a–f into the corresponding
diketones 6a–f. After testing several conditions, we found that
treating the corresponding aldol (5a–f) with an excess of PCC, in
the presence of molecular sieves, afforded the diketones 6a–f in
moderate yields. In order to avoid the generation of regioisomeric
pyrazole mixtures, symmetrical diketones were prepared, in all but
one case (6b, Table 1, entry 2).
We then explored the utility of this approach for the preparation
of b-ketoesters. Straightforwardly, the reaction of the commer-
cially available ethyl diazoacetate with benzaldehydes 4a–c and
boranes 2a–c afforded the corresponding aldols 5g–j, which were
transformed into the expected b-ketoesters 6g–j in moderate yields
(Table 2). Both triphenylborane and triethylborane both gave
moderate to good product yields in this variation of the three-
With the diketones 6a–f (Table 1) in hand, we next explored their
reactions with phenylhydrazine and p-methoxyphenylhydrazine
hydrochloride (Table 3). In reactions with the free hydrazines 7a–b
(Table 3), we employed ceric ammonium nitrate (CAN), which
was recently reported to improve yields in this transformation.14
The reaction with the unsymmetrical diketone 6b produced the
expected 1 : 1 (determined by 1H NMR) mixture of regioisomeric
pyrazoles 8a, (Table 3, entry 1). However, when symmetrical
diketones 6a,c–f were employed, several symmetrical tetrasub-
stituted pyrazoles 8a–f were obtained in moderate to excellent
yields (Table 3, entries 2–7). It is worth noting that the 1,2,3,4-
tetraaryl pyrazoles 8f–g (Table 3, entries 6 and 7) were efficiently
constructed in three steps from readily available starting materials
in a convergent, base-free, synthetic sequence that did not require
expensive 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
Table 2 Synthesis of substituted b-ketoesters
entry substrates R2 R3
Aldol, yield (%) Ketoesters, yield (%)
1
2
3
4
5
1, 2a, 4a
1, 2a, 4b
1, 2a, 4c
1, 2c, 4a
1, 2c, 4b
Et
Et Me
Et OMe 5i (74)
Ph
H
5g (51)
5h (75)
6g (35)
6h (30)
6i (35)
6j (40)
6k (41)
H
5j (38)
5k (40)
Ph Me
Conditions: i) diazoketone (1 eq.), aldehyde (1 eq.), trialkylborane (3 eq.),
Scheme 2 Synthesis of propylpyrazole triol (PPT), a selective estrogen
receptor modulator.
˚
THF, r. t. 1 h. ii) PCC, CH2Cl2, molecular sieves 4 A, r. t. 4 h.
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after demethylation of 8e with BBr3, as reported previously
(Scheme 2).16
The N-unsubstituted 2,4-diaryl-3-ethyl pyrazoles 10a and 10b
were also prepared when diketones 6b and 6c were reacted with
tosylhydrazine in refluxing acetonitrile (Scheme 3).17
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¨
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Conclusions
In conclusion, we have described a highly convergent, two-step
synthesis of 1,3-diketones and b-ketoesters from a-diazocarbonyl
compounds, trialkylboranes, and 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
1,2,3,4-tetraryl substituted pyrazoles in a three-step protocol. This
protocol precludes the use of strong bases and expensive Pd-
catalysis-mediated conditions. Furthermore, it offers a modular
approach for easily introducing different substituents by simply
varying the substituents in the starting materials.
13 H. C. Brown and U. S. Racherla, J. Org. Chem., 1986, 51, 427–432.
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17 A. Padwa, J. Org. Chem., 1965, 30, 1274–1275.
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