Aminolysis of 2,2-difluoro-4-alkoxy-1,3,2-dioxaborinanes: route to β-keto amides and β-enamino carboxamides

Article abstract of DOI:10.1016/j.tet.2007.08.085

4-Alkoxy substituted 1,3,2-dioxaborinanes 1, readily available from β-keto esters, undergo substitution reactions under mild reaction conditions with primary and secondary amines, deriving the 4-alkylamino analogue 2. Reactions of 1 with substituted phenylhydrazines gave the corresponding hydrazones, or pyrazolones, and 5-alkoxy-1H-pyrazoles as a mixture of products.

Full text of DOI:10.1016/j.tet.2007.08.085

Tetrahedron 63 (2007) 10902–10913
Aminolysis of 2,2-difluoro-4-alkoxy-1,3,2-dioxaborinanes:
route to b-keto amides and b-enamino carboxamides
ꢀ
Bogdan Stefane and Slovenko Polanc
*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asꢀkercꢀeva 5, SI-1000 Ljubljana, Slovenia
Received 6 April 2007; revised 2 August 2007; accepted 23 August 2007
Available online 30 August 2007
Abstract—4-Alkoxy substituted 1,3,2-dioxaborinanes 1, readily available from b-keto esters, undergo substitution reactions under mild re-
action conditions with primary and secondary amines, deriving the 4-alkylamino analogue 2. Reactions of 1 with substituted phenylhydrazines
gave the corresponding hydrazones, or pyrazolones, and 5-alkoxy-1H-pyrazoles as a mixture of products.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
salts30 and the enzymatic hydrolysis of b-keto nitriles.31
Each of the above methods for the synthesis of b-keto amides
has its own advantages and disadvantages, concerning the
reaction conditions, the yields of the reactions or the avail-
ability of the starting material. A few years ago, we described
a new synthetic route to pyrimidine N-oxides, starting from
1,3-diketones and carboxamide oximes.32 We found that
the reactions catalysed with BF3$Et2O gave pyrimidine
N-oxides in low yields. Later, we discovered that the low
yields were due to the formation of 1,3-diketonatoboron
difluorides, which were first described by Morgan and Tun-
stall,33 and are known as interesting intermediates in organic
synthesis.34 As part of our research program, which is
oriented at investigating the synthetic potential of 1,3-diketo-
natoboron difluorides and 2,2-difluoro-4-alkoxy-1,3,2-dioxa-
borinanes, we have found that they can be successfully used
for the synthesis of enaminones, pyrazoles, b-keto amides,
b-enamino carboxamides and pyrazolones.35 Additionally,
Christoffers et al. reported on a regioselective enamine
formation via b-diketonatoboron difluorides and their
application in the asymmetric Michael reaction.18a Here, we
report on our further research relating to the above-mentioned
topic.
b-Keto amide and b-enamino carboxamide classes of com-
pounds represent versatile and useful building blocks for the
synthesis of natural products1 and targets for pharmaceuti-
cals.2 Additionally, in the recent literature there are numerous
examples of where b-keto amides and b-enamino carbox-
amides have been used for the synthesis of heterocyclic com-
pounds, such as highly substituted furans,3 pyrazolones,4
pyrazoles,5 N-hydroxyindoles,6 diazepines,7 3-isoxazolols,8
b-lactams,9 4-hydroxycoumarins10 and indanones.11 The
enantioselective hydrogenation12 of b-enamino carbox-
amidesprovidesaccesstob-aminoacidsandtheirderivatives,
which are the components of a variety of interesting natural
products and targets for pharmaceutical research.13 Other
uses of b-keto amides and b-enamino carboxamides, as
starting materials, include, for example, enantioselective
halogenations,14 the multicomponent domino reaction,15
diastereoselective addition reactions,16 the carbenoid-medi-
ated chain extension,17 spirolactamisation,18 the synthesis
of 2,3-diketo amides19 and stereocontrolled cyclisation reac-
tions.20 Several methods have been reported for the synthesis
of b-keto amides. The available methods can be classified ac-
cording to the bond formed. The most general methods are
based on the nucleophilic amidations of electrophiles such
as b-keto acids (often prepared from protected b-keto es-
ters),21 b-keto esters,22 b-keto thioesters,23 ketene dimers,24
dioxinones,25 acylated Meldrum’s acids or 2,2-dimethyl-
2H,4H-1,3-dioxin-4-ones.8 Other approaches include the
condensation of ketone enolates with isocyanates26 or acti-
vated carbamates,27 the condensation of amide enolates with
esters28 or acyl chlorides,29 the fragmentation of isoxazolium
2. Results and discussion
The starting materials, 2,2-difluoro-4-alkoxy-1,3,2-dioxa-
borinanes 1a–e, are readily available from the corresponding
b-keto esters.17,35b,36 The treatment of b-keto esters in dry
dichloromethane or toluene solutions with 2 equiv of
BF3$Et2O for 24 h is the most successful method in our
hands (Chart 1). In the first stage, we examined the reactivity
of 1a in the presence of primary or secondary alkylamines.
They undergo successful aminolysis in acetonitrile, forming
* Corresponding author. Tel.: +386 1 2419 264; fax: +386 1 2419 220;
e-mail: bogdan.stefane@fkkt.uni-lj.si
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.085

ꢀ
B. Stefane, S. Polanc / Tetrahedron 63 (2007) 10902–10913
10903
F
B
F
B
able to carry out the chemoselective introduction of an ami-
do group to a multifunctional system (Scheme 1, e.g., 2l–
2p). The reaction of i-PrNH2, 3-picolylamine and allylamine
with 1e (readily available by the treatment of 3-acetyldihy-
drofuran-2(3H)-one with BF3$Et2O) resulted in the cleavage
of the lactone moiety, producing alcohol-functionalised ami-
do complexes (Scheme 1, e.g., 2q–2s). The method is, in
general, readily applicable for the preparation of a wide
range of 2,2-difluoro-4-alkylamino-1,3,2-dioxaborinanes
2,38 which Staskun has shown can be useful precursors for
the selective N-alkylations, C-5 halogenations and the syn-
thesis of quinolin-2-ones.39
F
B
F
O
F
O
F
O
O
O
O
Ph
OEt
OEt
Me
OEt
1a
1b
1c
F
F
B
F
O
F
O
B
O
O
Me
MeO2C
OMe
Me
O
1d
1e
Chart 1. Preparation of 2,2-difluoro-4-alkoxy-1,3,2-dioxaborinanes 1;
BF3$Et2O (2 equiv), CH2Cl2 or toluene, 25 ꢀC.
The structure of 2 was confirmed by X-ray structural
analysis and NMR spectroscopy, showing in the 13C NMR
spectrum, characteristic 19F–13C couplings in the range of
2.5–3.0 Hz for the ]C–O–BF2 bond sequence, and slightly
smaller, 2.0–1.5 Hz coupling, for the –C]O/BF2 bond se-
quence. Several observations regarding this preparation are
worth mentioning. (1) The reactions were carried out under
mild reaction conditions in the presence of a slight excess of
amine, followed by the simple isolation of the products. (2)
t-BuNH2, cysteamine, 2-aminoethylamine and 2,2-dimeth-
oxyethylamine underwent successful and chemoselective
reactions, in the latter case yielding a carbonyl-protected
amido derivative (Scheme 1, e.g., 2f). (3) The problem
associated with volatile or gaseous amines can be simply
overcome, applying the described procedure, by passing am-
monia or methylamine through the stirred acetonitrile solu-
tion of 1 (Scheme 1, e.g., 2g and 2l). The boronato difluoride
moiety activates the ester carbonyl group towards the attack
of an amine and the substitution products, amido complexes,
are obtained. This reactivity can be explained by the fact that
only the enol–borate structure is found in the solid form.
their 4-alkylamino analogues 2, and surprisingly the boronato
moiety is retained during the conversion (Scheme 1).
The results are different from those of the well-known Lewis
acid catalysed reaction of b-keto esters with amines forming
b-enamino esters.37 Initial studies on the aminolysis of 1a in-
dicated that when the reaction was carried out in acetonitrile
and with a slight excess (1.3 equiv) of the corresponding
amine at room temperature the desired 4-alkylamino ana-
logues 2a–h were isolated in excellent yields (81–98%). In
less-polar solvents (CH2Cl2, Et2O and toluene) the 1,3-
keto ester by-products become more noticeable. The chem-
istry was applicable to a wide range of alkylamines (primary,
secondary, t-BuNH2 and allylamine), which gave the corre-
sponding borinanes 2. When using 1,1-dimethylhydrazine
the resulting hydrazido boron complex was isolated
(Scheme 1, e.g., 2h). Similarly, the aminolysis of 1b or 1c
led to the formation of 2. Additionally, in the case of di-
methyl 2-acetylsuccinate-derived borinane 1d we were
F
F
O
F
F
O
B
F
B
O
F
O
B
F
B
O
F
O
O
F
B
Ph
NH
F
B
O
F
O
2d, 96%
F
O
Ph
NH
2c, 95%
NHt-Bu
Ph
NH
O
2e, 89%
N
O
Ph
N
2b, 93%
F
B
F
O
Ph
H2N Ph
NH
2a, 96%
O
MeO
2f, 91%
NH2
F
B
F
O
H
N
Me
HO
N
H
OMe
Ph
O
2s, 68%
NH2
F
B
2g, 92%
NH2
F
B
F
B
N
F
O
F
O
F
O
NH3
O
O
O
3-P
yCH
2NH2
Me2NNH2
R1
OR3
Ph
NH
Me
HO
N
2h, 81%
H
R2
1a-e
F
B
NMe2
F
F
B
2r, 50%
F
O
O
O
O
NH2
NHi-Pr
2i, 98%
Me
HO
F
B
NHi-Pr
H
F
O
N
O
F
B
N
F
O
F
F
F
B
2q, 45%
F
O
F
B
Me
NHi-Pr
2j, 92%
O
F
B
B
F
O
F
F
F
O
SH
O
O
O
Me
O
N
H
B
O
O
O
Me
NHMe
Me
CO2Me
NH
2k, 98%
N
H
Me
Me
N
H
2p, 95%
Me
N
CO2Me
CO2Me
2l, 83%
2o, 90%
CO2Me
2n, 71%
CO2Me
2m, 79%
N
Scheme 1. Preparation of 2,2-difluoro-4-alkylamino-1,3,2-dioxaborinanes 2; alkylamine (1.3 equiv) MeCN, 25 ꢀC, 0.5–4 h.

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B. Stefane, S. Polanc / Tetrahedron 63 (2007) 10902–10913
10904
Ponde et al. reported on transesterifications and transthio-
esterifications of b-keto esters using clay and proposed the
b-keto enolate transition-state model.40 On the other hand,
reacting 1 with aliphatic or aromatic alcohols or H2O (1–
3 equiv) at room temperature in MeCN did not produce
the expected transesterification products or the correspond-
ing carboxylic acids. In contrast, only b-keto esters were iso-
lated as the sole products. The same results were obtained by
the treatment of 1 with 1–3 equiv of NH2OH.
Compounds 2 can be thought of as protected b-keto amides,
which can be obtained after a suitable deprotection. Indeed,
the treatment of 2 with sodium acetate (5 equiv) in boiling
1:1 ethanol/water (v/v) afforded useful building blocks,41
b-keto amides 3, in acceptable yields (Scheme 2). After
a careful crystallisation (CH2Cl2/light petroleum) of the
crude mixture of tautomers 3g and 3g0 we were able to
isolate both tautomers, N-benzyl-2-oxo-1-cyclohexanecar-
boxamide (3g) and its enol form 3g0, as pure compounds.
In contrast, only a trace of enol tautomer was detected
Figure 1. ORTEP diagram with the heteroatom numbering of 3g0.
Our attention was then directed towards the arylhydrazino
compounds as nitrogen nucleophiles. As mentioned above,
reacting alkylhydrazines with 1a resulted in the formation
of the hydrazido boron complex (Scheme 1, e.g., 2h).
When using arylhydrazines such as 2,4-dinitrophenyl, 2-
nitro-4-cyanophenyl and heteroaryl hydrazines, the corre-
sponding b-hydrazono esters 5 were isolated (Table 1,
entries 1–3, 9 and 11). When 1a was treated with arylhydr-
azine hydrochlorides only traces of the products were
detected in the 1H NMR spectra of a crude reaction mixture
after a prolonged reaction time. Since some of the arylhydr-
azines (i.e., 4-bromophenylhydrazine, 4-fluorophenylhydr-
azine) are commercially available as hydrochloride salts,
the corresponding free hydrazines were obtained by neutra-
lisation with Na2CO3 and subsequent extraction. However,
a different reactivity was observed for the arylhydrazines.
As mentioned, the reaction of arylhydrazines bearing an
electron-withdrawing group (CN, NO2) led exclusively to
the formation of b-hydrazono esters 5, whereas reactions
with more nucleophilic phenylhydrazines resulted in the
formation of a mixture of pyrazolones 6 and 5-alkoxy-1H-
pyrazoles 7 (Scheme 3, Table 1). To test the solvent’s effect
on the product distribution and to establish possible syn-
thetic applicability for the formation of 5-alkoxypyrazoles
7 (which can be accessed via the O-alkylation of 5-hydroxy
derivatives in DMSO under basic conditions, albeit only in
moderate yields),42 we performed the reaction in several sol-
vents and at different temperatures. The best results were
1
(according to H NMR spectra) in the crude product 3f
(Scheme 2). In general, b-carbonyl compounds, such as
b-keto amides, exist in solutions as both enol and keto tauto-
mers. In the case of 3g and 3g0, we observed equilibrium in
the DMSO-d6 solutions after a few days at room tempera-
ture, while they remained unchanged in chloroform. The
structure of 3g0 was also confirmed using X-ray analysis
(Fig. 1).
A concise (one-step) approach was then designed to access
the b-amino carboxamides. The reaction was performed in
n-propanol using excess (5 equiv) of the corresponding
amine. The results obtained from the reaction of three alkyl-
amines and phenylhydrazine with 2 in n-propanol solutions
at 130 ꢀC in a sealed reaction vessel are summarised in
Scheme 2. The reactions were completed in 12 h and the
products 4a–4d were isolated in good-to-moderate yields.
The substrate 2o reacts (under the same reaction conditions),
for example, with benzylamine and propargylamine, provid-
ing the 3-(alkylaminoethylidene) pyrrolidine-2,5-dione de-
rivatives 4b and 4c after condensation and subsequent
cyclisation (Scheme 2).
O
N
O
O
O
O
N
O
Ph
NH
Ph
NH
Me
NH
3c, 97%
3d, 91%
O
O
O
O
3e, 63%
i
i
NHi-Pr
Ph
O
NHi-Pr
i
3b, 88%
F
F
B
3f, 95%
i
i
O
O
O
O
O
OH
O
R1
i
Me
N
NR3R4
i
NHCH2Ph
+
NHCH2Ph
3g'
R2
3g
2
CO2Me
3a, 79%
NH
O
(93%; 3g:3g' = 1.5:1)
NH
NH2
H
N
Ph
H2N
Me
Ph
N
O
N
Ph
Me
NH O
NH
O
N
NHCH2Ph
N
4a, 92%
4d, 48%
4b,72%
O
4c, 67%
O
Scheme 2. Transformations of 2,2-difluoro-4-alkylamino-1,3,2-dioxaborinanes 2; (i) AcONa (5 equiv), 1:1 EtOH/H2O (v/v), reflux, 2–16 h.

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B. Stefane, S. Polanc / Tetrahedron 63 (2007) 10902–10913
10905
Table 1. Reaction of 1 with hydrazines: products 5–7 produced via Scheme 3
Entry
R1
R2
R4
5 (Yield,a %)
6 (Yield,a %)
7 (yield,a %)
1
2
Ph
Ph
H
H
2,4-NO2C6H3
2-NO2-4-CNC6H3
5a43 (96)
5b (93)
—
—
—
—
Me
N
N
3
Ph
H
5c (95)
—
—
Me
C6H5
4-FC6H4
2,5-FC6H3
4-BrC6H4
3-CF3C6H4
2-NO2-4-CNC6H3
4-BrC6H4
NO2
4
5
6
7
8
9
10
11
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
H
H
H
H
H
H
—
—
—
—
6a44 (44)
6b (39)
6c (60)
6d (53)
6e (42)
—
7a45 (26)
7b (34)
7c (37)
7d (27)
7e (23)
—
—
5d (89)
—
5e (87)
H
MeO2CCH2
6f (49)
—
7f (16)
—
2-NO2-4-CNC6H3
a
Yields of isolated products are given.
obtained in acetonitrile, yielding 5-alkoxy-1H-pyrazoles 7
in the range of 16–37% (Table 1).
b-keto amides or b-enamino carboxamides, via their 4-alkyl-
amino analogues, hasbeendemonstrated. Additionally, when
2,2-difluoro-4-alkoxy-1,3,2-dioxaborinanes react with aryl-
hydrazines bearing electron-withdrawing substituents, the
corresponding hydrazones are obtained in good yields,
whereas the reaction with more nucleophilic arylhydrazines
resulted in the formation of pyrazolones and 5-alkoxy-1H-
pyrazoles.
R4
N
F
B
R4
N
F
O
R4NHN
R1
O
OR3
R2
O
O
N
i
N
+
+
OR3
R1
OR3
R1
R1
R2
R2
R2
1a-e
5
6
7
Scheme 3. Reactions of 1 with arylhydrazines; (i) R4NHNH2 (1.1 equiv),
MeCN, 25 ꢀC, 5–24 h.
4. Experimental
4.1. General
The structural phenomena of the B–X p binding affinity and
the resulting effect on the chemistry are suggested to be
manifested in practise. However, the binding affinity of
BF3 to carbonyls is considerably different from that of
BCl3. The evidence came from a comparison of the reactiv-
ity of 1a and its chloro analogue 8. One would expect the
2,2-dichloro-1,3,2-dioxaborinane analogue 8 (a so-far unde-
scribed compound) to have a lower activation barrier to-
wards the aminolysis than 1a. Arising from this fact, we
considered whether 8 might react similarly and provide an
extension of the methodology. The formation of 8 was
achieved by the treatment of ethyl benzoylacetate with a
solution of BCl3 in dry toluene at 25 ꢀC.
Solvents and starting compounds were obtained from com-
mercial sources (Fluka, Sigma and Aldrich). All reactions
were carried out in dry solvents. Light petroleum refers to
the fraction with the boiling point 40–60 ꢀC. Hydrazines
(4-fluorophenylhydrazine and 4-bromophenylhydrazine)
were obtained in the free form from the commercially avail-
able hydrochloride salts by neutralisation with Na2CO3 and
subsequent extraction into CH2Cl2. TLC was carried out on
Fluka silica gel TLC cards. All mps were determined on
a hot stage apparatus and are uncorrected. IR spectra were
recorded on a BioRad FTS 3000MX instrument. NMR spec-
tra were recorded on a Bruker Avance 300 DPX spectrome-
ter at 302 K. Chemical shifts are reported in d ppm,
The treatment of 2,2-dichloro-1,3,2-dioxaborinane 1f with
benzylamine or diisopropylamine in dry MeCN or CH2Cl2
solutions quantitatively led to the formation of ethyl
benzoylacetate (Scheme 4). It seems that in the case of
2,2-dichloro-1,3,2-dioxaborinanes the nucleophilic attack
at the boron moiety is much more favourable than that at
the carbonyl functionality, consequently resulting in decom-
plexation and ethyl benzoylacetate formation.
1
referenced to an internal TMS standard for H NMR and
chloroform-d (d 77.0) and DMSO-d6 (d 39.5) for 13C
1
NMR. The H–13C HMBC spectra were obtained with 512
time increments and 32 scans per t1 increment. The 15N
1
NMR spectrum was obtained from H–15N GHMQC spec-
trum and is reported in d ppm referenced to an external
MeNO2 standard. Microanalyses were performed on a
Perkin–Elmer 2400 series II CHNS/O analyser. Mass spectra
and high-resolution mass measurements were performed on
a VG-Analytical Autospec EQ instrument.
Cl
Cl
B
i
O
O
O
O
Ph
OEt
Ph
OEt
8
4.2. General procedure for the preparation of 2,2-di-
fluoro-4-alkoxy-1,3,2-dioxaborinanes 1a–d
Scheme 4. Reaction of 2,2-dichloro-1,3,2-dioxaborinane 1f with alkyl-
amines; (i) PhCH2NH2 or (i-Pr)2NH, dry MeCN or CH2Cl2, 25 ꢀC.
To a solution of the corresponding 1,3-keto ester (1 mmol) in
toluene (5 mL) boron trifluoride etherate (2 equiv) was
added at room temperature. After being stirred at room tem-
perature for 24 h, the reaction mixture was concentrated to
1/3 of its volume (in the case of ethyl benzoylacetate, ethyl
3. Conclusion
In summary, a convenient two-step procedure for the con-
version of 2,2-difluoro-4-alkoxy-1,3,2-dioxaborinanes to

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B. Stefane, S. Polanc / Tetrahedron 63 (2007) 10902–10913
10906
cyclohexanone-2-carboxylate and ethyl acetoacetate) and
then cooled (–30 ꢀC). The precipitated material was filtered
off and washed with 5:1 petroleum ether/EtOAc (5 mL),
yielding the pure product. In the case of 2-acetylbutyrolac-
tone and dimethyl 2-acetylsuccinate the reaction mixturewas
evaporated to dryness, yielding a yellowish oil that was used
in the next step without further purification.
4.3.2. 6-(tert-Butylamino)-2,2-difluoro-4-phenyl-1,3,2-di-
oxaborinane (2b). White solid, yield 93%; mp 185–
187 ꢀC (from MeCN). IR (KBr, n cmꢁ1): 3349, 2982,
1
1612, 1541, 1455, 1334, 1125, 1011, 920, 802, 770. H
NMR (300 MHz, CDCl3): d 1.51 (s, 9H), 5.71 (s, 1H),
5.83 (br s, 1H), 7.40–7.53 (m, 3H), 7.82–7.86 (m, 2H). 13C
NMR (75 MHz, CDCl3): d 28.9, 54.6, 85.1, 126.9, 128.6,
132.2, 133.1, 169.2, 172.3. 19F NMR (282.4 MHz,
CDCl3): d ꢁ142.6. MS (EI, 70 eV, m/z (%)): 267 (M+, 61),
210 (100), 105 (92), 57 (88). HRMS (EI) m/z calcd for
C13H16BF2NO2: 267.1242, found: 267.1251.
Compounds 1a, 1c and 1d were prepared according to the
previously reported procedure.18a,35a
4.2.1. 2,2-Difluoro-4-ethoxy-5H,6H,7H,8H-1,3,2-benzo-
dioxaborinane (1b). Brownish solid, yield 98%; mp 50–
52 ꢀC (from hexane). IR (KBr, n cmꢁ1): 2949, 1605, 1531,
1492, 1462, 1377, 1342, 1289, 1210, 1166, 1047, 1001,
4.3.3. 6-(Allylamino)-2,2-difluoro-4-phenyl-1,3,2-dioxa-
borinane (2c). White solid, yield 95%; mp 104–106 ꢀC
(from light petroleum/EtOAc). IR (KBr, n cmꢁ1): 3337,
3204, 1627, 1536, 1419, 1457, 1310, 1239, 1015, 802,
772, 685. 1H NMR (300 MHz, DMSO-d6): d 4.00–4.04
(m, 2H), 5.20–5.30 (m, 2H), 5.89–5.97 (m, 1H), 6.16 (s,
1H), 7.50–7.59 (m, 3H), 7.82–7.85 (m, 2H), 9.99 (br s,
1H). 13C NMR (75 MHz, DMSO-d6): d 42.3, 85.1, 117.2,
126.4, 128.9, 132.2, 132.6, 132.9, 168.0 (t, J¼2.6 Hz),
169.8 (t, J¼2.0 Hz). 19F NMR (282.4 MHz, CDCl3):
d ꢁ142.2. 15N NMR (60.8 MHz, DMSO-d6) d ꢁ261.2. MS
(EI, 70 eV, m/z (%)): 251 (M+, 71), 250 (75), 232 (44), 196
(39), 105 (100). HRMS (EI) m/z calcd for C12H12BF2NO2:
151.0929, found: 151.0936.
1
871, 826, 766. H NMR (300 MHz, CDCl3): d 1.41 (t, 3H,
J¼7.2 Hz), 1.62–1.78 (m, 4H), 2.25 (t, 2H, J¼6.4 Hz),
2.41 (t, 2H, J¼6.4 Hz), 4.51 (q, 2H, J¼7.2 Hz). 13C NMR
(75 MHz, CDCl3): d 13.9, 20.2, 21.2, 21.4, 31.0, 66.0,
95.3, 173.6 (t, J¼2.3 Hz), 183.1 (t, J¼1.7 Hz). 19F NMR
(282.4 MHz, CDCl3): d ꢁ141.8. MS (EI, 70 eV, m/z (%)):
218 (M+, 27), 124 (100), 68 (57). HRMS (EI) m/z calcd
for C9H13BF2O3: 218.0926, found: 218.0932.
4.2.2. 2,2-Difluoro-7-methyl-5H,6H-furo[2,3-d][1,3,2]di-
oxaborinane (1e). Colourless oil, yield 99%. IR (film, n
cmꢁ1): 3002, 1749, 1709, 1649, 1579, 1499, 1046, 920.
1H NMR (300 MHz, CDCl3): d 2.15–2.18 (m, 3H), 3.07 (t,
2H, J¼8.0 Hz), 4.85 (t, 2H, J¼8.0 Hz). 13C NMR
(75 MHz, CDCl3): d 20.5, 22.4, 74.2, 95.0, 179.8 (t,
J¼2.3 Hz), 180.7 (t, J¼1.7 Hz). MS (EI, 70 eV, m/z (%)):
176 (M+, 70), 161 (100), 95 (65), 64 (87). HRMS (EI) m/z
calcd for C6H7BF2O3: 176.0456, found: 176.0462.
4.3.4. 2,2-Difluoro-4-phenyl-6-(3-picolylamino)-1,3,2-di-
oxaborinane (2d). White solid, yield 96%; mp 184–
186 ꢀC (from MeCN). IR (KBr, n cmꢁ1): 3440, 2957,
1617, 1526, 1335, 1283, 1078, 950, 760, 711, 679. 1H
NMR (300 MHz, DMSO-d6): d 4.64 (s, 2H), 6.16 (s, 1H),
7.44 (dd, 1H, J1¼7.5 Hz, J2¼4.8 Hz), 7.51–7.61 (m, 3H),
7.76–7.84 (m, 3H), 8.54–8.60 (m, 2H), 10.09 (br s, 1H).
13C NMR (75 MHz, DMSO-d6): d 42.2, 85.9, 124.6,
127.3, 129.8, 133.0, 133.2, 133.5, 136.6, 149.9, 150.1,
168.9 (t, J¼2.6 Hz), 170.9 (t, J¼2.0 Hz). 19F NMR
(282.4 MHz, CDCl3): d ꢁ141.8. MS (EI, 70 eV, m/z (%)):
302 (M+, 43), 282 (61), 265 (100), 105 (67), 92 (68), 77
(42). Anal. Calcd for C15H13BF2N2O2: C, 59.64; H, 4.34;
N, 9.27. Found: C, 59.62; H, 4.57; N, 8.98.
4.3. General procedure for the reaction of 2,2-difluoro-
4-alkoxy-1,3,2-dioxaborinanes 2a–e with amines
To a solution of the corresponding amine (1.3 mmol) in
MeCN (5 mL), 2,2-difluoro-4-alkoxy-1,3,2-dioxaborinane
(1 mmol) was added at room temperature. The reaction mix-
ture was stirred at room temperature for 0.5–4 h. When prod-
uct precipitated from the reaction mixture, it was filtered off
and washed with cold MeCN (3 mL), otherwise the reaction
mixture was evaporated to dryness and the residue dissolved
in CH2Cl2 or EtOAc (30 mL), washed with water (2ꢂ
10 mL), dried over MgSO4 and evaporated to dryness. In
some cases products were purified by flash chromatography.
4.3.5. 6-[(2-Aminoethyl)amino]-2,2-difluoro-4-phenyl-
1,3,2-dioxaborinane (2e). White solid, yield 89%; mp
136–137 ꢀC (from Et2O/EtOAc). IR (KBr, n cmꢁ1): 3372,
3300, 3059, 1591, 1566, 1481, 1333, 1269, 1147, 1059,
1024, 748, 693. 1H NMR (300 MHz, (CD3)2CO): d 3.31 (t,
2H, J¼6.6 Hz), 3.43–3.47 (m, 2H), 3.68–3.73 (m, 2H),
3.81 (t, 1H, J¼6.6 Hz), 6.23 (s, 1H), 7.46–7.56 (m, 3H),
7.86–8.01 (m, 2H). 13C NMR (75 MHz, DMSO-d6):
d 40.2, 43.2, 85.4, 126.2, 128.9, 132.0, 132.9, 167.7 (t,
J¼2.6 Hz), 168.8 (t, J¼2.0 Hz). MS (EI, 70 eV, m/z (%)):
254 (M+, 7), 213 (89), 105 (90), 77 (100). HRMS (EI) m/z
calcd for C11H13BF2N2O2: 254.1038, found: 254.1032.
4.3.1. 2,2-Difluoro-4-phenyl-6-(1-piperidinyl)-1,3,2-dioxa-
borinane (2a). White solid, yield 96%; mp 167–169 ꢀC
(from EtOAc). IR (KBr, n cmꢁ1): 2949, 2856, 1612, 1494,
1368, 1304, 1248, 1108, 1072, 930, 764. 1H NMR
(300 MHz, DMSO-d6): d 1.66 (m, 6H), 3.72 (t, 2H,
J¼5.1 Hz), 3.82 (t, 2H, J¼5.1 Hz), 6.64 (s, 1H), 7.49–7.62
(m, 3H), 8.02–8.06 (m, 2H). 13C NMR (75 MHz, DMSO-
d6): d 32.2, 25.4, 25.7, 44.5, 46.9, 82.7, 126.9, 128.6,
132.2, 133.2, 164.5 (t, J¼2.6 Hz), 171.0 (t, J¼2.0 Hz). 19F
NMR (282.4 MHz, CDCl3): d ꢁ142.6. MS (EI, 70 eV, m/z
(%)): 297 (M+, 68), 262 (57), 214 (34), 174 (67), 105
(100), 77 (46). HRMS (EI) m/z calcd for C14H16BF2NO2:
4.3.6. 2,2-Difluoro-6-[(2,2-dimethoxyethyl)amino]-4-
phenyl-1,3,2-dioxaborinane (2f). White solid, yield 91%;
mp 124–125 ꢀC (from light petroleum/EtOAc). IR (KBr, n
cmꢁ1): 3292, 2957, 1630, 1536, 1494, 1458, 1298, 1233,
1
1129, 969, 890, 770. H NMR (300 MHz, CDCl3): d 3.34
297.1242,
found:
297.1250.
Anal.
Calcd
for
(s, 6H), 3.50 (d, 2H, J¼5.1 Hz), 4.52 (t, 1H, J¼5.1 Hz),
6.21 (s, 1H), 7.50–7.62 (m, 3H), 7.80–7.85 (m, 2H), 9.84
(br s, 1H). 13C NMR (75 MHz, DMSO-d6): d 41.6, 53.7,
C14H16BF2NO2: C, 60.25; H, 5.78; N, 5.02. Found: C,
59.91; H, 5.93; N, 5.43.

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B. Stefane, S. Polanc / Tetrahedron 63 (2007) 10902–10913
10907
85.0, 101.2, 126.3, 128.9, 132.2, 132.7, 168.2 (t, J¼2.3 Hz),
169.6 (t, J¼2.3 Hz). MS (EI, 70 eV, m/z (%)): 299 (M+, 3),
105 (32), 75 (100). HRMS (EI) m/z calcd for
C13H16BF2NO4: 299.1140, found: 299.1152. Anal. Calcd
for C13H16BF2NO4: C, 52.21; H, 5.39; N, 4.68. Found: C,
51.94; H, 5.63; N, 4.80.
J1¼4.8 Hz, J2¼7.6 Hz), 7.71 (d, 1H, J¼7.6 Hz), 8.52–8.56
(m, 2H), 10.02 (br s, 1H). 13C NMR (75 MHz, DMSO-d6):
d 22.0, 40.9, 87.2, 123.7, 132.2, 135.6, 148.8, 148.9, 167.4
(t, J¼2.3 Hz), 176.5 (t, J¼1.7 Hz). MS (CI, m/z (%)): 240
(MH+, 51), 220 (31), 156 (56), 92 (100), 65 (44). HRMS
(CI) m/z calcd for C10H12BF2N2O2: 239.0918, found:
239.0918.
4.3.7. 2,2-Difluoro-4-amino-6-phenyl-1,3,2-dioxabori-
nane (2g). White solid, yield 92%; mp 183–184 ꢀC (from
EtOAc). IR (KBr, n cmꢁ1): 3460, 3366, 3285, 1660, 1609,
1574, 1532, 1487, 1369, 1121, 1036, 991, 918, 772, 689.
1H NMR (300 MHz, DMSO-d6): d 5.93 (s, 1H), 7.33–7.45
(m, 3H), 7.75–7.78 (m, 2H), 8.41 (br s, 1H), 8.55 (br s,
1H). 13C NMR (75 MHz, DMSO-d6): d 84.1, 126.2, 128.1,
131.6, 132.7, 170.5 (t, J¼2.5 Hz), 171.3 (t, J¼2.0 Hz). MS
(EI, 70 eV, m/z (%)): 211 (M+, 76), 210 (100), 105 (65), 77
(40). HRMS (EI) m/z calcd for C9H8BF2NO2: 211.0616,
found: 211.0624. Anal. Calcd for C9H8BF2NO2: C, 51.24;
H, 3.82; N, 6.64. Found: C, 50.77; H, 3.93; N, 6.93.
4.3.12. 2,2-Difluoro-5-(2-methoxy-2-oxoethyl)-4-methyl-
6-(methylamino)-1,3,2-dioxaborinane (2l). White solid,
yield 83%; mp 116–117 ꢀC (from light petroleum/EtOAc).
IR (KBr, n cmꢁ1): 3411, 2955, 1739, 1621, 1522, 1445,
1348, 1301, 1175, 1055, 861, 777, 737, 697, 655. 1H
NMR (300 MHz, CDCl3): d 2.20 (s, 3H), 3.06 (d, 3H,
J¼5.0 Hz), 3.20 (s, 2H), 3.75 (s, 3H), 7.37 (br s, 1H). 13C
NMR (75 MHz, CDCl3): d 20.9, 27.9, 31.5, 52.8, 91.5,
168.8 (t, J¼2.7 Hz), 172.0, 176.5 (t, J¼1.8 Hz). MS (EI,
70 eV, m/z (%)): 235 (M+, 27), 216 (24), 176 (100), 110
(57), 97 (58). HRMS (EI) m/z calcd for C8H12BF2NO4:
235.0828, found: 235.0834. Anal. Calcd for C8H12BF2NO4:
C, 40.89; H, 5.15; N, 5.96. Found: C, 40.96; H, 5.28; N,
6.19.
4.3.8. 2,2-Difluoro-6-(2,2-dimethylhydrazino)-4-phenyl-
1,3,2-dioxaborinane (2h). White solid, yield 81%; mp
159–160 ꢀC (from Et2O/EtOAc). IR (KBr, n cmꢁ1): 3269,
1611, 1536, 1393, 1348, 1169, 1045, 974, 907, 865, 771.
1H NMR (300 MHz, CDCl3): d 2.61 (s, 6H), 6.52 (s, 1H),
7.50–7.61 (m, 3H), 7.91–7.94 (m, 2H), 10.09 (br s, 1H).
13C NMR (75 MHz, DMSO-d6): d 46.9, 81.6, 126.9,
128.9, 132.6, 132.8, 169.0 (t, J¼2.6 Hz), 172.6 (t,
J¼2.0 Hz). 19F NMR (282.4 MHz, CDCl3): d ꢁ142.0. MS
(EI, 70 eV, m/z (%)): 254 (M+, 35), 108 (100), 77 (41), 59
(79). HRMS (EI) m/z calcd for C11H13BF2N2O2: 254.1038,
found: 254.1046.
4.3.13. 2,2-Difluoro-5-(2-methoxy-2-oxoethyl)-4-methyl-
6-(1-pyrrolidinyl)-1,3,2-dioxaborinane (2m). White solid,
yield 79%; mp 98–100 ꢀC (from light petroleum/EtOAc). IR
(KBr, n cmꢁ1): 2969, 2885, 1733, 1596, 1569, 1477, 1431,
1
1341, 1316, 1236, 1170, 1086, 772. H NMR (300 MHz,
CDCl3): d 1.92 (tt, 2H, J1¼J2¼6.6 Hz), 2.01 (tt, 2H,
J1¼J2¼6.6 Hz), 2.11 (s, 3H), 3.41 (s, 2H), 3.65–3.74 (m,
4H), 3.76 (s, 3H). 13C NMR (75 MHz, CDCl3): d 21.5,
23.2, 26.9, 32.0, 48.8, 50.3, 52.5, 91.9, 166.0 (t,
J¼2.0 Hz), 171.8, 179.5 (t, J¼1.5 Hz). MS (EI, 70 eV, m/z
(%)): 275 (M+, 30), 256 (46), 216 (100), 147 (35), 118
(76), 97 (67), 70 (42), 55 (63). HRMS (EI) m/z calcd for
C11H16BF2NO4: 275.1141, found: 275.1151.
4.3.9. 2,2-Difluoro-4-(isopropylamino)-5H,6H,7H,8H-
1,3,2-benzodioxaborinane (2i). White solid, yield 98%;
mp 131–133 ꢀC (from light petroleum/EtOAc). IR (KBr, n
cmꢁ1): 3364, 2984, 1607, 1528, 1416, 1198, 1129, 1020,
1
883, 751, 656. H NMR (300 MHz, DMSO-d6): d 1.28 (d,
4.3.14. 2,2-Difluoro-5-(2-methoxy-2-oxoethyl)-4-methyl-
6-[(2-sulfanylethyl)amino]-1,3,2-dioxaborinane (2n).
White solid, yield 71%; mp 66–68 ꢀC (from light petro-
leum/EtOAc). IR (KBr, n cmꢁ1): 3395, 2956, 2577, 1736,
6H, J¼6.6 Hz), 1.71–1.75 (m, 4H), 2.12–2.17 (m, 2H),
2.33–2.37 (m, 2H), 4.21–4.33 (m, 1H), 5.98 (br s, 1H). 13C
NMR (75 MHz, DMSO-d6): d 20.0, 21.1, 21.3, 21.5, 30.0,
43.1, 94.7, 166.0 (J¼2.6 Hz), 172.4 (J¼2.0 Hz). 19F NMR
(282.4 MHz, CDCl3): d ꢁ141.6. MS (EI, 70 eV, m/z (%)):
231 (M+, 72), 173 (100), 123 (70). HRMS (EI) m/z calcd
for C10H16BF2NO2: 231.1242, found: 231.1249.
1
1602, 1522, 1438, 1347, 1299, 1197, 1051, 780. H NMR
(300 MHz, CDCl3): d 1.53 (t, 1H, J¼8.6 Hz), 2.22 (s, 3H),
2.78 (dt, 2H, J1¼8.6 Hz, J2¼6.3 Hz), 3.23 (s, 2H), 3.67
(dt, 2H, J1¼J2¼6.1 Hz), 3.76 (s, 3H), 7.66 (br s, 1H). 13C
NMR (75 MHz, CDCl3): d 21.1, 23.7, 31.6, 44.0, 52.9,
91.5, 168.5 (t, J¼2.0 Hz), 171.9, 177.7 (t, J¼2.0 Hz). MS
(EI, 70 eV, m/z (%)): 261 (M+ꢁHF, 76), 149 (97), 93 (86),
57 (100). Anal. Calcd for C9H14BF2NO4S: C, 38.46; H,
5.02; N, 4.98. Found: C, 38.40; H, 5.25; N, 4.88.
4.3.10. 2,2-Difluoro-6-(isopropylamino)-4-methyl-1,3,2-
dioxaborinane (2j). Colourless oil, yield 92%. IR (film, n
cmꢁ1): 3362, 2982, 1624, 1538, 1419, 1294, 1073, 1047,
981, 786. 1H NMR (300 MHz, CDCl3): d 1.25 (d, 6H,
J¼6.6 Hz), 2.04 (s, 3H), 4.15–4.26 (m, 1H), 5.25 (s, 1H),
6.52 (br s, 1H). 13C NMR (75 MHz, CDCl3): d 22.4, 22.9,
43.9, 88.0, 167.8, 177.5. MS (CI, m/z (%)): 191 (MH+,
50), 176 (55), 133 (67), 92 (100), 85 (64), 69 (91). HRMS
(CI) m/z calcd for C7H13BF2NO2: 190.0966, found:
190.0966.
4.3.15. 6-(Allylamino)-2,2-difluoro-5-(2-methoxy-2-oxo-
ethyl)-4-methyl-1,3,2-dioxaborinane (2o). White solid,
yield 90%; mp 43–45 ꢀC (from Et2O/EtOAc). IR (KBr, n
cmꢁ1): 3391, 2957, 1738, 1604, 1522, 1438, 1346, 1197,
1
1173, 1052. H NMR (300 MHz, CDCl3): d 2.20 (s, 3H),
3.23 (s, 2H), 3.75 (s, 3H), 4.07–4.11 (m, 2H), 5.25–5.35
(m, 2H), 5.83–5.95 (m, 1H), 7.45 (br s, 1H). 13C NMR
(75 MHz, CDCl3): d 20.8, 31.3, 43.4, 52.7, 91.5, 118.3,
131.2, 168.0 (t, J¼1.7 Hz), 171.8, 176.9 (t, J¼1.9 Hz). MS
(EI, 70 eV, m/z (%)): 261 (M+, 32), 242 (28), 202 (100), 97
(62). HRMS (EI) m/z calcd for C10H14BF2NO4: 261.0984,
found: 261.0991.
4.3.11. 2,2-Difluoro-4-methyl-6-(3-picolylamino)-1,3,2-
dioxaborinane (2k). White solid, yield 98%; mp 147–
149 ꢀC (from EtOAc). IR (KBr, n cmꢁ1): 3249, 3109,
1603, 1533, 1464, 1422, 1334, 1190, 1053, 964, 885, 787,
712. 1H NMR (300 MHz, DMSO-d6): d 2.01 (s, 3H),
4.54(d, 2H, J¼5.7 Hz), 5.41 (s, 1H), 7.42 (dd, 1H,

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B. Stefane, S. Polanc / Tetrahedron 63 (2007) 10902–10913
10908
4.3.16. 2,2-Difluoro-5-(2-methoxy-2-oxoethyl)-4-methyl-
6-(3-picolylamino)-1,3,2-dioxaborinane (2p). White
solid, yield 95%; mp 132–134 ꢀC (from Et2O/EtOAc).
IR (KBr, n cmꢁ1): 3233, 2966, 1730, 1614, 1518, 1432,
1308, 1225, 1206, 1143, 1054, 839, 710. 1H NMR
(300 MHz, CDCl3): d 2.22 (s, 3H), 3.21 (s, 2H), 3.71 (s,
3H), 4.66 (d, 2H, J¼5.6 Hz), 7.34 (ddd, 1H, J1¼0.8 Hz,
J2¼4.8 Hz, J3¼7.7 Hz), 7.68–7.73 (m, 1H), 7.92 (br s,
1H), 8.57 (d, 1H, J¼1.9 Hz), 8.60 (dd, 1H, J1¼1.5 Hz,
J2¼4.8 Hz). 13C NMR (75 MHz, DMSO-d6): d 20.4,
29.6, 41.5, 51.8, 92.0, 123.5, 132.5, 135.0, 148.6, 148.7,
167.1 (t, J¼2.5 Hz), 170.5, 175.7 (t, J¼2.0 Hz). MS (EI,
70 eV, m/z (%)): 312 (M+, 25), 253 (57), 92 (100).
HRMS (EI) m/z calcd for C13H15BF2N2O4: 312.1093,
found: 312.1105.
4.4. General procedure for the preparation of b-keto
amides
A mixture of 2,2-difluoro-4-alkylamino-1,3,2-dioxabori-
nane (1 mmol), sodium acetate (5 mmol), ethanol (5 mL)
and water (5 mL) was heated at reflux for 2–16 h. The sol-
vent was then removed under reduced pressure and the res-
idue dissolved in ethyl acetate (30 mL), washed with water
(2ꢂ10 mL), dried over magnesium sulfate and evaporated
to dryness. Products were in some cases purified by flash
chromatography on a silica gel using 3:5 EtOAc/light petro-
leum as eluent.
4.4.1. Methyl 4-oxo-3-(1-pyrrolidinylcarbonyl)penta-
noate (3a). Colourless oil, yield 79%. IR (film, n cmꢁ1):
2955, 2880, 1725, 1638, 1436, 1360, 1248, 1165. 1H NMR
(300 MHz, CDCl3): d 1.77–1.97 (m, 4H), 2.10 (s, 3H),
2.82 (d, 2H, J¼7.1 Hz), 3.36–3.65 (m, 4H), 3.58 (s, 3H),
3.89 (t, 1H, J¼7.1 Hz). 13C NMR (75 MHz, CDCl3):
d 24.1, 25.7, 27.6, 32.3, 46.1, 47.1, 51.7, 54.5, 166.7,
171.9, 202.0. MS (EI, 70 eV, m/z (%)): 227 (M+, 35), 209
(37), 184 (38), 126 (70), 98 (45), 70 (100). HRMS (EI) m/z
calcd for C11H17NO4: 227.1158, found: 227.1163.
4.3.17. 2,2-Difluoro-5-(2-hydroxyethyl)-6-(isopropyl-
amino)-4-methyl-1,3,2-dioxaborinane (2q). The colourless
oil obtained on workup was subjected to flash chromato-
graphy (5:3 light petroleum/EtOAc elution), colourless oil,
yield 45%, Rf¼0.25 (5:3 light petroleum/EtOAc). IR (film,
n cmꢁ1): 3559, 3383, 2978, 1601, 1520, 1466, 1285, 1200,
1049. 1H NMR (300 MHz, CDCl3): d 1.24 (d, 6H,
J¼6.9 Hz), 2.08 (s, 3H), 2.46 (t, 2H, J¼5.4 Hz), 3.01 (br s,
1H), 3.80 (t, 2H, J¼5.4 Hz), 4.14–4.23 (m, 1H), 7.90 (br s,
1H). 13C NMR (75 MHz, CDCl3): d 20.5, 22.2, 28.4, 43.7,
63.3, 96.7, 168.4, 174.0. 19F NMR (282.4 MHz, CDCl3):
d ꢁ142.0. MS (EI, 70 eV, m/z (%)): 235 (M+, 3), 169 (40),
111 (100). HRMS (EI) m/z calcd for C9H16BF2NO3:
235.1191, found: 235.1201.
4.4.2. N-Isopropyl-3-oxo-3-phenylpropanamide (3b).
White solid, yield 88%; mp 70–72 ꢀC (from CH2Cl2/light
petroleum). IR (KBr, n cmꢁ1): 3297, 2973, 1690, 1641,
1
1551, 1450, 1045, 756, 689. H NMR (300 MHz, CDCl3):
d 1.19 (d, 6H, J¼6.5 Hz), 3.93 (s, 2H), 4.03–4.23 (m, 1H),
6.19 (br s, 1H), 7.42–7.53 (m, 3H), 7.99–8.03 (m, 2H). 13C
NMR (75 MHz, CDCl3): d 22.6, 41.6, 45.6, 128.5, 128.8,
134.0, 136.3, 164.7, 196.3. MS (EI, 70 eV, m/z (%)): 205
(M+, 17), 190 (19), 105 (100), 77 (61), 58 (81). HRMS
(EI) m/z: calcd for C12H15NO2: 205.1103, found: 205.1110.
4.3.18. 2,2-Difluoro-5-(2-hydroxyethyl)-4-methyl-6-(3-
picolylamino)-1,3,2-dioxaborinane (2r). The colourless
oil obtained on workup was subjected to flash chromato-
graphy (5:3 light petroleum/EtOAc elution), white solid,
yield 50%, Rf¼0.21 (5:3 light petroleum/EtOAc); mp 70–
72 ꢀC (from Et2O/EtOAc). IR (KBr, n cmꢁ1): 3308, 3237,
3058, 2911, 1697, 1607, 1480, 1427, 1402, 1362, 1232,
1138, 1090, 1021, 903, 793, 766, 712. 1H NMR
(300 MHz, CDCl3): d 1.90 (s, 3H), 2.83 (t, 2H, J¼8.1 Hz),
3.27 (br s, 1H), 4.27 (t, 2H, J¼8.1 Hz), 4.43 (d, 2H,
J¼6.3 Hz), 7.27 (ddd, 1H, J1¼1.0 Hz, J2¼4.8 Hz,
J3¼7.9 Hz), 7.59–7.61 (m, 1H), 8.50–8.52 (m, 2H), 8.62
(br s, 1H). 13C NMR (75 MHz, CDCl3): d 16.2, 26.3, 44.2,
65.1, 87.1, 123.6, 134.3 (2C), 148.3, 148.8, 156.1, 174.0.
MS (EI, 70 eV, m/z (%)): 284 (M+, 2), 218 (40), 92 (100).
HRMS (EI) m/z calcd for C12H15BF2N2O3: 284.1144, found:
284.1152.
4.4.3. 3-Oxo-3-phenyl-N-(3-pyridinylmethyl)propan-
amide (3c). White solid, yield 97%; mp 100–102 ꢀC (from
Et2O/EtOAc). IR (KBr, n cmꢁ1): 3219, 3046, 1679, 1655,
1
1578, 1428, 1325, 1221, 1034, 756, 721, 688. H NMR
(300 MHz, CDCl3): d 4.01 (s, 2H), 4.51 (d, 2H,
J¼6.3 Hz), 7.24 (dd, 1H, J1¼4.8 Hz, J2¼7.5 Hz), 7.41–
7.74 (m, 5H), 7.96–8.00 (m, 2H), 8.50–8.54 (m, 2H). 13C
NMR (75 MHz, CDCl3): d 41.0, 45.0, 123.5, 128.5, 128.9,
133.7, 134.2, 135.4, 136.0, 148.8, 149.1, 166.0, 195.9. MS
(EI, 70 eV, m/z (%)): 254 (M+, 34), 107 (100), 77 (62).
HRMS (EI) m/z calcd for C15H14N2O2: 254.1055, found:
254.1063.
4.4.4. N-Allyl-3-oxo-3-phenylpropanamide (3d). White
solid, yield 91%; mp 54–56 ꢀC (from Et2O/EtOAc). IR
(KBr, n cmꢁ1): 3300, 3078, 1690, 1641, 1551, 1449, 1330,
1281, 1212, 757, 689. 1H NMR (300 MHz, DMSO-d6):
d 3.73–3.77 (m, 2H), 3.96 (s, 2H), 5.05–5.23 (m, 2H),
5.75–5.87 (m, 2H), 7.49–7.67 (m, 3H), 7.97–8.00 (m, 2H).
13C NMR (75 MHz, DMSO-d6): d 41.9, 47.7, 116.0,
129.2, 129.5, 134.3, 135.9, 137.2, 167.0, 195.6. MS (EI,
70 eV, m/z (%)): 204 (MH+, 15), 120 (25), 105 (100), 77
(72), 56 (87). HRMS (EI) m/z calcd for C12H13NO2:
204.1025, found: 204.1030.
4.3.19. 6-(Allylamino)-2,2-difluoro-5-(2-hydroxyethyl)-4-
methyl-1,3,2-dioxaborinane (2s). The colourless oil ob-
tained on workup was subjected to flash chromatography
(1:10 MeOH/CH2Cl2 elution), colourless oil, yield 68%,
Rf¼0.20 (1:10 MeOH/CH2Cl2). IR (film, n cmꢁ1): 3563,
3399, 2932, 1603, 1520, 1300, 1199, 1048. 1H NMR
(300 MHz, CDCl3):
d 2.08 (s, 3H), 2.48 (t, 2H,
J¼5.4 Hz), 3.25 (br s, 1H), 3.77 (t, 2H, J¼5.4 Hz), 4.00–
4.04 (m, 2H), 5.18–5.29 (m, 2H), 5.78–5.29 (m, 1H), 8.22
(br s, 1H). 13C NMR (75 MHz, CDCl3): d 28.8, 43.7,
63.0, 85.4, 97.1, 118.5, 132.1, 169.4, 174.8. MS (EI,
70 eV, m/z (%)): 233 (M+, 23), 202 (7), 111 (100), 69
(47). HRMS (EI) m/z calcd for C9H14BF2NO3: 233.1035,
found: 233.1030.
4.4.5. N-(3-Pyridinylmethyl)-3-oxo-3-phenylpropan-
amide (3e). Colourless oil, yield 63%. IR (film, n cmꢁ1):
3268, 3092, 1719, 1655, 1564, 1452, 1362, 1163, 1038,

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B. Stefane, S. Polanc / Tetrahedron 63 (2007) 10902–10913
10909
1
712. H NMR (300 MHz, CDCl3): d 2.28 (s, 3H), 3.49 (s,
4.5.1. (2Z)-3-(Allylamino)-3-phenyl-N-(3-picolyl)-2-pro-
penamide (4a). The colourless oil obtained on workup
was subjected to flash chromatography (1:1 light petro-
leum/EtOAc), colourless oil, yield 92%, Rf¼0.20 (1:1 light
petroleum/EtOAc). IR (film, n cmꢁ1): 3273, 2921, 1618,
1592, 1541, 1497, 1426, 1310, 1210, 1030, 922, 771, 703.
1H NMR (300 MHz, CDCl3): d 3.62–3.66 (m, 2H), 4.50
(d, 2H, J¼5.7 Hz), 4.50 (s, 1H), 5.07–5.25 (m, 2H), 5.47
(br s, 1H), 5.73–5.86 (m, 1H), 7.24–7.40 (m, 6H), 7.67–
7.71 (m, 1H), 8.50 (dd, 1H, J1¼1.7 Hz, J2¼4.5 Hz), 8.57
(d, 1H, J¼1.7 Hz), 9.12 (br s, 1H). 13C NMR (75 MHz,
CDCl3): d 40.2, 46.6, 88.2, 115.4, 123.4, 127.6, 128.1,
128.8, 135.1, 135.3, 135.6, 136.3, 148.1, 148.7, 162.3,
170.2. MS (ESI+, m/z (%)): 294 (MH+), 255. HRMS
(ESI+) m/z calcd for C18H20N3O: 294.1606, found:
294.1614.
2H), 4.50 (d, 2H, J¼6.0 Hz), 7.28 (dd, 1H, J1¼4.5 Hz,
J2¼7.5 Hz), 7.55 (br s, 1H), 7.64–7.66 (m, 1H), 8.52–8.56
(m, 2H). 13C NMR (75 MHz, CDCl3): d 31.1, 41.0, 49.2,
123.6, 133.7, 135.5, 148.9, 149.1, 165.6, 204.6. MS (EI,
70 eV, m/z (%)): 192 (MH+, 26), 107 (100), 92 (32).
HRMS (EI) m/z calcd for C10H12N2O2: 192.0899, found:
192.0905.
4.4.6. N-Isopropyl-2-oxo-1-cyclohexanecarboxamide
(3f). White solid, yield 95%; mp 101–103 ꢀC (from
CH2Cl2/light petroleum). IR (KBr, n cmꢁ1): 3219, 3079,
2986, 2873, 1704, 1638, 1553, 1457, 1385, 1196, 1131,
1073, 1034, 911, 735. 1H NMR (300 MHz, CDCl3): d 1.09
(d, 3H, J¼6.4 Hz), 1.12 (d, 3H, J¼6.4 Hz), 1.69–1.84 (m,
2H), 1.91–2.03 (m, 3H), 2.32–2.49 (m, 3H), 3.13 (dd, 1H,
J1¼5.6 Hz, J2¼9.8 Hz), 4.02–4.14 (m, 1H), 6.80 (br s,
1H). 13C NMR (75 MHz, CDCl3): d 22.60, 22.62, 24.1,
27.3, 31.4, 41.3, 42.1, 55.8, 167.8, 210.8. MS (EI, 70 eV,
m/z (%)): 183 (M+, 55), 125 (53), 114 (54), 98 (95), 58
(100). HRMS (EI) m/z calcd for C10H17NO2: 183.1259,
found: 183.1267.
4.5.2. (Z)-1-Allyl-3-(1-(benzylamino)ethylidene)pyr-
rolidine-2,5-dione (4b). The colourless oil obtained on
workup was subjected to flash chromatography (5:3 light pe-
troleum/EtOAc elution), white solid, yield 72%, Rf¼0.27
(5:3 light petroleum/EtOAc); mp ¼65–68 ꢀC (from light pe-
troleum/Et2O). IR (KBr, n cmꢁ1): 3302, 2918, 1736, 1660,
1
4.4.7. N-Benzyl-2-oxo-1-cyclohexanecarboxamide (3g).
Isolated after crystallisation of the mixture of compounds
3g and 3g0 (CH2Cl2/light petroleum), white solid, yield
28%; mp 89–91 ꢀC (from CH2Cl2/light petroleum). IR
(KBr, n cmꢁ1): 3252, 3080, 2945, 1706, 1639, 1558, 1385,
1247, 1192, 1130, 1077, 760, 738, 704. 1H NMR
(300 MHz, CDCl3): d 1.72–1.79 (m, 2H), 1.96–2.03 (m,
3H), 2.36–2.45 (m, 3H), 3.21 (dd, 1H, J1¼6.1 Hz,
J2¼10.8 Hz), 4.47 (d, 2H, J¼5.7 Hz), 7.26–7.34 (m, 5H),
7.36 (br s, 1H). 13C NMR (75 MHz, CDCl3): d 24.2, 27.2,
31.5, 42.1, 43.3, 55.8, 127.3, 127.5, 128.6, 138.1, 168.9,
210.4. MS (EI, 70 eV, m/z (%)): 231 (M+, 12), 106 (100),
91 (63). HRMS (EI) m/z calcd for C14H17NO2: 231.1259,
found: 231.1251. Anal. Calcd for C14H17NO2: C, 72.70; H,
7.41; N, 6.06. Found: C, 72.23; H, 7.58; N, 6.25.
1614, 1388, 1223, 1186, 1091, 935, 886, 745. H NMR
(300 MHz, CDCl3): d 1.93 (s, 3H), 3.21 (s, 2H), 4.11–4.14
(m, 2H), 4.45 (d, 2H, J¼6.3 Hz), 5.13–5.17 (m, 2H), 5.77–
5.90 (m, 1H), 7.26–7.38 (m, 5H), 8.93 (br s, 1H). 13C NMR
(75 MHz, CDCl3): d 16.0, 33.5, 40.0, 46.9, 87.8, 117.1,
126.7, 127.5, 128.9, 132.0, 138.2, 155.8, 171.3, 174.6. MS
(EI, 70 eV, m/z (%)):270 (M+, 83), 106 (53), 91 (100).
HRMS (EI) m/z calcd for C16H18N2O2: 270.1368, found:
270.1376. Anal. Calcd for C16H18N2O2: C, 71.09; H, 6.71;
N, 10.36. Found: C, 71.27; H, 6.93; N, 10.43.
4.5.3. (Z)-1-Allyl-3-(1-(prop-2-ynylamino)ethylidene)-
pyrrolidine-2,5-dione (4c). The colourless oil obtained on
workup was subjected to flash chromatography (5:3 light pe-
troleum/EtOAc), white solid, yield 67%, Rf¼0.18 (5:3 light
petroleum/EtOAc); mp¼102–104 ꢀC (from light petroleum/
EtOAc). IR (KBr, n cmꢁ1): 3294, 3249, 2925, 1725, 1668,
1597, 1480, 1433, 1397, 1318, 1273, 1217, 1134, 1107,
4.4.8. N-Benzyl-2-hydroxy-1-cyclohexene-1-carbox-
amide (3g0). Also isolated after crystallisation of the mix-
ture of compounds 3g and 3g0 (CH2Cl2/light petroleum),
white solid, yield 37%; mp 84–86 ꢀC (from CH2Cl2/light
petroleum). IR (KBr, n cmꢁ1): 3389, 2945, 1645, 1606,
1546, 1382, 1306, 1233, 924, 743, 700. 1H NMR
(300 MHz, CDCl3): d 1.68–1.72 (m, 4H), 2.12–2.15 (m,
2H), 2.26–2.30 (m, 2H), 4.52 (d, 2H, J¼5.7 Hz), 5.67
(br s, 1H), 7.28–7.40 (m, 5H), 14.09 (s, 1H). 13C
NMR (75 MHz, CDCl3): d 21.9, 22.5, 22.7, 29.3, 43.1,
96.8, 127.6, 127.7, 128.8, 138.2, 170.6, 172.3. MS (EI,
70 eV, m/z (%)): 231 (M+, 16), 106 (100), 91 (95).
HRMS (EI) m/z calcd for C14H17NO2: 231.1259, found:
231.1253.
1
1063, 922, 766. H NMR (300 MHz, CDCl3): d 2.04 (s,
3H), 2.29 (t, 1H, J¼2.5 Hz), 3.21 (s, 2H), 3.99 (dd, 2H,
J1¼2.5 Hz, J2¼6.3 Hz), 4.10–4.13 (m, 2H), 5.13–5.23 (m,
2H), 5.78–5.87 (m, 1H), 8.60 (br s, 1H). 13C NMR
(75 MHz, CDCl3): d 15.7, 32.4, 33.4, 40.0, 72.2, 79.5,
89.3, 117.2, 131.8, 154.7, 171.3, 174.4. MS (EI, 70 eV, m/z
(%)): 218 (M+, 53), 135 (54), 107 (100). HRMS (EI) m/z
calcd for C12H14N2O2: 218.1055, found: 218.1062. Anal.
Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found:
C, 65.81; H, 6.52; N, 13.14.
4.5.4. N-Benzyl-2-(2-phenylhidrazono)cyclohexanecarb-
oxamide (4d). The precipitated product from the reaction
mixture was filtered off to give pure product, a white solid,
yield 48%; mp¼170–174 ꢀC. IR (KBr, n cmꢁ1): 3315,
3225, 2938, 1661, 1604, 1543, 1495, 1447, 1427, 1360,
1208, 1148, 1096, 978, 890, 744, 696. 1H NMR
(300 MHz, CDCl3): d 1.62–2.02 (m, 5H), 2.21–2.47 (m,
3H), 3.32 (t, 1H, J¼5.5 Hz), 4.49 (d, 2H, J¼6.0 Hz), 6.83–
6.94 (m, 4H), 7.18–7.35 (m, 8H). 13C NMR (75 MHz,
CDCl3): d 23.3, 24.5, 25.0, 29.2, 43.6, 49.9, 112.9, 120.0,
127.3, 127.7, 128.6, 129.2, 138.5, 145.2, 147.9, 171.6. MS
4.5. General procedure for the preparation of
b-carboxamido enamines
In a typical experiment the solution of 2,2-difluoro-4-alkyl-
amino-1,3,2-dioxaborinane (1 mmol) and the corresponding
amine (5 equiv) in n-PrOH (5 mL) was heated with stirring
in Ace pressure tube at 130 ꢀC. After heating for 12 h, the re-
action mixture was evaporated under reduced pressure and
the residue purified by flash chromatography.

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B. Stefane, S. Polanc / Tetrahedron 63 (2007) 10902–10913
10910
(EI, 70 eV, m/z (%)): 321 (M+, 16), 214 (100), 91 (38).
HRMS (EI) m/z calcd for C20H23N3O: 321.1841, found:
321.1850. Anal. Calcd for C20H23N3O: C, 74.74; H, 7.21;
N, 13.07. Found: C, 75.01; H, 7.25; N, 13.30.
(s, 3H), 3.94 (t, 1H, J¼6.9 Hz), 7.72 (d, 1H, J¼9.0 Hz),
7.97 (dd, 1H, J1¼1.8 Hz, J2¼9.0 Hz), 8.57 (d, 1H,
J¼1.8 Hz), 10.63 (br s, 1H). 13C NMR (75 MHz, DMSO-
d6): d 15.4, 33.0, 49.4, 51.6, 52.3, 99.8, 116.1, 117.8,
130.6, 131.3, 138.1, 143.3, 152.6, 170.7, 171.4. MS (EI,
70 eV, m/z (%)): 348 (M+, 30), 317 (30), 256 (100), 210
(23). HRMS (EI) m/z calcd for C15H16N4O6: 348.1070,
found: 348.1081.
4.6. General procedure for the preparation
of hydrazones
To a stirred solution of 2,2-difluoro-4-alkoxy-1,3,2-dioxa-
borinane (1 mmol) in MeCN (5 mL) the corresponding aryl-
hydrazine (1.05 mmol) was added, which promptly
dissolved. The reaction mixture was stirred at room temper-
ature for 5–12 h. The precipitated material was filtered off,
washed with cold MeCN (3 mL) and then recrystallised.
4.7. General procedure for the preparation of pyrazol-
3-ones and 1H-pyrazoles
To a stirred solution of 2,2-difluoro-4-alkoxy-1,3,2-dioxa-
borinane (1 mmol) in MeCN (5 mL) the corresponding aryl-
hydrazine (1.1 mmol) was added, which promptly dissolved.
The reaction mixture was stirred at room temperature for
24 h. The solution was concentrated under reduced pressure,
and the residue purified by silica gel chromatography (5:1
light petroleum/EtOAc elution).
4.6.1. Ethyl 3-[(4-cyano-2-nitrophenyl)hydrazono]-3-
phenylpropenoate (5b). Yellow solid, yield 93%; mp
144–145 ꢀC (from EtOH). IR (KBr, n cmꢁ1): 3294, 2220,
1
1742, 1618, 1564, 1412, 1278, 1150, 922, 820, 760. H
NMR (300 MHz, CDCl3): d 1.29 (t, 3H, J¼7.2 Hz), 3.93
(s, 2H), 4.26 (q, 2H, J¼7.2 Hz), 7.43–7.48 (m, 3H), 7.72
(dd, 1H, J1¼1.5 Hz, J2¼9.0 Hz), 7.89–7.93 (m, 2H), 8.11
(d, 1H, J¼9.0 Hz), 8.53 (d, 1H, J¼1.5 Hz), 11.71 (br s,
1H). 13C NMR (75 MHz, CDCl3): d 13.9, 33.9, 61.5,
100.4, 117.1, 117.9, 126.5, 128.7, 130.0, 131.2, 131.4,
136.5, 138.1, 143.3, 147.7, 167.6. MS (EI, 70 eV, m/z
(%)): 352 (M+, 60), 306 (58), 147 (48), 77 (53). HRMS
(EI) m/z calcd for C18H16N4O4: 352.1172, found: 352.1184.
4.7.1. 2,5-Diphenyl-2,4-dihydro-3H-pyrazol-3-one (6a).44
After the usual workup and chromatography (using 5:1 light
petroleum/EtOAc as eluent), the title compound 6a was iso-
lated as a white solid, yield 44%, Rf¼0.14 (5:1 light petro-
leum/EtOAc); mp 129.5–132 ꢀC. IR (KBr, n cmꢁ1): 2957,
1
1710, 1593, 1495, 1333, 1181, 1120, 895, 756, 688. H
NMR (300 MHz, CDCl3): d 3.85 (s, 2H), 7.19–7.26 (m,
1H), 7.41–7.49 (m, 5H), 7.76–7.80 (m, 2H), 7.96–8.00 (m,
2H).
4.6.2. Ethyl 3-[(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)hy-
drazono]-3-phenylpropanoate (5c). Yellow solid, yield
95%; mp 100–102 ꢀC (from EtOH). IR (KBr, n cmꢁ1):
4.7.2. 2-(4-Fluorophenyl)-5-phenyl-2,4-dihydro-3H-pyr-
azol-3-one (6b). After the usual workup and chromato-
graphy (using 5:1 light petroleum/EtOAc as eluent), the
title compound 6b was isolated, yellowish solid, yield
39%, Rf¼0.10 (5:1 light petroleum/EtOAc); mp 149–
153 ꢀC. IR (KBr, n cmꢁ1): 1705, 1654, 1501, 1335, 1211,
1
3215, 1724, 1605, 1443, 1301, 764. H NMR (300 MHz,
CDCl3): d 1.29 (t, 3H, J¼7.2 Hz), 2.52 (s, 3H), 3.91 (s,
2H), 4.13 (s, 3H), 4.28 (q, 2H, J¼7.2 Hz), 7.43–7.46 (m,
3H), 7.77–7.81 (m, 2H), 10.76 (br s, 1H). 13C NMR
(75 MHz, CDCl3): d 14.0 (2C), 33.6, 40.0, 61.5, 117.4,
126.2, 128.8, 129.8, 136.4, 142.6, 143.7, 147.5, 167.7. MS
(EI, 70 eV, m/z (%)): 345 (M+, 100), 225 (35), 103 (91), 77
(68). HRMS (EI) m/z calcd for C16H19N5O4: 345.1437,
found: 345.1450.
1
1173, 1113, 836, 760, 691. H NMR (300 MHz, CDCl3):
d 3.86 (s, 2H), 7.09–7.15 (m, 2H), 7.45–7.47 (m, 3H),
7.75–7.78 (m, 2H), 7.93–7.98 (m, 2H). 13C NMR
(75 MHz, CDCl3): d 39.4, 115.4 (d, J¼22.5 Hz), 120.6 (d,
J¼8.0 Hz), 125.9, 128.9, 130.6, 130.7, 134.2 (d,
J¼3.0 Hz), 154.7, 159.9 (d, J¼244.5 Hz), 169.9. MS (EI,
70 eV, m/z (%)): 254 (M+, 100), 109 (52), 103 (60).
HRMS (EI) m/z calcd for C15H11FN2O: 254.0855, found:
254.0864.
4.6.3. Ethyl 3-[(4-cyano-2-nitrophenyl)hydrazono]buta-
noate (5d). The crude product was purified by silica gel
chromatography (5:3 light petroleum/EtOAc elution), yel-
low solid, yield 89%, Rf¼0.20 (1:1 light petroleum/EtOAc);
mp 110–113 ꢀC. IR (KBr, n cmꢁ1): 3329, 3113, 2982, 2222,
1736, 1623, 1564, 1528, 1410, 1287, 1180, 1069, 923, 856.
1H NMR (300 MHz, DMSO-d6): d 1.23 (t, 3H, J¼7.2 Hz),
2.09 (s, 3H), 3.52 (s, 2H), 4.14 (q, 2H, J¼7.2 Hz), 7.78 (d,
1H, J¼9.0 Hz), 7.93 (dd, 1H, J1¼9.0 Hz, J2¼1.9 Hz), 8.57
(d, 1H, J¼1.9 Hz), 10.66 (br s, 1H). 13C NMR (75 MHz,
DMSO-d6): d 14.0, 15.9, 43.8, 60.6, 99.5, 166.3, 117.8,
130.4, 131.3, 138.0, 143.3, 151.6, 169.1. MS (EI, 70 eV,
m/z (%)): 290 (M+, 100), 199 (95), 102 (78). HRMS (EI)
m/z calcd for C13H14N4O4: 290.1015, found: 290.1024.
4.7.3. 2-(2,5-Difluorophenyl)-5-phenyl-2,4-dihydro-3H-
pyrazol-3-one (6c). After the usual workup and chromato-
graphy (using 5:1 light petroleum/EtOAc as eluent), the title
compound 6c was isolated as a yellowish solid, yield 60%,
Rf¼0.14 (5:1 light petroleum/EtOAc); mp 111–112.5 ꢀC.
IR (KBr, n cmꢁ1): 3063, 1728, 1624, 1509, 1449, 1342,
1249, 1206, 1121, 858, 759, 687. 1H NMR (300 MHz,
CDCl3): d 3.83 (s, 2H), 7.00–7.08 (m, 1H), 7.15–7.22 (m,
1H), 7.26–7.32 (m, 1H), 7.43–7.48 (m, 3H), 7.72–7.75 (m,
2H). 13C NMR (75 MHz, CDCl3): d 38.0, 113.6 (dd,
J¼26.0, 1.5 Hz), 115.6 (dd, J¼24.0, 8.0 Hz), 117.6 (dd,
J¼22.5, 9.5 Hz), 125.42 (dd, J¼14.5, 10.5 Hz), 125.9,
128.9, 130.6, 130.9, 152.4 (dd, J¼249.5, 3.0 Hz), 155.8,
158.2 (dd, J¼244.0, 2.5 Hz), 170.1. MS (EI, 70 eV, m/z
(%)): 272 (M+, 100), 230 (19), 127 (23), 103 (50). HRMS
(EI) m/z calcd for C15H10F2N2O: 272.0761, found:
272.0770.
4.6.4. Dimethyl 2-[N-(4-cyano-2-nitrophenyl)ethanehy-
drazono]succinate (5e). Yellow solid, yield 87%; mp
102–103 ꢀC (from light petroleum/EtOAc). IR (KBr, n
cmꢁ1): 3318, 2954, 2226, 1734, 1624, 1567, 1524, 1283,
1157, 998, 918, 762. 1H NMR (300 MHz, DMSO-d6):
d 2.11 (s, 3H), 2.93 (d, 2H, J¼6.9 Hz), 3.62 (s, 3H), 3.69

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B. Stefane, S. Polanc / Tetrahedron 63 (2007) 10902–10913
10911
4.7.4. 2-(4-Bromophenyl)-5-phenyl-2,4-dihydro-3H-pyr-
azol-3-one (6d). After the usual workup and chromato-
graphy (using 5:1 light petroleum/EtOAc as eluent), the
title compound 6d was isolated as a white solid, yield
53%, Rf¼0.10 (5:1 light petroleum/EtOAc); mp 142–
145 ꢀC. IR (KBr, n cmꢁ1): 2961, 1709, 1481, 1329, 1115,
J¼22.5 Hz), 123.7 (d, J¼8.5 Hz), 125.4, 128.0, 128.5,
133.4, 135.1 (d, J¼3.0 Hz), 150.5, 155.1, 160.8 (d,
J¼245.5 Hz). MS (EI, 70 eV, m/z (%)): 282 (M+, 100),
253 (62), 102 (33), 95 (42). HRMS (EI) m/z calcd for
C17H15FN2O: 282.1168, found: 282.1177.
1
1069, 820, 759, 687, 646. H NMR (300 MHz, CDCl3):
4.7.9. 1-(2,5-Difluorophenyl)-5-ethoxy-3-phenyl-1H-pyr-
azole (7c). After the usual workup and chromatography (us-
ing 5:1 light petroleum/EtOAc as eluent), the title compound
7c was isolated as a white solid, yield 37%, Rf¼0.45 (5:1
light petroleum/EtOAc); mp 47.5–49 ꢀC. IR (KBr, n
cmꢁ1): 3066, 2986, 1626, 1562, 1514, 1387, 1250, 1178,
1027, 912, 868, 816, 760, 694. 1H NMR (300 MHz,
CDCl3): d 1.42 (t, 3H, J¼7.0 Hz), 4.23 (q, 2H, J¼7.0 Hz),
5.97 (s, 1H), 7.03–7.11 (m, 1H), 7.13–7.21 (m, 1H), 7.29–
7.43 (m, 4H), 7.79–7.83 (m, 2H). 13C NMR (75 MHz,
CDCl3): d 14.5, 68.2, 83.0, 115.4 (d, J¼26.0 Hz), 115.9
(dd, J¼23.0, 8.0 Hz), 117.2 (dd, J¼23.0, 9.0 Hz), 125.5,
126.8 (dd, J¼14.5, 10.5 Hz), 128.2, 128.5, 133.2, 152.3,
152.7 (dd, J¼249.5, 3.0 Hz), 156.0, 158.2 (dd, J¼244.0,
2.5 Hz). MS (EI, 70 eV, m/z (%)): 300 (M+, 100), 272 (85),
102 (50). HRMS (EI) m/z calcd for C17H14F2N2O:
300.1074, found: 300.1067.
d 3.86 (s, 2H), 7.45–7.56 (m, 5H), 7.76–7.79 (m, 2H),
7.89–7.94 (m, 2H). 13C NMR (75 MHz, CDCl3): d 39.5,
118.0, 120.2, 125.9, 128.9, 130.6, 130.8, 131.8, 137.2,
154.8, 170.0. MS (EI, 70 eV, m/z (%)): 314 (M+, 100), 169
(36), 103 (85). HRMS (EI) m/z calcd for C15H11BrN2O:
314.0055, found: 314.0046.
4.7.5. 5-Phenyl-2-[3-(trifluoromethyl)phenyl]-2,4-dihy-
dro-3H-pyrazol-3-one (6e). After the usual workup and
chromatography (using 5:1 light petroleum/EtOAc as elu-
ent), the title compound 6e was isolated as a brownish solid,
yield 42%, Rf¼0.15 (5:1 light petroleum/EtOAc); mp 123–
126 ꢀC. IR (KBr, n cmꢁ1): 3050, 2959, 1717, 1492, 1466,
1340, 1164, 1117, 1073, 893, 799, 756, 691. 1H NMR
(300 MHz, CDCl3): d 3.89 (s, 2H), 7.45–7.57 (m, 5H),
7.78–7.81 (m, 2H), 8.25–8.28 (m, 2H). 13C NMR
(75 MHz, CDCl3): d 39.6, 115.4 (q, J¼4.0 Hz), 121.5 (m,
2C), 123.9 (q, J¼272.5 Hz), 126.1, 129.0, 129.3, 130.5,
131.0, 131.3 (q, J¼32.5 Hz), 138.6, 155.1, 170.2. MS (EI,
70 eV, m/z (%)): 304 (M+, 100), 159 (35), 103 (93).
HRMS (EI) m/z calcd for C16H11F3N2O: 304.0824, found:
304.0830.
4.7.10. 5-Ethoxy-1-(4-bromophenyl)-3-phenyl-1H-pyr-
azole (7d). After the usual workup and chromatography (us-
ing 5:1 light petroleum/EtOAc as eluent), the title compound
7d was isolated as a yellowish solid, yield 27%, Rf¼0.40 (5:1
light petroleum/EtOAc); mp 88–90 ꢀC. IR (KBr, n cmꢁ1):
2982, 1587, 1558, 1501, 1471, 1377, 1155, 1043, 827,
735. 1H NMR (300 MHz, CDCl3): d 1.49 (t, 3H,
J¼7.0 Hz), 4.25 (q, 2H, J¼7.0 Hz), 5.98 (s, 1H), 7.30–
7.44 (m, 3H), 7.52–7.57 (m, 2H), 7.72–7.77 (m, 2H),
7.81–7.85 (m, 2H). 13C NMR (75 MHz, CDCl3): d 15.1,
68.6, 84.4, 119.6, 123.6, 125.9, 128.6, 129.0, 132.2, 133.7,
138.5, 151.3, 155.8. MS (EI, 70 eV, m/z (%)): 342 (M+,
100), 315 (45), 155 (40), 102 (73). HRMS (EI) m/z calcd
for C17H15BrN2O: 342.0368, found: 342.0378.
4.7.6. 2-(4-Bromophenyl)-5-methyl-2,4-dihydro-3H-pyr-
azol-3-one (6f). After the usual workup and chromatography
(using 5:1 light petroleum/EtOAc as eluent), the title com-
pound 6f was isolated as a yellow oil, yield 49%, Rf¼0.19
(5:1 light petroleum/EtOAc). IR (film, n cmꢁ1): 3230,
1625, 1585, 1492, 1400, 1362, 1333, 1148, 1007, 799,
1
761. H NMR (300 MHz, CDCl3): d 3.22 (s, 3H), 3.42 (s,
2H), 7.47–7.50 (m, 2H), 7.77–7.80 (m, 2H). 13C NMR
(75 MHz, CDCl3): d 17.0, 43.1, 117.8, 120.2, 131.8, 137.2,
156.6, 170.5. MS (EI, 70 eV, m/z (%)): 252 (M+, 100), 183
(28), 174 (50), 155 (42), 90 (37). HRMS (EI) m/z calcd for
C10H9BrN2O: 251.9898, found: 251.9892.
4.7.11. 5-Ethoxy-3-phenyl-1-[3-(trifluoromethyl)-
phenyl]-1H-pyrazole (7e). After the usual workup and
chromatography (using 5:1 light petroleum/EtOAc as elu-
ent), the title compound 7e was isolated as a yellow oil, yield
23%, Rf¼0.37 (5:1 light petroleum/EtOAc). IR (film, n
cmꢁ1): 3063, 2986, 1566, 1503, 1454, 1384, 1331, 1159,
4.7.7. 5-Ethoxy-1,3-diphenyl-1H-pyrazole (7a).45 After
the usual workup and chromatography (using 5:1 light petro-
leum/EtOAc as eluent), the title compound 7a was isolated
as a colourless oil, yield 26%, Rf¼0.37 (5:1 light petro-
leum/EtOAc). IR (film, n cmꢁ1): 3062, 2983, 1594, 1559,
1
1115, 892, 799, 741, 691. H NMR (300 MHz, CDCl3):
d 1.52 (t, 3H, J¼7.0 Hz), 4.28 (q, 2H, J¼7.0 Hz), 7.32–
7.60 (m, 6H), 7.84–7.88 (m, 2H), 8.06–8.09 (m, 1H),
8.17–8.20 (m, 1H). 13C NMR (75 MHz, CDCl3): d 14.5,
68.3, 84.1, 118.3 (q, J¼4.0 Hz), 122.2 (q, J¼4.0 Hz),
124.4 (q, J¼1.0 Hz), 123.9 (q, J¼272.5 Hz), 125.5, 128.2,
128.5, 129.3, 131.3 (q, J¼32.5 Hz), 133.1, 139.4, 151.1,
155.6. MS (EI, 70 eV, m/z (%)): 332 (M+, 100), 304 (87),
145 (70), 102 (90). HRMS (EI) m/z calcd for
C18H15F3N2O: 332.1137, found: 332.1146.
1
1503, 1458, 1393, 1265, 1152, 1048, 951, 759, 692. H
NMR (300 MHz, CDCl3): d 1.48 (t, 3H, J¼7.0 Hz), 4.24
(q, 2H, J¼7.0 Hz), 6.00 (s, 1H), 7.24–7.34 (m, 2H), 7.38–
7.45 (m, 4H), 7.81–7.87 (m, 4H).
4.7.8. 5-Ethoxy-1-(4-fluorophenyl)-3-phenyl-1H-pyr-
azole (7b). After the usual workup and chromatography (us-
ing 5:1 light petroleum/EtOAc as eluent), the title compound
7b was isolated as a yellowish oil, yield 34%, Rf¼0.25 (5:1
light petroleum/EtOAc). IR (film, n cmꢁ1): 2984, 2940,
1561, 1514, 1477, 1389, 1213, 1157, 1043, 951, 835, 735,
694. 1H NMR (300 MHz, CDCl3): d 1.48 (t, 3H,
J¼7.0 Hz), 4.23 (q, 2H, J¼7.0 Hz), 5.99 (s, 1H), 7.11–
7.17 (m, 2H), 7.31–7.45 (m, 3H), 7.77–7.87 (m, 4H). 13C
NMR (75 MHz, CDCl3): d 14.6, 68.1, 83.6, 115.5 (d,
4.7.12. 1-(4-Bromophenyl)-5-methoxy-3-methyl-1H-pyr-
azole (7f). After the usual workup and chromatography (us-
ing 5:1 light petroleum/EtOAc as eluent), the title compound
7f was isolated as a yellow oil, yield 16%, Rf¼0.35 (5:1 light
petroleum/EtOAc). IR (film, n cmꢁ1): 2936, 1587, 1562,
1509, 1488, 1449, 1404, 1198, 1149, 1070, 1047, 1009,
1
827. H NMR (300 MHz, CDCl3): d 2.26 (s, 3H), 3.91 (s,

ꢀ
B. Stefane, S. Polanc / Tetrahedron 63 (2007) 10902–10913
10912
3. Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi, L. M.
Tetrahedron 2003, 59, 4661–4671.
3H), 5.49 (s, 1H), 7.48–7.51 (m, 2H), 7.57–7.60 (m, 2H). MS
(EI, 70 eV, m/z (%)): 266 (M+, 100), 155 (57), 75 (43). 13
C
4. Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Mantellini,
F.; Tietze, L. F. Tetrahedron 2001, 57, 5855–5863.
5. Dodd, D. S.; Martinez, R. L. Tetrahedron Lett. 2004, 45, 4265–
4267.
NMR (75 MHz, CDCl3): d 14.5, 58.8, 86.1, 118.9, 123.0,
124.0, 131.8, 149.1, 155.9. HRMS (EI) m/z calcd for
C11H11BrN2O: 266.0055, found: 266.0061.
6. Stephansen, H.; Zaragoza, F. Tetrahedron Lett. 1999, 40, 5799–
5802.
4.8. 2,2-Dichloro-4-ethoxy-6-phenyl-1,3,2-dioxa-
borinane (8)
7. Messeri, T.; Pentassuglia, G.; Di Fabio, R. Tetrahedron Lett.
2001, 42, 3227–3230.
8. (a) Sørensen, U. S.; Falch, E.; Krogsgaard-Larsen, P. J. Org.
Chem. 2000, 65, 1003–1007; (b) Miriyala, B.; Wiliamson,
J. S. Tetrahedron Lett. 2003, 44, 7957–7959.
9. Cerreti, A.; D’Annibale, A.; Trogolo, C.; Umani, F.
Tetrahedron Lett. 2000, 41, 3261–3264.
10. Kalinin, A. V.; De Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.;
Snieckus, V. Tetrahedron Lett. 1998, 39, 4995–4998.
11. Wessig, P.; Glombitza, C.; M€uller, G.; Teubner, J. J. Org.
Chem. 2004, 69, 7582–7591.
12. (a) Ikemoto, N.; Tellers, D. M.; Dreher, S. D.; Liu, J.; Huang,
A.; Rivera, N. R.; Njolito, E.; Hsiao, Y.; McWilliams, J. C.;
Williams, J. M.; Armstrong, J. D.; Sun, Y.; Mathre, D. J.;
Grabowski, E. J. J.; Tillyer, R. D. J. Am. Chem. Soc. 2004,
126, 3048–3049; (b) Bartoli, G.; Bosco, M.; Dalpozzo, R.;
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Bosco, M.; Marcantoni, E.; Massaccesi, M.; Rinaldi, S.;
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13. For reviews see: (a) Abdel-Magid, A. F.; Cohen, J. H.;
Mayanoff, C. A. Curr. Med. Chem. 1999, 6, 955–969; (b)
Cole, D. C. Tetrahedron 1994, 50, 9517–9582; (c)
Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
Ed.; Wiley-VCH: New York, NY, 1997.
To a solution of ethyl benzoylacetate (1.92 g, 10 mmol) in
toluene (60 mL) borontrichloride (1 M, 11 mL, 11 mmol)
was added at room temperature. After being stirred at
room temperature for 24 h, the reaction mixture was evapo-
rated to dryness and the residue was treated with Et2O
(30 mL) and the precipitated material was filtered off yield-
ing pure product, white hygroscopic solid, 2.43 g (89%); mp
123–126 ꢀC (dec). IR (KBr, n cmꢁ1): 2924, 1599, 1568,
1
1508, 1462, 1378, 1334, 1233, 1094, 1057, 947. H NMR
(300 MHz, CDCl3): d 1.50 (t, 3H, J¼7.0 Hz), 4.64 (q, 2H,
J¼7.0 Hz), 6.11 (s, 1H), 7.48–7.53 (m, 2H), 7.62–7.67 (m,
1H), 7.94–7.97 (m, 2H). 13C NMR (75 MHz, CDCl3):
d 14.1, 67.6, 84.4, 128.0, 129.0, 131.1, 134.4, 174.5,
178.3. MS (EI, 70 eV, m/z (%)): 237 (M+ꢁCl, 75), 209
(74), 105 (100). HRMS (EI) m/z calcd for C11H11BClO3
[MꢁCl]+: 237.0490, found: 237.0490.
Acknowledgements
The Ministry of Higher Education, Science and Technology
of the Republic of Slovenia as well as the Slovenian
Research Agency (P1-0230-0103 and J1-6693-0103) is
gratefully acknowledged for financial support. We thank
ˇ
Dr. D. Zigon and Dr. B. Kralj (Center for Mass Spectros-
ꢀ
14. For review see: Ibrahi, H.; Togni, A. Chem. Commun. 2004,
1147–1155.
copy, ‘Jozef Stefan’ Institute, Ljubljana, Slovenia) for the
ꢀꢀ
ꢀ ꢀ
mass measurement and A. Brescak and J. Delibasic for
technical support. Dr. M. Polak (Slovenian NMR Center)
for 15N NMR measurement.
ꢂ
15. Lieby-Muller, F.; Constantieux, T.; Rodriguez, J. J. Am. Chem.
Soc. 2005, 127, 17176–17177.
ꢂ
ꢂ˜
16. Flores-Morales, V.; Fernandez-Zertuche, M.; Ordonez, M.
Tetrahedron: Asymmetry 2003, 14, 2693–2698.
17. Hilgenkamp, R.; Zercher, C. K. Tetrahedron 2001, 57, 8793–
8800.
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