Hydrogenation of BF2 complexes with 1,3-dicarbonyl ligands

Article abstract of DOI:10.1016/j.tet.2009.01.017

The catalytic hydrogenation (H₂, Pd/C) of a set of BF₂ complexes with a 1,3-dicarbonyl structural unit leading to monocarbonyl compounds has been studied. The transformation presented is general for the aryl-substituted derivatives and occurs under mild conditions (H₂, 1 bar, 25 °C) in methanol or THF.

Full text of DOI:10.1016/j.tet.2009.01.017

Tetrahedron 65 (2009) 2339–2343
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Hydrogenation of BF2 complexes with 1,3-dicarbonyl ligands
ˇ
*
Bogdan Stefane , Slovenko Polanc
ˇ
ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, SI-1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic hydrogenation (H2, Pd/C) of a set of BF2 complexes with a 1,3-dicarbonyl structural unit
leading to monocarbonyl compounds has been studied. The transformation presented is general for the
aryl-substituted derivatives and occurs under mild conditions (H2, 1 bar, 25 ꢀC) in methanol or THF.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 29 October 2008
Received in revised form 2 December 2008
Accepted 5 January 2009
Available online 14 January 2009
1. Introduction
methodology was recently applied by Garcia-Garibay et al. for the
synthesis of (þ) and (ꢁ)-
a
-cuparenone.7
The catalytic hydrogenation of 1,2- and 1,3-diketo derivatives
employing a variety of catalysts, including copper, nickel, cobalt,
platinum, palladium and other metals, has been well documented.1
The early investigations of Pd-catalyzed hydrogenations revealed
a strong connection between the preparation of the palladium-on-
carbon catalyst and the structure–reactivity dependence of the
carbonyl compound on the outcome of the reaction.2 The difference
between aliphatic and aromatic carbonyls is marked, and catalyst
preference differs. The hydrogenation of aromatic carbonyls occurs
mainly by conversion to the benzyl alcohols. When hydrogenolysis
is desired it is facilitated by strong acids and elevated temperature.3
To the best of our knowledge, no examples of the reduction of BF2
complexes derived from 1,3-dicarbonyls had been reported at the
outset of our study. However, their preparation proved facile, as
might have been anticipated on the basis of the isolation of these
complexes derived from 1,3-diketones.4 Such BF2 complexes are
very often recognized as intermediates in the boron trifluoride-
catalyzed acylation of ketones with anhydrides.5 The best pro-
cedure for their preparation is the treatment of methylene chloride
or toluene solutions of the corresponding 1,3-dicarbonyls with 1.5–
2.0 equiv of boron trifluoride etherate at room temperature.6 Using
this method, crystalline BF2 complexes are obtained in excellent
yields. Until now a hydrolysis to the parent 1,3-dicarbonyl com-
pounds was the only studied chemistry of these species. Recently,
we reported on the transformations of 1 and 5 using a variety of
2. Results and discussion
Herein, we demonstrate the reactivity of structurally different
(alkyl-, aryl-, alkoxy- and alkylamino-substituted) BF2 complexes
with 1,3-dicarbonyl ligands under catalytic hydrogenation condi-
tions, enabling a facile approach towards the corresponding mono
carbonyl compounds. The initial experiments to determine the
optimal reaction conditions were carried out on 1,3-diketonato-
boron difluorides 1a and 1b (Scheme 1). The treatment of 1a with
H2 (1 bar) in MeOH or THF solutions at room temperature in the
presence of Pd (10% on carbon) resulted, after 24 h, in the complete
deoxygenation of substrate 1a, thus giving 1,3-diphenylpropane
(2a) in an excellent yield. The same procedure applied to the methyl
and n-butyl analogues 1b and 1c yielded the corresponding alco-
hols 2b and 2c as the sole products.
R1
F
O
F
O
B
H2; 10% Pd-C
THF
Ph
R
Ph
R
2a; R = Ph, R1 = H; 88%
2b; R = Me, R1 = OH; 98%
2c; R = n-Bu, R1 = OH; 71%
1a; R = Ph
1b; R = Me
1c; R = n-Bu
Scheme 1. Catalytic hydrogenation of BF2 complexes 1.
nitrogen nucleophiles, providing enaminones,
b-ketoamides and
nitrogen heterocycles.6a,c,d Additionally, at the same time, Chris-
Recent publications on the reductive deoxygenation of keto-
amides and esters involved SmI2 additives8 and Ru3(CO)12
,
pro-
9
toffers et al. reported on
b-diketonatoboron difluorides as in-
termediates in an asymmetric Michael reaction.6b Furthermore, our
viding monocarbonyl compounds together with the corresponding
hydroxy and dihydroxy derivatives. As shown in Table 1, we applied
our conditions to 1,3-ketoamide and ester substrates. Under the
described reaction conditions the difluoroboron complex 5a un-
dergoes the same
b-deoxygenation process, giving a synthetically
* Corresponding author. Tel.: þ386 1 2419264; fax: þ386 1 2419220.
useful building block, 6a.10 To establish whether investigated BF2
ˇ
E-mail address: bogdan.stefane@fkkt.uni-lj.si (B. Stefane).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.017

ˇ
2340
B. Stefane, S. Polanc / Tetrahedron 65 (2009) 2339–2343
Table 1
F
O
F
O
F
B
O
F
O
B
Hydrogenation of various BF2 complexes 4
H2; 10% Pd-C
THF
O
F
O
F
O
B
Ph
NH2
Ph
NHNMe2
H2; 10% Pd-C
THF
R1
R2
5j
6j; 48%
R1
R2
Scheme 3. Catalytic hydrogenation of hydrazido derivative 3j.
6
5
Compounds 5 and 6
R1
R2
Yielda
stereoselectivity.14 Herein, we describe an alternative approach to
6i, starting with the b-ketoester–BF2 complex 5i. It is worth men-
a
b
c
d
eb
fb
C6H5
4-MeOC6H4
C6H5
C6H5
C6H5
OEt
OEt
66
83
88
92
92
89
NHi-Pr
NEt2
NHCH2CH]CH2
NHCH2CH]CH2
tioning that under the applied reaction conditions (H2, 1 bar, THF,
25 ꢀC, 5–24 h) no hydrogenolysis of the benzylic moiety in 6h and 6i
is observed. The hydrazido derivative 5j underwent a N–N cleavage
reaction, resulting in the formation of the amido product 6j, with
the –O–B(F2)–O] moiety retained (Scheme 3).
In addition, substrates 8 and 10, containing the furan-3-yl
moiety, were readily reduced to tetrahydrofuranyl derivatives
without affecting the 1,3-dicarbonyl moiety. The isolated BF2 amido
complex 11 showed, under the conditions of the reaction workup,
a greater stability than the initially reduced ester analogue of 8,
which led to ethyl 3-oxo-3-(tetrahydrofuran-3-yl)propanoate (9) as
the final product (Scheme 4).
4-MeOC6H4
g
C6H5
C6H5
87
91
N
h
NHBn
NH
i
C6H5
89
OH
a
Yields of isolated products are given.
2-Propene unit is also hydrogenated resulting in R2¼NHn-Pr, 6e and 6f.
b
O
O
OEt
chelates show different reactivity comparing to 1,3-diketo de-
rivatives, we have performed the control experiment employing
a treatment of ethyl 3-oxo-3-phenylpropanoate (3a) and N-benzyl-
3-oxo-3-phenylpropanamide (3b) under the same reaction
conditions.
O
7
BF3OEt2
toluene
25 °C, 24 h
F
O
F
O
B
O
O
H2; Pd-C
THF, 25 °C, 24 h
OH
O
OEt
OEt
8; 69%
O
O
H2; 10% Pd-C
THF, 25 °C
O
O
9; 81%
Ph
R
Ph
3a; R = OEt
3b; R = NHBn
R
n-BuNH2
MeCN, 25 °C, 1h
4a; R = OEt; (94%)
4b; R = NHBn; (96%)
F
O
F
O
F
O
F
O
H2; Pd-C
B
B
Scheme 2. Catalytic hydrogenation of 3a and 3b.
THF, 25 °C, 24 h
NHn-Bu
10; 81%
Scheme 4. Catalytic hydrogenation of 3-furanyl derivatives.
NHn-Bu
The hydrogenation resulted in the formation of ethyl 3-hydroxy-
3-phenylpropanoate (4a, 94%) and N-benzyl-3-hydroxy-3-phenyl-
propanamide (4b, 96%), respectively (Scheme 2).11 These results are
different from that discussed by Hirota et al.,12 wherein de-
oxygenated products were obtained using Pd/C as a catalyst. On the
other hand, benzoyl–benzyl transformations may not always be
straightforward processes,13 especially when other functional
groups, such as benzyl moiety, as in our case (Table 1, example h and
i), are present. However, the above control experiments, testing two
different 1,3-dicarbonyls, confirmed the enhanced reactivity of BF2
complexes compared to the uncoordinated 1,3-ketoesters and 1,3-
ketoamides. Further, we examined if we could extend this meth-
O
O
11; 66%
We also turned our attention to the amido complex 12. After
several attempts to obtain the reduction product we changed the
catalyst from Pd/C to Rh/Al2O3 and applied a longer reduction time
and higher H2 pressures. In the latter case, only the reduction of the
phenyl ring occurred, leaving the –O–B(F2)–O] structural unit
intact (Scheme 5).
F
F
F
F
odology to BF2 complexes derived from b-ketoamides. The latter
B
B
H2 (70 psi)
Rh-Al2O3
have been prepared using the methodology, recently described by
us and Christoffers et al., starting from the corresponding
O
O
O
O
N
H
N
H
THF, 25 °C, 24 h
b
-ketoester–BF2 complexes and alkyl amines.6b–d Under standard
Ph
reaction conditions (1 bar H2, 10% Pd/C, THF, 25 ꢀC, 5–24 h) 5c un-
derwent a smooth reduction, forming the corresponding amide 6c
in a good yield. As shown in Table 1, this hydrogenation procedure
can be successfully applied to a range of amido BF2 complexes
bearing different substituents, thus forming the corresponding
3-arylpropanamides 6c–6i in excellent yields. Additionally, with the
examples 5e and 5f, a simultaneous reduction of the allylamino
moiety occurred (Table 1, example e and f). As is evident from the
literature, 6i has been the subject of numerous patent applications
in connection with indinavir and indinavir-like compounds.
Asymmetric alkylations and aminations of chiral amide cuprates
derived from 6i were achieved in excellent yields and
12
13; 79%
Scheme 5. Catalytic hydrogenation of 12.
The examples 10 and 126d seem to open up the possibility of
employing certain BF2 complexes as protecting groups in the 1,3-
dicarbonyl chemistry.
3. Conclusions
In summary, we have presented a new transformation of 1,3-
dicarbonyl–BF2 chelates under very mild reaction conditions using

ˇ
B. Stefane, S. Polanc / Tetrahedron 65 (2009) 2339–2343
2341
a H2, Pd/C catalyst. This reaction was demonstrated on a series of
4.3. General procedure for the preparation of BF2 complexes
aryl-substituted derivatives and it was found to be, to a certain
extent, substrate dependent. The method could produce several
industrially and pharmaceutically important substances in
a straightforward manner. The experiments revealed that the –O–
BF2–O] moiety can be applied in certain cases as a protecting
group for 1,3-dicarbonyls under the appropriate reaction
conditions.
To a solution of the corresponding amine (1.3 mmol) in
MeCN (5 mL), 2,2-difluoro-4-ethoxy-1,3,2-dioxaborinane 5b
(1.0 mmol) was added at room temperature. The reaction mix-
ture was stirred at room temperature for 1 h. After the reaction
was complete, the reaction mixture was concentrated in vacuo
and the residue was treated with Et2O (10 mL) and filtered off
yielding pure product.
4. Experimental
4.3.1. [N-Allyl-3-(hydroxy-
kO)-3-(4-methoxyphenyl)-
4.1. General methods
acrylamidato-
k
O0](difluoro)boron (5f)
A yellowish solid (197 mg, 70%). Rf¼0.18 (EtOAc/petroleum
ether¼3:5). IR (KBr): 3387, 3022, 1616, 1531, 1506, 1436, 1335, 1268,
Solvents and starting compounds were obtained from com-
mercial sources (Fluka, Sigma and Aldrich). Light petroleum refers
to the fraction with the boiling point 40–60 ꢀC. 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 spectra were recorded on
a Bruker Avance 300 DPX spectrometer at 302 K. Chemical shifts
1234, 1180, 934, 837, 785, 651 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d
3.83 (s, 3H, –OCH3), 4.03–4.06 (m, 2H, –CH]CH2), 5.20–5.30 (m,
2H, –NHCH2–), 5.76–5.91 (m, 1H, –CH]CH2), 5.87 (s, 1H,
PhC(O)]CHCONH–), 6.66 (t, J¼5.5 Hz, 1H, –NH–), 6.86 (AA0XX0,
J¼8.5 Hz, 2H, –Ph), 7.80 (AA0XX0, J¼8.5 Hz, 2H, –Ph). 13C NMR
(300 MHz, CDCl3): d 43.2, 55.4, 114.0, 118.5, 129.0, 131.5, 163.1, 168.9
are reported in
d
ppm, referenced to an internal TMS standard for
(t, J¼2.5 Hz), 172.4 (t, J¼1.5 Hz). MS (CI) m/z (%): 281 (Mþ, 25),
HRMS calcd for C13H14BF2NO3: 281.1035; found: 281.1040. Ele-
mental analysis calcd for C13H14BF2NO3: C, 55.55; H, 5.02; N, 4.98.
Found: C, 55.78; H, 4.98; N, 5.09.
1H NMR, chloroform-d (
d
77.0), DMSO-d6
(d
39.5) for 13C NMR.
Microanalyses were performed on a Perkin–Elmer 2400 series II
CHNS/O analyser. Mass spectra and high-resolution mass mea-
surements were performed on a VG-Analytical Autospec EQ
instrumet.
4.3.2. (1R,2S)-Difluoro{3-(hydroxy-
1H-inden-1-yl]-3-phenylacrylamidato-
k
O)-N-[2-hydroxy-2,3-dihydro-
k
O0}boron (5i)
4.2. General procedure for the hydrogenation of BF2
complexes
To a solution of (1S,2R)-1-aminoindan-2-ol (150 mg, 1 mmol)
in MeCN (5 mL), 2,2-difluoro-4-ethoxy-1,3,2-dioxaborinane 5a
(246 mg, 1.1 mmol) was added at room temperature. The re-
action mixture was stirred at room temperature for 1 h. After the
reaction was complete, the reaction mixture was concentrated in
vacuo and the residue was purified by flash chromatography
(EtOAc/petroleum ether¼3:5) yielding a white solid (220 mg,
The BF2 complex (1 mmol) in THF (10 mL) was added to 10% Pd/
C (100 mg), or Rh/Al2O3 (50 mg) in the case of 12, and the mixture
was hydrogenated for 5–24 h at room temperature and 1 bar, or
4.83 bar (70 psi) in the case of 12. The suspension was filtered
through a pad of Celite and washed with MeOH (100 mL). The
solvent was removed under a reduced pressure, and the residue
was purified by silica gel column chromatography to give pure
products.
64%). Mp¼141.5–144.0 ꢀC. Rf¼0.25 (EtOAc/petroleum ether¼3:5).
20
[
a
]
ꢁ98.0 (c 5.0, Me2CO). IR (KBr): 3563, 3355, 1708, 1611, 1526,
D
1489, 1458, 1299, 1234, 1070, 1030, 770 cmꢁ1. 1H NMR (300 MHz,
CDCl3):
d
2.54 (br s, 1H, –OH), 2.89 (dd, J¼17.0, 2.0 Hz, 1H,
–OHCHCH2–), 3.12 (dd, J¼17.0, 5.0 Hz, 1H, –OHCHCH2–), 4.58
(ddd, J¼7.5, 5.0, 2.0 Hz, 1H, –(NH)CHCH(OH)CH2–), 5.37 (dd,
J¼7.5, 5.0 Hz, 1H, –(NH)CHCH(OH)CH2–), 5.96 (s, 1H,
PhC(O)]CHCONH–), 7.14–7.28 (m, 5H, –Ph), 7.31–7.38 (m, 2H,
–NH, and –Ar–), 7.42–7.50 (m, 1H, –Ar–), 7.79–7.84 (m, 2H, –Ar–).
4.2.1. 1,3-Diphenylpropane (2a)15a
Preparation of the title compound according to the general
procedure described above gave, after purification on SiO2 (EtOAc/
petroleum ether¼1:7), 172 mg (88%) of a colourless oil. Rf¼0.61
(EtOAc/petroleum ether¼1:7). IR (NaCl-plates): 3062, 3026, 2932,
13C NMR (300 MHz, DMSO-d6):
d 39.7, 58.5, 72.9, 84.5, 124.7,
2856, 1601, 1495, 1453, 1080, 1028, 745, 698 cmꢁ1
.
1H NMR
125.4, 127.0, 127.6, 128.6, 128.9, 132.4, 132.7, 138.3, 139.6 169.1 (t,
J¼2.5 Hz), 172.9 (t, J¼1.5 Hz). MS (EI) m/z (%): 343 (Mþ, 25). El-
emental analysis calcd for C18H16BF2NO3: C, 63.01; H, 4.70; N,
4.08. Found: C, 62.94; H, 4.71; N, 4.08.
(300 MHz, CDCl3)
d 1.88–1.98 (m, 2H, –CH2CH2CH2–), 2.62 (t,
J¼7.5 Hz, 4H, –CH2CH2CH2–), 7.12–7.27 (m, 10H, –Ph).
4.2.2. Phenylbutan-2-ol (2b)15b
Purification on SiO2 (EtOAc/petroleum ether¼3:5) gave 147 mg
(98%) of a yellowish oil. Rf¼0.54 (EtOAc/petroleum ether¼3:5). IR
(NaCl-plates): 3367, 3027, 2966, 2928, 1603, 1495, 1454, 1373, 1126,
4.3.3. Ethyl 3-phenylpropanoate (6a)15d
Purification on SiO2 (EtOAc/petroleum ether¼3:5) gave 117 mg
(66%) of a yellowish oil. Rf¼0.26 (EtOAc/petroleum ether¼1:35). IR
(NaCl-plates): 3029, 2982, 2936, 1735, 1497, 1450, 1373, 1152, 1039,
1055, 745, 699 cmꢁ1. 1H NMR (300 MHz, CDCl3):
3H, –CH3), 1.71–1.79 (m, –CH2CH(OH)CH3), 1.82–1.85 (br s, 1H),
2.65–2.87 (m, 2H, PhCH2–), 3.61–3.69 (m, 1H, –CH2CH(OH)CH3),
7.18–7.33 (m, 5H, –Ph).
d
1.21 (d, J¼6.0 Hz,
748, 700 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
1.22 (t, J¼7.0 Hz, 3H,
–OCH2CH3), 2.58–2.64 (t, J¼7.5 Hz, 2H, –CH2CH2CO2Et), 2.95 (t,
J¼7.5 Hz, 2H, –CH2CH2CO2Et), 4.12 (q, J¼7.0 Hz, 2H, –OCH2CH3),
7.16–7.30 (m, 5H, –Ph).
4.2.3. 1-Phenyheptan-3-ol (2c)15c
The crude material obtained was purified on SiO2 (EtOAc/pe-
troleum ether¼1:5) to give 137 mg (71%) of 2c as a colourless oil.
Rf¼0.21 (EtOAc/petroleum ether¼1:5). IR (NaCl-plates): 3391, 2931,
4.3.4. Ethyl 3-(4-methoxyphenyl)propanoate (6b)15e
Purification on SiO2 (EtOAc/petroleum ether¼1:35) gave 173 mg
(83%) of a yellow oil. Rf¼0.35 (EtOAc/petroleum ether¼1:35). IR
(KBr): 2982, 1731, 1613, 1584, 1246, 1175 cmꢁ1. 1H NMR (300 MHz,
2859, 1547, 1455, 1032, 993, 745, 699 cmꢁ1 1H NMR (300 MHz,
.
CDCl3):
d
0.93 (t, J¼7.0 Hz, 3H, –CH3), 1.34–1.51 (series of m, 7H,
CDCl3):
d
1.24 (t, J¼7.0 Hz, 3H, –OCH2CH3), 2.59 (t, J¼7.5 Hz, 2H,
–CH(OH)(CH2)3), 1.74–1.84 (m, 2H, –CH2CH(OH)–), 2.65–2.80 (m,
2H, PhCH2–), 3.75–3.86 (m, 1H, –CH2CH(OH)CH2–), 7.14–7.30 (m,
5H, –Ph).
–CH2CH2CO2Et), 2.90 (t, J¼7.5 Hz, 2H, –CH2CH2CO2Et), 3.80 (s, 3H,
–OCH3), 4.13 (q, J¼7.0 Hz, 2H, –OCH2CH3), 6.82 (AA0XX0, J¼8.5 Hz,
2H, –Ph), 7.12 (AA0XX0, J¼8.5 Hz, 2H, –Ph).

ˇ
B. Stefane, S. Polanc / Tetrahedron 65 (2009) 2339–2343
2342
4.3.5. N-Isopropyl-3-phenylpropanamide (6c)15f
(dt, J¼5.0, 2.0 Hz, 1H, –(NH)CHCH(OH)CH2–), 5.33 (dd, J¼8.5, 5.0 Hz,
1H, –(NH)CHCH(OH)CH2–), 5.95 (d, J¼8.0 Hz, 1H, –NH–), 7.02–7.05 (m,
1H, –Ar–), 7.14–7.34 (m, 8H, –Ph and –Ar–). 13C NMR (300 MHz, CDCl3):
Purification on SiO2 (EtOAc/petroleum ether¼1:1) gave 168 mg
(88%) of a white solid. Mp¼83.0–86.5 ꢀC. Mp(lit.)¼89–90 ꢀC. Rf¼0.31
(EtOAc/petroleum ether¼1:1). IR (KBr): 3301, 2968, 1639, 1544,
d
31.9, 38.6, 39.5, 57.5, 73.5,124.4,125.2,126.4,127.1,128.2,128.5,128.6,
1452, 1379, 1233, 1173, 982, 750, 700 cmꢁ1
.
1H NMR (300 MHz,
139.9, 140.4, 140.7, 172.7. MS (EI) m/z (%): 282 (MHþ, 35). Elemental
analysis calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C, 76.98;
H, 6.82; N, 4.92.
CDCl3):
d
1.06 (d, J¼6.5 Hz, 6H, –CH(CH3)2), 2.42 (t, J¼8.0 Hz, 2H,
–CH2CO–), 2.95 (t, J¼7.5 Hz, 2H, PhCH2–), 3.96–4.10 (m, 1H, –NH
CH(CH3)2), 5.16 (br s, 1H, –NH–), 7.18–7.32 (m, 5H).
4.3.12. Difluoro[3-(hydroxy-kO)-3-phenylacrylamidato-k
O0]
4.3.6. N,N-Diethyl-3-phenylpropanamide (6d)15g
boron (6j)6d
Purification on SiO2 (EtOAc/petroleum ether¼3:5) gave 188 mg
(92%) of a yellowish oil. Rf¼0.28 (EtOAc/petroleum ether¼3:5). IR
(NaCl-plates): 2970, 2933, 1642, 1454, 1431, 1265, 1138, 1076,
Purification on SiO2 (MeOH/CH2Cl2¼1:20) gave 101 mg (48%) of
a white solid. Mp¼187.5–190.0 ꢀC. Mp(lit.)¼186.5–188.5 ꢀC. Rf¼0.30
(MeOH/CH2Cl2¼1:20). IR (KBr): 3471, 3372, 1656, 1609, 1525, 1487,
701 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
1.07–1.13 (m, 6H,
1368, 1030, 986, 772, 687 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 6.06
–N(CH2CH3)2), 2.56–2.62 (m, 2H, –CH2CO–), 2.96–3.01 (m, 2H,
PhCH2–), 3.22 (t, J¼7.0 Hz, 2H, –N(CH2CH3)2), 3.37 (t, J¼7.0 Hz, 2H,
–N(CH2CH3)2), 7.16–7.31 (m, 5H, –Ph).
(s, 1H, PhC(O)]CHCONH2), 7.50–7.63 (m, 3H, –Ph), 7.81–7.85 (m,
2H, –Ph), 9.21 (br s, 2H, PhC(O)]CHCONH2).
4.3.13. [Ethyl 3-(3-furyl)-3-(hydroxy-
O0](difluoro)boron (8)
A solution of 1,3-diketoester 7 (477 mg, 2.6 mmol) in dry toluene
(10 mL) was treated with BF3$OEt2 (5.2 mmol, 2.0 equiv). The solution
was left at 25 ꢀC for 24 h and then concentrated in vacuo. The crude
material was suspended in Et2O (5 mL) and filtered off, yielding a pure
product (415 mg, 69%) as white solid. Mp¼141.5–144.0 ꢀC. Rf¼0.55
(EtOAc/petroleum ether¼3:5). IR (KBr): 3458, 1616, 1541, 1416, 1393,
1345, 1260, 1163, 1071, 1007, 901, 868, 789 cmꢁ1. 1H NMR (300 MHz,
kO)acrylatato-
4.3.7. 3-Phenyl-N-propylpropanamide (6e)15h
k
Purification on SiO2 (EtOAc/petroleum ether¼3:5) gave 176 mg
(92%) of a white solid. Mp¼46.5–49.0 ꢀC. Mp(lit.)¼52–54 ꢀC. Rf¼0.23
(EtOAc/petroleum ether¼3:5). IR (KBr): 3301, 2962, 2932, 2870,
1644, 1548, 1231, 1155, 749, 700 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
0.85 (t, J¼7.5 Hz, 3H, –NHCH2CH2CH3), 1.44 (dt, J¼7.0, 7.0 Hz, 2H,
–NHCH2CH2CH3), 2.46 (t, J¼8.0 Hz, 2H, –CH2CO–), 2.96 (t, J¼7.5 Hz,
2H, PhCH2–), 3.16 (dt, J¼7.0, 7.0 Hz, 2H, –NHCH2CH2CH3), 5.45 (br s,
1H, –NH–), 7.16–7.30 (m, 5H, –Ph).
CDCl3):
d
1.44 (t, J¼7.0 Hz,3H, –CH3), 4.55(q, J¼7.0 Hz, 2H. –CH2–), 5.66
(s, 1H, C(O)]CHCO–), 6.68 (dd, J¼1.5, 1.0 Hz, 1H, furan-4-H), 7.49 (dd,
4.3.8. 3-(4-Methoxyphenyl)-N-propylpropanamide (6f)
J¼1.5,1.5 Hz,1H, furan-5-H), 8.13 (dd, J¼1.5,1.0 Hz,1H, furan-2-H). 13C
Purification on SiO2 (CH2Cl2) gave 197 mg (89%) of a colourless
oil. Rf¼0.25 (CH2Cl2). IR (NaCl-plates): 3296, 2957, 1638, 1541, 1508,
NMR (300 MHz, DMSO-d6): d 14.0, 66.0, 83.5, 107.9, 121.9, 144.7, 147.2,
174.4 (t, J¼2.0 Hz),175.3(t, J¼1.5 Hz). MS(EI)m/z (%): 230 (Mþ, 33),136
(50), 95 (100). HRMScalcd for C9H9BF2O4: 230.0562; found: 230.0569.
Elemental analysis calcd for C9H9BF2O4: C, 47.00; H, 3.94. Found: C,
46.86; H, 4.06.
1242,1026, 813 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
0.58 (t, J¼7.5 Hz,
3H, –NHCH2CH2CH3), 1.45 (dt, J¼7.0, 7.0 Hz, 2H, –NHCH2CH2CH3),
2.42 (t, J¼7.0 Hz, 2H, –CH2CO–), 2.90 (t, J¼7.0 Hz, 2H, PhCH2–), 3.13–
3.20 (m, 2H, –NHCH2CH2CH3), 3.78 (s, 3H, –OCH3), 5.41 (br s, 1H,
–NH–), 6.81 (AA0XX0, J¼8.5 Hz, 2H, –Ph), 7.11 (AA0XX0, J¼8.5 Hz, 2H,
4.3.14. Ethyl 3-oxo-3-(tetrahydrofuran-2-yl)propanoate (9)
–Ph). 13C NMR (CDCl3):
d
11.3, 22.8, 30.9, 38.8, 41.2, 55.2, 113.9,
Purification on SiO2 (EtOAc/petroleum ether¼3:5) gave 169 mg
(81%) of a colourless oil. Rf¼0.39 (EtOAc/petroleum ether¼3:5). IR
(NaCl-plates): 2982, 2872,1744,1716,1645,1468,1027, 917 cmꢁ1. 1H
129.3, 133.0, 158.0, 172.1. MS (CI) m/z (%): 221 (Mþ, 63). HRMS calcd
for C13H19NO2: 221.1416; found: 221.1420.
NMR (300 MHz, CDCl3):
d
1.27 (q, J¼7.0 Hz, 3H, –CH3), 2.10–2.17 (m,
4.3.9. 1-(3-Phenylpropanoyl)piperidine (6g)15i
2H, –CH2–), 3.31–3.42 (m, 1H, –CH–), 3.53 (s, 2H, –COCH2CO–),
3.74–3.96 (m, 2H, –OCH2CH2–), 3.93 (d, J¼6.5 Hz, 2H, –OCH2CH–),
Purification on SiO2 (EtOAc/petroleum ether¼3:5) gave 188 mg
(87%) of a colourless oil. Rf¼0.23 (EtOAc/petroleum ether¼3:5). IR
(NaCl-plates): 2934, 2855, 1639, 1441, 1379, 1251, 1218, 1024, 750,
4.20 (q, J¼7.0 Hz, 2H, –CH2CH3). 13C NMR (300 MHz, CDCl3):
d 14.0,
28.8, 48.4, 51.0, 61.4, 68.2, 69.1, 166.8, 202.3. MS (CI) m/z (%): 209
(MþNaþ, 90). HRMS calcd for C9H14O4Na: 209.0790; found:
209.0790.
701 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 1.39–1.61 (m, 6H, piperidine
–CH2–), 2.57–2.62 (t, J¼7.5 Hz, 2H, –CH2CO–), 2.93–2.98 (t, J¼7.5 Hz,
2H, PhCH2–), 3.30 (t, J¼5.5 Hz, 2H, piperidine –CH2–), 3.54 (t,
J¼5.5 Hz, 2H, piperidine –CH2–), 7.13–7.29 (m, 5H, –Ph).
4.3.15. [N-Butyl-3-(3-furyl)-3-(hydroxy-
O0](difluoro)boron (10)
To a solution of n-butylamine (376 mg, 5.2 mmol) in MeCN
(5 mL), 2,2-difluoro-4-alkoxy-1,3,2-dioxaborinane (912 mg,
kO)acrylamidato-
k
4.3.10. N-Benzyl-3-phenylpropanamide (6h)15j
Purification on SiO2 (EtOAc/petroleum ether¼1:1) gave 266 mg
(91%) of a white solid. Mp¼83.0–86 ꢀC. Mp(lit.)¼83–84 ꢀC. Rf¼0.20
(EtOAc/petroleum ether¼1:1). IR (KBr): 3291, 1639, 1544, 1497,
8
4.0 mmol) was added at room temperature. The reaction mixture
was stirred at room temperature for 1 h. After the reaction was
complete, the reaction mixture was concentrated in vacuo and the
residue was purified by flash chromatography (EtOAc/petroleum
ether¼1:5) yielding a white solid (822 mg, 80%). Mp¼72.0–75.0 ꢀC.
Rf¼0.27 (EtOAc/petroleum ether¼3:5). IR (KBr): 3375, 2959, 1634,
1535, 1379, 1339, 1164, 1007, 870, 787, 737 cmꢁ1. 1H NMR (300 MHz,
1450, 1067, 1030 cmꢁ1 1H NMR (300 MHz, CDCl3):
. d 2.50 (t,
J¼7.5 Hz, 2H, PhCH2–), 2.98 (t, J¼7.5 Hz, 2H, –CH2CO–), 4.37 (d,
J¼6.0 Hz, 2H, –NHCH2Ph), 5.75 (br s, 1H, –NHCH2Ph), 7.11–7.32 (m,
10H, 2ꢂ–Ph).
4.3.11. (1S,2R)-N-(2-Hydroxy-2,3-dihydro-1H-inden-1-yl)3-
phenylpropanamide (6i)
CDCl3):
d
0.93 (t, J¼7.5 Hz, 3H, –CH3), 1.32–1.69 (m, 4H, –CH2CH2–),
3.43–3.49 (m, 2H, –NHCH2–), 5.59 (s, 1H, –CO]CHCO–), 6.45 (br s,
1H, –NH–), 6.59–6.60 (m, 1H, furan-4-H), 7.41–7.42 (m, 1H, furan-5-
H), 7.99–8.00 (m, 1H, furan-2-H). 13C NMR (300 MHz, DMSO-d6):
Purification on SiO2 (EtOAc/petroleum ether¼3:5) gave 250 mg
(89%) of a white solid. Mp¼159–161 ꢀC. Rf¼0.15 (EtOAc/petroleum
ether¼3:5). IR (NaCl-plates): 3443, 3306, 3218, 1646, 1616, 1551, 1452,
d
13.5, 19.8, 30.9, 40.8, 84.7, 107.8, 122.1, 144.2, 145.4, 167.2 (t,
1196, 1049, 735 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
2.52–2.68 (m, 2H,
J¼2.5 Hz),168.6 (t, J¼1.5 Hz). MS (EI) m/z (%): 257 (Mþ, 59), 215 (29),
185 (64), 95 (100). Elemental analysis calcd for C11H14BF2NO3: C,
51.40; H, 5.49; N, 5.45. Found: C, 51.69; H, 5.60; N, 5.38.
–CH2CO–), 2.87 (dd, J¼16.5, 2.0 Hz, 1H, –CH(OH)CH2–), 3.03 (t,
J¼7.5 Hz, 2H, PhCH2–), 3.11 (dd, J¼16.5, 5.0 Hz,1H, –CH(OH)CH2–),4.49

ˇ
B. Stefane, S. Polanc / Tetrahedron 65 (2009) 2339–2343
2343
Mallat, T.; Orglmeister, E.; Baiker, A. Chem. Rev. 2007, 107, 4863; (d) Ager, D. J.;
Laneman, S. A. Tetrahedron: Asymmetry 1997, 8, 3327.
2. (a) Anderson, L. C.; MacNaughton, N. W. J. Am. Chem. Soc. 1942, 64, 1456; (b)
Meschke, R. W.; Hartung, W. H. J. Org. Chem. 1960, 25, 137.
4.3.16. [N-Butyl-3-(hydroxy-
kO)-3-(tetrahydrofuran-2-
yl)acrylamidato-
k
O0](difluoro)boron (11)
Purification on SiO2 (EtOAc/petroleum ether¼3:5) gave 172 mg
(66%) of
a
white solid. Mp¼39.5–43.0 ꢀC. Rf¼0.42 (MeOH/
3. For examples see: (a) Zymalkowski, F. Katalytische Hydrierung im Organisch-
Chemischen Laboratorium; Ferdinand Enke: Stuttgart, 1965; (b) Freifelder, M.
Catalytic Hydrogenation in Organic Synthesis; John Wiley & Sons: New York, NY,
1978; pp 78–88; (c) Rylander, P. N. In Best Synthetic Methods: Hydrogenation
Methods; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Academic: New York,
NY, 1985; pp 66–77.
4. (a) Morgan, G. T.; Tunstall, R. H. J. Chem. Soc. 1924, 125, 1963; (b) Mikhailov,
B. M.; Vaver, V. A.; Bubnov, Y. N. Dokl. Akad. Nauk SSSR 1959, 126, 575; (c)
Mikhailov, B. M.; Bubnov, Y. N. Izv. Akad. Nauk SSSR, Otd. Khim. Nauk 1960, 3,
1872; (d) Mikhailov, B. M.; Bubnov, Y. N. Izv. Akad. Nauk SSSR, Otd. Khim. Nauk
1960, 3, 1883.
CH2Cl2¼1:20). IR (KBr): 3370, 2962, 2937, 2876, 1620, 1540, 1443,
1331, 1150, 1049, 912, 793 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 0.92–
0.96 (m, 3H, –CH3), 1.31–1.43 (m, 2H, –CH2–), 1.53–1.64 (m, 2H,
–CH2–), 2.10–2.23 (m, 2H, –CH2–), 3.00–3.14 (m, 1H, –CH–), 3.22–
3.46 (m, 2H, –NHCH2–), 3.80–4.00 (m, 4H, –CH2OCH2–), 5.32 (s, 1H,
–CO]CHCO–), 6.70 (br s, 1H, –NH–). 13C NMR (300 MHz, CDCl3):
d
13.5, 19.8, 30.5, 30.8, 40.7, 45.1, 68.3, 70.7, 86.4, 168.5 (t, J¼2.5 Hz),
180.1 (t, J¼1.5 Hz). MS (EI) m/z (%): 261 (Mþ, 2), 242 (91), 218 (63),
69 (100), 57 (37). HRMS calcd for C11H18NO3BF2: 261.1348; found:
261.1353.
5. For early examples, see: (a) Hauser, C. R.; Swamer, F. W.; Adams, J. T. Org. React.
1954, 8, 59; (b) Youssefyeh, R. D. J. Am. Chem. Soc. 1963, 85, 3901; (c) Musso, H.;
Fiige, K. Justus Liebigs Ann. Chem. 1963, 668, 15; (d) Crimmins, T. F.; Hauser, C. R.
J. Org. Chem. 1967, 32, 2615.
ˇ
6. (a) Stefane, B.; Polanc, S. New J. Chem. 2002, 26, 28; (b) Christoffers, J.;
4.3.17. [N-(2-Cyclohexylethyl)-2-(hydroxy-
carboxamidato-
O0](difluoro)boron (13)
kO)cyclohex-1-ene-1-
ˇ
Kreidler, B.; Unger, S.; Frey, W. Eur. J. Org. Chem. 2003, 2845; (c) Stefane, B.;
ˇ
Polanc, S. Synlett 2004, 698; (d) Stefane, B.; Polanc, S. Tetrahedron 2007, 63,
k
10902.
Purification on SiO2 (EtOAc/petroleum ether¼3:5) gave 236 mg
(79%) of a white solid. Mp¼99.5–102.0 ꢀC. Rf¼0.38 (EtOAc/petro-
leum ether¼3:5). IR (NaCl): 3380, 2924, 2849, 1638, 1541, 1447,
7. Natarajan, A.; Ng, D.; Yang, Z.; Garcia-Garibay, M. A. Angew. Chem., Int. Ed. 2007,
46, 6485.
8. Kamochi, Y.; Kudo, T.; Masuda, T.; Takadate, A. Chem. Pharm. Bull. 2005, 53, 1017.
9. Motohiro, A.; Teruyuki, K.; Yoshihisa, W. J. Mol. Catal. 1993, 80, 383.
10. For recent examples see: (a) Peng, C.; Wang, Y.; Wang, J. J. Am. Chem. Soc. 2008,
130, 1566; (b) Taber, D. F.; Sheth, R. B.; Joshi, P. V. J. Org. Chem. 2005, 70, 2851;
(c) Yan, T.-H.; Chien, C.-T.; Tsai, C.-C.; Lin, K.-W.; Wu, Y.-H. Org. Lett. 2004, 6,
4965; (d) Mizojiri, R.; Urabe, H.; Sato, F. J. Org. Chem. 2000, 65, 6217.
11. Isolated yields of the pure products are given. To confirm that 3-hydroxy de-
rivatives are formed, the reactions were repeated three times and repeatable
results were obtained. The structures of the products were confirmed by 1H
NMR, HRMS and additionally with authentic samples.
1419, 1254, 1200, 884, 747 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d 0.85–
1.00 (m, 2H, cyclohexane-CH2), 1.12–1.34 (m, 6H, cyclohexane-CH2),
1.47–1.55 (m, 2H, –NHCH2CH2–), 1.67–1.76 (m, 8H, cyclohexane-
CH2), 2.10–2.16 (m, 2H, –CH2C(O)]C(CO)CH2–), 2.33–2.38 (m, 2H,
–CH2C(O)]C(CO)CH2–), 3.45–3.52 (sim m, 2H, –NHCH2–), 6.04 (br
s, 1H, –NH–). 13C NMR (300 MHz, DMSO-d6):
d 20.9, 21.4, 21.8, 26.0,
26.3, 30.5, 33.0, 35.2, 36.4, 39.1, 94.1, 168.0, 174.9. MS (EI) m/z (%):
299 (Mþ, 64), 203 (70), 173 (100), 125 (36), 55 (39). HRMS calcd for
C15H24NO2BF2: 299.1868; found 299.1877. Elemental analysis calcd
for C15H24NO2BF2: C, 60.22; H, 8.09; N, 4.68. Found: C, 60.46; H,
8.20; N, 4.55.
12. Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2001, 57, 4817.
13. (a) Shotwell, J. B.; Krygowski, E. S.; Hines, J.; Koh, B.; Huntsman, E. W. D.; Choi,
H. W.; Schneekloth, J. S.; Wood, J. L.; Crews, C. M. Org. Lett. 2002, 4, 3087; (b)
Deering, C. F.; Huckabee, B. K.; Lin, S.; Porter, K. T.; Rossman, C. A.; Wemple, J.
Org. Process Res. Dev. 2000, 4, 596; (c) Giichi, G.; Kayoko, O.; Tetsuya, O.; Isuke, I.
Chem. Pharm. Bull. 1985, 33, 4422; (d) Rabjohn, N.; Rosenburg, D. W. J. Org.
Chem. 1959, 24, 1192; (e) Von Kindler, K.; Hedemann, B.; Scha¨rfe, E. Justus Lie-
bigs Ann. Chem. 1948, 560, 215.
14. (a) Myers, A. G.; Barbay, J. K.; Zhong, B. J. Am. Chem. Soc. 2001, 123, 7207; (b)
McWilliams, C. J.; Armstrong, J. D., III; Zheng, N.; Bhupathy, M.; Volante, R. P.;
Reider, P. J. J. Am. Chem. Soc. 1996, 118, 11970; (c) Zheng, N.; Armstrong, J. D., III;
McWilliams, J. C.; Volante, R. P. Tetrahedron Lett. 1997, 38, 2817; (d) Askin, D.;
Wallace, M. A.; Vacca, J. P.; Reamer, R. A.; Volante, R. P.; Shinkai, I. J. Org. Chem.
1992, 57, 2771.
Acknowledgements
The Ministry of Higher Education, Science and Technology of the
Republic of Slovenia and the Slovenian Research Agency (P1-0230-
0103) are gratefully acknowledged for their financial support. We
ˇ
thank Dr. D. Zigon and Dr. B. Kralj (Center for Mass Spectroscopy,
15. (a) Mori, A.; Mizusaki, T.; Miyakawa, Y.; Ohashi, E.; Haga, T.; Maegawa, T.;
Mongushi, Y.; Sajiki, H. Tetrahedron 2006, 62, 11925; (b) Kamitanaka, T.; Hikida,
T.; Hayashi, S.; Kishida, N.; Matsuda, T.; Harada, T. Tetrahedron Lett. 2007, 48,
8460; (c) Buszek, K. R.; Brown, N. J. Org. Chem. 2007, 72, 3125; (d) Campan˜a, A.
G.; Este´vez, R. E.; Fuentes, N.; Robles, R.; Cuerva, J. M.; Bun˜uel, E.; Ca´rdenas, D.;
ꢀ
‘Jozef Stefan’ Institute, Ljubljana, Slovenia) for the mass spectros-
ˇˇ
ˇ ´
copy measurements, and A. Brescak and G. Milicic for laboratory
assistance. The authors thank Dr. Paul McGuiness for critical read-
ing of the manuscript.
´
Olitra, J. E. Org. Lett. 2007, 9, 2195; (e) Amatore, M.; Gosmini, C.; Perichon, J. J.
Org. Chem. 2006, 71, 6130; (f) De Kimpe, N.; Sulmon, P.; Moe¨ns, L.; Schamp, N. J.
´
Org. Chem. 1986, 51, 3839; (g) Concellon, J.; Huerta, M.; Bardales, E. Tetrahedron
References and notes
2004, 60, 10059; (h) Dietrich, H.; Lehmann, C. Ger. Offen. 2,043,800, 1971.
(Chem. Abstr. 1970, 74, 141794b ); (i) Shiina, I.; Kawakita, Y. Tetrahedron 2004,
60, 4729; (j) Kunishima, M.; Kawachi, C.; Hioki, K.; Terao, K.; Tani, S. Tetrahedron
2001, 57, 1551.
1. For reviews see: (a) Rylander, P. N. Hydrogenation Methods; Academic: New
York, NY, 1985; (b) Bode, S. E.; Wolberg, M.; Mu¨ller, M. Synthesis 2006, 557; (c)