Highly regioselective halogenation of 1-phenyl-3-(3,5-dimethoxyphenyl)- propane-1,3-dione

Article abstract of DOI:10.1016/j.tet.2011.01.051

Halogenation of 1-phenyl-3-(3,5-dimethoxyphenyl)-propane-1,3-dione (1) with N-X reagents take place regioselectively at the α position (except for fluorination), while halogenation of its BF₂ derivative 3 take place regioselectively at position

Full text of DOI:10.1016/j.tet.2011.01.051

Tetrahedron 67 (2011) 2103e2109
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Highly regioselective halogenation of 1-phenyl-3-(3,5-dimethoxyphenyl)-
propane-1,3-dione
ꢀ
*
ꢀ
Petra Galer, Berta Kosmrlj, Boris Sket
ꢀ
ꢀ
University of Ljubljana, Faculty of Chemistry, 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:
Halogenation of 1-phenyl-3-(3,5-dimethoxyphenyl)-propane-1,3-dione (1) with NeX reagents take place
Received 14 September 2010
Received in revised form 24 December 2010
Accepted 18 January 2011
regioselectively at the
a position (except for fluorination), while halogenation of its BF2 derivative 3 take
place regioselectively at position 2 in the activated phenyl ring. When the molar ratio of substrate to
reagent is changed from 1:1.1 to 1:2.1 or 1:2.8, halogenation takes place at positions 2 and 6 of the ar-
omatic ring. Crystallization of a BF2 derivative from protic solvent led to hydrolysis of the BF2 group.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 25 January 2011
Keywords:
1,3-Diketones
1,3-DioxaeBF2 derivatives
Regioselective halogenation
1. Introduction
For electron-rich substrates like phenols and anisole, reactions
are so rapid that they can be carried out with a dilute solution of Br2
Halo substituted organic compounds are important intermediates
in organic synthesis and are also of biological interest, since in several
cases the halogen atom can change the biological activity. Halogen
atomscanbeintroducedintoorganicmoleculesbydifferentmethods,
which include electrophilic, nucleophilic or radical pathways.
or Cl2 in water at room temperature, or with aqueous HBr in
DMSO.16 There are also other reagents, such as N-chloro and
N-bromo imides17 (especially NBS and NCS), HOCl,18 HOBr etc., for
this purpose. Iodine is the least reactive of the halogens in aromatic
substitution.19 Except for electron-rich substrates, an oxidizing
agent must be present to oxidize I2 to a better electrophile.20e23 On
the other hand ICl is a better iodinating agent than iodine itself.24
N-Iodo amides reagents can also be used.25
Aldehydes and ketones can be halogenated at the
a position
with bromine, chlorine, and iodine,1 but the reaction is not suc-
cessful with fluorine.2 Compounds containing an active methylene,
such as b-keto esters and b-diketones, have been fluorinated with
NeF reagents,3 with F2/N2eHCOOH4 or acetyl hypofluorite.5 Silyl
6
enol ethers can be fluorinated with XeF2 or 5% F2 in N2 at ꢀ78 ꢁC in
2. Results and discussion
FCCl3.7
b-Diketones and b-keto esters can also be chlorinated,
Although it is not very difficult to introduce a halogen atom at the
position in compounds with active methylenes, such as b-dike-
brominated or iodinated and numerous reagents and methods are
described in the literature.8
a
tones or into activated aromatic rings, the problem appears when
two such or several reactive centers are present within the same
molecule. In these cases it is not so easy to introduce the halogen
atom at the desired position only. For this reason, 1-phenyl-3-(3,5-
dimethoxyphenyl)-propane-1,3-dione 126 was used as a model
compound for our studies. It contains a 1,3-dicarbonyl moiety and
a highly activated aromatic ring with two methoxy groups. In ace-
tonitrile solution the ketoeenol equilibrium of 1 is shifted toward
the enol form predominately (we have determined by 1H NMR
spectroscopy that less than 5% of the diketone form is present).
As halogenation agents we chose: 1-chloromethyl-4-fluoro-
1,4-diazoniabicyclo[2,2,2]octane bis tetrafluoroborate (FeTEDA)
and 1-hydroxy-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane bis tet-
rafluoroborate (NFTh) for fluorination; N-halo succinimide and
There are also other reagents and methods to introduce a halo-
gen atom into aromatic compounds.9 Direct fluorination of aro-
matic rings with F210 is not feasible at room temperature because of
the extreme reactivity of F2, but this can be accomplished at low
temperatures.11 Fluorination has also been reported with acetyl
hypofluorite,12 XeF2,13 NeF reagents, such as FeTEDA14 or
(CF3SO2)2NF,15 and by the Schiemann reaction as the most common
method for introducing fluorine into aromatic rings. Aromatic
compounds can be chlorinated or brominated by treatment with
bromine or chlorine in the presence of a catalyst.
* Corresponding author. Tel.: þ386 1 2419 100; fax: þ386 1 2419 220; e-mail
ꢀ
address: boris.sket@fkkt.uni-lj.si (B. Sket).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.051

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P. Galer et al. / Tetrahedron 67 (2011) 2103e2109
N-halo saccharin for chlorination,27 bromination,28 and iodina-
tion.25a All experiments were carried out at room temperature.
Conversions were determined by 1H NMR spectra and products
were purified by crystallization from hexane/CH2Cl2.
Table 2
Preparation and halogenations of compound 3a
Fluorination of compound 1 was carried out in acetonitrile so-
lution using FeTEDA as the most promising reagent for electro-
philic fluorination. The crude reaction mixture was analyzed by 1H
and 19F NMR spectroscopy. In the 1H NMR spectrum besides signals
corresponding to 1, two other sets of signals appeared. There was
a doublet with coupling constant 49.2 Hz at
d
¼6.45 ppm corre-
sponding to the product 2a (Table 1), as well as two dd signals at
6.82 ppm (J¼7.1, 3.0 Hz) and 7.16 ppm (J¼4.7, 3.0 Hz) belonging to
product 5a (see also Table 2) in which fluorination took place at
position 2 in the activated phenyl ring. In the 19F NMR spectrum
two signals also appeared: dd at
coupling constant¼49.2 Hz and a ddd at
d
¼ꢀ186.78 ppm with geminal HeF
d
¼ꢀ142.51 ppm corre-
sponding to compound 5a. To improve the regioselectivity of
fluorination, we also tested NFTh,29 and determined that both re-
active positions were again fluorinated and a mixture of 2a and 5a
was obtained. On the other hand chlorination,30 bromination, and
iodination using NXS/LiClO4 systems in CH3CN solution were
completely regioselective, and 2b, 2c, and 2d were formed as the
sole products (Table 1).
Entry
Reagent
mol ratio of 3/reagent
Product
Time (h)
Yieldd (%)
1
2
3
4
5
6
7
8
NFThb
1:2.8
1:1.1
1:1.1
1:2.8
1:1.1
1:1.1
1:2.1
1:1.1
4a
4b
4b
6b
4c
4c
6c
4d
6d
4d
6d
6d
41
48
5
24
1.5
5
78
81
79
86
83
NCSc
NCSacc
NCSacc
NBSc
NBSacc
NBSacc
NISc
63
89
20
48
27e
12e
27e
36e
83
Table 1
Halogenation of compound 1a
9
NISacc
NISacc
1:1.1
1:2.1
3
10
20
a
Solvent: CH3CN; mol ratio of 3/reagent¼1:1.1; rt.
b
c
50% NFTh/Al2O3.
Irradiated with
Isolated yield.
Relative yield.
l¼360 nm.
d
e
Similar results were obtained using N-halo saccharin which is
a better source of electrophilic halogen.31 No halogenation of the
activated phenyl ring took place. Next, using 1H and 13C NMR
spectroscopy, we determined that a-halo substituted compounds
are present as the 1,3-diketone. At this time we have no explanation
for the dramatic change from predominantly enol form of 1 to the
keto form upon halogenation.
These results led us to believe that for aryl ring halogenation, the
diketo functionality should be deactivated. Using a known litera-
ture procedure32 the BF2 derivative of 1 was prepared (Table 2) in
which BF2 is a strong electron withdrawing group. The structure of
3 was determined by 1H, 13C, 19F, and 11B NMR spectroscopy. In the
Entry
1
Reagent
Product
Time (h)
4c
Conv (%)
89
Yieldd (%)
FeTEDA
2a
5a
2a
5a
2b
2b
2c
2c
2d
2d
76e
13e
76e
24e
90
93
87
63
90
2
NFThb
13c
100
3
4
5
6
7
8
NCS
NCSacc
NBS
NBSacc
NIS
NISacc
0.5
0.5
0.5
0.5
0.5
0.5
100
100
100
74
100
100
1H NMR spectrum besides other signals, a singlet at
d
¼7.20 ppm
appeared, corresponding to the proton bonded at C2. In the 13C
NMR spectrum two signals of nearly equal intensity at
¼183.0 and
183.2 ppm were observed, corresponding to C1 and C3 atoms. The
11B NMR spectrum showed one singlet at 1.46 ppm, while in the 19
NMR spectrum two singlets at
¼ꢀ140.19 and ꢀ140.25 ppm with
integral ratios of 0.19:1.00 were observed. We are unable to explain
92
d
a
Solvent: CH3CN; mol ratio of 1/reagent/LiClO4¼1:1.1:0.6; rt.
b
c
50% NFTh/Al2O3; mol ratio of 1/reagent/LiClO4¼1:2.2:0.6.
F
At 0 ꢁC.
Isolated yield.
Relative yield.
d
e
d

P. Galer et al. / Tetrahedron 67 (2011) 2103e2109
2105
Table 3
that discrepancy but the same observation has been reported in the
literature32,33 for several BF2 derivatives of symmetric and asym-
Hydrolysis of compounds 4 and 6
metric substituted 1,3-diarylpropane-1,3-diones. The authors33
Entry
Substrate
Product
X
Isolated yield
explained that the spectra of the BF2 derivative of b-diketones are
1
2
3
4
5
6
4a
4b
4c
6b
6c
6d
5a
5b
5c
7b
7c
7d
F
90
92
97
96
93
95
Cl
Br
Cl
Br
I
unusual as the expected BeF coupling is not observed due to fast
relaxation of quadrupolar boron nucleus. Taking all these NMR data
into account we believe that the central ring in the derivative is
nearly symmetric and that the fundamental state of 3 can be de-
scribed as a hybrid of two resonance form 3(R1) and 3(R2) (Fig. 1).
Fig. 1. Possible resonance forms for BF2 derivative of 3.
Fig. 3. Hydrolysis of 3. Changes in 1H NMR spectra with time.
Table 4
Fluorination of BF2 derivative 3 was carried out at room tem-
perature with 10% excess of NFTh/Al2O3 in acetonitrile (Table 2).
After 21 h, we determined that 70% conversion had taken place.
Thus, an additional 0.6 mmol of reagent was added and the reaction
was continued for 20 h. On the basis of 1H, 13C, and 19F NMR spectra
we concluded that fluorination had occurred only at position 2 in
the electron-rich aryl ring. In the 1H NMR spectrum besides two dd
Kinetics of hydrolysis of derivative 3
signals at
d
¼6.82 ppm (J¼7.1, 3.0 Hz) and
d
¼7.14 ppm (J¼4.4,
3.0 Hz) corresponding to H4 and H6 of the activated phenyl ring,
two singlets at 3.92 and 3.86 ppm for two methoxy group appeared.
Besides other signals, the 13C NMR spectrum showed two doublets
at 156.0 ppm (J¼2.3 Hz) and 149.1 ppm (J¼12.9 Hz) corresponding
to the carbons bonded to the methoxy groups. Clearly, the dime-
thoxy-substituted aromatic ring is no longer symmetrical.
t (s)
c (mol Lꢀ1
)
cꢀ1 (L molꢀ1
)
0
0.0228
0.0216
0.0204
0.0193
0.0185
43.77
46.27
49.08
51.82
53.89
360
840
1260
1680
Chlorination, bromination, and iodination were carried out with
NXS (10% excess) in acetonitrile solution that was irradiated. We
determined that the BF2 derivative 3 was stable to irradiation
(
l
¼360 nm) in acetonitrile (Fig. 2). Whereas chlorination and
When we changed molar ratio of substrate to reagent from 1:1.1
to 1:2.1, or 1:2.8 in the case of chlorination, halogenation took place
at positions C2 and C6 in the electron-rich phenyl ring. The struc-
tures of products were determined on the basis of 1H, 13C, and 19F
NMR spectra. In the 1H NMR spectrum only one signal was ob-
served for the methoxy protons and in the 13C NMR spectrum only
one signal for the carbons bearing the methoxy groups is seen.
Thus, the substituted dimethoxyphenyl ring must be symmetrical.
All halogenated BF2 derivatives were crystallized from the
mixture of aprotic solvents like CH2Cl2, hexane etc. When crystal-
lization was carried out with a protic solvent, such as methanol or
ethanol hydrolysis of the BF2 group took place (Table 2). This re-
action can be followed by a change of color of the suspension from
yellow to nearly white. Compounds 5aec and 7bed were isolated
practically in quantitative yields (Table 3). On the basis of 1H and
13C NMR spectroscopic data, we concluded that the 1,3-diketo
fragment is predominantly in the enol form where a strong intra-
molecular hydrogen bond occurs and less than 5% of diketo form is
seen in equilibrium.
bromination led to regioselective halogenation at C2 of the elec-
tron-rich aromatic ring, iodination resulted in the mixture of
starting compound, 2-iodo derivative 4d and 2,6-diiodo derivative
6d (Table 2), which was inseparable without hydrolysis of the BF2
group. We also wanted to study the chemoselectivity of haloge-
nation and NXSacc was used instead of NXS. The regioselectivity of
reactions were nearly the same as in previous cases: 4b, 4c and the
mixture of 4d and 6d was formed (Table 2).
The kinetics of hydrolysis of BF2 derivative 3 were determined
using 1H NMR spectroscopy at 338 K in an NMR tube. For this
purpose 6 mg of derivative 3 was dissolved in 0.75 mL CD3CN and
Fig. 2. UV spectra of 2ꢂ10ꢀ5 M CH3CN solution of derivative 3 after different irradia-
tion times with
l
¼360 nm.
10 mL of D2O was added. To determine the change of concentration

2106
P. Galer et al. / Tetrahedron 67 (2011) 2103e2109
of 3 with time, the ratio of integrals for the protons of both enol
forms were used (Fig. 3). After 28 min, the signal for diketone form
1 appeared, so the integral for the methylene group of this com-
pound was also used in the calculation of decreasing concentration
of compound 3. From the results obtained we determined that the
reciprocal of concentration per unit time intervals is in a linear
correlation. We can conclude that the hydrolysis is a second order
reaction, as shown in Table 4.
oil) was decomposed partially on silica gel. We were unable to
obtain satisfactory EA. (b) With 50% NFTh/Al2O3 reagent: substrate
1 (284 mg, 1 mmol) and LiClO4 (64 mg, 0.6 mmol) were dissolved in
CH3CN (30 mL). The reaction mixture was stirred at 0 ꢁC for 10 min,
then NeFTh was added (1.408 g of 50% NFTh/Al2O3 was suspended
in 70 mL of CH3CN, undissolved Al2O3 was filtered off, 1.1 mmol)
and stirring was continued for an additional 13 h. The solvent was
evaporated under reduced pressure, CH2Cl2 (30 mL) was added,
and undissolved solids were filtered off. After removal of CH2Cl2,
separation of compounds 2a and 5a (relative ratio of 2a/5a¼3:1)
was done by repeated crystallization of 5a with EtOH, while oily
product 2a was remained in solution and had never been purified
wholly according to all spectral data. 1H NMR (CDCl3, 300 MHz,
3. Conclusion
Halogenation of 1-phenyl-3-(3,5-dimethoxyphenyl)-propane-
1,3-dione 1 with NeX reagents takes place regioselectively in the
a
position of the 1,3-dione moiety. Deactivation of the diketo por-
29 ꢁC)
d ppm 8.08 (m, 2H, o-Ph), 7.60 (m, 1H, p-Ph), 7.48 (m, 2H, m-
tion of the molecule via complexation with BF2, leads to regiose-
lective halogenation at C2 in electron-rich phenyl ring. When the
molar ratio of substrate to reagent 1:2.1 or 1:2.8 is used, 2,6-dis-
ubstituited halo products are obtained. Crystallization of the BF2
derivatives from protic solvents, such as methanol or ethanol leads
to hydrolysis of BF2 group. The results described in the present
paper can be very important for regioselective halogenation of 1,3-
diarylpropane-1,3-diones and similar compounds.
Ph), 7.23 (dd, 2H, J¼2.3 , 0.8 Hz), 6.67 (t, 1H, J¼2.3 Hz), 6.45 (d, 1H,
13
J¼49.2 Hz), 3.83 (s, 6H). C NMR (CDCl3, 75 MHz, 29 ꢁC)
d ppm
191.1 (d, J¼20.4 Hz), 190.7 (d, J¼19.7 Hz), 160.9 (s), 135.1 (d,
J¼1.9 Hz), 134.5 (s), 133.6 (d, J¼2.1 Hz), 129.8 (d, J¼3.5 Hz), 128.8 (s),
107.4 (s), 107.3 (d, J¼3.4 Hz), 96.5 (d, J¼198.8 Hz), 55.6 (s). 19F NMR
(CDCl3, 282 MHz, 25 ꢁC)
d
¼ꢀ186.78 ppm (dd, 1F, J¼49.2 , 0.9 Hz).
IR (NaCl)
n
¼1680, 1594, 1456, 1206, 1158 cmꢀ1. CIMS (m/z) 325.1
(MNaþ). CI-HRMS for C17H15FO4Naþ: calcd 325.0852, found
325.0845.
4. Experimental section
4.1. General procedure
4.3. Procedures for preparations of 2b30ed
Photochemical reactions were performed in Photochemical
Reactors LTD MLU18, equipped with a black-light blue lamp
(FL15BLB, Sankyo Denki, Japan) emitting at 352 nm. UV spectra
were obtained using a UVevis spectrophotometer (Varian Cary 50
Conc.). Chromatographic separations were performed using PLC
plates Silica gel 60 (Merck).
(a) With NXS reagents: substrate 1 (142 mg, 0.5 mmol) and
LiClO4 (32 mg, 0.3 mmol) were dissolved in CH3CN (10 mL). The
reaction mixture was stirred at room temperature for 15 min. NXS
(0.55 mmol) was added and stirring was continued for an addi-
tional 30 min. After removal of the solvent, the rest was dissolved in
CH3COOEt (15 mL), washed with water (3ꢂ10 mL), dried over
Na2SO4, filtered and the solvent was evaporated. The crude reaction
product was crystallized with methanol and the following quanti-
ties of pure products were obtained: 2b (143 mg, 90%), 2c (158 mg,
87%), 2d (184 mg, 90%), as a white solid. (b) With NXSacc reagents:
the reactions were carried out also with NXSacc under the same
reaction conditions as previously mentioned. After evaporation, the
residue was dissolved in CH2Cl2 (10 mL), washed with satd aq
NaHCO3 (3ꢂ10 mL), dried over Na2SO4, filtered and the solvent was
evaporated in vacuum. The solid was suspended in MeOH (4 mL)
and, to remove the unwanted saccharin, undissolved pure products
were filtered to obtain 2b (148 mg, 93%), 2c (114 mg, 63%), 2d
(188 mg, 92%).
NMR Spectrawererecorded at 302 Kon a Bruker Avance DPX 300
spectrometer operating at 300 MHz, 75 MHz, and 282 MHz for 1H,
13C, and 19F, and at 298 K on a Varian Unity Inova 300 MHz spec-
trometer, operating at 282 MHz for 19F and at 97 MHz for 11B. Proton
and carbon spectra were referenced toTMS as the internal standard.
Some 1H and 13C chemical shifts were determined relative to the 1H
or 13C signal of the solvent: CDCl3 (1H:
d
7.259 ppm, 13C:
d
77.00 ppm); CD2Cl2 (1H:
d
5.320 ppm, 13C:
d
54.00 ppm); acetone-
d6 (1H:
d
2.063 ppm, 13C:
d
29.92 ppm). 19F NMR spectra were ref-
erenced to CCl3F as an external standard, 11B NMR spectra was
calibrated to external BF3$OEt2. Chemical shifts are given on the
d
scale (ppm). Coupling constants (J) are given in hertz. Mass spectra
and high-resolution mass spectra were obtained with a Q-TOP Pre-
mier instrument. Data are reported as m/z (relative intensity). In-
frared spectra were recorded on a BIO-RAD Excalibur Series
spectrophotometer using samples in potassium bromide disks. El-
emental analyses were performed with a PerkineElmer 2400 Series
II CHNS/O Analyzer. All spectral data obtained for new compounds
4.3.1. 2-Bromo-1-phenyl-3-(3,5-dimethoxyphenyl)-propane-1,3-di-
one (2c). White solid, mp 128.0e129.0 ꢁC. 1H NMR (CDCl3,
300 MHz, 29 ꢁC)
d
ppm 7.98 (m, 2H, o-Ph), 7.60 (m, 1H, p-Ph), 7.47
(m, 2H, m-Ph), 7.11 (d, 2H, J¼2.3 Hz), 6.67 (t, 1H, J¼2.3 Hz), 6.51 (s,
13
1H), 3.79 (s, 6H). C NMR (CD2Cl2, 75 MHz, 29 ꢁC)
189.2, 161.8, 136.2, 134.9, 134.4, 129.7, 129.6, 107.4, 106.9, 56.2, 52.9.
d ppm 189.5,
€
are reported here. Melting points were measured on Buchi 535.
IR (KBr)
n
¼1704, 1678, 1593, 1450, 1358, 1305, 1286, 1206, 1154,
4.2. Detailed synthetic protocols
1067, 1028, 858, 681, 628 cmꢀ1. CIMS (m/z) 387.0 (MNaþþ2), 385.0
(MNaþ). CI-HRMS for C17H15BrO4Naþ: calcd 385.0051, found
385.0061. EA for C17H15BrO4: calcd 56.22%C, 4.16%H; found 55.75%
C, 4.07%H.
4.2.1. 2-Fluoro-1-phenyl-3-(3,5-dimethoxyphenyl)-propane-1,3-di-
one (2a). (a) With FeTEDA reagent: substrate 1 (284 mg, 1 mmol)
and LiClO4 (64 mg, 0.6 mmol) were dissolved in CH3CN (15 mL). The
reaction mixture was stirred at 0 ꢁC for 10 min and then FeTEDA
(390 mg, 1.1 mmol) was added and stirring was continued for an
additional 4 h. The solvent was evaporated under reduced pressure
and CH2Cl2 (30 mL) was added, undissolved solid were filtered off.
After removal of CH2Cl2, the crude reaction mixture (relative ratio
of compounds 2a/5a¼6:1) was subjected to preparative TLC (SiO2,
hexane/CH3COOEt¼3:1). On the basis of 1H NMR spectra and ele-
ment analysis, we established that the product 2a (a light-brown
4.3.2. 2-Iodo-1-phenyl-3-(3,5-dimethoxyphenyl)-propane-1,3-dione
(2d). White solid, mp 151.0e152.0 ꢁC. 1H NMR (CDCl3, 300 MHz,
29 ꢁC)
d
ppm 7.98 (m, 2H, o-Ph), 7.59 (m, 1H, p-Ph), 7.46 (m, 2H, m-
Ph), 7.11 (d, 2H, J¼2.3 Hz), 6.89 (s, 1H), 6.66 (t, 1H, J¼2.3 Hz), 3.79 (s,
13
6H). C NMR (CD2Cl2, 75 MHz, 29 ꢁC)
135.6, 134.7, 133.8, 129.7, 129.6, 107.4, 106.7, 56.2, 34.4. IR (KBr)
¼1697, 1670, 1592, 1450, 1423, 1358, 1302, 1285, 1205, 1155, 1068,
1026, 857, 680 cmꢀ1. CIMS (m/z) 433.0 (MNaþ). CI-HRMS for
d ppm 190.6, 190.3, 161.8,
n

P. Galer et al. / Tetrahedron 67 (2011) 2103e2109
2107
C17H15IO4Naþ: calcd 432.9913, found 432.9923. EA for C17H15IO4:
calcd 49.78%C, 3.69%H; found 49.69%C, 3.62%H.
4.4.1. 2,2-Difluoro-4-(2-chloro-3,5-dimethoxyphenyl)-6-phenyl-2H-
1,3,2-dioxaborinin (4b). Yellow solid, mp 132.0e134.0 ꢁC. 1H NMR
(acetone-d6, 300 MHz, 29 ꢁC)
d ppm 8.33 (m, 2H, o-Ph), 7.86 (m, 1H,
4.3.3. 2,2-Difluoro-4-(-3,5-dimethoxyphenyl)-6-phenyl-2H-1,3,2-di-
oxaborinin (3). Diketone 1 (1.42 g, 5 mmol) was dissolved in ben-
p-Ph), 7.70 (m, 2H, m-Ph), 7.49 (s, 1H), 7.02 (d, 1H, J¼2.8 Hz), 6.98 (d,
1H, J¼2.8 Hz), 4.00 (s, 3H), 3.93 (s, 3H). 13C NMR (acetone-d6,
zene (25 mL) and BF3eetherate (700
mL, 5.5 mmol) was added in
75 MHz, 29 ꢁC)
d ppm 185.7, 185.4, 160.6, 158.0, 137.1, 135.2, 132.6,
100 mL flask, equipped with a reflux condenser. The solution was
refluxed for 1 h. The reaction mixture was refrigerated over the
night, the precipitate was filtered to obtain 3 as a fluorescent-yel-
low solid (1.46 g, 88%), which was further crystallized with the
mixture of CH2Cl2/hexane. Mp 174.5e175.2 ꢁC. 1H NMR (CD2Cl2,
130.5, 130.4, 113.7, 107.5, 104.8, 100.4, 57.3, 56.6. 19F NMR (CDCl3,
282 MHz, 25 ꢁC)
ppm ꢀ138.98 (s), ꢀ139.04 (s); ratio of integrals
1.00:3.80. IR (KBr)
d
n
¼1707, 1538, 1492, 1366, 1317, 1303, 1283, 1207,
1163, 104, 782, 687, 612 cmꢀ1. CIMS (m/z) 391.1 (MNaþþ2), 389.1
(MNaþ). CI-HRMS for C17H14BClF2O4Naþ: calcd 389.0539, found
389.0533. EA for C17H14BClF2O4: calcd 55.70%C, 3.85%H; found
55.75%C, 4.07%H.
300 MHz, 29 ꢁC)
d ppm 8.16 (m, 2H, o-Ph), 7.74 (m, 1H, p-Ph), 7.60
(m, 2H, m-Ph), 7.26 (d, 2H, J¼2.3 Hz), 7.20 (s, 1H), 6.80 (t, 1H,
J¼2.3 Hz), 3.89 (s, 6H). 13C NMR (CDCl3, 75 MHz, 29 ꢁC)
d ppm 183.2,
183.0, 161.1, 135.3, 133.8, 131.9, 129.2, 128.9, 107.6, 106.5, 93.7, 55.7.
4.4.2. 2,2-Difluoro-4-(2-bromo-3,5-dimethoxyphenyl)-6-phenyl-2H-
1,3,2-dioxaborinin (4c). Yellow solid, mp 135.0e137.0 ꢁC. 1H NMR
19F NMR (acetone-d6, 282 MHz, 29 ꢁC)
d
ppm ꢀ140.19 (s), ꢀ140.25
11
(s); ratio of integrals 0.19:1.00. B NMR (CDCl3, 97 MHz, 25 ꢁC)
(acetone-d6, 300 MHz, 29 ꢁC)
d ppm 8.34 (m, 2H, o-Ph), 7.88 (m, 1H,
d
ppm 1.46 (s). IR (KBr)
n
¼1542, 1370, 1288, 1210, 1169, 1050,810,
p-Ph), 7.71 (m, 2H, m-Ph), 7.44 (s, 1H), 7.00 (d, 1H, J¼2.8 Hz), 6.95 (d,
775, 597 cmꢀ1. CIMS (m/z) 355.1 (MNaþ), 333.1 (MHþ). CI-HRMS for
C17H16BF2Oþ4 : calcd 333.1110, found 333.1110. EA for C17H15BF2O4:
calcd 61.48%C, 4.55%H; found 61.57%C, 4.39%H.
1H, J¼2.8 Hz), 4.00 (s, 3H), 3.94 (s, 3H). 13C NMR (CD2Cl2, 75 MHz,
29 ꢁC)
d ppm 185.6, 184.7, 160.8, 158.3, 136.8, 136.5, 132.2, 130.0,
129.9, 107.3, 104.2, 102.8, 100.3, 57.4, 56.6. 19F NMR (CDCl3, 282 MHz,
25 ꢁC)
ppm ꢀ138.95 (s), ꢀ139.01 (s); ratio of integrals 1.00:3.92. IR
(KBr)
d
4.3.4. 2,2-Difluoro-4-(2-fluoro-3,5-dimethoxyphenyl)-6-phenyl-2H-
1,3,2-dioxaborinin (4a). BF2 derivative 3 (332 mg, 1 mmol) had
been dissolved in CH3CN (20 mL) before NFTh was added (1.408 g of
50% NFTh/Al2O3 was suspended in 50 mL of CH3CN, undissolved
Al2O3 was filtered off, 1.1 mmol). After stirring for 21 h at room
temperature, a 70% conversion was determined by 1H NMR spectra.
Thus, an additional NFTh (0.3 mmol) was added and the reaction
mixture was stirred for an additional 20 h. The solvent was evap-
orated under reduced pressure, CH2Cl2 (25 mL) was added and
undissolved solid was filtered off. After removal of CH2Cl2, the
residue was crystallized with MeOH to obtain 4a (273 mg, 78%) as
a yellow solid. Mp 188.9e190.0 ꢁC. 1H NMR (CDCl3, 300 MHz, 29 ꢁC)
n
¼1706, 1541, 1492, 1366, 1317, 1301, 1210, 1165, 1080, 1043,
972, 782 cmꢀ1. CIMS (m/z) 435.0 (MNaþþ2), 433.0 (MNaþ). CI-HRMS
for C17H14BBrF2O4Naþ: calcd 433.0034, found 433.0049. EA for
C17H14BBrF2O4: calcd 49.68%C, 3.43%H; found 49.69%C, 3.62%H.
4.5. Procedure for preparations of 6bed with NXSacc
reagents
BF2 derivative
3 (332 mg, 1 mmol) and NCSacc (609 mg,
2.8 mmol), or NBSacc (550 mg, 2.1 mmol), or NISacc (649 mg,
2.1 mmol) were dissolved in CH3CN (36 mL/chlorination; 20 mL/
bromination, iodination). The reaction mixture was stirred at room
temperature for 24 h in the case of chlorination and 20 h for bro-
mination and iodination. The solvent was evaporated and the rest
was suspended in MeOH (2ꢂ3 mL), to remove the unwanted sac-
charine. The precipitate was filtered, crystallized with hexane/
CH2Cl2 to obtain as the yellow solids: 6b (345 mg, 86%), 6c (436 mg,
89%), 6d (484 mg, 83%).
d
ppm 8.15 (m, 2H, o-Ph), 7.72 (m,1H, p-Ph), 7.57 (m, 2H, m-Ph), 7.44
(s, 1H), 7.14 (dd, 1H, J¼4.4 , 3.0 Hz), 6.82 (dd,1H, J¼7.1 , 3.0 Hz), 3.92
(s, 3H), 3.86 (s, 3H). 13C NMR (CDCl3, 75 MHz, 29 ꢁC)
ppm 184.5 (d,
d
J¼1.3 Hz), 178.7 (d, J¼3.7 Hz), 156.0 (d, J¼2.3 Hz), 149.9 (s), 149.1 (d,
J¼12.9 Hz), 148.2 (d, J¼254.1 Hz), 135.6 (s), 131.9 (s), 129.2 (s), 120.8
(d, J¼6.8 Hz), 108.2 (d, J¼2.4 Hz), 102.3 (s), 98.3 (d, J¼18.9 Hz), 56.6
(s), 56.1 (s). 19F NMR (CDCl3, 282 MHz, 25 ꢁC)
d
ppm ꢀ183.13 (dd, 1F,
J¼7.1 , 4.4 Hz), ꢀ139.36 (s) and ꢀ139.43 (s); (2F); ratio of integrals
1.00:3.71. IR (KBr)
n
¼1541, 1491, 1367, 1337, 1287, 1208, 1168, 1077,
4.5.1. 2,2-Difluoro-4-(2,6-dichloro-3,5-dimethoxyphenyl)-6-phenyl-
2H-1,3,2-dioxaborinin (6b). Yellow solid, mp 236.7e237.5 ꢁC. 1H
1039, 779, 689, 618 cmꢀ1. CIMS (m/z) 373.1 (MNaþ). CI-HRMS for
C17H14BF3O4Naþ: calcd 373.0835, found 373.0832. EA for
C17H14BF3O4: calcd 58.32%C, 4.03%H; found 58.36%C, 3.78%H.
NMR (CDCl3, 300 MHz, 29 ꢁC)
d
ppm 8.13 (m, 2H, o-Ph), 7.74 (m, 1H,
p-Ph), 7.56 (m, 2H, m-Ph), 6.76 (s, 1H), 6.68 (s, 1H), 3.96 (s, 6H). 13C
NMR (CD2Cl2, 75 MHz, 29 ꢁC)
ppm 186.2, 184.0, 155.8, 137.0, 134.6,
131.8, 130.1, 130.0, 112.6, 100.9, 99.7, 57.5. 19F NMR (CDCl3, 282 MHz,
25 ꢁC)
ppm ꢀ138.05 (s), ꢀ138.12 (s); ratio of integrals 1.00:3.36. IR
(KBr)
d
4.4. Procedure for preparations of 4bed
d
(a) With NXS and irradiation: BF2 derivative
0.5 mmol) and NXS reagent (0.55 mmol) was dissolved in CH3CN
(10 mL) before being irradiated in quartz tube with
¼360 nm (for
3
(166 mg,
n
¼1583, 1550, 1469, 1432, 1384, 1318, 1299, 1221, 1065, 1043,
972, 820, 740 cmꢀ1. CIMS (m/z) 427.0 (MNaþþ4), 425.0 (MNaþþ2),
423.0 (MNaþ). CI-HRMS for C17H13BCl2F2O4Naþ: calcd 423.0150,
found 423.0154. EA for C17H13BCl2F2O4: calcd 50.92%C, 3.27%H;
found 50.93%C, 3.15%H.
l
the reaction times, see Table 2). After irradiation, the solvent was
evaporated, the corresponding residue was suspended in MeOH
(5 mL), to remove the unwanted succinimide, the undissolved or-
ganic was filtered, crystallized with CH2Cl2/hexane, and filtered to
obtain 4b (148 mg, 81%); 4c (171 mg, 83%), as a yellow solid. We
were unable to separate the mixture of compounds 4d/6d (with
relative ratio 2:1). (b) With NXSacc reagents: BF2 derivative 3
(166 mg, 0.5 mmol) and NXSacc (0.55 mmol) was dissolved in
CH3CN (10 mL). The reaction mixture was stirred at room temper-
ature (for the reaction times, see Table 2). After evaporation of the
solvent MeOH (5 mL) was added, the precipitate was filtered and
crystallized with hexane/CH2Cl2 to obtain 4b (145 mg, 79%), 4c
(129 mg, 63%) and the mixture of 4d/6d (relative ratio of com-
pounds 4d/6d¼1:1). Product 4d was not isolated in pure form.
4.5.2. 2,2-Difluoro-4-(2,6-dibromo-3,5-dimethoxyphenyl)-6-phenyl-
2H-1,3,2-dioxaborinin (6c). Yellow solid, mp 254.0e256.0 ꢁC. 1H
NMR (CD2Cl2, 300 MHz, 29 ꢁC)
d
ppm 8.14 (m, 2H, o-Ph), 7.77 (m,
1H, p-Ph), 7.60 (m, 2H, m-Ph), 6.78 (s, 1H), 6.67 (s, 1H), 3.97 (s, 6H).
13C NMR (CD2Cl2, 75 MHz, 29 ꢁC)
ppm 186.3, 186.1, 157.4, 138.2,
136.9, 131.8, 130.1, 130.0, 101.2, 100.5, 99.2, 57.5. 19F NMR (CDCl3,
282 MHz, 25 ꢁC)
ppm ꢀ137.85 (s), ꢀ137.92 (s); ratio of integrals
1.00:3.48. 11B NMR (CDCl3, 97 MHz, 25 ꢁC)
ppm 1.45 (s). IR (KBr)
d
d
d
n
¼1589, 1546, 1468, 1378, 1296, 1219, 1063, 1043, 971, 818,
706 cmꢀ1. CIMS (m/z) 514.9 (MNaþþ4), 512.9 (MNaþþ2), 510.9
(MNaþ). CI-HRMS for C17H13BBr2F2O4Naþ: calcd 510.9139, found

2108
P. Galer et al. / Tetrahedron 67 (2011) 2103e2109
510.9157. EA for C17H13BBr2F2O4: calcd 41.68%C, 2.67%H; found
41.74%C, 2.39%H.
300 MHz, 29 ꢁC)
(m, 1H, p-Ph), 7.48 (m, 2H, m-Ph), 6.65 (s, 1H), 6.35 (s, 1H), 3.95 (s,
d
ppm 15.73 (br s, OH), 7.92 (m, 2H, o-Ph), 7.58
13
6H). C NMR (CDCl3/CD2Cl2, 75 MHz, 29 ꢁC)
d
ppm 188.6, 181.9,
4.5.3. 2,2-Difluoro-4-(2,6-diiodo-3,5-dimethoxyphenyl)-6-phenyl-2H-
1,3,2-dioxaborinin (6d). Yellow solid, mp 249.0e250.5 ꢁC. 1H NMR
154.7, 137.9, 133.7, 132.6, 128.5, 126.9, 111.2, 98.5, 97.7, 56.5. IR
(KBr)
n
¼1581, 1455, 1432, 1345, 1215, 1042, 812, 776, 735,
(CD2Cl2, 300 MHz, 29 ꢁC)
d
ppm 8.15 (m, 2H, o-Ph), 7.78 (m, 1H, p-Ph),
7.60 (m, 2H, m-Ph), 6.82 (s, 1H), 6.72 (s, 1H), 3.97 (s, 6H). 13C NMR
(CD2Cl2, 75 MHz, 29 ꢁC)
ppm 186.3, 184.0, 155.8, 137.0, 134.7, 131.8,
696 cmꢀ1. CIMS (m/z) 379.0 (MNaþþ4), 377.0 (MNaþþ2), 375.0
(MNaþ). CI-HRMS for C17H14Cl2O4Naþ: calcd 375.0167, found
375.0150. EA for C17H14Cl2O4: calcd 57.81%C, 4.00%H; found
57.61%C, 3.67%H.
d
130.1, 130.0, 112.6, 101.0, 99.8, 57.5. 19F NMR (CDCl3, 282 MHz, 25 ꢁC)
d
ppm ꢀ137.25 (s), ꢀ137.32 (s); ratio of integrals 1.00:3.37. 11B NMR
(CDCl3, 97 MHz, 25 ꢁC)
d
ppm 1.41 (s). IR (KBr)
n
¼1566, 1538, 1466,
4.6.5. 1-Phenyl-3-(2,6-dibromo-3,5-dimethoxyphenyl)-propane-1,3-
1374,1294,1220,1061,1042, 970, 818 cmꢀ1. CIMS (m/z) 606.9 (MNaþ).
CI-HRMS for C17H13BF2I2O4Naþ: calcd 606.8862, found 606.8852. EA
for C17H13BF2I2O4: calcd 34.97%C, 2.24%H; found 35.01%C, 1.93%H.
dione (7c). White solid, mp 195.0e196.5 ꢁC. 1H NMR (CD2Cl2,
300 MHz, 29 ꢁC)
d
ppm 15.64 (br s, eOH), 7.92 (m, 2H, o-Ph), 7.57
(m, 1H, p-Ph), 7.48 (m, 2H, m-Ph), 6.60 (s, 1H), 6.31 (s, 1H), 3.95 (s,
13
6H). C NMR (CD2Cl2, 75 MHz, 29 ꢁC)
d ppm 192.1, 182.1, 157.2,
4.6. Procedure for preparations of 5aec and 7bed
142.4, 134.4, 133.4, 129.3, 127.6, 100.6, 98.9, 98.1, 57.4. IR (KBr)
n
¼1605, 1576, 1462, 1425, 1340, 1213, 1040, 810, 782, 688 cmꢀ1
.
Compound 4aec or 6bed (1 mmol) was suspended in MeOH
(5 mL) and heated to the reflux. During heating, the reaction can be
followed by the change of color of the suspensions from yellow to
nearly white. After cooling in refrigerator, the pure products were
filtered to obtain: 5a (272 mg, 90%) and 5b (293 mg, 92%) as a light
yellow solid, 5c (352 mg, 97%) and 7b (339 mg, 96%), and 7c
(411 mg, 93%) and 7d (509 mg, 95%) as white solids.
CIMS (m/z) 466.9 (MNaþþ4), 464.9 (MNaþþ2), 462.9 (MNaþ), 444.9
(MHþþ4), 442.9 (MHþþ2), 440.9 (MHþ). CI-HRMS for C17H15Br2Oþ4 :
calcd 440.9337, found 440.9348. EA for C17H14Br2O4: calcd 46.18%C,
3.19%H; found 46.10%C, 3.08%H.
4.6.6. 1-Phenyl-3-(2,6-diiodo-3,5-dimethoxyphenyl)-propane-1,3-di-
one (7d). White solid, mp 207.5e208.0 ꢁC. 1H NMR (CD2Cl2,
300 MHz, 29 ꢁC)
d
ppm 15.62 (br s, eOH), 7.93 (m, 2H, o-Ph), 7.57
4.6.1. 1-Phenyl-3-(2-fluoro-3,5-dimethoxyphenyl)-propane-1,3-di-
one (5a). Light yellow solid, mp 114.1 ꢁC. 1H NMR (CDCl3, 300 MHz,
(m, 1H, o-Ph), 7.49 (m, 2H, m-Ph), 6.47 (s, 1H), 6.27 (s, 1H), 3.94 (s,
13
6H). C NMR (CD2Cl2, 75 MHz, 29 ꢁC)
d ppm 196.1, 182.1, 160.5,
29 ꢁC)
d
ppm 8.15 (m, 2H, o-Ph), 7.72 (m, 1H, p-Ph), 7.57 (m, 2H, m-
149.4, 134.5, 133.3, 129.3, 127.6, 98.2, 96.0, 74.1, 57.5. IR (KBr)
Ph), 7.45 (s, 1H), 7.16 (dd, 1H, J¼4.7 , 3.0 Hz), 6.82 (dd, 1H, J¼7.1 ,
n
¼1603, 1564, 1459, 1415, 1333, 1212, 1040, 810, 778, 693 cmꢀ1
.
3.0 Hz), 3.93 (s, 3H), 3.87 (s, 3H). 13C NMR (CDCl3, 75 MHz, 29 ꢁC)
CIMS (m/z) 558.9 (MNaþ), 536.9 (MHþ). CI-HRMS for C17H15I2Oþ4 :
calcd 536.9060, found 536.9074. EA for C17H14I2O4: calcd 38.09%C,
2.63%H; found 38.05%C, 2.72%H.
d
ppm 185.7 (d, J¼1.1 Hz), 182.0 (d, J¼3.4 Hz), 155.7 (d, J¼2.4 Hz),
148.9 (d, J¼13.1 Hz), 146.4 (d, J¼248.9 Hz), 135.6 (s), 135.2 (s), 132.6
(s), 129.3 (d, J¼0.5 Hz), 128.7 (s), 127.3 (s), 124.3 (d, J¼9.3 Hz), 105.1
(d, J¼1.8 Hz), 102.2 (d, J¼3.0 Hz), 98.2 (d, J¼14.2 Hz), 56.6 (s), 55.8
Acknowledgements
(s). 19F NMR (CDCl3, 282 MHz, 25 ꢁC)
d
ppm ꢀ142.52 (ddd, 1F, J¼7.1 ,
4.7 , 1.0 Hz). IR (KBr)
n
¼1598, 1541, 1360, 1231, 1202, 1164, 1061, 843,
We are deeply indebted to Prof. Dr. Mahesh K. Lakshman for
772, 686, 623 cmꢀ1. CIMS (m/z) 325.1 (MNaþ). CI-HRMS for
C17H15FO4Naþ: calcd 325.0852, found 325.0848. EA for C17H15FO4:
calcd 67.54%C, 5.00%H; found 67.39%C, 4.92%H.
ꢀ
ꢀ
discussions, Drs. Bogdan Kralj, Dusan Zigon, Prof. Dr. Janez Plavec,
and Dr. Marjan Jereb. Financial support from the Ministry of Science
and Technology of Slovenia and the Slovenian Research Agency is
acknowledged.
4.6.2. 1-Phenyl-3-(2-chloro-3,5-dimethoxyphenyl)-propane-1,3-di-
one (5b). Light yellow solid, mp 96.0e97.5 ꢁC. 1H NMR (acetone-d6,
Supplementary data
300 MHz, 29 ꢁC)
d ppm 8.07 (m, 2H, o-Ph), 7.65 (m, 1H, p-Ph), 7.56
(m, 2H, m-Ph), 6.84 (d, 1H, J¼2.8 Hz), 6.82 (d, 1H, J¼2.8 Hz), 6.81 (s,
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.01.051.
1H), 3.96 (s, 3H), 3.89 (s, 3H). 13C NMR (acetone-d6, 75 MHz, 29 ꢁC)
d
ppm 189.3, 185.1, 160.4, 157.5, 139.0, 135.6, 133.9, 129.9, 128.2,
112.3, 106.5, 102.7, 99.2, 57.0, 56.3. IR (KBr)
n
¼1594, 1573, 1456,
References and notes
1346, 1290, 1206, 1169, 1091, 1042, 816, 780, 692 cmꢀ1. CIMS (m/z)
343.1 (MNaþþ2), 341.1 (MNaþ), 319.1 (MHþ). CI-HRMS for
C17H16ClOþ4 : calcd 319.0737, found 319.0741. EA for C17H15ClO4:
calcd 64.06%C, 4.74%H; found 63.68%C, 4.38%H.
ꢁ
1. For a monograph, see De Kimpe, N.; Verhe, R. The Chemistry of a Haloketones,
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29 ꢁC)
d ppm 16.10 (br s, eOH), 7.94 (m, 2H, o-Ph), 7.55 (m, 1H, p-
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Ph), 7.47 (m, 2H, m-Ph), 6.70 (d, 1H, J¼2.8 Hz), 6.61 (s, 1H), 6.58 (d,
1H, J¼2.8 Hz), 3.91 (s, 3H), 3.84 (s, 3H). 13C NMR (CD2Cl2, 75 MHz,
29 ꢁC)
d ppm 190.3, 184.0, 160.7, 157.9, 141.1, 135.2, 133.3, 129.3,
127.7, 106.1,102.0, 101.1, 99.0, 57.2, 56.4. IR (KBr)
n
¼1588,1572,1455,
1343, 1207, 1167, 1081, 1040, 815, 777, 690 cmꢀ1. CIMS (m/z) 387.0
(MNaþþ2), 385.0 (MNaþ), 365.0 (MHþþ2), 363.0 (MHþ). CI-HRMS
for C17H16BrOþ4 : calcd 363.0232, found 363.0220. EA for
C17H15BrO4: calcd 56.22%C, 4.16%H; found 56.24%C, 4.29%H.
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dione (7b). White solid, mp 161.2e161.3 ꢁC. 1H NMR (CD2Cl2,

P. Galer et al. / Tetrahedron 67 (2011) 2103e2109
2109
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ꢀ
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