Synthesis of gem-difluorides from aldehydes using DFMBA

Article abstract of DOI:10.1016/j.jfluchem.2005.02.004

Synthesis of gem-difluorides from aldehydes was effectively achieved using DFMBA and Et₃N-3HF under microwave irradiation or conventional thermal heating. Both aromatic and aliphatic aldehydes could be converted to the corresponding gem-difluor

Full text of DOI:10.1016/j.jfluchem.2005.02.004

Journal of Fluorine Chemistry 126 (2005) 721–725
www.elsevier.com/locate/fluor
Synthesis of gem-difluorides from aldehydes using DFMBA
*
Tsukasa Furuya, Tsuyoshi Fukuhara, Shoji Hara
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Received 17 January 2005; received in revised form 7 February 2005; accepted 7 February 2005
Available online 16 March 2005
Abstract
Synthesis of gem-difluorides from aldehydes was effectively achieved using DFMBA and Et N-3HF under microwave irradiation or
3
conventional thermal heating. Both aromatic and aliphatic aldehydes could be converted to the corresponding gem-difluorides in good yields.
2005 Elsevier B.V. All rights reserved.
#
Keywords: Microwave-irradiation; Aldehyde; Fluorination; gem-Difluoride
1
. Introduction
oven constant during the reaction by controlling the power.
When p-t-butylbenzaldehyde (1a) was subjected to the
reaction with DFMBA under microwave irradiation at
180 8C for 20 min, the expected gem-difluoro compound
(2a) could be obtained in 61% yield but 1a still remained in
the reaction mixture (Entry 1 in Table 1). Additional use of
Introduction of a gem-difluoromethyl group into bioactive
compounds can enhance or change their activity dramatically
1,2]. Therefore, much effort has been paid to develop a novel
[
and efficient method to introduce the gem-difluoromethyl
group into molecules [3–8]. Direct conversion of a carbonyl
group to the gem-difluoride is the most straightforward
method and diethylaminosulfur trifluoride (DAST) [9,10] and
Et N-3HF as a fluoride source was found to be effective to
3
accelerate the reaction. By the addition of 0.2 equiv. of
Et N-3HF, the yield of 2a could be improved to 89% (Entry
3
TM
its modifications such as Deoxofluor [11–13] have been
2). The best result was obtained by using 1 equiv. of Et N-
3
most frequently used for such purpose. However, they incur a
problem of thermal stability and a novel method using more
stable reagents has been desired [14–16]. Recently, a, a-
difluoroamines were reported as a thermally stable fluorina-
tion reagent [17–20], and we reported that a hydroxyl group of
sugars can be effectively converted to a fluoride by N,N-
diethyl-a, a-difluoro-(m-methylbenzyl)amine (DFMBA)
under microwave irradiation [19,20]. We report here an
application of DFMBA for synthesis of the gem-difluoro
compounds from the aldehydes.
3HF and 2 equiv. of DFMBA to 1a, and 2a was obtained in
96% yield (Entry 3). When the reaction was carried out
using 1.5 equiv. of DFMBA (Entry 4), at lower temperature
(Entry 5), or for a shorter time (Entry 6), the yields of 2a
decreased. When the reaction mixture was heated by a
conventional oil bath at 180 8C for 20 min, the yield of 2a
slightly decreased (Entry 7). However, in this reaction, the
effect of microwave was not so clear as in the previous cases
[19,20].
Under similar reaction conditions, various aromatic
aldehydes (1a–e) and aliphatic aldehydes (1f–j) could be
converted to the corresponding gem-difluoro compounds
(
2a–j) in high to good yields (Table 2).
Under the reaction conditions, the ester group (1c, i),
2
. Results and discussion
alkoxy group (1b, e), hydroxyl group (1d), and double bond
1g, h, j) remained unchanged. The reaction of DFMBAwith
The reaction was carried out using a microwave oven for
organic synthesis which can keep the temperature in the
(
ketone is very slow under the reaction conditions. When a
mixture of benzaldehyde and acetophenone was subjected to
the reaction with DFMBA and Et N-3HF, the benzaldehyde
*
Corresponding author. Tel.: +81 11 706 6556; fax: +81 11 706 6556.
E-mail address: hara@org-mc.eng.hokudai.ac.jp (S. Hara).
3
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.02.004

722
T. Furuya et al. / Journal of Fluorine Chemistry 126 (2005) 721–725
Table 1
was selectively converted to difluoromethylbenzene and
a
gem-Difluorination of aldehydes using DFMBA
most of the acetophenone remained unchanged. Therefore,
in the reaction with 4-formylbenzophenone (4), which has
both ketone and aldehyde groups in the molecule, the
aldehyde group was selectively converted to the gem-
difluoride and 4-difluoromethylbenzophenone (5) could be
obtained in 92% yield (Scheme 1). Under the reaction
conditions, the conversion of the ketone part to the gem-
b
Entry
Et
0
3
N-3HF (equiv. to 1a)
Temperature (8C)
Yield (%)
1
2
3
180
180
180
180
170
180
180
61
19
difluoride was observed by FNMR only in low yield
(<3%).
0.2
1
89
96 (80)
90
c
4
1
5
1
88
d
6
e
1
91
3. Experimental
7
1
93
a
If otherwise not mentioned, the reactions were carried out for 20 min
3
.1. General methods
under micowave irradiation using 2 equiv. of 3 to 1a.
b
c
d
e
19
F NMR yield based on 1a. In parenthesis, isolated yield.
.5 equiv. of 3 to 1a was used.
The microwave irradiation was carried out for 10 min.
Oil bath heating was used instead of microwave irradiation.
1
The melting points were measured with a Yanagimoto
micro melting-point apparatus and are uncorrected. The IR
1
spectra were recorded using a JASCO FT/IR-410. The H
NMR (270 MHz) spectra were recorded in CDCl on a JEOL
3
JNM-EX270 FT NMR and the chemical shift, d, is referred
Table 2
a
Reaction of aldehydes with DFMBA
b
Aldehyde
Reaction conditions
Product
Yield (%)
80
1
80 8C, 20 min
1
80 8C, 20 min
88
1
1
80 8C, 20 min
50 8C, 30 min
85
61
1
80 8C, 20 min
84
1
1
1
80 8C, 20 min
80 8C, 20 min
80 8C, 20 min
75
71
77
1
1
70 8C, 20 min
80 8C, 20 min
60
(70)
a
Reactions were carried out using 2 equiv. of DFMBA and 1 equiv. of Et
19
Isolated yield based on substrate used and in parenthesis, FNMR yield.
3
N-3HF to 1.
b

T. Furuya et al. / Journal of Fluorine Chemistry 126 (2005) 721–725
723
TM
introduced into a reactor of a Teflon
PFA tube with a
diameter of 10 mm sealed at one end. The open end of the
reactor was connected to a reflux condenser. Then, the
reaction mixture was submitted for 20 min to microwave-
irradiation and during the irradiation, the temperature was
kept at 180 8C. After cooling, the reaction mixture was
poured into an aqueous NaHCO solution. The product was
extracted with ether three times and the combined ethereal
layers were dried over MgSO . Purification by column
3
4
chromatography (silica gel/hexane-ether) gave 2a in 80%
À1
1
Scheme 1.
yield. IR: (neat) n 2966, 1622, 1379, 1076, 1027 cm . H
NMR d 1.33 (s, 9H), 6.63 (t, J = 56.6 Hz, 1H), 7.42–7.50 (m,
4
1
9
13
H). F NMR d À110.48 (d, J = 56.8 Hz, 2F) [23]. C
NMR d 31.19 (3C, –C(CH ) ), 34.84(–C(CH ) ), 114.89 (t,
J = 236.5 Hz, –CHF ), 125.29 (t, J = 5.8 Hz, C-1), 125.60
2
1
9
13
to TMS. F NMR (376 MHz) spectra and C NMR
100 MHz) were recorded in CDCl on a JEOL JNM-A400II
FT NMR and the chemical shift, d, are referred to CFCl
3
3
3 3
(
3
(2C, C-3, C-5), 131.50 (t, J = 22.3 Hz, 2C, C-2, C-6), 153.98
(C-4).
3
1
9
13
(
F) and TMS ( C), respectively. The EI-high-resolution
mass spectra were measured on a JEOL JMS-700TZ.
Microwave irradiation was carried out using an IDX
microwave oven for organic synthesis (0–300 W, IMCR-
3.2.2. 1-Difluoromethyl-3,4-dimethoxybenzene (2b) [13]
IR: (neat) n 2964, 2942, 2841, 1612, 1523, 1268,
À1
1
1025 cm . H NMR d 3.91 (s, 3H), 3.92 (s, 3H), 6.60 (t,
2
5003) having temperature control. Et N-3HF was pur-
3
1
9
chased from Aldrich Chemical Co. and distilled before use.
Aldehydes (1a–h, j) were purchased from Tokyo Kasei Co.
Butyl 5-oxopentanoate (1i) was prepared by PCC oxidation
of butyl 5-hydroxypentanoate obtained by transesterification
of d-valerolactone. 4-Formylbenzophenone (4) was pre-
pared by the oxidation of 4-(bromomethyl)acetophenone
J = 56.4 Hz, 1H), 6.89–7.07(m, 3H). F NMR d À108.70
1
3
(d, J = 56.8 Hz, 2F) [13]. C NMR d 55.83 (–OCH ), 55.85
3
(–OCH ), 107.87 (t, J = 9.9 Hz, C-1), 110.54 (C-5), 114.83
3
(t, J = 236.1 Hz, –CHF ), 118.65 (t, J = 14.0 Hz, C-6),
2
126.79 (t, J = 22.7 Hz, C-2), 149.12 (C-3 or C-4), 150.78 (C-
3 or C-4).
[
21].
3
.2.3. Methyl p-difluoromethylbenzoate (2c)
White solid. mp 36.5–37 8C. IR: (KBr) n 2964, 1723,
3
.2. Preparation of DFMBA
À1
1
1 .
J = 56.0 Hz, 1H), 7.59 (d, J = 8.1 Hz, 2H), 8.13 (d,
281, 1014 cm
H NMR d 3.95 (s, 3H), 6.69 (t,
DFMBA was prepared by a modification of reported
procedure [22]. To a CH Cl (50 ml) solution of N,N-
1
9
J = 8.1 Hz, 2H). F NMR d À112.85 (d, J = 56.2 Hz,
2
2
1
2F). C NMR d 52.38 (–OCH ), 113.97 (t, J = 238.6 Hz, –
3
diethyl-m-methylbenzamide (13.8 g, 72 mmol), was added
at 0 8C a CH Cl (20 ml) solution of oxalic chloride (9.9 g,
3
CHF ), 125.62 (t, J = 5.8 Hz, 2C, C-2, C-6), 129.93 (2C, C-
2
2
2
7
4
8 mmol). After the addition, the mixture was stirred at
0 8C for 2 h. Then the mixture was cooled to 0 8C again,
3, C-5), 132.27 (C-4), 138.42 (t, J = 57.5 Hz, C-1), 166.24
(C O). HRMS (EI): calc. for C H O F : 186.0492; found:
186.0493.
9
8 2 2
and Et N-3HF (8.7 g, 53 mmol) and Et N (10.1 g
3
3
1
00 mmol) were added successively. The mixture was
stirred at room temperature for 2 h and a generated
precipitate was removed by filtration. The precipitate was
washed with CH Cl (100 ml) and the combined filtrate
3.2.4. 2,6-Di-t-butyl-4-difluoromethylphenol (2d)
White solid. mp 78.5–79 8C. IR: (KBr) n 3634, 2955,
1442, 1372, 1077, 1005 cm . H NMR d 1.45 (s, 18H), 5.46
À1 1
2
2
1
(s, 1H), 6.57 (t, J = 57.2 Hz, 1H), 7.31 (s, 2H). F NMR d
9
was concentrated under reduced pressure. A hexane
100 ml) was added to the residue and the generated
1
3
(
À107.68 (d, J = 56.8 Hz, 2F). C NMR d 30.08 (6C, –
solid was removed by filtration again. The solid was
washed with a hexane (50 ml) and the filtrate was
concentrated under reduced pressure. The distillation of
the residue gave DFMBA (12.6 g, 59 mmol) in 82% yield
C(CH ) ), 34.38 (2C, –C(CH ) ), 115.77 (t, J = 236.7 Hz, –
3
3
3 3
CHF ), 122.55 (t, J = 5.8 Hz, 2C, C-2, C-6), 125.24 (t,
2
J = 22.2 Hz, C-1), 136.19 (C-4),155.81 (2C, C-3, C-5).
HRMS (EI): calc. for C H OF : 256.1639; found:
256.1637.
1
5
22
2
(bp 81–83 8C/4 mmHg). Glassware can be used. All
operations should be carried out under minimum contact
to moisture.
3.2.5. 1-Difluoromethyl-4-methoxynaphthalene (2e)
À1
1
IR: (neat) n 2970, 1586, 1229, 1011 cm . H NMR d
4.03 (s, 3H), 6.78 (d, J = 7.8 Hz, 1H), 7.04 (t, J = 55.3 Hz,
1H), 7.51–7.63 (m, 3H), 8.11–8.15 (m, 1H), 8.32–8.35 (m,
3
.2.1. Synthesis of p-difluoromethyl-t-butylbenzene (2a)
23]
p-t-Butylbenzaldehyde (162 mg, 1 mmol), DFMBA
426 mg, 2 mmol), and Et N-3HF (161 mg, 1 mmol) were
[
1
9
13
1H). F NMR d À109.65 (d, J = 55.5 Hz, 2F). C NMR d
(
55.64 (–OCH ), 102.14 (2C, C ), 115.98 (t, J = 235.7 Hz,
3 Ar
3

724
T. Furuya et al. / Journal of Fluorine Chemistry 126 (2005) 721–725
–
CHF ), 121.84 (t, J = 21.0Hz, C-1), 122.69 (C ), 123.37
2 Ar
3.3. The reaction of DFMBA and Et N-3HF with a mixture
3
(
(
C ), 125.70 (C ), 125.88 (t, J = 8.7 Hz, C ), 127.60
Ar
of benzaldehyde and acetophenone
Ar
Ar
C ), 130.72 (C ), 157.68 (C-4). HRMS (EI): calc. for
Ar Ar
C H OF : 208.0700; found: 208.0697.
10
Benzaldehyde (106 mg, 1 mmol), acetophenone
182 mg, 1 mmol), DFMBA (426 mg, 2 mmol), and Et N-
1
2
2
(
3HF (161 mg, 1 mmol) were introduced into a reactor of a
3
3
.2.6. 1,1-Difluoroundecane (2f) [24]
À1
1
TM
Teflon PFA tube and submitted to microwave-irradiation
IR: (neat) n 2926, 1467, 1403, 1118 cm . H NMR d
.88 (t, J = 6.7 Hz, 3H), 1.18–1.50 (m, 16H), 1.71-1.92 (m,
0
2
at 1808 C for 20 min. After cooling, the reaction mixture was
1
9
H), 5.79 (tt, J = 57.2, J = 4.6 Hz, 1H). F NMR d À116.31
poured into an aqueous NaHCO solution and extracted with
3
1
dt, J = 57.4, J = 17.1 Hz, 2F) [24]. C NMR d 14.09 (C-
3
(
ether. Fluorobenzene (96 mg, 1 mmol) was added as an
internal standard, and difluoromethylbenzene was found to
be formed in 82% yield with 2% yield of 1,1-difluor-
1
2
1), 22.12 (t, J = 5.4 Hz, C-3), 22.68, 29.06, 29.31, 29.37,
9.45, 29.55, 31.98, 34.09 (t, J = 20.6 Hz, C-2), 117.50 (t,
1
9
19
J = 231.1 Hz, ÀCHF2).
oethylbenzene from F NMR. Difluoromethylbenzene:
F
NMR d À110.5 (d, J = 56.0 Hz) [9], 1,1-difluoroethylben-
1
9
3
.2.7. 1,1-Difluoro-10-undecene (2g)
zene: F NMRd À87.6 (q, J = 18.2 Hz) [26].
3.4. 4-Difluoromethylbenzophenone (5)
À1
1
IR: (neat) n 2928, 2856, 1641, 1402, 1123 cm . H
NMR d 1.18–1.47 (m, 12H), 1.71–1.92 (m, 2H), 2.00–2.06
(
m, 2H), 4.90–5.03 (m, 2H), 5.79 (tt, J = 57.1, J = 4.7 Hz,
1
9
1
H), 5.74–5.89 (m, 1H). F NMR d À116.32 (dt, J = 57.37,
White solid. mp 70–71 8C. IR: (KBr) n 2924, 1651,
1284 cm . H NMR d 6.73 (t, J = 56.1 Hz, 1H), 7.49–7.53
1
3
À1 1
J = 17.09 Hz, 2F). C NMR d 22.08 (t, J = 5.4 Hz, C-3),
8.86, 29.02 (2C), 29.24, 29.28, 33.76, 34.05 (t, J = 20.5 Hz,
C-2), 114.15 (C-11), 117.49 (t, J = 237.4 Hz, –CHF2),
2
(m, 2H), 7.61–7.65 (m, 3H), 7.80–7.82 (m, 2H), 7.88 (d,
1
9
J = 8.6 Hz, 2H). F NMR d À112.68 (d, J = 56.0 Hz, 2F).
1
3
1
found: 190.1540.
39.15 (C-10). HRMS (EI): calc. for C H F : 190.1533;
1
C NMR d 114.02 (t, J = 238.6 Hz, –CHF
J = 5.8 Hz, 2C, C-3, C-5), 128.44 (2C), 130.07 (2C), 130.22
2C), 132.87, 137.00, 137.77 (t, J = 22.2 Hz, C-4), 139.69,
2
), 125.57 (t,
1 20 2
(
3
.2.8. 3,3-Difluoro-1-phenyl-1-propene (2h) [25]
IR: (neat) n 3030, 1658, 1388, 1139, 1015 cm . H
NMR d 6.18–6.33 (m, 1H), 6.25 (dt, J = 5.4, J = 56.0 Hz,
195.90 (C O). HRMS (EI): calc. for C14
found: 232.0693.
H F : 232.0700;
10 2
À1
1
1
9
1
H), 6.84–6.92 (m, 1H), 7.31–7.46 (m, 5H). F NMR d
1
3
À110.18 to À110.36 (m, 2F) [25]. C NMR d 115.37 (t,
References
J = 232.5 Hz, –CHF ), 120.95 (t, J = 23.5 Hz, C-2), 127.22
2
[
[
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1] V.P. Kukhar, V.A. Soloshonok (Eds.), Fluorine-Containing Amino
(
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1
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3
.2.9. Butyl 5,5-difluoropentanoate (2i)
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1
IR: (neat) n 2963, 1736, 1175 cm . H NMR d 0.94 (t,
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J = 7.3 Hz, 3H), 1.31–1.45 (m, 2H), 2.38 (t, J = 7.6 Hz,
[
2
J = 6.6 Hz, 2H), 5.83 (tt, J = 56.8, J = 4.2 Hz, 1H).
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9
1
F
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3
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[
d 13.65 (–CH ), 17.55 (t, J = 5.8 Hz, C-3), 19.09,
3
[
9] W.J. Middleton, J. Org. Chem. 40 (1975) 574–578.
3
0.60, 33.05 (C-2), 33.35 (t, J = 10.3 Hz, C-4), 64.40
–OCH –), 116.89 (t, J = 237.8 Hz, –CHF ), 172.89
[
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related aminosulfurans, in: Organic Reactions, vol. 35, Wiley, New
York, 1988, pp. 513–637.
(
2
2
(C=O). HRMS (EI): calc. for C H O F : 194.1119;
9 16 2 2
found: 194.1119.
[
[
[
[
11] G.S. Lal, G.P. Pez, R.J. Pesaresi, F.M. Prozonic, Chem. Commun.
(
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3
.2.10. 8,8-Difluoro-2,6-dimethyl-2-octene (2j)
IR: (neat) n 2966, 2924, 1439, 1402, 1121, 1039 cm
À1
.
13] R.P. Singh, D. Chakraborty, J.M. Shreeve, J. Fluorine Chem. 111
1
H NMR d 0.97 (d, J = 6.5 Hz, 3H), 1.17–1.44 (m, 2H), 1.60
s, 3H), 1.55–2.04 (m, 5 H), 1.69 (s, 3H), 5.05–5.11 (m, 1H),
(
2001) 153–160.
(
14] J. Cochran, Chem. Eng. News 57 (1979) 4.
1
9
5
.86 (tt, J = 57.0, J = 4.2 Hz, 1H). F NMR d À115.25 to
[15] W.J. Middleton, Chem. Eng. News 57 (1979) 43.
1
3
[
16] P.A. Messina, K.C. Mange, W.J. Middleton, J. Fluorine Chem. 42
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À114.98 (m, 2F). C NMR d 17.63, 19.53, 25.16, 25.70,
7.47 (t, J = 5.4 Hz, C-6), 36.98 (C-4), 40.87 (t, J = 19.8 Hz,
C-7), 117.12 (t, J = 237.0 Hz, –CHF ), 124.05 (C-3), 131.73
(
2
[
17] V.A. Petrov, S. Swearingen, W. Hong, W.C. Petersen, J. Fluorine
2
Chem. 109 (2001) 25–31.
(
C-2). HRMS (EI): calc. for C H F : 176.1376; found:
10 18 2
[18] H. Hayashi, H. Sonoda, K. Fukumura, T. Nagata, Chem. Commun.
1
76.1375.
(2002) 1618–1619.

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(