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Y. Kimura, T. Warashina / Tetrahedron Letters xxx (2017) xxx–xxx
Table 1
Preparation of dichloromethyl alkyl ethers.
1
R
Methoda
Temp (°C)
Time (h)b
Product
Isolated yield (%)
bp
lit. bp
°C/torr
°C/torr
1a
1b
1c
1d
1e
1e
Me
Et
n-Pr
n-Bu
i-Bu
i-Bu
Ac
Ac
Bd
Bd
Bd
Be
25–30
40
60
60
60
7 + 24
6 + 14
2 + 7
2 + 7
2 + 7
2a
2b
2c
2d
2e
2e
71
68
76
83–84
82–85.56a
107.36b
54–56/23
68–72/101
59/20
42/15
59–60/34
1296b
83(97)f
79
48–49/153
33.5–34.0/86b
60
3 + 16
84
a
b
c
d
e
f
Method A; 1: (COCl)2: NMF = 1.5:1:0.1 Method B; 1: (COCl)2: NMF = 1.0:1.3:0.1.
Dropwised time of (COCl)2 + stirring time.
1.5 mol of 1 and 1.0 mol of (COCl)2 were used.
0.10 mol of 1 and 0.13 mol of (COCl)2 were used.
0.50 mol of 1e and 0.65 mol of (COCl)2 were used.
Number in parentheses refer to conversion by NMR.
13.5 g (0.1 mol) at 25–30 °C for 7 h. (the condenser was
cooled with ice-water) The mixture was stirred for a further 24 h
at the same temperature until generation of the gas had
stopped. The mixture was distilled through a 300 mm vigreux col-
umn to give 81.4 g of 2a (71% yield) having bp 83–84 °C (lit6a 82–
85.5 °C).
0.1 equiv.
Me2NCHO
0.1 equiv.
PhMeNCHO
HCCl2OBu
2d
HCO2Bu
HCCl2OBu
2d
(COCl)2
(COCl)2
1d
ND (NMR)
97 % (NMR)
Scheme 2. Comparison of catalysts for preparation of 2d.
GCMS: m/z = 79 (M-35, base peak): 81 (M-35+2) = 3:1.
1H NMR (300 MHz, CDCl3): d 3.68 (s, 3H, CH3), 7.34 (s, 1H, CH).
13C NMR (75 MHz, CDCl3): d 52.56, 98.82.
Cl
Cl
H
O
O
O
O
Method B
O
2d
Oxalyl chloride 83.1 g (0.65 mol) was slowly added dropwise to
a mixture of isobutyl formate 51 g (0.5 mol) and N-methylfor-
manilide 6.75 g (0.05 mol) at 60 °C during 3 h. After the
addition, the mixture was stirred for a further 16 h at the same
temperature until generation of the gas had stopped. The mixture
was distilled through a 300 mm vigreux column to give 66.2 g
of 2e (84% yield) having bp 59–60 °C/34 torr (lit6b 33.5–34.0 °C/8
torr).
GCMS: m/z = 85, 83, 78, 57 (base peak), 56, 43, 41.
1H NMR (300 MHz, CDCl3): d 0.96 (d, J = 6.6 Hz, 6H, CH3), 1.88–
2.01 (m, 1H, CH), 3.75 (d, J = 6.6 Hz, 2H, CH2), 7.34 (s, 1H, CH).
13C NMR (75 MHz, CDCl3): d 19.04, 27.61, 72.51, 98.13.
(1 torr = 133.32 Pa).
FeCl3
CHO
91 % yield
Scheme 3. Direct formylation of 1,3-benzodioxole.
When ca. 10% of the oxalyl chloride had been added, the evolu-
tion of gas was stopped whereupon a solid or heavy liquid layer
was observed in the bottom of the flask. The precise reason is
not clear; however (chloromethylene)-dimethyliminium chloride
(DMF Vilsmeier reagent) generated from DMF and (COCl)2, which
is a crystalline solid, does not dissolve in the reaction medium. In
contrast, (chloromethylene)methylphenyliminium chloride (NMF
Vilsmeier reagent) is reported as a liquid9,10 and the appearance
of the reaction was homogeneous throughout.
References
A formylation reaction was demonstrated using 2d prepared by
this method (Scheme 3). Thus, a dichloromethane solution of 1,3-
benzodioxole, 2d, and iron (III) chloride (1:1:1) was stirred at 5
°C for 1 and gave a 91% yield of 1,3-benzodioxole-5-carboaldehyde
(piperonal) by an aqueous work up, which was purified by bulb to
bulb distillation (180 °C/5 torr) in 67% yield. Mp 36.1 °C (lit.11 35–
36 °C). Piperonal is known as an ingredient of perfume, and many
methods have been proposed.12 However, a direct formylation of
1,3-benzodioxole has never been reported.
This procedure for the preparation of dichloromethyl alkyl
ethers, through its use of readily available non-toxic reagents,
and its simplicity, might be considered as a convenient method
for both laboratory and industrial use.
4. Lang, JF. US Patent 5138099 (1992); Chem. Abstr. 1992, 117, 233593. We have
attempted to repeat the experiment using 2a isolated by our new method,
which resulted in 90% yield of fluorobenzaldehydes (o/p = 15/85) at room
temperature for 1 h.
7. Dabee A, Gauthier P, Senet J-P. Eur. Patent 710641 (1996); Chem. Abstr. 1996,
125, 33168.
10. We attempted synthesis of NMF-Vilsmeier reagent from equimolar reaction of
NMF and OXOC in ether. Evaporation in vacuo afforded hygroscopic solid, but it
cannot be taken out the flask as the solid form.
Representative experiments
12. Dio T, Yoshida Y, Yasuda S, Watanabe Y, Fujitsu S. WO 2010/041643; Chem.
Abstr. 2010, 152, 453806 and references cited therein.
Method A
Oxalyl chloride 127 g (1 mol) was slowly added dropwise to a
mixture of methyl formate 90 g (1.5 mol) and N-methylformanilide