Direct formylation of enol ethers using cyanuric chloride and N,N-dimethylformamide

Article abstract of DOI:10.1002/jccs.200400101

A new method to prepare α,β-unsaturated enol aldehydes is described. 3-Ethoxymethacrolein (1) and 5-formyl-3,4-dihydro-2H-pyran (5) were effectively prepared from enol ethers and the Vilsmeier-Haack type complex, derived from cyanuric chloride and DMF. One byproduct, amidine 4, was also characterized.

Full text of DOI:10.1002/jccs.200400101

Journal of the Chinese Chemical Society, 2004, 51, 671-674
671
Note
Direct Formylation of Enol Ethers Using Cyanuric Chloride and
N,N-Dimethylformamide
Duen-Ren Hou1* (
Jing-Yu Jian (
Department of Applied Chemistry, National University of Kaohsiung, 700 Kaohsiung University Road,
), Chong-Si Sun (
), Wu-Sian Sie (
),
) and Yun Hsu (
)
Kaohsiung City, 811, Taiwan, R.O.C.
A new method to prepare a,b-unsaturated enol aldehydes is described. 3-Ethoxymethacrolein (1) and
5-formyl-3,4-dihydro-2H-pyran (5) were effectively prepared from enol ethers and the Vilsmeier-Haack type
complex, derived from cyanuric chloride and DMF. One byproduct, amidine 4, was also characterized.
Key words: Formylation; Enol ether; a,b-Unsaturated aldehyde; Vilsmeier-Haack complex.
a,b-Unsaturated enol aldehydes, such as 3-ethoxy-
The application of cyanuric chloride (2) has drawn at-
tention recently.5-9 Cyanuric chloride, a white solid at room
temperature, is commercially available, inexpensive and
easy to handle, which makes it an ideal reagent for the chlori-
nation of alcohols.5,8 In addition, the formate protection of
various alcohols using the combination of cyanuric chloride
and DMF has also been reported.6 The active intermediate in
these reactions, the Vilsmeier-Haack type complex (3),10-14
implied the possible application to the formylation of enol
ethers. Herein, we report our study in preparing the a,b-un-
saturated enol aldehydes from enol ethers and cyanuric chlo-
ride/DMF.
methacrolein (1), are useful precursors to heterocyclic com-
pounds.2 Breitmaier’s group developed a multi-step synthe-
sis to 2-methyl malonic dialdehyde tetraethylacetal, then hy-
drolyzed to give the compound 1.2 Nair et al. have reported
the Vilsmeier formylation of propionaldehyde diethyl acetal
in the presence of N,N-dimethylformamide (DMF) and phos-
phorous oxychloride (POCl3) to give the ethoxymethacrolein
in 26% yield.3 Although this method provides a quick en-
trance to the compound 1, the evolution of gaseous HCl and
the difficult work-up/purification procedures are problem-
atic. Babler’s group also reported the crossed-Claisen con-
densation of methyl formate and propanal to give the com-
pound 1 in 61% yield after the alkylation with ethyl bromide.4
However, this long procedure and the extremely moisture
sensitive reaction condition also limit its application. There-
fore, developing a direct method to prepare 1 could be useful.
As shown in Scheme I, the Vilsmeier type complex was
prepared by mixing cyanuric chloride with DMF in dichloro-
methane at room temperature for 3 h.6 Then the ethyl pro-
penyl ether was added to the reaction and gently refluxed (60
°C, oil bath) for another 4 h. The reaction was basified with
K2CO3(aq), extracted, dried and concentrated to give an oily,
crude product. The aldehyde 1 was then harvested with flash
column chromatography, or vacuum distillation (22-30%
yield). During our search to improve the yield, we found that
unlike Nair’s synthesis, 2-methyl-3-(dimethylamino)prop-
Cl
N
Cl
EtO
N
N
O
1
2
Cl
Scheme I
Cl
Cl
O
N
Cl
N
N
Cl
N
2, CH2Cl2
N
N
O
N
O
N
3
N
RT, 3 h
Cl
Cl
O
OEt
Me2N
N
OEt
31 %
1
+
60 °C, 4 h
4
30 %

672 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Hou et al.
2-enal was not formed in this reaction.3 Instead, an amidine
byproduct 4 was isolated (31% yield). The proposed reaction
mechanism to account for the formation of 1 and 4 is shown
in Schemes II and III, respectively. The key precursor to the
aldehyde 1, the iminium enol 5, comes from the substitution
and deprotonation of enol ether with the complex 3. On the
other hand, the formation of 4 is intriguing since it is consti-
tuted with ethoxy, N,N-dimethylformamidine and carbamic
acid ester. Evidently, these three components come from
ethyl propenyl ether, DMF and cyanuric chloride. Although
the detailed mechanism to form 4 is not clear at this moment,
the linkage between the carbamic carbon and the dimeth-
ylformamidine suggests the existence of other ionic com-
plexes, such as 6. The presence of the carbamic acid ethyl es-
ter also indicates the decomposition of enol ether to release
ethanol (Scheme III). This competitive process significantly
reduces the yield of the desired aldehyde 1. Although the iso-
lated yield is similar to that using Nair’s method, this reaction
generates much less HCl(g) and its work-up is easier than the
reaction using phosphorous oxychloride.
To further examine the scope of this reaction, other enol
ethers were also tested. The results are summarized in Table
1. 2,3-Dihydropyran gives the corresponding aldehydes 8 in
25% yield. The aldehyde 9 from the formylation of 2,3-dihy-
drofuran is contaminated with other impurities and has a poor
yield. In addition to the competitive pathway shown above,
this low yield is also due to the liability of the aldehyde 9.15
For the reaction of n-butyl vinyl ether, we were disappointed
to find that this reaction only gives a complex, unidentified
mixture, which thwarts further purification. This tar-like
product was examined with mass spectroscopy directly. In-
deed, the corresponding mass of 10 was found, and its high-
resolution mass analysis also matched the composition of the
aldehyde 10. We believe that the formylation of this terminal
alkene also occurs, but the product may undergo further reac-
tions due to the presence of a-acidic proton in 10.
In conclusion, we have developed a short, easy and eco-
nomical synthesis to 3-ethoxymethacrolein using ethyl pro-
penyl ether and cyanuric chloride/DMF. This methodology
may also apply to preparation of other a,b-unsaturated enol
Scheme II
Cl
Cl
OEt
N
O
N
OEt
N
H2O
O
OEt
OEt
C3N3Cl2
3
H
C3N3Cl2
1
O
5
Scheme III The proposed mechanism to 4
Cl
Cl
O
Cl
N
N
N
Cl
O
EtOH
N
N
N
O
Me2N
N
OEt
N
K2CO3
3
4
Cl
Cl
N
6
Table 1. Formation of a,b-Unsaturated Enol Aldehydes
Entry
1
enol
product
reaction temp. reaction time (h) Yield (%)
EtO
EtO
60 °C
25 °C
4
22
25
O
O
O
O
2
48
8
O
O
3
4
25 °C
25 °C
48
48
5
9
O
n-BuO
n-BuO
-
O
10

Direct Formylation of Enol Ethers
aldehydes.
J. Chin. Chem. Soc., Vol. 51, No. 3, 2004 673
5-Formyl-3,4-dihydro-2H-pyran (5)
Cyanuric chloride (7.0 g, 38.0 mmol) suspended in
DMF (3.6 mL, 46 mmol) and CH2Cl2 (10 mL) was stirred at
room temperature for 3 h. 3,4-Dihydro-2H-pyran (3.0 g, 35.6
mmol) was added to the slurry, and the reaction was stirred at
room temperature for another 48 h. The reaction was cooled
to 0 °C, and sat. K2CO3(aq) (20 mL) was poured into the reac-
tion. The reaction mixture was further diluted with water (20
mL), CH2Cl2 (50 mL) and stirred for 1 h. The precipitate was
removed by filtration, the organic layer was separated, and
the aqueous solution was further extracted with CH2Cl2 (25
mL ´ 2). The combined organic solution was washed with
EXPERIMENTAL SECTION
General
CH2Cl2 was distilled from CaH2; DMF was dried over 4
Å molecular sieves. All other chemicals were purchased from
Aldrich or Arcos Organics and used without further purifica-
tion. 1H and 13C NMR spectra were obtained on Varian 200 or
300 MHz spectrometers and referenced to TMS or residual
CHCl3. Analytical TLC was carried out using Merck alumi-
num-backed 0.2 mm silica gel 60 F254 plates. Column chro-
matography was conducted using Merck silica gel 60 (230-
400 mesh).
water (20 mL), sat. NaCl(aq) (20 mL), dried over Na2SO4(s)
,
and concentrated to give the crude oily product. The crude
product was further purified with column chromatography
(silica gel, ethyl acetate/n-hexane = 3/7(v/v), Rf = 0.29) to
give a colorless oil of 5 (1.0 g, 25%). 1H NMR (CDCl3, 300
MHz) d 9.10 (s, 1H), 7.26 (s, 1H), 4.14 (t, J = 5.4 Hz, 2H),
2.20 (t, J = 6.3 Hz, 2H), 1.84 (m, 2H). 13C NMR (CDCl3, 75.5
MHz) d 190.4, 165.1, 119.3, 68.3, 20.4, 16.5. The spectros-
copy data were consistent with those reported previously.17
3-Ethoxymethacrolein (1)
Cyanuric chloride (7.7 g, 41.8 mmol) suspended in
DMF (3.6 mL, 46 mmol) and CH2Cl2 (10 mL) was stirred at
room temperature for 3 h. Ethyl propenyl ether (3.0 g, 34.8
mmol) was added to the slurry, and the reaction was gently
refluxed in a 60 °C oil bath for another 4 h. The reaction was
cooled to 0 °C, and sat. K2CO3(aq) (40 mL) was poured into the
reaction. The reaction mixture was further diluted with water
(20 mL), CH2Cl2 (50 mL) and stirred for 1 h. The precipitate
was removed by filtration, then the organic layer was sepa-
rated, and the aqueous solution was further extracted with
CH2Cl2 (25 mL ´ 2). The combined organic solution was
washed with water (20 mL), sat. NaCl(aq) (20 mL), dried over
Na2SO4(s), and concentrated to give the crude oily product.
The crude product was further purified with column chroma-
tography (silica gel, ethyl acetate/n-hexane = 1/1(v/v), Rf =
3-Formyl-4,5-dihydro-furan (9)
Cyanuric chloride (3.5 g, 19.0 mmol) suspended in
DMF (1.8 mL, 23 mmol) and CH2Cl2 (5 mL) was stirred at
room temperature for 3 h. 4,5-Dihydro-furan (1.2 g, 17.0
mmol) was added to the slurry, and the reaction was stirred in
a 0 °C ice-water bath for another 18 h. Sat. K2CO3(aq) (15 mL)
and water (15 mL) were poured into the reaction. The reac-
tion mixture was extracted with CH2Cl2 (20 mL ´ 3). The
combined organic solution was washed with water (20 mL),
sat. NaCl(aq) (20 mL), dried over Na2SO4(s), and concentrated
to give the crude oily product. The crude product can be par-
tially purified with column chromatography (silica gel, ethyl
acetate/n-hexane = 3/7(v/v), Rf = 0.28) to give the compound
1
0.58) to give a colorless oil of 1 (0.86 g, 22%). H NMR
(CDCl3, 200 MHz) d 9.19 (s, 1H), 6.95 (s, 1H), 4.15 (q, J =
7.4 Hz, 2H), 1.64 (s, 3H), 1.36 (t, J = 7.4 Hz, 3H). 13C NMR
(CDCl3, 50.3 MHz) d 191.6, 167.6, 119.9, 70.9, 15.3, 6.3.
The spectroscopy data were consistent with those reported by
Nair et al.3 The crude product could also be distilled under
vacuum (0.3 torr) to give 1 (b.p. 42-45 °C, 1.1 g, 30%) and the
dimethylformamidine 4 (b.p. 75-80 °C, 1.55 g, 31%) as col-
orless oil. The spectroscopy data of 4: 1H NMR (CDCl3, 300
MHz) d 8.40 (s, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.08 (s, 3H),
3.03 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H). IR (neat) 2981, 2359,
1670, 1619, 1432, 1340, 1240, 1060 cm-1; 13C NMR (CDCl3,
75.5 MHz) d 164.3, 162.8, 61.3, 41.2, 35.1, 14.3. MS (FAB):
145 (M + H+), 99, 73, 44. HRMS (ESI): calcd for C6H13N2O2,
145.0972, found 145.0973. The reported 1H NMR chemical
shift of Me2NCH=NCOOR: d 8.64.16
1
9 (0.08 g, 5%). H NMR (CDCl3, 300 MHz) d 9.65 (s, 1H),
7.32 (t, J = 1.2 Hz, 1H), 4.66 (t, J = 9.6 Hz, 2H), 2.87 (dt, J =
9.6 Hz, J = 1.2 Hz, 2H). MS (EI) m/z: 98. The spectroscopy
data were consistent with those reported previously.15
Formylation of n-butyl vinyl ether
Cyanuric chloride (0.42 g, 2.3 mmol) suspended in
DMF (165 mL, 2.1 mmol) and CH2Cl2 (1 mL) was stirred at
room temperature for 3 h. n-Butyl vinyl ether (191 mg, 1.9
mmol) was added to the slurry, and the reaction was stirred
for another 48 h at room temperature. Sat. K2CO3(aq) (2 mL)
and water (2 mL) were poured into the reaction. The reaction
mixture was extracted with CH2Cl2 (5 mL ´ 3). The combined

674 J. Chin. Chem. Soc., Vol. 51, No. 3, 2004
Hou et al.
103, 3030.
organic solution was washed with water (3 mL), sat. NaCl(aq)
(3 mL), dried over Na2SO4(s), and concentrated to give the
crude oily product. The crude product was analyzed with
mass spectroscopy (FAB): m/z 129 [M + H]+, 101, 73; HRMS
[M + H] + calcd for C7H13O2, 129.0916, found 129.0917.
4. Babler, J. H.; Liptak, V. P.; Trautmann, J. A.; Zayia, G. H.
Synth. Commun. 1996, 26, 1943.
5. Luca, L. D.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2002,
4, 553.
6. Luca, L. D.; Giacomelli, G.; Porcheddu, A. J. Org. Chem.
2002, 67, 5152.
7. Falorni, M.; Porcheddu, A.; Taddei, M. Tetrahedron Lett.
1999, 40, 4395.
ACKNOWLEDGMENT
8. Sandler, S. J. Org. Chem. 1970, 35, 396.
9. Lin, C.-H.; Kin, C.-E.; Chen, C.-C.; Liao, L.-F. J. Chin.
Chem. Soc. 2001, 48, 1069.
10. For a general review on the chemistry of Vilsmeier-Haack
complexes: (a) Meth-Cohn, O.; Stanforth, S. P. In Compre-
hensive Organic Synthesis; Trost, B. M., Ed.; Pergamon
Press: New York, 1991; Vol. 2; pp 777-794. (b) Marson, C.
M. Tetrahedron 1992, 48, 3659.
This work was supported by the National Science
Council (NSC 91-2113-M390-001), Taiwan, R.O.C. The au-
thors also thank Prof. Shiuh-Tzung Liu at National Taiwan
University for helpful comments and Prof. Ding-Tzai Li
(NUK) for obtaining the HRMS.
11. Benazza, T.; Uzan, R.; Beaupere, D.; Demailly, G. Tetrahe-
dron Lett. 1992, 33, 4901.
Received August 12, 2003.
12. Hanessian, S.; Plessas, N. K. J. Org. Chem. 1969, 34, 2163.
13. Dods, K. F.; Roth, J. S. Tetrahedron Lett. 1969, 3, 165.
14. Arnold, Z.; Sorm, F. Collect. Czech. Chem. Commun. 1958,
23, 452.
REFERENCES
15. Vader, J.; Koopmans, R.; and Groot, A. E. Tetrahedron 1988,
44, 2663.
16. Vyas, D. M.; Chiang, Y.; Benigni, D.; Doyle, T. W. J. Org.
Chem. 1987, 52, 5601.
1. Present address: Department of Chemistry, National Central
University. No. 300, Jung-Da Rd., Jung-Li City, Taoyuan,
Taiwan 320.
2. Breitmaier, E.; Ulrich, F.-W.; Potthoff, B.; Bohme, R.; Bas-
tian, H. Synthesis, 1987, 1.
17. Skattebøl, L. J. Org. Chem. 1970, 35, 3200.
3. Nair, V.; Vietti, D. E.; Cooper, C. S. J. Am. Chem. Soc. 1981,