Large scale synthesis of acetylene dicarboxaldehyde mono and diacetal

Article abstract of DOI:10.1016/j.tetlet.2004.01.022

An easy, high yield, large scale, and atom economical, synthesis of the valuable acetylene dicarboxaldehyde dimethyl and tetramethyl acetals was described starting from 2,5-dimethoxy-2,5-furan.

Full text of DOI:10.1016/j.tetlet.2004.01.022

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1829–1832
Large scale synthesis of acetylene dicarboxaldehyde
mono and diacetal
q
Rufine Aku ꢀe -G ꢀe du and Beno ^ı t Rigo*
Groupe de Recherche sur l’Inhibition de la Prolif ꢀe ration Cellulaire (EA 2692) Ecole des Hautes Etudes Industrielles,
1
3 rue de Toul, 59046 Lille, France
Received 11 December 2003; revised 5 January 2004; accepted 7 January 2004
Abstract—An easy, high yield, large scale, and atom economical, synthesis of the valuable acetylene dicarboxaldehyde dimethyl and
tetramethyl acetals was described starting from 2,5-dimethoxy-2,5-furan.
Ó 2004 Elsevier Ltd. All rights reserved.
1
Acetylene dicarboxaldehyde (1) and its precursors
mono and bis acetals 2, 3 (Fig. 1) are useful starting
materials, which have found many applications in dipo-
magnesium salt of acetylene, which is very bulky and
difficult to stir, leading to very bad yields.
1g
1a–e
1a;f–i
1a;f;g;j
lar cycloaddition,
Diels-Alder,
Michael,
Wittig reactions. A major drawback for a larger use of
or
We now report an easy, high yield, large scale prepa-
ration of acetals 2b and 3b from inexpensive 2,5-dime-
1k
2
3
these compounds is their high price or difficulties in their
preparation, which preclude their large scale synthesis.
thoxy-2,5-dihydrofuran (4). Indeed it appears to us that
this compound contains all the carbon atoms of acetyl-
ene dicarboxaldehyde (1) and is a cyclic diacetal while 3
is a linear diacetal, and we envisioned the general pro-
cess described in Scheme 3.
The main literature procedures leading to acetals 2 or 3
are described in Schemes 1 and 2. According to Scheme
to obtain 100 g of diacetal 3a, it would be necessary
to use 350 g of triethyl orthoformate, 690 g of KOH and
150 g of tetrabutylammonium hydrogen sulfate.
1f;l
1
,
The first step was realized with only slight variation of a
4
1
literature method. This led to a near quantitative yield
of 95% pure 3,4-dibromo-2,5-dimethoxytetrahydrofuran
1f;g
According to Scheme 2, it would be necessary to use
00 g of triethyl orthoformate, 38 g of magnesium, and
20 l of gaseous acetylene. During this last procedure, it
(5) as a mixture of three geometric isomers in a 43/40/17
5
ratio. This mixture was not purified and was used
4
5
1f;g
directly for the next step. It was reported that when
the previous syntheses were used it was easier to obtain 2a
is difficult to avoid precipitation of the intermediate bis
O
O
R
R
R
R
O
O
O
O
R
R
H
(i)
(ii)
(iii)
Br
O
O
O
O
OHC
C
C
CHO
OHC
C
C
C C
3
H
C C
O
Br
1
2a R = Et
b R = Me
3a R = Et
3b R = Me
Scheme 1. Synthesis of acetal 3a from acroleine. Reactions conditions:
þ
2
ꢀ
(
i) Br
2
,
HC(OEt)
3
(75%); (ii) KOH, Bu
4
N HSO
4
(64%); (iii)
Figure 1.
HC(OEt)
3
, ZnCl (61%).
2
Keywords: 2,5-Dimethoxy-2,5-dihydrofuran; Acetylene dicarboxalde-
hyde; Atom economy.
q
Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.01.022
(
i)
(ii)
H
C
C
H
BrMg
C
C
MgBr
3
*
Corresponding author. Tel.: +33-28-384858; fax: +33-28-384804;
e-mail: rigo@hei.fr
Scheme 2. Synthesis of acetal 3a from acetylene. Reaction conditions:
(i) EtBr, Mg; (ii) HC(OEt) (65%).
3
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.022

1830
R. Aku ꢀe -G ꢀe du, B. Rigo / Tetrahedron Letters 45 (2004) 1829–1832
Br
Br
last reaction, diacetal 3a (47%) and by-product 12 (47%)
were isolated. Modification of these conditions led to
use solid KOH and THF (reflux, 24 h), in the presence of
trismethoxyethoxyethylamine as a phase transfer agent.
The near quantitative (98% isolated, 95% pure) yield of
(
i)
Step 1
O
O
O
O
O
O
4
5 98%
Br
Br
3
b reflects the efficiency of this inexpensive phase
transfer agent. Only evaporation of solvents and
CH Cl /H O partition was necessary to obtain tetra-
(
(
ii)
Step 2
Step 3
Step 4
5
RO
RO
OR
OR
2
2
2
methoxy diacetal 3b, which was not purified but used
9
directly for the next reaction.
6
b R = Me 81%
iii)
RO
RO
OR
OR
6
C
C
In previous works it was reported that the formic
acid
1
0;11
monodeprotection of diacetal 3a (R ¼ Et) (50/
1g
3
b R = Me 98%
1
00 HCO
2
H/CHCl
3
, 12 h, 20 °C, 75%) was easier than
(
iv)
H
OR
OR
the one of 3b, which was then deprotected in harsher
conditions (50/100 HCO H/CHCl , 3 h, 40 °C, 52%). We
have found that a near quantitative yield (98% isolated,
3b
C
C
O
2
3
2
b R = Me 98 %
H N
O
O
2 2 2
95% pure) of 2b was obtained when a HCO H/CH Cl
2
3
solution of 3b was allowed to stand in the dark at room
temperature for 3 days. The good purity (Figs. 3 and 4)
of crude mono protected acetal 2b was sufficient for
7
TrisMethoxyEthoxyEthylAmine
Scheme 3. Synthesis of acetal 3a from dimethoxydihydrofuran.
Reactions conditions: (i) Br , CH Cl (98%); (ii) MeOH, H SO (81%);
iii) THF, KOH, TMEEA (98%); (iv) HCO H/CH Cl (98%).
12
most of the uses.
2
2
2
2
4
(
2
2
2
3
2
2
1
1
000
500
000
500
000
and 3a than their methoxy analogs 2b and 3b. Conse-
quently, in a first approach to Step 2 we tried to obtain
the tetraethy l diacetal 3b, and opening of the furan ring
was performed in ethanol. This led to about 40% of a
mixture of 6a (R ¼ Et) and 6b containing large amounts
6
6
of by-products 8 (two isomers), 9, and 10 (Fig. 2). In
order to suppress the trans-acetalization giving 8, etha-
nol was replaced by methanol. Tetramethyl diacetal 6b
was then obtained contaminated by a low amount of
ester 11, which probably comes from the solvolysis of
lactone 10. Addition of trimethyl orthoformate as
5
0
00
7
scavenger of the water formed did not improve the
yields, but working with a large amount of methanol
and one equimolar quantity of sulfuric acid yield leads
to a better yield of bromoacetal 6b. At the end of the
reaction, sulfuric acid was neutralized by addition of
triethylamine, and methanol was evaporated. Extraction
of the residue with heptane gives 81% of isolated prod-
uct 6b, with purity better than 90%. This compound was
1
1.0
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
ppm (f1)
Figure 3. NMR spectrum of the crude monoacetal 2b showing the
main impurities.
8
not purified but used directly for the next reaction.
First attempts to obtain compounds 3 were realized by
treatment of 6a with potassium tert-butoxide in DMSO
60000
5
4
3
2
1
0
0000
0000
0000
0000
0000
(
in the presence of tetrabutylammonium chloride. In this
80% yield), or NaOH (2 equiv 60 °C, 36 h) in H
2
O/THF,
Br
EtO
Br
OEt
Br
Br
O
O
O
O
O
8
9
10
Br
Br
Me
O
OH
EtO
EtO
OEt
OEt
O
1
1.0
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
11
12
ppm (f1)
Figure 2. By-products observed during the study of steps 2 and 3.
Figure 4. NMR spectrum of the crude monoacetal 2b.

R. Aku ꢀe -G ꢀe du, B. Rigo / Tetrahedron Letters 45 (2004) 1829–1832
1831
In summary, by using easily available 2,5-dimethoxy-
,5-dihydrofuran as starting material, we have accom-
plished an efficient and economic synthesis of acetylenic
orated. Potassium hydroxide (5.5 mol equiv), TMEEA
and THF were added and the mixture was refluxed for
24 h. Part of THF was evaporated, water was added and
the mixture was extracted with ether, leading to 75%
2
acetals 2a and 2b. We have performed these reactions in
1
1
00–300 g scale with no purification of intermediates
yields of 3b (95% pure) for steps 2 and 3. H NMR
(CDCl ) d ppm: 3.85 (s, 12H), 5.22 (s, 1H).
and without appreciable changes in the yields. The
experimental simplicity, the mild reaction conditions
and the atom economy of the processes described are
especially noteworthy.
3
Step 4.
4,4-Dimethoxybut-2-ynal (2b): A mixture of crude 3b
(
from the previous reaction) in CH Cl (600 mL) and
2
2
formic acid (556 g, 12 mol) was kept in the dark for three
days. The solution was partitioned three times with
1
. Experimental procedure
4
water (200 mL). The organic phase was dried (MgSO )
and evaporated giving 74 g of 2b (75% from 4) as a
brown-yellow oil whose purity (95%) was sufficient for
1
13
H and C NMR spectra were obtained on a Varian
Gemini 2000 at 200 and 50 MHz, respectively.
1
most of the utilizations. H NMR (CDCl
3
) d ppm: 3.42
(
s, 6H), 5.32 (d, J ¼ 0:5 Hz, 1H), 9.28 (d, J ¼ 0:5 Hz,
13
Step 1.
1H); C NMR (CDCl ): d ppm: 53.1, 83.1, 88.4, 92.7,
3
176.4.
3
,4-Dibromo-2,5-dimethoxytetrahydrofuran (5): While
controlling the reaction temperature (15 °C), bromine
122.8 g, 0.77 mol) was added to a cooled (ice) solution
of 4 (100 g, 0.77 mol) in CH Cl . Upon decolorization,
NMR spectra of crude monoacetal 2b are displayed in
Figures 3 and 4.
(
2
2
solvent was evaporated and the crude, low colored
semisolid mass (5), was used in the next step. Mixture of
1
three isomers; H NMR (CDCl
3
) d ppm: 43% of isomer
Acknowledgements
mp 88 °C [3.48 (s, 3H), 3.50 (s, 3H), 4.16 (dd, J ¼ 9:6,
3
.9 Hz, 1H), 4.26 (dd, 9.6, 3.9 Hz, 1H), 4.94 (d,
We thank Johnson and Johnson Pharmaceutical
Research and Development, and the Norbert Segard
Foundation for financial support.
J ¼ 3:9 Hz, 1H), 5.21 (d, J ¼ 3:9 Hz, 1H)], 17% of iso-
mer mp 56 °C [3.47 (s, 6H), 4.42 (dd, J ¼ 1:9, 0.7 Hz,
2
H), 5.23 (dd, 1.9, 0.7 Hz, 2H)], 40% of isomer mp 72 °C
[
3.50 (s, 6H), 4.18 (dd, J ¼ 2, 1.3 Hz, 2H), 5.29 (dd, 2,
1
.3 Hz, 2H)].
References and notes
Step 2.
0
0
0
1. (a) Gorgues, A. Janssen Chim. Acta 1986, 4, 21–26; (b)
Gorgues, A.; Le Coq, A. Tetrahedron Lett. 1979, 20, 4829–
2
,5-Dibromo-1 1 4 4-tetramethoxybutane (6b): Sulfuric
acid (75.4 g, 0.77 mol) was added (30 min) to a hot
solution of crude 5 (from the previous reaction) in
MeOH (3900 mL) (nitrogen). The solution was refluxed
for 72 h then cooled at room temperature. Triethylamine
98 mL, 0.77 mol) was added then solvents were evapo-
rated. Residue was stirred and refluxed three times with
00 mL of heptane. The crude, yellow oil 6b, obtained
after evaporation of heptane was used in the next
4832; (c) Henkel, K.; Weygand, F. Chem. Ber. 1943, 76B,
812–821; (d) Ramanaiah, K. C. V.; Stevens, E. D.; Trudell,
M. L.; Pagoria, P. F. J. Heterocyclic Chem. 2000, 37,
1597–1602; (e) Fr ꢁe re, P.; Belyasmine, A.; Gouriou, Y.;
Jubault, M.; Gorgues, A.; Duguay, G.; Wood, S.;
Reynolds, C. D.; Bryce, M. R. Bull. Soc. Chim. Fr. 1995,
(
1
32, 975–984; (f) Gorgues, A.; Simon, A.; Le Coq, A.;
5
Hercouet, A.; Corre, F. Tetrahedron 1986, 42, 351–370; (g)
Gorgues, A.; Stephan, D.; Belyasmine, A.; Khanous, A.;
Le Coq, A. Tetrahedron 1990, 46, 2817–2826; (h) Gorgues,
A.; Le Coq, A. Chem. Commun. 1979, 767–768;
1
step. H NMR (CDCl ) d ppm: 3.45 (s, 12H), 4.35 (d,
J ¼ 7:9 Hz, 2H), 4.59 (d, J ¼ 7:9 Hz, 2H).
3
(
i) Stephan, D.; Gorgues, A.; Belyasmine, A.; Le Coq, A.
Step 3.
Chem. Commun. 1988, 263–264; (j) Blanco, L.; Bloch, R.;
Bugnet, E.; Deloisy, S. Tetrahedron Lett. 2000, 41, 7875–
7878; (k) Barrett, A. G. M.; Hamprecht, D.; Ohkubo, M.
J. Org. Chem. 1997, 62, 9376–9378; (l) Le Coq, A.;
Gorgues, A. Org. Synth. Coll. 1988, 6, 954–957; Monta n~ a,
A. M.; Fernandez, D.; Pag ꢁe s, R.; Filippou, A. C.; Kociok-
K o€ hn, G. Tetrahedron 2000, 56, 425–439.
1
,1,4,4-Tetramethoxybut-2-yne (3b): A stirred mixture of
crude 6b (from the previous reaction), KOH (140 g,
.5 mol) and TMEEA (0.06 mol, 20.2 g) in THF
300 mL) was refluxed for 24 h. Solvent was evaporated,
water (500 mL) was added, and the solution was parti-
tioned three times with ether (500 mL). The crude,
yellow oil 3b, obtained after drying (MgSO ) and
2
(
2
3
. 3,3-Diethoxy-1-propyne (Scheme 1): 329 €/25 g (Lancas-
ter); 3a: 75 €/1 g (Acros); 2a: 78 €/1 g (Acros); 4: 191 €/
4
1
000 g (Alfa Aesar).
evaporation of ether was used in the next step.
. 2,5-dimethoxy-2,5-dihydrofuran (4) is a commercial syn-
thon, which is very versatile: Kass, N. C.; Limborg, F.;
Fakstorp, J. Acta Chem. Scand. 1948, 2, 109–115; Baus-
sanne, I.; Chiaroni, A.; Riche, C.; Royer, J.; Husson, H. -P.
Tetrahedron Lett. 1994, 35, 3931–3934; Merz, A.; Meyer,
Alternatively, it is not necessary to perform an heptane
extraction of compound 6b: the crude mixture obtained
after neutralization of 6b with triethylamine was evap-

1832
R. Aku ꢀe -G ꢀe du, B. Rigo / Tetrahedron Letters 45 (2004) 1829–1832
T. Synthesis 1999, 1, 94–99; Malanga, C.; Mannucci, S.
Tetrahedron Lett. 2001, 42, 2023–2025; Katritzky, A. R.;
Metha, S.; He, H.-Y. J. Org. Chem. 2001, 66, 148–152.
been described: BASF A.-G. Ger. Offen. 1994, 4.223.889;
Chem. Abstr. 1994, 120, 216711.
8. Product 6b is difficult to purify but remaining impurities
are removed during the treatment of the next step.
9. If one needs very pure product for another use, 3b can be
4
. Gagnaire, D.; Vottero, P. Bull. Soc. Chim. Fr. 1963, 2779–
784.
2
1
0
5
. If one needs very pure product for another use, the three
optical isomers of dibromide 3 can be separated then
purified as described in literature (chromatography and
purified by distillation:
1
E
13 ¼ 101–103 °C;
E
1
¼ 70–
g
73 °C.
10. Acid hydrolysis of acetal 3a is very difficult: Wohl, A.;
Bernreuter, E. Ann. Chem. 1930, 481, 1–29.
4
crystallization) .
. Brecker, L.; Kreiser, W.; Ernst, L.; Hopf, H. Collect.
Czech. Chem. Commun. 1999, 64, 1154–1158.
6
7
11. Gorgues, A. Bull. Soc. Chim. Fr. 1974, 529–530.
12. If one needs very pure product 2b can be purified by
1
g
. Utilization of trimethyl orthoformate as water scavenger
during methanolysis of 2,5-dimethyl-2,5-dihydrofuran has
distillation: E14 ¼ 75–78 °C. This compound remains
unaltered for years when kept at )40 °C.