A practical synthesis of phenylpropargyl aldehyde from phenylacetylene and N-formylmorpholine

Article abstract of DOI:10.1021/op9900582

A synthesis of phenylpropargyl aldehyde is described employing formylation of a phenylacetylenic Grignard reagent with N-formylmorpholine. This method afforded the product in excellent yield.

Full text of DOI:10.1021/op9900582

Organic Process Research & Development 2000, 4, 46−48
A Practical Synthesis of Phenylpropargyl Aldehyde from Phenylacetylene and
N-Formylmorpholine
Atsuhiko Zanka*
Technological DeVelopment Laboratories, Fujisawa Pharmaceutical Co. Ltd., 2-1-6 Kashima, Yodogawa-ku,
Osaka, 532-8514, Japan
Abstract:
Scheme 1. Route to FK453 from phenylpropargyl aldehyde
1)
(
A synthesis of phenylpropargyl aldehyde is described employing
formylation of a phenylacetylenic Grignard reagent with N-
formylmorpholine. This method afforded the product in excel-
lent yield.
Results and Discussion
1
In a previous paper we described a practical synthesis
1
of FK453, a novel nonxanthine adenosine A receptor
antagonist Via (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-
acryloylate (4), the product of a 1,3-dipolar cycloaddition
reaction between alkyne (2), prepared from phenylpropargyl
aldehyde (1), and 1-aminopyridinium salt (3) (Scheme 1).
For the first scale up trial, aldehyde (1) was synthesized from
trans-cinnamaldehyde (5) by a slight modification of the
2
reported method (Scheme 2). This process was satisfactorily
scaled up; however, several serious drawbacks were noted
from the viewpoint of the final production procedure. One
problem was that aldehyde (1) and the various intermediates
are of a highly irritant nature, such that attention must be
paid to avoid contact with these agents. A more fundamental
problem was that aldehyde (1) prepared by this route
contained small amounts of impurities, which were suspected
to prompt decomposition of 1. In effect, whilst quantitative
purification by distillation on a laboratory scale was possible,
about 28% of the aldehyde decomposed and/or polymerized
Scheme 2. Route to phenylpropargyl aldehyde (1) from
trans-cinnamaldehyde (5)
1
to yield intractable tarry byproducts on a 100 kg scale. A
DTA (differential thermodynamic analysis) study indicated
that aldehyde (1) started to decompose at 96 °C (Figure 1).
The stability test under adiabatic conditions also presented
the same profile. According to these results, purification by
1
distillation (91-93 °C/6 mmHg) might be dangerous and
should be excluded from larger scale synthesis. Thus, this
procedure had to be modified to a more safe and efficient
process.
reported excellent results converting phenylacetylenic Grig-
nard reagent (7) to 1 using 2-(N-formyl-N-methyl)amino-
3
pyridine. The success of their method was ascribed to the
As an alternative approach to aldehyde (1), formylation
of phenylacetylene (6) was attractive (Scheme 3). Several
methods for coupling Grignard reagents with formamides
are known in the literature.3 In 1978, Comins and Meyers
ready formation of a six-membered chelate ring, which
prevented further reaction with Grignard reagent. Fr e´ chet et
al. also emphasized the role of chelation in formylation of
-7
4
Grignard reagents with several N-formylamines. The im-
proved yield using 2-(N-formyl-N-methyl)aminopyridine
compared with using N-formylpiperazine or DMF was
attributed to inhibition of secondary alcohol formation
resulting from further reaction with Grignard reagent. On
the other hand, reports from Olah and Arangashi have
appeared in which excellent results were obtained by using
(
1) Zanka, A.; Uematsu, R.; Morinaga, Y.; Yasuda, H.; Yamazaki, H. Org.
Process Res. DeV. 1999, 3, 389.
(
2) Allen, C. F. H.; Edens, C. O., Jr. Organic Syntheses; Wiley: New York,
1
955; Collect. Vol. III, p 731.
(
(
(
(
(
3) Comins, D.; Meyers, A. I. Synthesis 1978, 403.
4) Amaratunga, W.; Fr e´ chet, J. M. J. Tetrahedron Lett. 1983, 24, 1143.
5) Olah, G. A.; Prakash, G. K. S.; Arvanaghi, M. Synthesis 1984, 228.
6) Olah, G. A.; Arvanaghi, M. Angew. Chem., Int. Ed. Engl. 1981, 20, 878.
7) Olah, G. A.; Ohannesian, L.; Arvanaghi, M. J. Org. Chem. 1984, 49, 3856.
5
6
7
DMF, N-formylpiperazine, and N-formylmorpholine. Quite
4
6
•
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10.1021/op9900582 CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry
Published on Web 12/01/1999

Table 1. Effect of hydrolysis conditions on the yield after
coupling Grignard reagent (7) with N-formylamine
%
of
temp(°C)/
a
entry
N-formylamine
DMF
DMF
DMF
HCl (equiv) time (min) yield (%)
1
2
3
4
5
6
7
8
3(2.0)
6(2.0)
6(2.0)
3(2.0)
3(2.0)
3(2.0)
3(2.0)
6(2.0)
0/30
20/30
20/120
20/420
0/30
0/30
20/30
20/30
34(40)b
65
59
DMF
81
43(31)
b
N-formylpiperidine
N-formylmorpholine
N-formylmorpholine
N-formylmorpholine
88
94
96
a
Yield was determined by quantitative HPLC. b Recovered yield from the
separated aqueous layer.
Figure 1. DTA study of aldehyde (1).
following results. A higher concentration of hydrochloric acid
afforded smooth hydrolysis (entry 2). However, under these
conditions, further reaction of the aldehyde (1) with hydrogen
chloride and/or dimethylamine occurs; thus, the extraction
must be conducted quickly after the completion of the
reaction (entry 2, 3). Since this could not be done effectively
on a large scale, this method was not developed further. On
the other hand, reaction at 20-25 °C gave improvement in
the yield (entry 4). Despite these excellent results, the
obtained aldehyde (1) contained small amounts of unknown
byproducts and required further purification by distillation.
Envisaging avoidance of further reactions, we examined other
formamides derived from weakly basic amines. Amongst
several formamides, N-formylmorpholine was especially
attractive, since this pure grade reagent is readily available
in large quantities and is easily prepared and inexpensive
Scheme 3. Route to phenylpropargyl aldehyde (1) from
phenylacetylene (6)
recently, an efficient synthesis of 1 was described by Journet
8
et al. The mild conditions for hydrolysis of the incipient
($6/kg, in bulk quantities) from BASF Co. The coupling of
intermediate (8) were considered essential to prevent further
reaction of the acetylenic aldehyde with dimethylamine.
However, despite these excellent results, the requirement for
a large amount of phosphate solution and MTBE for back
extraction are problematic from the viewpoint of high
throughput, which is one of the main issues for a cost-
effective synthesis.
the Grignard reagent (7) with N-formylmorpholine proceeded
smoothly, and the further reactions in question did not occur
at all, regardless of the amount of hydrogen chloride. These
excellent results were presumably attributed to the weak
basicity of morpholine (pK
a
) 8.3) compared with that of
dimethylamine (pK ) 10.7). Interestingly, the hydrolysis
a
step was complete in only 30 min, whilst 7 h was required
in the case of DMF (entry 3, 4, 7, 8). The explanation for
this unexpected difference in hydrolysis is not clear at this
point, but our best speculation is that morpholine as a weak
base enhances smooth hydrolysis under mild conditions,
preventing further reactions of 1. As a result of these findings,
the aldehyde (1) was synthesized in higher yield (96%,
quantitative HPLC) and better quality (98% HPLC area,
phenylacetylene: 2% HPLC area) than the product from
route A (95% HPLC area, after distillation) and thus could
be immediately used in the following step after exchange of
solvents.
Herein, I wish to report the results of endeavours aimed
at efficient formylation of phenylacetylenic Grignard reagent
(7), without side-reactions. Whilst 2-(N-formyl-N-methyl)-
aminopyridine was not commercially available and required
several steps for preparation, DMF is inexpensive and readily
available in large quantities. Thus, our process research was
initiated by coupling Grignard reagent (7) with DMF,
focusing on optimizing the hydrolysis conditions. As pointed
out by Olah and Arvanaghi, no further reaction was involved,
and secondary alcohol was not detected when the reaction
was carried out with avoidance of an excess of Grignard
reagent. However, in our early studies, the yield was low
when only a slight excess hydrochloric acid was used in the
hydrolysis at 0-5 °C, aimed at avoiding excess use of
The ester (4) was synthesized in excellent quality (99.8%
chemical purity) and good yield (59%) according to the
1
reported method, and no new impurities were identified in
reagent and further reactions of 1 with dimethylamine. (Table
the material.
8
1
, entry 1). As pointed out by previous authors the yield of
1
was greatly affected by the hydrolysis step. Examination
Conclusions
of the optimum conditions in the work-up afforded the
In this paper, a practical and facile synthesis of phenyl-
propargyl aldehyde is described. The use of inexpensive and
readily available N-formylmorpholine as the formylation
(
8) Journet, M.; Cai, D.; DiMichele, L. M.; Larsen, R. D. Tetrahedron Lett.
1
998, 39, 6427.
Vol. 4, No. 1, 2000 / Organic Process Research & Development
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47

reagent and optimized work up conditions gave a product
with superior quality to the material from the first pilot plant
scale campaign without a distillation purification process.
at 35 °C to avoid precipitation, was slowly added N-
formylmorpholine (226 g, 1.96 mol) at 35 °C. After the
mixture stirred for an additional 30 min, this solution was
added to 6% hydrochloric acid in water (1000 mL) at <25
°C. After the mixture stirred for 30 min at 20-25 °C, toluene
(1000 mL) was added to this reaction mixture. The layers
were separated, and the aqueous layer was re-extracted with
toluene (500 mL). The combined organic layer was then
washed with 10% brine (1000 mL). The organic layer
contained 122 g of phenylpropargylaldehyde (1) (96% yield)
by quantitative HPLC. Removal of solvents afforded phen-
ylpropargylaldehyde (1) as an oil (98% HPLC area), identical
Experimental Section
Pure grade N-formylmorpholine is available in bulk
quantities from BASF Co. Phenylacetylene was obtained
from Wychem Co. and was distilled before use to remove a
small amount of water. All other chemicals were obtained
from the usual commercial suppliers.
Phenylpropargyl Aldehyde (1). Ethylbromide (10.7 g,
97.9 mmol) and a small amount of iodine were added to
1
metallic magnesium (28.4 g, 1.17 mol) in dry THF (1000
mL) and heated to 35 °C. After the mixture stirred for 1 h,
ethylbromide (128 g, 1.17 mol) was slowly added at about
with authentic material ( H NMR, HPLC).
Acknowledgment
3
5 °C, and the solution was refluxed for a further 1 h. Control
We especially thank Dr. David Barrett, Medicinal Chem-
istry Research Laboratories, Fujisawa Pharmaceutical Co.
Ltd., for his interest and ongoing advice in this work.
of exotherm in the reaction was achieved by controlling the
addition speed of ethylbromide. Phenylacetylene (6) (100
g, 0.979 mol) was added to the prepared Grignard reagent
at about 35 °C, after which the reaction was continued at
the same temperature until no more ethane was evolved. To
the prepared acetylenic Grignard reagent (7), which was kept
Received for review June 24, 1999.
OP9900582
48
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Vol. 4, No. 1, 2000 / Organic Process Research & Development