An innovative approach to the synthesis of substituted benzaldehydes through carbanion induced ring transformation of suitably functionalized 2H-pyran-2-ones

Article abstract of DOI:10.1016/j.tetlet.2004.05.095

An innovative route for the synthesis of substituted benzaldehydes has been delineated through a ring transformation reaction of suitably functionalized 2H-pyran-2-ones by methylglyoxaldimethylacetal followed by Amberlyst 15 or acid catalyzed cleavage of

Full text of DOI:10.1016/j.tetlet.2004.05.095

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5743–5745
An innovative approach to the synthesis of substituted
benzaldehydes through carbanion induced ring transformation
q
of suitably functionalized 2H-pyran-2-ones
Ramendra Pratap, Diptesh Sil and Vishnu Ji Ram*
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
Received 23 March 2004; revised 6 May 2004; accepted 14 May 2004
Available online 11 June 2004
Abstract—An innovative route for the synthesis of substituted benzaldehydes has been delineated through a ring transformation
reaction of suitably functionalized 2H-pyran-2-ones by methylglyoxaldimethylacetal followed by Amberlyst 15 or acid catalyzed
cleavage of the intermediate acetal in good yield.
Ó 2004 Published by Elsevier Ltd.
The versatility of the formyl group for generating
molecular diversity through C–C and C–heteroatom
bond formation is widely recognized. Formyl deriva-
masked substituted benzaldehydes 3 followed by either
Amberlyst 15 or acid catalyzed acetal cleavage to yield
substituted benzaldehydes 4.
1
tives are widely used as ligands for the synthesis of metal
chelates. The synthesis of formylbiaryls and formylaryl–
heteroaryls is of significant importance as they are useful
building blocks for the construction of various synthetic
and natural products.
6-Aryl-4-methylsulfanyl-2H-pyran-2-one-3-carbonitrile
12
1a,
nitrile 1b,
3-carbonitrile 1c and methyl 6-aryl-4-methylsulfanyl-
6-aryl-4-piperidin-1-yl-2H-pyran-2-one-3-carbo-
13
6-aryl-4-pyrrolidin-1-yl-2H-pyran-2-one-
13
14
2
H-pyran-2-one-3-carboxylate 1d, were obtained from
The formyl group is generally introduced to aromatic
2
the reaction of aryl methyl ketones and ketene dithio-
acetal, the cyclic aminals 1b,c being prepared on further
reaction of the 6-aryl-4-methyl-sulfanyl-2H-pyran-2-
one-3-carbonitrile 1a with piperidine and pyrrolidine in
refluxing methanol and isolated as usual. These lactones
1a–d were used as precursors for carbanion induced ring
transformation reactions, using methylglyoxaldimethyl-
acetal 2 as carbanion source, generated in situ by the
action of powdered KOH in DMF.
3
systems by Gatterman, Gatterman–Koch, and Vils-
4
meier–Haack reactions and also by formylation with
5
6
orthoformate, formyl fluoride–BF
7
3
and dichloro-
. Besides these methods they
methyl methyl ether–AlCl
are also prepared by oxidation of methyl or hydroxy-
methyl arenes and by reduction of nitriles, amides
and acid chlorides. The wide-ranging applications and
limitations of existing procedures prompted us to de-
velop a novel route to the synthesis of highly function-
alized substituted benzaldehydes. Recently, Junjappa
and co-workers reported the synthesis of formyl het-
eroarenes through heterocyclization of 1-bis(methoxy)-
3
8
9
10
11
The topography of the 2H-pyran-2-ones 1 is such that
they can be considered as cyclic ketene hemithioacetals
1a,d and cyclic ketene hemiaminals 1b,c, C-6 of which is
highly susceptible to nucleophilic attack due to extended
conjugation and the presence of the an electron with-
drawing substituent at position 3 of the pyran ring.
Masked substituted benzaldehydes were synthesized
by stirring an equimolar mixture of 1, methylglyoxal-
dimethylacetal 2 and powdered KOH in dry DMF at
room temperature for 24 h, followed by pouring onto
crushed ice with vigorous stirring for 1h whilst main-
taining a neutral pH by adding 10% aqueous HCl. The
1
4
-bis(methylthio)-3-butene-2-one. We now report an
innovative synthesis of substituted benzaldehydes
through ring transformation of suitably functionalized
2
H-pyran-2-ones 1 by methylglyoxaldimethylacetal 2 to
q
Communication No. 6546.
Corresponding author. Tel.: +91-522-2212411; fax: +91-522-22234-
*
05; e-mail: vjiram@yahoo.com
0
040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.05.095

5744
R. Pratap et al. / Tetrahedron Letters 45 (2004) 5743–5745
precipitate obtained was filtered, washed with water and
finally the crude product was purified on a Si gel column
to afford the masked substituted benzaldehydes 3 as
viscous liquids or low melting solids. Hydrolysis either
by stirring with Amberlyst 15 in chloroform or refluxing
with 4% ethanolic HCl gave the corresponding substi-
tuted benzaldehydes 4. The Amberlyst 15 catalyzed
acetal hydrolysis of the masked substituted benzalde-
hydes 3 was found to be a high yielding, cleaner, reac-
tion compared to the acid catalyzed reaction (40–65%
yields).
All the compounds synthesized were characterized by
15
elemental and spectroscopic analyses. This methodol-
ogy provides a novel route for the synthesis of a wide
variety of highly functionalized substituted benzalde-
hydes in high yield and in only two steps.
Acknowledgements
D.S. is grateful to CSIR for a senior research fellowship.
The authors are also thankful to SAIF, Central Drug
Research Institute, Lucknow for providing spectro-
scopic data and elemental analyses for the synthesized
compounds.
The reaction is possibly initiated by attack of the carb-
anion generated in situ from methylglyoxaldimethyl-
acetal
2 at C-6 with ring-closing followed by
decarboxylation and dehydration to yield 3, which on
acetal hydrolysis by Amberlyst 15 or ethanolic-HCl (4%)
led to the substituted benzaldehydes 4. The synthetic
strategy followed is far superior to known procedures
with respect to ease of work-up, mild reaction condi-
tions and cost effectiveness (Table 1).
References and notes
1
2
. Mohata, P. K.; Kumar, U. K. S.; Sriram, V.; Illa, H.;
Junjappa, H. Tetrahedron 2003, 59, 2631.
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X
O
Y
OCH3
+
OCH3
3. (a) Toniolo, L.; Graziani, M. J. Organomet. Chem.
1980, 194, 221; (b) Grounse, N. N. Org. React. 1949, 5,
Ar
O
O
2
1
2
90.
a) X= SCH
b) X=piperidinyl, Y=CN
c) X=pyrrolidinyl, Y=CN
d) X=SCH3 , Y=COOCH
3
, Y=CN
4
. (a) Blaser, D.; Calmes, M.; Daunis, J.; Natt, F.; Tardy-
Delassus, A.; Jacquier, R. Org. Prep. Proced. Int. 1993, 25,
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Cohn, O.; Goon, S. J. Chem. Soc., Perkin Trans. 1 1997,
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Meth-Cohn, O.; Tarnowski, B. In Advances in Heterocy-
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M.; Montero, A.; Peseke, K. Synthesis 2001, 1686.
3
O
O
O
Y
X
X
OH
CH(OCH3)2
X
O
Y
O
Ar
OCH3
Ar
H
Y
5. Gross, S.; Rieche, A.; Matthey, G. Chem. Ber. 1963, 96,
08.
6. Olah, G. A.; Kuhn, S. J. J. Am. Chem. Soc. 1960, 82,
380.
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8; (b) Lewin, A. H.; Parker, S. R.; Fleming, N. B.; Carrol,
H CO
3
3
Y
CHO H+
2
X
CH(OCH3)2
7
8
9
8
F. I. Org. Prep. Proced. Int. 1978, 10, 201.
Ar
Ar
. Frey, L. F.; Marcantonio, K.; Frantz, D. E.; Murry, J. A.;
Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Tetrahe-
dron Lett. 2001, 42, 6815.
3
4
Scheme 1.
. Zil’berman, E. N.; Pyryalova, P. S. J. Gen. Chem. USSR
1
963, 33, 3348.
1
0. (a) Zakharkin, L. I.; Khorlina, I. M. Bull. Acad. Sci.
USSR, Div. Chem. Sci. 1959, 2046; (b) Muraki, M.;
Mukaiyama, T. Chem. Lett. 1975, 875; (c) Godjoian, G.;
Singaram, B. Tetrahedron Lett. 1997, 38, 1717.
Table 1. Derivatives of 3 and 4 produced according to Scheme 1
3, 4
Ar
X
Y
Yield (%)
1
1
1. (a) Cha, J. S.; Brown, H. C. J. Org. Chem. 1993, 58, 4732;
(b) Maier, W. F.; Chettle, S. J.; Rai, R. S.; Thomas, G.
J. Am. Chem. Soc. 1986, 108, 2608.
2. (a) Ram, V. J.; Haque, N.; Singh, S. K.; Hussaini, F. A.;
Shoeb, A. Indian J. Chem. 1993, 32B, 1993; (b) Tominaga,
Y.; Ushirogochi, A.; Matsuda, Y.; Kobayashi, G. Chem.
Pharm. Bull. 1984, 32, 3395.
3
4
a
b
c
d
e
f
C
C
6
6
H
H
5
5
SCH
3
CN
CN
CN
CN
CN
CN
CN
CN
62
59
95
90
91
90
95
Piperidinyl
SCH
Pyrrolidinyl
4-FC
4-ClC
4-BrC
6
H
4
3
25
50
6
H
4
6
H
4
SCH
SCH
SCH
SCH
SCH
3
3
3
3
3
46
4-CH
4-CH
3
SC
C
6
H
4
2196
50
1
3. (a) Ram, V. J.; Verma, M.; Hussaini, F. A.; Shoeb, A.
Liebigs Ann. Chem. 1991, 1229; (b) Ram, V. J.; Nath, M.;
Srivastava, P.; Sarkhel, S.; Maulik, P. J. Chem. Soc. 2000,
g
h
i
3
6
H
4
94
93
––
90
C
C
C
10
10
10
H
H
H
7
38
36
7
7
CO
CN
CN
2
Me
3719.
4. (a) Ram, V. J.; Verma, M.; Hussaini, F. A.; Shoeb, A.
J. Chem. Res. (S) 1991, 98; (b) Tominaga, Y.; Ushirogo-
j
Piperidinyl
SCH
52
4192
1
k
Thienyl
3

R. Pratap et al. / Tetrahedron Letters 45 (2004) 5743–5745
5745
chi, A.; Matsuda, Y. J. Heterocycl. Chem. 1987, 24,
557.
5. Typical procedure: Compound 3a:
-phenyl-4-methylsulfanyl-2H-pyran-2-one-3-carbonitrile
0.24 g, 1mmol), methylglyoxaldimethylacetal (0.12 mL,
mmol) and powdered KOH (60 mg, 1mmol) in dry DMF
15 mL) was stirred at room temperature for 24 h and
ArH) 7.45 (s, 2H, ArH), 7.68 (s, 1H, ArH); IR (KBr)
À1
þ
1
2210 cm (CN); MS m=z 306 (M +1).
1
A
mixture of
Typical procedure A for Compound 4a: A solution of 3a
(0.1g, 0.33 mmol) in chloroform (10 mL) was stirred with
Amberlyst 15 (30 mg) for 1 h. During this period complete
conversion of the acetal to the corresponding aldehyde
was observed. The catalyst was removed by filtration and
evaporation of the solvent led to the desired compound in
95% yield.
Typical procedure B for Compound 4a: A solution of 3a
(0.1g) in 4% ethanolic-HCl (15 mL) was refluxed for 1h.
After evaporation of the solvent water (50 mL) was added.
Extraction with chloroform followed by evaporation and
purification on Si gel (chloroform–hexane (2:3) as eluent)
6
(
1
(
poured onto crushed ice with vigorous stirring, then
neutralized with 10% HCl. The separated solid was
filtered, washed with water, dried and purified by Si gel
column chromatography, using hexane–chloroform (7:3)
as eluent, mp 108 °C NMR (200 MHz, CDCl
3
) d 2.62 (s,
), 5.61(s, 1H , CH), 7.45–
.48 (m, 4H, ArH), 7.61(d, J ¼ 8:5, 2H, ArH) 7.68 (s, 1H,
3
7
3 3
H, SCH ), 3.47 (s, 6H, OCH
À1
þ
ArH); IR (KBr) 2218 cm (CN); MS m=z 300 (M +1).
Compound 3b: oil, d 1.26 (s, 2H, CH ), 1.78–1.83 (m, 4H,
CH ), 3.18–3.23 (m, 4H, NCH ), 3.46 (s, 6H, OCH ), 5.61
s, 1H, CH), 7.18 (s, 1H, ArH), 7.42–7.47 (m, 4H, ArH),
gave 4a in 60% yield, mp 108 °C; d 2.67 (s, 3H, SCH
3
),
2
7.48–7.55 (m, 3H, ArH), 7.60–7.65 (m, 2H, ArH), 7.72 (s,
1H, ArH), 7.96 (s, 1H, ArH), 10.39 (s, 1H, CHO); IR
2
2
3
À1
þ
(
(KBr) 1704 cm (CO), 2215 (CN); MS m=z 254 (M +1).
Compound 4b: mp 1 1° 0C ; d 1.57–1.62 (m, 2H, CH ),
1.71–1.82 (m, 4H, CH ), 3.18–3.26 (m, 4H, NCH ), 7.36–
À1
7
.59 (d, J ¼ 6:28, 2H, ArH); IR (KBr) 2216 cm (CN);
2
þ
MS m=z 337 (M +1). Compound 3c: oil; d 2.63 (s, 3H,
2
2
SCH
(
3
), 3.48 (s, 6H, OCH
m, 2H, ArH), 7.41(s, 1H , ArH), 7.54–7.63 (m, 3H, ArH);
3
), 5.61 (s, 1H, CH), 7.17–7.27
7.55 (m, 6H, ArH), 7.69 (s, 1H, ArH), 10.31 (s, 1H, CHO);
À1
IR (KBr) 1704 cm
(CO), 2215 (CN); MS m=z 291
),
7.10–7.19 (m, 3H, ArH), 7.50–7.59 (m, 2H, ArH), 7.85 (s,
À1
þ
þ
IR (KBr) 2219 cm (CN); MS m=z 318 (M +1). Com-
pound 3d: mp 92 °C; d 1.98–2.05 (m, 4H, CH
(M +1). Compound 4c: mp 1 28°C; d 2.60 (s, 3H, SCH
3
2
), 3.46 (s,
), 5.59 (s, 1H, CH),
À1
6
6
2
2
H, OCH
3
), 3.64–3.70 (m, 4H, NCH
2
1H, ArH), 10.33 (s, 1H, CHO); IR (KBr) 1703 cm (CO),
þ
.78 (s, 1H, ArH), 7.15 (s, 1H, ArH), 7.40 (d, J ¼ 8:66,
2217 (CN); MS m=z 272 (M +1). Compound 4d: mp
H, ArH), 7.52 (d, J ¼ 8:66, 2H, ArH); IR (KBr)
136 °C; d 2.03–2.12 (m, 4H, CH
NCH ), 7.04 (s, 1H, ArH), 7.41–7.46 (m, 3H, ArH), 7.50–
7.54 (m, 2H, ArH), 10.39 (s, 1H, CHO); IR (KBr)
2
), 3.70–3.76 (m, 4H,
À1
þ
257 cm (CN); MS m=z 357 (M +1). Compound 3e:
2
mp 122 °C; d 2.62 (s, 3H, SCH
3 3
), 3.46 (s, 6H, OCH ), 5.60
À1
þ
(
7
2
s, 1H, CH), 7.41 (s, 1H, ArH), 7.46 (d, J ¼ 9:0, 2H, ArH)
1690 cm
(CO), 2197 (CN); MS m=z 311 (M +1).
), 7.47–
7.52 (m, 2H, ArH), 7.63–7.67 (m, 3H, ArH), 7.93 (s, 1H,
.61(d, J ¼ 9:0, 2H, ArH), 7.63 (s, 1H, ArH), IR (KBr)
Compound 4e: mp 1 83°C; d 2.67 (s, 3H, SCH
3
À1
þ
210 cm (CN); MS m=z 379 (M +1). Compound 3f: oil;
), 2.61(s, 3H, SCH ), 3.46 (s, 6H,
), 5.60 (s, 1H, CH), 7.33 (d, J ¼ 8:35, 2H, ArH) 7.44
À1
d 2.53 (s, 3H, SCH
OCH
(
(
3
3
ArH), 10.39 (s, 1H, CHO); IR (KBr) 1699 cm (CO),
þ
3
2219 (CN); MS m=z 333 (M +1). Compound 4f: oil; d 2.54
d, J ¼ 1:36, 1H, ArH) 7.53 (d, J ¼ 8:35, 2H, ArH) 7.65
(s, 3H, SCH ), 2.67 (s, 3H, SCH
ArH), 7.55 (d, J ¼ 8:50, 2H, ArH), 7.69 (s, 1H, ArH), 7.95
3
3
), 7.35 (d, J ¼ 8:50, 2H,
À1
d, J ¼ 1:36, 1H, ArH); IR (KBr) 2220 cm (CN); MS
þ
À1
m=z 346 (M +1). Compound 3g: oil; d 2.43 (s, 3H, CH
3
),
), 5.62 (s, 1H, CH),
(s, 1H, ArH), 10.38 (s, 1H, CHO); IR (KBr) 1705 cm
þ
2
.63 (s, 3H, SCH
3
), 3.48 (s, 6H, OCH
3
(CO), 2219 (CN); MS m=z 300 (M +1). Compound 4g: mp
7
.29 (d, J ¼ 8:1, 2H, ArH) 7.46 (d, J ¼ 1:2, 1H, ArH) 7.52
126 °C; 2.45 (s, 3H, CH
3 3
), 2.67 (s, 3H, SCH ), 7.32 (d,
J ¼ 7:6, 2H, ArH), 7.53 (d, J ¼ 7:6, 2H, ArH), 7.71(s, 1H,
(
(
d, J ¼ 8:1, 2H, ArH) 7.68 (d, J ¼ 1:2, 1H, ArH); IR
À1
þ
KBr) 2219 cm (CN); MS m=z 314 (M +1). Compound
ArH), 7.96 (s, 1H, ArH), 10.39 (s, 1H, CHO); IR (KBr)
(CO), 2212 (CN); MS m=z 268 (M +1).
À1
þ
3
h: oil; d 2.56 (s, 3H, SCH
3
), 3.48 (s, 6H, OCH
3
), 5.66 (s,
1699 cm
1
ArH) 7.92–7.94 (m, 2H, ArH); IR (KBr) 2215 cm (CN);
MS m=z 350 (M +1). Compound 3i: oil; d 2.55 (s, 3H,
H, CH), 7.39–7.55 (m, 6H, ArH), 7.61 (d, J ¼ 1:15, 1H,
Compound 4h: oil; d 2.61(s, 3H, SCH
9H, ArH) 10.42 (s, 1H, CHO); IR (KBr) 1702 cm (CO),
2216 (CN); MS m=z 304 (M +1). Compound 4j: oil; d 1.66
3
), 7.42–7.98 (m,
À1
À1
þ
þ
SCH
1
3
), 3.35 (s, 6H, OCH
H, CH), 7.49–7.94 (m, 8H, ArH), 8.05 (s, 1H, ArH); IR
3
), 3.96 (s, 3H, OCH
3
), 5.66 (s,
(s, 2H, CH
NCH ), 7.38 (s, 1H, ArH), 7.43 (s, 1H, ArH), 7.47–7.78
2 2
), 1.78–1.89 (m, 4H, CH ), 3.25–3.30 (m, 4H,
2
À1
þ
(
KBr) 2218 cm (CN); MS m=z 383 (M +1). Compound
(m, 5H, ArH), 7.93 (d, J ¼ 7:42, 2H, ArH), 10.41 (s, 1H,
À1
3
j: oil; d 1.50–1.56 (m, 2H, CH
2
), 1.78–1.83 (m, 4H, CH
2
),
), 5.65 (s, 1H,
CHO) ; IR (KBr) 1704 cm (CO), 2215 (CN); MS m=z 341
þ
3.17–3.23 (m, 4H, CH ), 3.47 (s, 6H, OCH
CH), 7.11 (s, 1H, ArH), 7.12–7.90 (m, 8H, ArH); IR (KBr)
2
3
(M +1). Compound 4k: mp 1 28°C; d 2.67 (s, 3H, SCH
7.14–7.19 (m, 1H, ArH), 7.46–7.52 (m, 2H, ArH), 7.70 (d,
3
),
À1
þ
2213 cm (CN); MS m=z 387 (M +1). Compound 3k: mp
78 °C; d 2.61(s, 3H, SCH ), 3.45 (s, 6H, OCH ), 5.57 (s,
1H, CH), 7.07–7.12 (m, 1H, ArH), 7.40 (d, J ¼ 5:1, 1H,
J ¼ 1:66, 1H, ArH), 7.97 (d, J ¼ 1:66, 1H, ArH), 10.36 (s,
À1
3
3
1H, CHO); IR (KBr) 1703 cm (CO), 2218 (CN); MS m=z
260 (M +1).
þ