A one-pot synthesis of (±) cryptostylines I, II, III

Article abstract of DOI:10.1081/SCC-120015817

A one-pot synthesis of cryptostylines I, II, III, via the Pictet-Spengler reaction is reported.

Full text of DOI:10.1081/SCC-120015817

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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 4, pp. 621–625, 2003
A One-Pot Synthesis of
(1) Cryptostylines I, II, III
2
1,4
Somsak Ruchirawat,1,2,3, Vanida Bhavakul,
*
and Malinee Chaisupakitsin2
1Chulabhorn Research Institute, Bangkok, Thailand
2Department of Chemistry, Faculty of Science,
Mahidol University, Bangkok, Thailand
3Programme on Research and Development of
Synthetic Drugs, Institute of Science and Technology
forResearch and Development,
Mahidol University, Salaya, Thailand
4Department of Chemistry, Faculty of Science,
King Mongkut’s University of Technology,
Thonburi, Bangkok, Thailand
ABSTRACT
A one-pot synthesis of cryptostylines I, II, III, via the Pictet–Spengler
reaction is reported.
*Correspondence: Somsak Ruchirawat, Chulabhorn Research Institute,
Vipavadee Rangsit Highway, Bangkok 10210, Thailand; E-mail: somsak@
tubtim.cri.or.th.
621
DOI: 10.1081/SCC-120015817
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622
Ruchirawat, Bhavakul, and Chaisupakitsin
Key Words: 1-Aryltetrahydroisoquinoline alkaloids; Pictet-Speng-
lerreaction.
Cryptostylines I, II, III, are rare 1-aryltetrahydroisoquinoline alka-
loids which have been isolated from Cryptostylis fulva[1] and Cryptostylis
erythroglosa.[2] Several asymmetric syntheses[3] and racemic syntheses[1,4]
of the cryptostylines have been reported, all involving multi-steps with
discreet operations. In continuation with our interest in the application of
[5]
the Pictet–Spenglereraction forthe synthesis of alkaloids,
our work on the application of this reaction to the one-pot synthesis of
we report
cryptostyline I, cryptostyline II, and cryptostyline III in this article.
[6]
The Pictet–Spenglereraction
is a classical reaction involving the
electrophilic substitution of activated aromatic compounds with an
iminium intermediate. The reaction is commonly used for the synthesis
of 1,2,3,4-tetrahydroisoquinoline and carboline alkaloids. Recent investi-
gations have applied the reaction to the stereospecific synthesis[7] of these
compounds as well as to solid phase synthesis.[8] The reaction has also
recently been extended to the synthesis of other related compounds.[9]
Normally the Pictet–Spengler reaction requires acids as the condensing
agent, but in some special cases the reaction proceeds under neutral
conditions. Recently it was shown that cyclization reactions for
carboline formation can also be performed with hypervalent iodine
compounds.[10]
The Pictet–Spenglerreaction has also been applied to the synthesis of
a 1-phenyltetrahydroisoquinoline intermediate, in which dopamine can
be condensed with benzaldehyde in the presence of dilute hydrochloric
acid, whereas for a similar cyclization in the case of homoveratrylamine,
phosphoric acid was required.[11]

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Cryptostylines I, II, III
623
Wefound thatformic acidcould convenientlybeemployedasboth acid
and solvent forthe condensation of 3,4-dimethoxyphenylethylamine
(homoveratrylamine) with aromatic aldehydes to yield the correspond-
ing 1-aryltetrahydroisoquinoline derivatives. Condensation of homover-
atrylamine with piperonal in formic acid at an oil bath temperature of
110ꢀC for 7 h gave the required product, norcryptostyline I, in 58%
yield after purification by crystallization of the oxalate salt. Having
successfully effected the required cyclization by the action of formic
acid, we then investigated the ‘‘one pot’’ synthesis of cryptostylines
I, II, III. Since cyclization could be effected by formic acid and
N-methylation by formaldehyde and formic acid is well documented[12]
we anticipated that by adding formaldehyde to the above cyclization
reactionn we would be able to effect both the cyclization and
N-methylation in sequence to produce the required compound in
one pot.
The above prediction was realized by heating homoveratrylamine
with piperonal in formic acid at 110ꢀC for7 h then adding 37%
formaldehyde and continuing heating the reaction mixture for a
further 4 h. After work-up and purification by preparative layer
chromatography, cryptostyline I was isolated in 61% yield. Similarly,
cryptostylines II and III could be synthesized by heating homoveratryl-
amine with veratraldehyde and 3,4,5-trimethoxybenzaldehyde in
formic acid followed by N-methylation with formaldehyde in 69
and 79% yield respectively after purification by preparative layer
chromatography.
In conclusion, the above synthesis fits with one of the criteria of the
ideal synthesis[13] requiring that consecutive reactions should be carried
out in the same medium. Due to environmental concerns, use of less
solvent is very much favored. We have found that formic acid, as the
solvent, serves as an excellent acid for the Pictet–Spengler reaction and
also acts as a good reducing agent in the further methylation of the
intermediate so obtained.
EXPERIMENTAL
Representative Procedure
A
mixture of 2-(3,4-dimethoxyphenyl) ethylamine (0.362 g,
2.00 mmol) and 3,4-methylenedioxybenzaldehyde (0.360 g, 2.40 mmol)
in 99% formic acid (4 mL) was heated in an oil bath at 110ꢀC for7 h,

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624
Ruchirawat, Bhavakul, and Chaisupakitsin
then 2 mL of 37% formaldehyde was added and the mixture was further
heated for 4 h. The excess of formic acid and formaldehyde was removed
by distillation and the mixture was then cooled and made basic with 1 M
sodium carbonate. The solution was extracted twice with methylene
chloride. The organic extracts were combined, washed with water,
dried over anhydrous sodium sulfate, filtered and evaporated to dryness
to give brown solid which was recrystallized from ether to give the
product (0.399 g) as a white solid.
Cryptostyline I (61%): M.p. 117–118ꢀC (ether) (Lit.[1] 117–118ꢀC);
IR (KBr) 2949, 1609, 1511, 1369, 1245, 1217, 1140, 1036 cmꢁ1; 1H NMR
(400 MHz, CDCl3) ꢀ 2.25 (s, 3H, NCH3), 2.59 (dt, 1H, J ¼ 4.0, 11.0 Hz),
2.72 (dt, 1H, J ¼ 3.3, 15.6 Hz), 3.12 (m, 2H), 3.62, 3.85 (s, 3H, OCH3),
4.12 (s, 1H, CH), 5.93 (d, 2H, JAB ¼ 0.7 Hz, OCH2O), 6.17 (s, 3H, ArH ),
6.59 (s, 3H, ArH ), 6.71 (s, 3H, ArH ), 6.76 (m, 2H, ArH ); 13C NMR
(100 MHz, CDCl3) ppm 28.9, 44.1, 52.1, 55.7, 55.8, 70.6, 100.9, 107.4,
109.3, 110.7, 111.4, 122.8, 126.5, 130.2, 137.7, 146.8, 147.0, 147.4, 147.8;
MS (EI) m/z 327 (Mþ, 28), 206 (100).
Cryptostyline II (69%): M.p. 101–102ꢀC (ether) (Lit.[1] 103–104ꢀC);
1
IR (KBr) 2894, 1465, 1355, 1220, 1190, 824 cmꢁ1; H NMR (400 MHz,
CDCl3) ꢀ 2.24 (s, 3H, NH), 2.60 (dt, 1H, J ¼ 4.0, 11.1 Hz), 2.76 (m, 1H),
3.14 (m, 2H), 3.58 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.85 (s, 3H,
OCH3), 3.89 (s, 3H, OCH3), 4.11 (s, 1H, CH ), 6.14 (s, 1H, ArH ), 6.60
(s, 1H, ArH ), 6.76 (d, 1H, J ¼ 1.7 Hz), 6.82 (s, 1H, ArH ), 6.83 (d, 1H,
J ¼ 1.7 Hz); 13C NMR (100 MHz, CDCl3) ppm 28.8, 44.2, 52.4, 55.6, 55.7,
55.8, 70.9, 110.3, 110.6, 111.4, 122.0, 126.3, 130.4, 136.0, 146.9, 147.4,
148.3, 149.0; MS (EI) m/z 343 (Mþ, 17 ), 206 (100).
Cryptostyline III (79%): M.p. 140–141ꢀC (EtOH) (Lit.[1] 141–142ꢀC);
1
IR (KBr) 2948, 1463, 1360, 1220, 1182, 812 cmꢁ1; H NMR (400 MHz,
CDCl3) ꢀ 2.25 (s, 3H, NCH3), 2.59 (m, 1H), 2.72 (m, 1H), 3.12 (m, 2H),
3.61 (s, 3H, OCH3), 3.82 (s, 6H, 2 ꢂ OCH3), 3.85 (s, 6H, 2 ꢂ OCH3), 4.06
(s, 1H, CH ), 6.17 (s, 1H, ArH ), 6.59 (s, 1H, ArH ), 4.50 (s, 2H, ArH );
13C NMR (100 MHz, CDCl3) ppm 28.8, 44.4, 52.5, 55.7, 55.9, 56.1, 60.8,
71.6, 106.4, 110.7, 111.4, 126.4, 130.1, 137.2, 139.4, 146.9, 147.5, 153.0;
MS (EI) m/z 373 (Mþ, 13), 206 (100).
ACKNOWLEDGMENTS
We acknowledge financial support from the Thailand Research Fund
(TRF) and the facilities at the Department of Chemistry, Mahidol
University, provided by the PERCH programme.