Oxa-Pictet-Spengler reaction in water. Synthesis of some (±)-1-aryl-6,7-dimethoxyisochromans

Article abstract of DOI:10.1016/j.cclet.2009.11.009

An acid catalyzed oxa-Pictet-Spengler reaction 'on water' leading to the synthesis of a variety of 1-aryl-6,7-dimethoxyisochromans is described. The aqueous chemistry is a much cleaner, efficient, cheaper and simple method for synthesis. The scope of reac

Full text of DOI:10.1016/j.cclet.2009.11.009

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 261–264
www.elsevier.com/locate/cclet
Oxa-Pictet–Spengler reaction in water. Synthesis of
some (ꢀ)-1-aryl-6,7-dimethoxyisochromans
Aamer Saeed
Department of Chemistry, Quaid-I-Azam University, 45320 Islamabad, Pakistan
Received 18 August 2009
Abstract
An acid catalyzed oxa-Pictet–Spengler reaction ‘on water’ leading to the synthesis of a variety of 1-aryl-6,7-dimethoxyisochro-
mans is described. The aqueous chemistry is a much cleaner, efficient, cheaper and simple method for synthesis. The scope of
reactions was extended to thia-Pictet–Spengler reaction to afford the some isothiochromans.
# 2009 Aamer Saeed. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Oxa-Pictet–Spengler reaction; In water; 1-Aryl-6,7-dimethoxyisochromans; Isothiochromans
Isochroman (3,4-dihydro-1H-benzo[c]pyran) is a common structural motifin many bioactive natural products such as
1,6,8-trihydroxy-3-heptyl-7-carboxyisochroman[1], anantibioticandtopoisomeraseIIinhibitorfromthePenicillumsp.,
pseudodeflectusin[2], aselective humancancercytotoxinfromAspergilluspseudodeflectus, isochromansfromsoftwood
lignin [3] and the malewing gland pheromone of bumble-beewax moth Aphomia sociella[4] or a part of complex natural
products such as stephaoxocanine [5] a novel dihydroisoquinoline alkaloid from Stephania cepharantha, glucoside B an
aphid insect pigment derivative [6] and pyranonaphthoquinones frenolicin B, lactoquinomycin A and kalafungin [7]. 1-
Phenyl- and 1-(3-methoxy-4-hydroxy)phenyl-6,7-dihydroxyisochromans identified in extra-virgin olive oil [8] exhibit
beneficial antioxidant effects and antiplatelet activity [9,10]. 3,7-Dimethoxy-8-hydroxy-6-methoxyisochroman isolated
from Penicillium corylophilium and its synthetic analogues exhibit plant growth regulatory and herbicidal activities [11].
6,7-Dimethoxyisochromans substituted at C-1 with arylpiperazines are hypotensivewith peripheral and central activities
and are adrenergic antagonists [12]. A novel isochroman derivative inhibited apoptosis in vascular endothelial cells
through depressing the levels of integrin b4, p53 and reactive oxygen species (ROS) [13].
In literature, two important routes generally applicable to the isochroman synthesis include cyclodehydration of
homophthalyl alcohols [14] and the Lewis acid assisted cyclization of phenethyl alcohols known as the oxa-Pictet–
Spengler reaction. The latter is a variation of the Pictet–Spengler reaction reported ca 80 years after the original
reaction, in which a phenethyl alcohol reacts with a carbonyl compound to give a 1-substitued isochroman derivative
[15]. Originally, zinc chloride HCl gas, p-toluenesulfonic acid or Lewis acids such as titanium tetrachloride, aluminum
chloride or stannic chloride were used as Friedel–Crafts catalysts along with high reaction temperatures [16]. The
reaction was usually carried out in dioxane, nitrobenzene, benzene, dichloromethane or methanol as solvent. Later on,
E-mail address: aamersaeed@yahoo.com.
1001-8417/$ – see front matter # 2009 Aamer Saeed. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.11.009

262
A. Saeed / Chinese Chemical Letters 21 (2010) 261–264
it was observed that the activated substrates such as 2-(3,4-dihydroxy)-phenylethanol undergo the oxa-Pictet–Spengler
reaction under mild conditions: catalytic amount of p-toluenesulfonic acid in methanol at low temperature, oleic acid
in methanol [9,17] or boron triflouride etherate in dichloromethane [7]. In case of oleic acid the time required to
achieve the satisfactory yields varied from 24 h for aldehydes, 48 h to one week for ketones nonetheless, the yields
were lower. Recently Zeolite-catalyzed [18] and the bismuth triflate-catalyzed [19] oxa-Pictet–Spengler reaction have
been reported which provide the excellent yields but reaction time varied from 15 to 20 h, and carcinogenic solvent
toluene was employed. Consequently, all of the aforementioned methods require an expensive and/or a moisture-
sensitive catalyst and a dry organic solvent and there is little concern given to the environment, cost, safety, or
simplicity of operation. Taking into consideration the human health and environmental concerns, ‘Green Chemistry’,
intended to decrease or eliminate the use or generation of hazardous substances during chemical reactions, is receiving
much attention these days. In this context, there has been an ever-growing interest in synthetic organic reactions in
water [20] herein we describe a clean synthesis of some isochromans in an environmentally friendly aqueous medium.
1. Results and discussion
Although water is the most inexpensive, safe and non-hazardous green solvent, its use as a medium for organic
reactions has been limited in spite of the fact that many biochemical processes in nature go on in the presence of water
molecules. Owing to its polarity many organic substrates appear to be insoluble in water giving suspensions, therefore,
it was considered that presence of water will result in low reaction rates and yields of the products. Later on, after the
identification of the hydrophobic, solvation and stereochemical effects in water there has been an excited boost in
attempting organic reactions in water. It is suggested that reactions ‘‘on water’’ actually go on through small amounts
of dissolved solutes. It occurs at the aqueous–organic interface therefore vigorous stirring of the reaction mixture is
considered to be helpful. The ultimate goal of aqueous chemistry is to carry out organic reactions in vitro under mild
conditions even in the absence of enzyme catalysis [21].
The reaction conditions were optimized for reaction of 3-methoxybenzaldehyde with 2-(3,4-dimethoxyphenyl)
ethanol with respect to solvent, catalyst, reaction time and temperature and the results are illustrated in Table 1.
Variously substituted benzaldehydes were condensed with 2-(3,4-dimethoxyphenyl)ethanol in presence of a
catalytic amount of p-toluenesulfonic acid or concentrated hydrochloric acid or sulphuric acid in water (Scheme 1).
Table 1
Synthesis of 1d under different reaction conditions.
Entry
Solvent
Catalyst
Reaction temperature (8C)
Reaction time (min)
Yield (%)
1
2
3
4
5
6
7
8
–
p-TsOH
–
–
0.5
85
–
H2O
H2O
H2O
H2O
H2O
MeOH
MeOH
rt to reflux
40–60
60–80
reflux
reflux
reflux
rt
>300
150
120
40
HCl/H2SO4
HCl
55
60
87
81
89
60
HCl
p-TsOH
p-TsOH
p-TsOH
40
120
>300
No reaction at room temperature for 1d or other substrates in water under any of reaction conditions. The yields were slightly better when 1.2 equiv of
aldehyde was used but reaction mixture needed purification. Reaction concentration: phenethyl alcohol: water (1 mmol: 40 mL).
Scheme 1.

A. Saeed / Chinese Chemical Letters 21 (2010) 261–264
263
Table 2
Synthesis and characterization data of the isochromans (1a–r) & isothiochromans (1s–u).
Entry
1
R
X
Mp (8C)
75–76 [9]
Reaction time (min)
Yield (%)
C1-H (d ppm)
1
a
b
c
d
e
f
H
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
40
45
45
40
40
40
40
40
45
45
50
50
50
45
55
55
50
55
60
65
80
91
88
98
87
89
90
94
89
88
97
86
97
98
98
80
81
86
81
58
71
56
5.58
4.85
5.64
5.65
5.43
5.59
5.60
6.10
6.13
6.16
5.61
5.64
5.62
5.63
5.69
5.56
5.50
5.51
5.05
5.11
5.20
2
C6H5CH CH
3-CH3O
4-CH3O
3-CH3O-4-OH
3,4-di(CH3O)
3,4,5-tri(OCH3)
2-F
55–57
3
83–85
4
88–90(97–98 [9])
5
oil
6
81–83(80–81 [9])
oil
7
g
h
i
8
82–83
9
3-F
87–88
10
11
12
13
14
15
16
17
18
19
20
21
j
4-F
92–93
k
l
2-Cl
118–119
3-Cl
84–86
83–85
89–91
91–92
92–94
81–83
84–86
94–95
122–124
98–100
m
n
o
p
q
r
s
4-Cl
4-(CH3)2N
3-NO2
4-NO2
3-HO
4-HO
4-Cl
t
3-pyridyl
3-NO2
S
u
S
The products 1a–r were obtained in high purity and yields by refluxing a vigorously stirred suspension of
phenylethanol and aldehydes in water for 40–55 min [22]. The isochromans were characterized by the typical C1-H
singlet at d 5.50–6.19 except for 1b for which a doublet with J = 3.9 Hz was observed (Table 2). The non-planar nature
of tetrahydropyran ring was indicated by separate 1H multiplets for each proton of the C-3 and C-4 methylenes.
The reaction was carried out using meta or para substituted aromatic aldehydes as ortho-benzaldehydes are known
to give lower yields due to steric reasons except for 2-F substituent which is isosteric with hydrogen.
In case of non activated substrates like unsubstituted phenethyl alcohol, with no activating substituents on phenyl
ring, the reaction did not occur to an appreciable extent therefore, phenethyl alcohols with electron-withdrawing
groups are not expected to react under these conditions.
In order to evaluate the scope of method it was extended to thia-Pictet–Spengler reaction. Thus condensation of
benzaldehydes with 2-(3,4-dimethoxyphenyl)ethanethiol [23] afforded the corresponding isothiochromans in good
yields. The reaction time was relatively higher and Rf values were lower compared to the isochromans. The
characteristic C1-H singlet also appeared at lower d values compared that of to their oxa-analogues.
In conclusion, we have demonstrated an environmentally friendly method for the synthesis of isochromans by oxa-
Pictet–Spengler reaction in water. The reaction in water shows several advantages such as short reaction times, high
yields, mild and cheap catalyst, lack of side-product formation and lack of need for work up, as the products can
directly be filtered off.
Acknowledgment
The author gratefully acknowledges the Higher Education Commission of Pakistan for the financial assistance.
References
[1] N. Imamura, T. Ishikawa, T. Ohtsuka, et al. Biosci. Biotech. Biochem. 64 (2000) 2216.
[2] A. Ogawa, C. Murakami, S. Kamisuki, et al. Bioorg. Med. Chem. Lett. 14 (2004) 3539.
[3] (a) J. Peng, F. Lu, J. Ralph, Phytochemistry 50 (1999) 659;
(b) J. Ralph, J. Peng, F. Lu, Tetrahedron Lett. 39 (1998) 4963.
[4] G. Kunesch, P. Zagatti, A. Pouverau, et al. Z. Naturforsch 42 (1987) 657.
[5] N. Kashiwaba, S. Morooka, M. Kimura, et al. J. Nat. Prod. 59 (1996) 803.

264
A. Saeed / Chinese Chemical Letters 21 (2010) 261–264
[6] D.W. Cameron, R.I.T. Cromartie, D.G.I. Kingston, et al. J. Chem. Soc. (1964) 51.
[7] C.N. Eid, J. Shim, J. Bikker, et al. J. Org. Chem. 74 (2009) 423.
[8] J. Malstrom, C. Christophersen, J.C. Frisvad, Phytochemistry 54 (2000) 301.
[9] P. Lorenz, M. Zeh, J.M. Lobenhoffer, et al. Free Radical. Res. 39 (2005) 535.
[10] (a) G.I. Togna, A.R. Togna, M. Franconi, et al. J Nutr. 133 (2003) 2532;
(b) A. Bianco, F. Coccioli, M. Guiso, et al. Food Chem. 77 (2001) 405.
[11] (a) D.A. Bianchi, N.E. Blanco, N. Carrillo, et al. J. Agric. Food Chem. 52 (2004) 1923;
(b) H.G. Cutler, G. Majetich, X. Tian, et al. J. Agric. Food Chem. 45 (1997) 1422.
[12] (a) L.G. Humber, J. Heterocycl. Chem. 12 (1975) 591;
(b) J.M. McCall, R.B. McCall, R.E. TenBrink, et al. J. Med. Chem. 25 (1982) 75.
[13] L. Zhang, X. Zhu, B. Zhao, et al. Vascul. Pharmacol. 48 (2008) 63.
[14] (a) J.N. Srivasta, D.N. Chaudary, J. Org. Chem. 27 (1962) 4337;
(b) D. Mukhopadhyay, D.N. Chaudary, J. Indian Chem. Soc. 40 (1963) 433.
[15] D.A. Bianchi, F. Rua, T.S. Kaufmann, Tetrahedron Lett. 45 (2004) 411.
[16] M. Guiso, C. Marra, C. Cavarischia, Tetrahedron Lett. 42 (2001) 6531.
[17] M. Guiso, A. Bianco, C. Marra, et al. Eur. J. Org. Chem. (2003) 3407.
[18] A. Hegedus, Z. Hell, Org. Biomol. Chem. 4 (2006) 1220.
[19] C. Lherbet, D. Soupaya, C. Baudoin-Dehoux, et al. Tetrahedron Lett. 49 (2008) 5449.
[20] (a) Anastas, T.C. Williamson, Green Chemistry: Frontiers in Benign Chemical Syntheses and Processes, Oxford, New York, 1998, pp. 1-360;
(b) P.A. Grieco, Organic Synthesis in Water, Blackie Academic & Professional, London, 1998, pp. 1–305.
[21] (a) J.E. Klijin, J.B.F.N. Engberts, Nature 435 (2005) 746;
(b) S. Narayan, J. Muldoon, M.G. Finn, et al. Angew. Chem. Int. Ed. 44 (2005) 3275;
(c) R. Breslow, C.J. Rizzo, J. Am. Chem. Soc. 113 (1991) 4340;
(d) G.B. Jacobson, C.T. Lee Jr., Sandro, et al. J. Org. Chem. 64 (1999) 1207.
[22] Typical procedures: Avigorously stirred suspension of 2-(3,4-dimethoxyphenyl)ethanol (0.182 g, 1 mmol) and 2-fluorobenzaldehyde (0.124 g,
1 mmol) and a catalytic amount of p-toluenesulfonic acid in water (40 ml) was refluxed for 40 min. The completion of reaction was indicated
by TLC using hexane ethyl acetate (7:3). The product was filtered off directly followed by recrystallization from ethyl acetate to afford 1-(2-
fluorophenyl)-6,7-dimethoxyisochroman (0.89 mmol, 89%) TLC (Rf): 0.37; Mp.:82–83 8C; 1H NMR (CDCl3): d 6.75 (s, 1H, H-5), 6.26 (s, 1H,
H-8), 6.10 (s, 1H, H-1), 4.16 (td, 1H, J = 4.8, 5.1, H-3) and 3.94 (td, 1H, J = 3.9, 2.7, H-3), 3.89 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.03 (td, 1H,
J = 4.2, 5.4, H-4), 2.74 (td, 1H, J = 4.2, 3.9, H-4), 1-aryl ring: 7.07–7.19 (m, 3H, H-30, 50, 40); 7.29 (m, 1H, H-60); EIMS m/z: 289, 288, 193, 165.
Analysis calc. for C17H17FO3: C, 70.82, H, 5.94% found, C, 70.80, H, 5.96%. A vigorously stirred suspension of 2-(3,4-dimethoxypheny-
l)ethanethiol (0.182 g, 1 mmol) and 4-chlororobenzaldehyde (0.124 g, 1 mmol), and a catalytic amount of p-toluenesulfonic acid in water
(40 ml) was refluxed for 60 min. The product was purified by preparative TLC hexane ethyl acetate (7:2) to afford 1-(4-Chlorophenyl)-6,7-
dimethoxyisothiochroman (0.58 mmol, 58%) TLC (Rf): 0.37; Mp.:94–95 8C; 1H NMR (CDCl3,): d 4.39 (s, 1H, H-5), 4.66 (s, 1H, H-8), 5.05 (s,
1H, H-1), 4.16 (td, 1H, J = 4.8, 5.1, H-3) and 3.94 (td, 1H, J = 3.9, 2.7, H-3), 3.86 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.10 (m, 1H, H-4), 2.79
(m, 1H, H-4), 1-aryl ring: 7.17 (d, J = 8.2 Hz, 2H, H-20, 60); 7.22 (d, J = 8.2 Hz, 2H, H-30, 50); EIMS m/z: 320, 322, 197. Analysis calc. for
C17H17ClSO2: C, 63.64; H, 5.34; S, 9.99% found, C, 63.31; H, 5.48; S, 10.07%.
[23] E. Campagine, B.G. Heaton, J. Org. Chem. 29 (1964) 2372.