A case of pictet-spengler revisited: Application to the synthesis of dihydroisocoumarins

Article abstract of DOI:10.1081/SCC-200048399

The reaction of Pictet-Spengler was revisited, and its modified conditions were applied to develop a general methodology toward the synthesis of dihydroisocoumarins containing a no-electron rich aromatic ring.

Full text of DOI:10.1081/SCC-200048399

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A Case of Pictet‐Spengler
Revisited: Application
to the Synthesis of
Dihydroisocoumarins
N. Choukchou‐Braham a , B. Mostefa‐Kara a , N.
Cheikh a , M. A. Didi a & D. Villemin b
a Laboratoire de Catalyse et de Synthèse en Chimie
Organique, Département de Chimie, Faculté des
Sciences, Université Abou‐Bekr Belkaid, Tlemcen,
Algeria
b Ecole Nationale Supérieure d'Ingénieurs de Caen
(ENSICAEN), Université de Caen, UMR6507, 6,
boulevard du Maréchal Juin, Caen, F‐14050, Cedex,
France
Version of record first published: 28 Jul 2007.
To cite this article: N. Choukchou‐Braham, B. Mostefa‐Kara, N. Cheikh, M. A. Didi &
D. Villemin (2005): A Case of Pictet‐Spengler Revisited: Application to the Synthesis of
Dihydroisocoumarins, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:2, 169-178
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Synthetic Communicationsw, 35: 169–178, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200048399
A Case of Pictet-Spengler Revisited:
Application to the Synthesis of
Dihydroisocoumarins
N. Choukchou-Braham, B. Mostefa-Kara, N. Cheikh, and M. A. Didi
`
Laboratoire de Catalyse et de Synthese en Chimie Organique,
´
´ ´
Departement de Chimie, Faculte des Sciences, Universite Abou-Bekr
Belkaid, Tlemcen, Algeria
D. Villemin
´ ´
Ecole Nationale Superieure d’Ingenieurs de Caen (ENSICAEN),
´
Universite de Caen, UMR6507, CaenCedex, France
Abstract: The reaction of Pictet-Spengler was revisited, and its modified conditions
were applied to develop a general methodology toward the synthesis of dihydroisocou-
marins containing a no-electron rich aromatic ring.
Keywords: Dihydroisocoumarins, benzylic alcohol, Pictet-Spengler reaction
INTRODUCTION
Among the different classes of natural products that have been studied for their
biological activities, isocoumarins have received limited attention. Mellein
(Fig. 1), an Aspergillus Mellius metabolite isolated by Nishikawa in 1933,
is the first example in such a class known for presenting antibacterial
activity.[1,2] Hydrangenol, an allergenic[3–6] natural product and AI-77-B,
Received in Poland October 25, 2004
Address correspondence to D. Villemin, Ecole Nationale Superieure d’Ingenieurs
´
´
´
´
de Caen (ENSICAEN), Universite de Caen, UMR6507, 6, boulevard du Marechal
Juin, Caen F-14050 Cedex, France. Fax: (33)231 45 28 77; E-mail: villemin@
ensicaen.fr

170
N. Choukchou-Braham et al.
Figure 1. Dichloroisocoumarin and some examples of natural dihydroisocoumarins.
an isolate from Bacillus Pumilus with gastroprotective[7] effects, are other ex-
amples of isocoumarins that have been targeted for organic synthesis.[8–19]
To the best of our knowledge, not enough attention has been devoted to the
full investigation of the biological activity of this class of products.
During the course of our research aiming at developing novel antialler-
genic and anti-inflammatory compounds, 3,4-dichloroisocoumarin (Fig. 1)
attracted our attention. Although it is considered as a potent serine protease
inhibitor with a wide range of activity, it exhibits none toward beta-lacta-
mases.[20] Therefore, we decided to investigate the activity of different dihy-
droisocoumarins (DHICs) analogous to the dichloroisocoumarin.
To such an end, we felt a need to develop a general method that would
lead to different DHICs from the same precursor and in considerable
amounts whenever required. We report herein the synthesis of different
DHICs through the application of modified Pictet-Spengler conditions.
RESULTS AND DISCUSSION
In our retrosynthetic analysis, we envisaged a conceptually appealing yet
simple approach based on the Pictet-Spengler reaction conditions. Although

Pictet-Spengler Reaction in Synthesis of Dihydroisocoumarins
171
that reaction is a variant of the Mannich one and therefore uses an amine, we
conjectured that it would also work when an alcohol is involved through
probably a slightly different mechanism. Hence, the DHIC framework
would arise from the alcohol 3a–f through chloromethylation, followed by
chromium oxidation (Fig. 2). It is noteworthy that the Pictet-Spengler
reaction is reported to work only when the aromatic ring is electron-rich to
promote the ring closing. In our case, we successfully tried it on a nonsubsti-
tuted ring and obtained good yields. On the other hand, conditions previously
reported for the chloromethylation uses formaldehyde along with hydrochloric
acid. In our case, we replaced the highly toxic formaldehyde by para-formal-
dehyde, which produced good yields as well.
Hence, treating aldehyde 4a–f with benzyl Grignard produced the
equivalent homobenzylic alcohol 3a–f with excellent yields (Scheme 1).
Subsequent chloromethylation using either formaldehyde solution in water
or para-formaldehyde in acidic medium at a temperature between 50 and
608C generated the corresponding isochromans 2a–f. It is to be noted that
only in the case of 3f that dehydration producing stilbene occurred along
with the right product. In all other cases, ring formation was faster than
dehydration. Finally, oxidation using chromium trioxide[21,22] in aqueous
acetic acid at room temperature afforded the DHICs 1a–f with yields
ranging from 66 to 82%. All compounds were identified by proton Nuclear
Magnetic Resonance (NMR) and Fourier Transformed Infrared (FT-IR)
spectroscopy.
CONCLUSION
We have shown that simple modification of the Pictet-Spengler conditions,
mainly heating and substituting formaldehyde by its correspondent polymer,
produces DHICs in good yields. Activation of the aromatic ring with an
electron-donor group is not necessary in this case, and it is therefore
possible to obtain a whole plethora of compounds in this manner. Work for
the synthesis of potential protease inhibitors analogous to 3,4-dichloroisocou-
marin is currently undergoing and will be communicated in due time.
Figure 2. Retrosynthetic analysis of dihydroisocoumarins.

172
N. Choukchou-Braham et al.
Scheme 1.
EXPERIMENTAL
The PMR spectra were recorded on a Bruker AC250 instrument using tetra-
methylsilane (TMS) as internal standard reference. Unless specified, CDCl3
was used as the solvent of choice. Infrared spectra were recorded on a Jasco
FT-IR 430 spectrometer in CHCl3 with absorptions in cm21. Melting points
(mp) were determined on a Buchi-Tottoli 510 with no correction. Flash
chromatography was performed by using Kiesegel 40 to 63 mm silicagel.
Tetrahydrofuran (THF) and diethylether were distilled on Na/benzophenone
˚
prior to use. Dioxane was dried on 4 A molecular sieves prior to use.
Synthesis of Homobenzylic Alcohol (3a–f)
General Procedure
To a solution of benzylmagnesium chloride freshly prepared in ether (10 mL)
from magnesium (0.6 g, 23.8 mmol) and benzyl chloride (3 g, 23.8 mmol) was
added at 08C to a solution of aldehyde 4a–f (15.89 mmol) in ether (5 mL).
After stirring for 2 hr at room temperature, the reaction mixture was
quenched with saturated ammonium chloride. The two phases were
separated, and the aqueous layer was extracted twice with ether. The
combined organic layers were then washed once with brine and dried over
MgSO4. Filtration followed by concentration in vacuo produced the corre-
sponding residue that was purified by flash chromatography.

Pictet-Spengler Reaction in Synthesis of Dihydroisocoumarins
173
(+)-1-Phenylpropan-2-ol (3a)
Obtained from acetaldehyde; viscous liquid; yield 93%; Rf ¼ 0.41 (eluent:
1
AcOEt/C6H12 ¼ 10/90); C9H12O; H NMR d: 1.25 (t, 3H, CH3), 2.45–
2.90 (m, 2H, PhCH2), 3.45 (m, 1H, PhCH2CH), 7.20 (m, 5H, Ph); IR: 3374
(O–H), 2965–2923 (C–H), 1448 (C55Car), 1081 (C–O).
(+)-1-Phenylpentan-2-ol (3b)
Obtained from butanal; viscous liquid; yield 86%; Rf ¼ 0.13 (eluent: AcOEt/
1
C6H12 ¼ 10/90); C11H16O; H NMR d: 0.94 (t, 3H, CH3), 1.49 (m, 4H, –
CH2–), 2.42–2.90 (m, 2H, PhCH2), 3.52 (m, 1H, PhCH2CH), 7.28
(m, 5H,Ph); IR: 3464 (O–H), 3114 (C–Har), 1470–1554 (C55Car), 1109
(C–O–).
(+)-1-Phenylnonan-2-ol (3c)
Obtained from octanal; viscous liquid; yield 89%; Rf ¼ 0.37 (eluent: AcOEt/
1
C6H12 ¼ 10/90); C15H24O; H NMR d: 0.98 (t, 3H, CH3), 1.37 (m, 12H, –
CH2), 2.39–2.78 (m, 2H, PhCH2), 3.79 (m, 1H, PhCH2CH), 7.31
(m, 5H,Ph); IR (CHCl3): 3408 (O–H), 3126 (C–Har), 1475–1539 (C55Car),
1103 (C–O–).
(+)-1,2-Diphenylethanol (3d)
Obtained from benzaldehyde; white solid; mp 668C; yield 77%; Rf ¼ 0.37
(eluent: AcOEt/C6H12 ¼ 20/80); C14H14O; 1H NMR d: 2.65 (broad,
1H,O–H), 3.00 (m, 2H, PhCH2CH); 4.89 (m, 1H, PhCH2CHPh), 7.20–7.33
(m, 10H, 2Ph); IR: 3400 (O–H, broad), 3022–2924 (C55Har), 2862 (C–
Hal), 1490–446 (C55Car), 1033 (C–O).
(+)-1-(40-Methoxyphenyl)-2-Phenylethanol (3e)
Obtained from 4-methoxy-benzaldehyde; white solid, mp 618C; yield 91%;
Rf ¼ 0.22 (eluent: AcOEt/C6H12 ¼ 20/80); C15H16O; 1H NMR d: 1.85
(broad, 1H, OH), 2.99 (m, 2H, PhCH2CH), 3.80 (s, 3H, OCH3), 4.84
(m, 1H, PhCH2CH), 6.85–7.33 (m, 9H, Ph); IR: 3283 (O–H, broad),
3020–2929 (C–Har), 2850 (C–Hal), 1509–1450 (C55Car), 1247 (Car–O–
C), 1031 (C–O).
(+)-1-(40-Chlorophenyl)-2-Phenylethanol (3f)
Obtained from 4-chloro-benzaldehyde; white solid; mp 598C; yield
82%; Rf ¼ 0.32 (eluent: AcOEt/C6H12 ¼ 20/80); C14H13OCl; 1H NMR

174
N. Choukchou-Braham et al.
d: 2.75–2.90 (m, 2H, PhCH2CH), 3.40 (broad, 1H, OH), 4.75 (m, 1H,
PhCH2CH), 7.10–7.30 (m, 9H, Ph); IR: 3413 (O–H, broad), 3000–2900
(C–Har), 2850 (C–Hal), 1483–1448 (C–Car), 1030 (C55O), 827 (C55Cl).
Synthesis of Isochromans 2a–f
General Procedure
Dry hydrogen chloride was bubbled for 2 hr at 50–608C in a mixture of
alcohol 3a–f (4.44 mol), formaldehyde (0.85 g, 9.90 mmol) or para-formal-
dehyde (0.89 g) instead of and concentrated hydrochloric acid (0.53 g,
5.46 mmol) in dry dioxane (10 mL). After cooling down to room temperature,
the mixture was poured into ice water, and the product was extracted three
times with 25 mL of ether. The combined organic layers were then washed
once with a 10% solution of NaHCO3, water and then dried over calcium
chloride. Filtration and concentration in vacuum produced then a residue
that was purified by flash chromatography.
(+)-3-Methylisochroman (2a)
Prepared from (+)-1-phenylpropan-2-ol (3b); viscous liquid; yield 50%;
Rf ¼ 0.60 (eluent: AcOEt/C6H12 ¼ 10/90); C10H12O; 1H NMR d: 1.33
(d, 3H, CH3), 2.74 (m, 2H, PhCH2), 3.68 (m, 1H, PhCH2CH), 4.85–5.24
(m, 2H,PhCH2O–), 7.12 (m, 4H, Ph); IR: 3023 (C–Har), 2925–2890 (C–
Har), 1110 (C–O–C), 1492–1604 (C55Car).
(+)-3-Propylisochroman (2b)
Prepared from (+)-1-phenylpentan-2-ol (1b); viscous liquid; yield 64 %;
Rf ¼ 0.29 (eluent:AcOEt/C6H12 ¼ 10/90); C12H16O; 1H NMR d: 0.98
(m, 3H, CH3), 1.57 (m, 4H, –CH2–), 2.74–2.94 (m, 2H, PhCH2), 3.68
(m, 1H,PhCH2CH), 4.82 (m, 3H, PhCH2–O), 7.14–7.20 (m, 4H, Ph); IR:
3166 (C–Har), 2996 (C–Har), 1554 (C55ar), 1101 (C–O–C).
(+)-3-Heptylisochroman (2c)
Prepared from (+)-1-phenylnonan-2-ol (3c); viscous liquid; yield 83%;
Rf ¼ 0.43 (eluent: AcOEt/C6H12 ¼ 10/90); C16H24O; 1H NMR d: 0.87
(t, 3H, CH3), 1.29–1.88 (m, 12H, –CH2–), 2.63 (m, 2H, PhCH2), 3.68
(m, 1H, PhCH2CH), 4.64–4.84 (m, 2H, PhCH2O–), 7.07–7.36 (m,4H, Ph);
IR: 3126 (C–Har), 2854 (C–Har), 1539 (C55Car), 1103 (C–O–C).

Pictet-Spengler Reaction in Synthesis of Dihydroisocoumarins
175
(+)-3-Phenylisochroman (2d)
Prepared from (+rpar;-1,2-diphenylethanol (3d); viscous liquid; yield 93%;
Rf ¼ 0.59 (eluent: AcOEt/C6H12 ¼ 20/80); C15H14O; 1H NMR d: 3.36
(m, 2H, PhCH2CH), 3.69 (s, 2H, PhCH2O), 5,03 (m, 1H, PhCH2CH), 7.08–
7.35 (m, 9H, 2Ph); IR: 3030–2936 (C–Har), 2860 (C–Hal), 1493–1447
(C55Car), 1206(C–O–C).
(+)-3-(40-Methoxyphenyl) Isochroman (2e)
Prepared from (+)-1-(40-methoxy-phenyl)-2-phenylethanol (3e); viscous
liquid; yield 93%; Rf ¼ 0.53 (eluent: AcOEt/C6H12 ¼ 20/80); C16H16O2;
1H NMR d: 3.74 (m, 2H, PhCH2CH), 3.83 (s, 3H, OCH3), 4.42 (s, 2H,
PhCH2O–), 4.58–4.67 (m, 1H, PhCH2CH), 7.23–7.58 (m, 8H, Ph); IR:
3010–2930 (C–Har), 2850 (C–Hal), 1504–1453 (C55Car), 1251 (Car–O–
C), 1178 (C–O–C).
(+)-3-(40-Chlorophenyl) Isochroman (2f)
Prepared from (+)-1-(40-chloro-phenyl)-2-phenylethanol (3f); viscous liquid;
yield 86%; Rf ¼ 0,60 (AcOEt/C6H12 ¼ 20/80); C15H13OCl; 1H NMR d:
3.22-3.41 (m, 2H, PhCH2CH), 3.68 (s, 2H, PhCH2O–), 4.99
(m, 1H,PhCH2CH), 7.03–7.28 (m, 8H, Ph); IR (CHCl3): 3029–2950 (C–
Har), 2841 (C–Hal), 1491–1447 (C55Car), 1207 (C–O–C), 822 (C–Cl).
Synthesis of 3,4-dihydroisocoumarins 1a–f
General Procedure
A mixture of CrO3 (1.5 g, 15 mmol), water (2.5 mL) and glacial acetic acid
(5 mL) were poured into a solution of isochroman 2a–f (2.8 mmol) in
glacial acetic acid (10 mL) while stirring. The mixture was then stirred for
an additional 2 hr, followed by TLC before 10 mL of water was added. The
product was extracted with chloroform twice, and the combined organic
layers were washed with 10% Na2CO3. Drying over MgSO4, filtration and
concentration produced a residue that was purified by flash chromatography.
(+)-3-Methyl-3,4-dihydroisocoumarin (1a)
Obtained from (+)-3-methyl-isochroman (2a); viscous liquid; yield 82%;
Rf ¼ 0.49 (AcOEt/C6H12 ¼ 10/90); C10H10O2; 1H NMR d: 1.51–1.53
(d, 3H, CH3), 2.93 (m, 2H, PhCH2), 4.64–4.72 (m, 1H, PhCH2CH),

176
N. Choukchou-Braham et al.
7.22–7.56 (m, 4H, Ph); IR: 3160 (C–Har), 2979 (C–Hal), 1718 (C55O),
1452–1604 (C55Car), 1116 (C–O–C).
(+)-3-Propyl-3,4-dihydroisocoumarin (1b)
Obtained from (+)-3-propyl-isochroman (2b); viscous liquid; yield 81%;
1
Rf ¼ 0.25 (AcOEt/C6H12 ¼ 10/90); C16H22O2; H NMR d: 0.96 (m, 3H,
CH3), 1.66 (m, 4H, –CH2–), 2.94 (m, 2H, PhCH2), 4.56 (m, 1H,
PhCH2CH), 7.20–7.58 (m, 3H, H5, H6 and H7), 8.08 (m, 1H, H8); IR: 3127
(C–Har), 1713 (C55O), 1519 (C55Car), 1112 (C–O–C).
(+)-3-Heptyl-3,4-dihydroisocoumarin (1c)
Obtained from (+)-3-heptylisochroman (2c); viscous liquid; yield 66%;
Rf ¼ 0.29 (AcOEt/C6H12 ¼ 10/90); C16H22O2; 1H NMR d: 0.88 (t, 3H,
CH3), 1.28–1.88 (m, 12H, –CH2–), 2.97 (m, 2H, PhCH2), 4.48–4.55
(m, 1H, PhCH2CH), 7.22–7.52 (m, 3H, H5, H6, H7), 8.10 (m, 1H, H8); IR:
3100 (C–Har), 2927–2856 (C–Hal), 1725 (C55O, 1459–1606 (C55Car),
1116 (C–O–C).
(+)-3-Phenyl-3,4-dihydroisocoumarin (1d)
Obtained from (+)-3-phenyl-isochromane (2d); viscous liquid; yield 77%;
Rf ¼ 0.28 (AcOEt/C6H12 ¼ 20/80); C15H12O2; 1H NMR d: 3.28–3.39
(m, 2H, PhCH2CH), 5.03 (m, 1H, PhCH2CH), 7.20–7.38 (m, 9H, 2Ph); IR:
3062 (C–Har), 2925 (C–Hal), 1727 (C55O), 1452 (C55Car), 1112 (C–O–C)
(+)-3-(40-Methoxyphenyl)-3,4-dihydroisocoumarin (1e)
Obtained from (+)-3-(40-methoxyphenyl) isochroman (2e); white solid; mp
1
109; yield 80%; Rf ¼ 0.46 (AcOEt/C6H12 ¼ 20/80); C16H14O3; H NMR
d: 3.88 (s, 3H, OCH3), 3.96 (m, 2H, PhCH2CH), 4.66 (m, 1H, PhCH2CH),
6.84–7.96 (m, 8H, Ph); IR: 3000 (C–Har), 2890 (C–Hal), 1684 (C55O),
1513–1427 (C55Car), 1110(C–O–C).
(+)-3-(40-Chlorophenyl)-3,4-dihydroisocoumarin (1f)
Obtained from (+)-3-(40-chlorophenyl) isochroman (2f); white solid; mp 91,
1
yield 78%; Rf ¼ 0.26 (AcOEt/C6H12 ¼ 20/80); C15H11O2Cl; H NMR d:
3.91 (m, 2H, PhCH2CH), 4.62 (m, 1H, PhCH2CH), 6.89–7.90 (m, 8H, Ph);
IR: 3090 (C–Har), 2896 (C–Hal),1683 (C55O), 1424 (C55Car), 1091
(C–O–C), 808 (C–Cl).

Pictet-Spengler Reaction in Synthesis of Dihydroisocoumarins
ACKNOWLEDGMENTS
177
´ ´
We thank the Comite Mixte d’Evaluation et de Prospective de Cooperation
´
Interuniversitaire Franco-Algerienne (CMEP) for its financial support
(03MDU581).
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