Metal triflates: Efficient catalysts for oxa-pictet-spengler reaction

Article abstract of DOI:10.2174/157017810791824883

A screening of different metal triflates as catalysts was performed to get isochromans through an oxa-Pictet-Spengler reaction. Good to high yields were obtained for various aliphatic or aromatic aldehydes and β-arylethanols. A mechanism involving catalys

Full text of DOI:10.2174/157017810791824883

420
Letters in Organic Chemistry, 2010, 7, 420-423
Metal Triflates: Efficient Catalysts for Oxa-Pictet-Spengler Reaction
Benaissa Bouguerne1,2, Christian Lherbet*,1,2 and Michel Baltas1,2
1CNRS; Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique, LSPCMIB, UMR-5068; 118
Route de Narbonne, F-31062 Toulouse Cedex 9, France
2Université de Toulouse, UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique,
LSPCMIB, 118 route de Narbonne, F-31062 Toulouse Cedex 9, France
Received October 12, 2009: Revised April 09, 2009: Accepted April 15, 2009
Abstract: A screening of different metal triflates as catalysts was performed to get isochromans through an oxa-Pictet-
Spengler reaction. Good to high yields were obtained for various aliphatic or aromatic aldehydes and ꢀ-arylethanols. A
mechanism involving catalysis by in situ liberated triflic acid to catalyse the isochroman ring formation is proposed.
Keywords: Metal triflate, oxa-Pictet-Spengler, catalysis.
Table 1. Synthesis of Isochroman Under Different Reaction
Conditions
The oxygenated version of the Pictet-Spengler reaction,
called Oxa-Pictet-Spengler, consists of a condensation of ꢀ-
aryl ethanol with a carbonyl derivative to give the
isochroman ring [1]. This reaction was reported for the first
time by Wunsch et al. in 1992 [2]. Since then, different
methods have been reported to prepare isochromans [3-5].
The isochroman template is present in structures of different
drugs [1,6-8] or in natural products [1].
MeO
MeO
catalyst
OH
CHO
O
MeO
0.01 eq
MeO
Toluene, 80°C
O2N
In the previous work, we described the synthesis of
iso(thio)chromans from 2-phenylethanol derivatives or 2-
phenylethanethiol and different aldehydes in the presence of
catalytic amounts of bismuth(III) triflate [9]. The catalytic
activity of Bi(OTf)3 could be attributed to traces of triflic
acid generated in situ [10]. The numerous advantages of
metal catalysts make them highly attractive for chemical
synthesis from environmental and economic points of view.
In this study, we disclose the usefulness of metal triflate to
provide isochroman from ꢀ-aryl ethanol. This work provides
also insights into the catalytic role of metal triflates in the
reaction. We have also examined the scope of the reaction in
the presence of different reactants.
NO2
Entry
Catalyst
Time (h)
Yieldsa (%)
1
2
3
4
5
6
7
8
---
18
1
16
>99
>99
>99
91
Bi(OTf)3 0.01 eq
In(OTf)3 0.01 eq
Sc(OTf)3 0.01 eq
Zn(OTf)2 0.01 eq
Yb(OTf)3 0.01 eq
Y(OTf)3 0.01 eq
Cu(OTf)2 0.01 eq
1
1
1
1
>99
>99
94
Initially, the condensation of 3,4-dimethoxyphenyl
ethanol (1 eq) and 4-nitrobenzaldehyde (1 eq) was used as a
model reaction for the screening of seven different metal
triflate catalysts.
1
1
aYields for the isolated isochroman.
The reaction was carried out in toluene at 80°C in the
presence of a catalytic amount (0.01 eq) of metal triflate. The
reaction was monitored by TLC analysis following the
disappearance of the starting alcohol. The reaction was
completed in maximum 1.5h and isochroman was obtained
in almost quantitative yield (entries 2-8, Table 1) after work-
up and silica gel purification. The same reaction was realized
in the absence of metal to recover essentially the starting
material and the isochroman product in 16% yield after 18
hours (entry 1, Table 1).
In order to get insights into the mechanism of the
reaction, we explored different reaction conditions. We
investigated first the catalytic role of each metal triflate.
Dumeunier et al. have demonstrated in a related reaction
acylation of alcohols in the presence of metal triflates that
the true catalyst was the liberated triflic acid instead of the
metal triflate [11]. In that respect, we conducted our reaction
in the presence of 10% mol triflic acid in toluene at 80°C.
After 1h, the reaction was completed affording the
isochroman derivative in quantitative yield (entry 1, Table 2).
Thus the strong proton donating abilities of triflic acid
(Brønsted acid properties) catalyzed the reaction very
efficiently.
*Address correspondence to this author at the LSPCMIB – UMR/CNRS
5068 - Université Paul Sabatier, 31062 Toulouse cedex 9, France; Tel:
33.5.61.55.68.07; Fax: 33.5.61.55.60.11; E-mail: lherbet@chimie.ups-tlse.fr
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Metal Triflate – Catalyzed Oxa-Pictet Spengler Reaction
Letters in Organic Chemistry, 2010, Vol. 7, No. 6
421
In order to investigate the role of traces of water in the
mechanism of chroman formation, we conducted each
reaction of metal triflate with the two same reagents in
toluene and in the presence of molecular sieves (4ꢀ) [12].
Under these conditions, only traces of isochroman were
observed in the reaction mixture along with starting
compounds (entry 3, Table 2). This points out the
importance of water molecules for the reaction to occur.
Next, in order to neutralize the traces of triflic acid,
2,4,6-tri-tert-butyl pyridine (TTBP), a very hindered base,
was added to the reaction media. This base is known to not
interact with metal catalysts [13]. Under these conditions, no
product was observed in the presence of various metal
triflates (Table 2, entry 4).
These experiments taking together showed that metal
triflates do not act as Lewis acids but as a source of triflic
acid. Unlike triflic acid (corrosive and toxic), less toxic
metal triflates are eco-friendly and easy-handled reagents.
Table 2. Insights on the Catalytic Role of Metal Triflate
MeO
MeO
In order to verify more precisely the role of residual
water, we decided to add triflic acid to a solution of copper
triflate and molecular sieves. The reaction resulted in a
modest 48% yield. These findings proved that water impacts
on the mechanism by two ways: 1) by hydrolyzing the metal
triflate catalyst; 2) by acting as a base to remove the acidic
hydrogen in the aromatic cycle. A possible mechanism is
depicted in Scheme 1.
catalyst
OH
CHO
O
MeO
MeO
0.01 eq
Toluene, 80°C
O2N
NO2
Traces of water molecules may provide the initial source
of triflic acid. Then ꢁ-arylethanol condensates with the
aldehyde activated by triflic acid to form a hemiacetal
intermediate, which undergoes cyclization affording the
isochroman ring.
Entry
Catalyst
Time (h)
Yieldsa (%)
1
2
3
TfOH 0.1 eq
M(OTf)n 0.01 eq
M(OTf)n 0.01 eq
4 ꢀ MSb
1
1
1
>99
>99
traces
We next examined the generality of this methodology for
the synthesis of isochromans from 3,4-dimethoxy-
phenylethanol using different catalysts and carbonyl
derivatives (Table 3). Both aromatic (entries 1-4, Table 3),
aliphatic aldehydes (entries 5-6) or ethyl ꢁ-ketobutyrate
(entries 7-8) were applicable to this reaction. Furthermore we
found that the reaction is slower with copper (II) triflate
(entries 3, 5 and 9, Table 3). It should be noted that the
4
5
M(OTf)n 0.01 eq
0.1 eq TTBP
1
1
0
Cu(OTf)2 0.01 eq , 4 ꢀ MSb
48
TfOH 0.05 eq
aYields for the isolated isochroman.
bMolecular sieves (MS) were activated at 150°C under high vacuum.
M(OTf)3
MeO
H2O
O
MeO
R
CHO
R
Metal salt
TfOH
MeO
TfO
H
O
H
O
MeO
H
R
R
MeO
MeO
MeO
MeO
TfO
H2O
O
H
O
OH
R
H
Scheme 1. Mechanism for the oxa-Pictet-Spengler reaction.

422 Letters in Organic Chemistry, 2010, Vol. 7, No. 6
Bouguerne et al.
Table 3. Scope of the Reaction Catalyzed by Metal Triflate
metal triflate
0.01 eq
O
OH
RC(O)R1
Toluene, 80°C
R
R1
Yieldsa (%)
Substrate
Entry
RC(O)R1
Metal Triflate
Time (h)
1
2
4-NO2-Ph-CHO
4-NO2-Ph-CHO
4-CH3O-Ph-CHO
4-CH3O-Ph-CHO
CH3(CH2)4-CHO
CH3(CH2)4-CHO
CH3COCH2COOEt
CH3COCH2COOEt
4-NO2-Ph-CHO
4-NO2-Ph-CHO
4-NO2-Ph-CHO
Cu(OTf)2
Bi(OTf)3
Cu(OTf)2
Bi(OTf)3
Cu(OTf)2
Bi(OTf)3
Cu(OTf)2
Bi(OTf)3
Cu(OTf)2
Bi(OTf)3
Sc(OTf)3
1.5
1
>99
>99
3
3
86
H3CO
4
1.5
3
91
OH
5
6
90
H3CO
1
>99
7
2
67
8
2
91
9
3
40 (N/I)b
56 (N/I)b
48 (17)b
OH
10
11
2
2
N
H
12
13
14
4-CH3O-Ph-CHO
4-CH3O-Ph-CHO
CH3COCH2COOEt
Sc(OTf)3
Bi(OTf)3
Sc(OTf)3
1.5
1
66
98
85
OH
2
S
aYields for isolated compounds.
bSecond product observed (N/I: not isolated).
reaction with benzaldehyde bearing electron-rich substituent
such as p-methoxybenzaldehyde (entries 3-4) proceeds
slower than for benzaldehyde bearing electron-poor
substituent such as p-nitrobenzaldehyde (entries 1-2).
In conclusion, an efficient, simple, and eco-friendly
method has been described for the synthesis of isochromans
by employing condensation reaction of different ꢀ-aryl
ethanol, aldehydes, and ꢀ-diketones in toluene using metal
triflates as a mild Brønsted acid precursor. The use of these
easy-handled catalysts by comparison with triflic acid should
find utility in the synthesis of natural products.
In the case of tryptophol (entries 9-11), the yields for the
isochroman ring formation are around 50%. That could be
explained by the presence of a second product. After
different investigations by 1H and 13C NMR and mass
spectrometry, we elucidated the structure as a 2,2’-
bis(indoyl)-4-nitrophenylmethane derivative (See note b in
Table 3). Bis(indoyl)alkane derivatives are easily accessible
in the presence of Lewis acid or Brønsted acid [14].
EXPERIMENTAL
All chemicals were obtained from Aldrich or Acros
Organics and used without further purification. Nuclear
magnetic resonance spectra were recorded on a Bruker AC
300 spectrometer (1H and 13C NMR), and mass spectra were
measured on a Nermag R10-10C mass spectrometer.
OH
HN
Typical Procedure
HN
To a solution of alcohol (1 eq, 0.37 mmol) and aldehyde
(1 eq, 0.37 mmol) in toluene (3 mL), was added M(OTf)n
(0.01 eq) at room temperature. The reaction mixture was
warmed up to 80°C and stirred until completion followed by
TLC. The mixture was cooled and concentrated under
reduced pressure. Then ethyl acetate (20 mL) was added and
the organic layer washed with water (2 x 20 mL), dried over
MgSO4 and concentrated under reduced pressure to give the
isochroman derivative. In some cases, the products had to be
purified by flash chromatography. Some compounds
reported in Table 3 could be compared with those of the
previously reported spectroscopic data (entries 1 [15], 3 [3]).
O2N
OH
Furthermore, the reactions with 2-(3-thienyl)ethanol with
4-methoxybenzaldehyde or ethyl acetoacetate afforded the
corresponding isochromans in good yields depending on the
catalyst. In fact Sc(OTf)3 was found to be less efficient by
comparison with Bi(OTf)3 with 4-methoxybenzaldehyde
(entries 12-13).

Metal Triflate – Catalyzed Oxa-Pictet Spengler Reaction
Letters in Organic Chemistry, 2010, Vol. 7, No. 6
423
The spectral data of isochromans reported in Table 3 are
summarized below.
1H); 13C NMR (CDCl3) ꢀ 14.1; 26.1; 28.7; 47.2; 74.7; 122.7;
126.7; 132.9; 140.4, 169.7; LRMS: (DCI/NH3, m/z) calc. for
C12H16O3S: 240.1. Found: 241.1 (M+H+).
3,4-dihydro-6,7-dimethoxy-1-pentyl-1H-isochromene
(Entry 5)
Colorless oil. 1H NMR (CDCl3) ꢀ0.89 (m, 3H); 1.39 (m,
6H); 1.76 (m, 2H); 2.58 (m, 1H); 2.89 (m, 1H); 3.72 (m,
1H); 3.84 (s, 3H); 3.85 (s, 3H); 4.66 (dd, J = 8.1 Hz, J = 2.9
Hz, 1H); 6.54 (s, 1H); 6.58 (s, 1H); 13C NMR (CDCl3) ꢀ
14.0; 22.6; 24.9; 28.6; 31.9; 36.0; 55.8; 55.9; 63.1; 75.5;
107.9; 111.4; 125.9; 130.4; 147.3 (2C); LRMS : (DCI/NH3,
ACKNOWLEDGEMENT
The authors are grateful to the “Ministère de
l’Enseignement et de la Recherche Scientifique” for financial
support (BB).
+
m/z) calc. for C16H24O3: 264.2. Found: 282.1 (M+NH4 ).
REFERENCES
[1]
[2]
[3]
[4]
For a review: Larghi, E.L.; Kaufman, T.S. The oxa-Pictet-Spengler
cyclization: synthesis of isochromans and related pyran-type
heterocycles. Synthesis 2006, 187.
Wünsch, B.; Zott, M. Chiral 2-benzopyran-3-carboxylates by oxa-
Pictet-Spengler reaction of (S)-3-phenyllactic acid derivatives.
Liebigs Ann. Chem. 1992, 39.
Hegedüs, A.; Hell, Z. Zeolite-catalyzed simple synthesis of
isochromans via the oxa-Pictet-Spengler reaction. Org. Biomol.
Chem. 2006, 4, 1220.
Ethyl 2-(3,4-dihydro-6,7-dimethoxy-1-methyl-1H-isochro-
men-1-yl)acetate (Entry 7)
1
Colorless liquid. H NMR (CDCl3) ꢀ1.18 (t, J = 7.1 Hz,
3H); 1.61 (s, 3H); 2.72 (m, 1H+2H); 2.88 (d, J = 13.7 Hz,
1H); 3.83 (s, 3H); 3.84 (s, 3H); 3.94 (m, 2H); 4.08 (m, 1H);
6.55 (d, J = 6.3 Hz, 2H); 13C NMR (CDCl3) ꢀ 14.1; 27.7;
28.6; 46.5; 55.7; 56.0; 59.8; 60.1; 74.9; 108.3; 111.2; 125.4;
132.8; 147.4; 147.5; 170.1; LRMS: (DCI/NH3, m/z) calc. for
C16H22O5: 294.2. Found: 295.1 (M+H+).
Saito, A.; Takayama, M.; Yamazaki, A.; Numaguchi, J.; Hanzawa,
Y. Synthesis of tetrahydroisoquinolines and isochromans via Pictet-
Spengler reactions catalyzed by Brønsted acid-surfactant-combined
catalyst in aqueous media. Tetrahedron 2007, 63, 4039.
Saeed, A.; Mumtaz, A. Microwave-accelerated Synthesis of Some
(±)-1-Aryl-5-chloroisochromans. Chin. J. Chem. 2008, 26, 1647.
Lakshminarayana, N.; Rajendra Prasad, Y.; Gharat, L.; Thomas,
A.; Ravikumar, P.; Narayanan, S.; Srinivasan, C.V.; Gopalan, B.
Synthesis and evaluation of some novel isochroman carboxylic acid
derivatives as potential anti-diabetic agents. Eur. J. Med. Chem.
2009, 44, 3147.
Shishido, Y.; Wakabayashi, H.; Koike, H.; Ueno, N.; Nukui, S.;
Yamagishi, T.; Murata, Y.; Naganeo, F.; Mizutani, M.; Shimada,
K.; Fujiwara, Y.; Sakakibara, A.; Suga, O.; Kusano, R.; Ueda, S.;
Kanai, Y.; Tsuchiya, M.; Satake, K. Discovery and stereoselective
synthesis of the novel isochroman neurokinin-1 receptor antagonist
'CJ-17,493'. Bioorg. Med. Chem. 2008, 16, 7193.
Zhang, L.; Zhu, X.; Zhao, B.; Zhao, J.; Zhang, Y.; Zhang, S.; Miao,
J. A novel isochroman derivative inhibited apoptosis in vascular
endothelial cells through depressing the levels of integrin beta4,
p53 and ROS. Vascul. Pharmacol. 2008, 48, 63.
Lherbet, C.; Soupaya, D.; Baudoin-Dehoux, C.; André, C.; Blonski,
C.; Hoffmann, P. Bismuth triflate-catalyzed oxa- and thia-Pictet-
Spengler reactions: access to iso- and isothio-chroman compounds.
Tetrahedron Lett. 2008, 49, 5449.
Bouguerne, B.; Hoffmann, P.; Lherbet, C. Bismuth triflate as a safe
and readily handled source of triflic acid: Application to the oxa-
Pictet-Spengler reaction. Synth. Commun. 2010, 40, 915.
Dumeunier, R.; Markó I.E. On the role of triflic acid in the metal
triflate-catalysed acylation of alcohols. Tetrahedron Lett. 2004, 45,
825.
The same reaction catalyzed by Bi(OTf)3 was performed with an
other dehydrating reagent such as MgSO4 (2 eq) in the light of the
basicity of 4 ꢁ MS (See: Hasegawa, M.; Ono, F.; Kanemasa, S.
Molecular sieves 4ꢁ work to mediate the catalytic metal
enolization of nucleophile precursors: application to catalyzed
enantioselective Michael addition reactions. Tetrahedron Lett.
2008, 49, 5220). The isochroman was obtained in 22% yield
showing that H2O has a direct impact on the reaction.
Fillon, E.; Fishlock, D. Scandium triflate-catalyzed intramolecular
Friedel–Crafts acylation with Meldrum's acids: insight into the
mechanism. Tetrahedron 2009, 65, 6682.
Pore, D.M.; Desai, U.V.; Thopate, T.S.; Wadgaonkar, P.P. A mild,
expedient, solventless synthesis of bis(indoyl)alkanes using silica
sulfuric acid as a reusable catalyst. ARKIVOC 2006, 12, 75 and
references therein.
1,3,4,9-tetrahydro-1-(4-nitrophenyl)pyrano[3,4-b]indole
(Entry 11)
[5]
[6]
Yellow solid. 1H NMR (CDCl3) ꢀ 2.87 (m, 1H); 3.12 (m,
1H); 4.02 (m, 1H); 4.31 (m, 1H); 5.91 (s, 1H); 7.18 (m, 2H);
7.27 (d, J = 7.1 Hz, 1H); 7.49 (br s, 1H); 7.57 (d, J = 8.7 Hz,
2H+1H); 8.22 (d, J = 8.7 Hz, 2H); 13C NMR (CDCl3) ꢀ 22.1;
64.9; 75.0; 109.3; 111.1; 118.5; 120.0; 122.5; 124.0; 126.8;
129.1; 131.9; 136.2; 146.7; 148.1; LRMS: (DCI/NH3, m/z)
calc. for C17H14N2O3: 294.1. Found: 295.1 (M+H).
[7]
2,2’-Bis(indoyl)-4-nitrophenylmethane (Entry 11, side
product)
[8]
[9]
1
Yellow foam. H NMR (CDCl3) ꢀ2.16 (broad s, 2H);
2.85 (m, 4H); 3.86 (m, 4H); 6.35 (s, 1H); 7.15 (m, 4H); 7.25
(d, J = 7.3 Hz, 2H); 7.32 (d, J = 8.6 Hz, 2H); 7.54 (d, J = 7.2
Hz, 2H); 8.10 (d, J = 8.7 Hz, 2H); 8.71 (broad s, 2H); 13C
NMR (CDCl3) :ꢀ27.3; 40.7; 62.3;110.1; 111.2; 118.6; 119.8;
122.3; 123.9; 128.1; 129.2;134.5; 136.0; 147.0; 148.1;
LRMS: (DCI/NH3, m/z) calc. for C27H25N3O: 455.2. Found:
456.2 (M+H).
[10]
[11]
[12]
5,7-dihydro-7-(4-methoxyphenyl)-4H-thieno[2,3-c]pyran
(Entry 12)
1
Brown crystal upon standing. H NMR (CDCl3) ꢀ 2.71
(m, 1H); 2.98 (m, 1H); 3.82 (s, 3H); 3.92 (m, 1H); 4.24 (m,
1H); 5.76 (s, 1H); 6.86 (d, J = 5.1 Hz, 1H); 6.89 (d, J = 8.8
Hz, 2H); 7.17 (dd, J = 5.0 Hz, J = 0.8 Hz, 1H); 7.32 (d, J =
8.7 Hz, 2H); 13C NMR (CDCl3) ꢀ 26.2; 55.2; 64.2; 77.3;
113.8; 123.7; 126.8; 129.2; 133.8; 137.2; 159.7; LRMS:
(DCI/NH3, m/z) calc. for C14H12O2S: 246.1. Found: 247.0
(M+H+).
[13]
[14]
Ethyl 2-(5,7-dihydro-7-methyl-4H-thieno[2,3-c]pyran-7-
yl)acetate (Entry 14)
1
Colorless oil. H NMR (CDCl3) ꢀ 1.22 (t, J = 7.1 Hz,
[15]
Chimirri, A.; De Sarro, G.; De Sarro, A.; Gitto, R.; Grasso, S.;
Quartarone, S.; Zappalà, M.; Giusti, P.; Libri, V.; Constanti, A.;
Chapman, A.G. 1-Aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones:
novel AMPA receptor antagonists. J. Med. Chem. 1997, 40 , 1258.
3H); 1.67 (s, 3H); 2.69 (t, J = 5.5 Hz, 2H); 2.75 (d, J = 13.9
Hz, 1H); 2.90 (d, J = 13.9 Hz, 1H); 3.98 (m, 2H); 4.13 (q, J =
7.2 Hz, 2H); 6.75 (d, J = 5.1 Hz, 1H); 7.14 (d, J = 5.0 Hz,