A variation of the Pictet-Spengler reaction via a sequential reduction-cyclization reaction of N-acylcarbamates: synthesis of 1-substituted tetrahydroisoquinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.09.073

A new variation of the Pictet-Spengler reaction for the synthesis of 1-substituted tetrahydroisoquinoline derivatives has been developed. The reaction employs the reduction of N-acylcarbamates by DIBAL-H followed by simultaneous cyclization mediated by BF₃·OEt₂. The synthetic potential of this method has been illustrated by the synthesis of the tetrahydroisoquinoline alkaloids, (±)-xylopinine, (±)-laudanosine, (±)-8-oxo-O-methylbharatamine, and (±)-isoindoloisoquinolone.

Full text of DOI:10.1016/j.tetlet.2007.09.073

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Tetrahedron Letters 48 (2007) 8182–8184
A variation of the Pictet–Spengler reaction via a sequential
reduction–cyclization reaction of N-acylcarbamates: synthesis
of 1-substituted tetrahydroisoquinoline derivatives
Chutima Kuhakarn,b,* Nattakan Panyachariwatb and Somsak Ruchirawata,*
aChulabhorn Research Institute, Vipavadee Rangsit Highway, Bangkok 10210, Thailand
bDepartment of Chemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
Received 18 July 2007; revised 6 September 2007; accepted 13 September 2007
Available online 18 September 2007
Abstract—A new variation of the Pictet–Spengler reaction for the synthesis of 1-substituted tetrahydroisoquinoline derivatives has
been developed. The reaction employs the reduction of N-acylcarbamates by DIBAL-H followed by simultaneous cyclization
mediated by BF3ÆOEt2. The synthetic potential of this method has been illustrated by the synthesis of the tetrahydroisoquinoline
alkaloids, ( )-xylopinine, ( )-laudanosine, ( )-8-oxo-O-methylbharatamine, and ( )-isoindoloisoquinolone.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Isoquinoline alkaloids are a large family of natural
products and display a broad variety of biological activ-
ities.1a Among the members of this class of compounds,
tetrahydroisoquinoline derivatives constitute a major
group. Many of them exhibit important biological activ-
ities, for example, anti-inflammatory, anti-microbial,
anti-leukemic, and anti-tumor properties.1b,c Accord-
ingly, these have encouraged the development of a
number of synthetic methodologies for the construction
of the tetrahydroisoquinoline core and have been a
subject of several reviews.2 The Pictet–Spengler reaction
is one of the most effective methods and serves as a
convenient method for the construction of racemic as
well as asymmetric tetrahydroisoquinoline derivatives
and related heterocyclic systems.2b,3 The reaction
involves the cyclization of imines or iminium ions
derived from the condensation of b-arylethylamine
derivatives with aldehydes or their synthetic equivalents.
The reaction was traditionally carried out in a protic
solvent with an acid catalyst.4,5 However, the intrinsically
poor electrophilicity of the protonated imine means that
a variation involving the condensation of N-acyl or N-
sulfonyl b-arylethylamine with aldehydes is often
required.6 The transformation proceeds by intramole-
cular electrophilic aromatic substitution by the activated
iminium-type intermediate, formed from the aldehyde
with an activated nitrogen moiety under Lewis acid
promotion.
Recently, N,O-acetal TMS ethers have been demon-
strated to be precursors for the in situ generation of
N-acyliminium ions.7a,b N,O-Acetal TMS ethers can be
easily prepared from N-acylcarbamates by sequential
partial reduction of the amide carbonyl using DIBAL-
H followed by TMSOTf trapping of the resulting
hemiaminal. In the presence of a suitable Lewis acid,
the N,O-acetal TMS ethers formed N-acyliminium inter-
mediates, which could be trapped with nucleophiles.
Synthetic applications of this methodology have also
been demonstrated.7c,d
Our research group has long been interested in the
development of efficient syntheses of tetrahydroisoquin-
oline-containing alkaloids.8 We herein report an alterna-
tive strategy leading to the synthesis of ( )-xylopinine
(1), ( )-laudanosine (2), ( )-8-oxo-O-methylbharata-
mine (3), and ( )-isoindoloisoquinolone (4) by means
of a sequential reduction followed by Lewis acid
promoted cyclization, in a new modification of the
Pictet–Spengler type cyclization process (Scheme 1).
To begin the study, N-acylcarbamates 7 were conve-
niently prepared in two high-yielding steps from 2-
(3,4-dimethoxyphenyl)ethylamine (5) as shown in
Scheme 2. The starting 2-(3,4-dimethoxyphenyl)ethyl-
amine (5) was treated with various acid chlorides under
*
Corresponding authors. Tel.: +66 2 201 5155; fax: +66 2 354 7151
(C.K.); e-mail addresses: scckk@mahidol.ac.th; somsak@cri.or.th
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.073

C. Kuhakarn et al. / Tetrahedron Letters 48 (2007) 8182–8184
8183
MeO
N
OEt
MeO
MeO
MeO
MeO
MeO
O
O
R
N
N
Me
OMe
OMe
OMe
OMe
1; Xylopinine
2; Laudanosine
MeO
MeO
N
OEt
R
O
MeO
MeO
MeO
MeO
N
O
N
O
3; 8-Oxo-O-methylbharatamine
4; Isoindoloisoquinolone
Scheme 1. Synthetic plan.
MeO
b
MeO
MeO
MeO
generally higher than those previously recorded for acid
catalyzed Pictet–Spengler condensation of N-acyl or N-
sulfonyl b-arylethylamines with aldehydes.6c,d Attempts
to prepare tetrahydroisoquinoline derivatives from
precursors with no activating benzene ring substituents
under similar conditions met with failure,10 the oxyge-
nated aromatic ring is essential for successful cycliza-
tion. In contrast to Suh’s observations, attempts to
trap the hemiaminal formed by the TMSOTf–pyridine
system failed to provide the N,O-acetal TMS ether,
and only fragmentation products were isolated, that is,
the corresponding aldehyde and 2-(3,4-dimethoxy-
phenyl)ethylcarbamic acid ethyl ester. Furthermore, in
a pairwise comparison, treatment of 2-(3,4-dimethoxy-
phenyl)ethylcarbamic acid ethyl ester with phenylacet-
aldehyde under acid catalyzed Pictet–Spengler conditions
(HCO2H, 110 ꢁC, 7 h) gave 8c in low yield (20%).
a
N
OEt
NH2
NH
MeO
MeO
O
O
O
R
R
5
6
7a; R = CH3
b; R = Ph
c; R = CH2Ph
d; R = CH2-3,4-(MeO)2C6H3
e; R = CH2-2-BrC6H4
f; R = 2-BrC6H4
Scheme 2. Synthesis of N-acylcarbamate precursors 7. Reagents and
conditions: (a) RCOCl, Na2CO3, 1:1 v/v CH2Cl2/H2O; (b) n-BuLi,
THF, À78 ꢁC then ethyl chloroformate.
biphasic conditions (80–96% yields), and the resulting
amides were lithiated with n-BuLi followed by trapping
with ethyl chloroformate to yield N-acylcarbamates 7a–f
with yields ranging from 72% to 98%.
As shown in Table 1, upon treatment of N-acylcarba-
mates 7 with 1.5 equiv of DIBAL-H in hexane followed
by sequential addition of BF3ÆOEt2, smooth production
of the 1-substituted tetrahydroisoquinoline derivatives 8
was observed.9 Yields were good to excellent and were
Having constructed the tetrahydroisoquinoline core,
further elaborations of 8d to ( )-xylopinine (1) and
( )-laudanosine (2); 8e to ( )-8-oxo-O-methylbharata-
mine (3) and 8f to ( )-isoindoloisoquinolone (4) were
straightforward following the previously reported
Table 1. Sequential partial reduction-Lewis acid mediated cyclization of N-acylcarbamates 7
MeO
MeO
MeO
MeO
1) DIBAL-H, CH2Cl2, -78 oC, 1h
2) BF3 OEt2, -78 oC, 1 h
N
OEt
N
OEt
O
O
R
O
R
8a; R = CH3
b; R = Ph
c; R = CH2Ph
d; R = CH2-3,4-(MeO)2C6H3
e; R = CH2-2-BrC6H4
f; R = 2-BrC6H4
7
Entry
7; R =
Product (% yield)
1
2
3
4
5
6
CH3
Ph
CH2Ph
CH2–3,4(MeO)2C6H3
CH2–2-BrC6H4
2-BrC6H4
8a; 76
8b; 80
8c; 98
8d; 83
8e; 83
8f; 71

8184
C. Kuhakarn et al. / Tetrahedron Letters 48 (2007) 8182–8184
5154–5158; (c) Hegedus, A.; Hell, Z. Tetrahedron Lett.
¨
procedures. Treatment of 8d with triflic anhydride/
DMAP efficiently gave ( )-8-oxoxylopinine, which under-
went reduction by LiAlH4 to provide ( )-xylopinine (1)
(75%, 2 steps).11 Reduction of 8d by LiAlH4 afforded
( )-laudanosine (2) in 91% yield.6d The alkaloids ( )-
8-oxo-O-methylbharatamine (3) and ( )-isoindolo-
isoquinolone (4) were obtained in 95% and 78% yields,
respectively, by lithium–bromine exchange of 8e and 8f
using t-BuLi, followed by cyclization.6d
2004, 45, 8553–8555.
5. For recent catalytic asymmetric Pictet–Spengler reactions:
(a) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc.
2006, 128, 1086–1087; (b) Taylor, M. S.; Jacobsen, E. N. J.
Am. Chem. Soc. 2004, 126, 10558–10559.
6. (a) Orazi, O. O.; Corral, R. A.; Giaccio, H. J. Chem. Soc.,
Perkin Trans. 1 1986, 1977–1982; (b) Silveira, C. C.;
Bernardi, C. R.; Braga, A. L.; Kaufman, T. S. Tetrahedron
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P.; Mollov, N. M. Synthesis 1987, 204–206; (d) Comins,
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Selective Organic Transformations; Thyagarajan, B. S.,
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7. (a) Suh, Y.-G.; Shin, D.-Y.; Jung, J.-K.; Kim, S.-H. Chem.
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Tetrahedron Lett. 2005, 46, 573–575.
In conclusion, we have developed a new variation of the
Pictet–Spengler tetrahydroquinoline synthesis in which
the N-acyliminium intermediates were formed by partial
reduction of N-acylcarbamates by DIBAL-H followed
by sequential addition of BF3ÆOEt2. This procedure
appears to be useful, in terms of synthetic efficiency,
short reaction time, and mild conditions (À78 ꢁC).
Therefore, the N-acylcarbamates serve as convenient
precursors for construction of 1-substituted tetrahydro-
isoquinolines, which can be further elaborated to the
synthesis of tetrahydroisoquinoline-containing natural
products. Application of this strategy to the diastereo-
selective synthesis is forthcoming.
8. (a) Ruchirawat, S.; Chaisupakitsin, M.; Patranuwatana,
N.; Cashaw, J. L.; Davis, V. E. Synth. Commun. 1984, 14,
1221–1228; (b) Ruchirawat, S.; Tontoolarug, S.; Saha-
kitpichan, P. Heterocycles 2001, 55, 635–640; (c) Ruch-
irawat, S.; Bhavakul, V.; Chaisupakitsin, M. Synth.
Commun. 2003, 33, 621–625.
Acknowledgments
9. General procedure: To a solution of N-acylcarbamate
(1.0 equiv) in dry CH2Cl2 (ca. 0.1 M) at À78 ꢁC under an
argon atmosphere, was added dropwise DIBAL-H (1.0 M
solution in hexane, 1.5 equiv). After 1 h, the mixture was
treated with BF3ÆOEt2 (1.5 equiv) and was stirred at
À78 ꢁC for 1 h before being quenched with 15% aqueous
sodium potassium tartrate (5 mL), and diluted with
dichloromethane (5 mL). The mixture was warmed to
room temperature and extracted with dichloromethane
(2 · 20 mL). The combined organic layers were washed
with water (20 mL), brine (20 mL), dried (Na2SO4),
filtered, and concentrated (aspirator then vacuo). The
crude product was purified by column chromatography
(SiO2, ethyl acetate/hexanes as eluent) or crystallization.
10. Under similar conditions (DIBAL-H, À78 ꢁC, 1 h then
BF3ÆOEt2, À78 ꢁC, 1 h), the reaction of compound 9
yielded phenylacetaldehyde (60%) and phenethylcarba-
mic acid ethyl ester (10) (69%), implying that the reduc-
tion took place smoothly but that the cyclization was
difficult.
We acknowledge financial support from the Thailand
Research Fund (TRF) and the Center for Innovation
in Chemistry: Postgraduate Education and Research
Program in Chemistry (PERCH-CIC). We are also
grateful for the facilities provided by the Department
of Chemistry, Mahidol University.
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BnCHO
+
N
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O
Bn
9
10
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