Regioselectivity of Pictet-Spengler cyclization: Synthesis of halotetrahydroisoquinolines

Article abstract of DOI:10.1016/S0040-4039(01)01189-3

The regioselectivity of the Pictet-Spengler cyclization for the synthesis of isoquinolines depends on the aryl substituent at C-2. The ratio of halotetrahydroisoquinoline 4 to isoquinoline 3 increases with increasing electrophilicity of the aromatic ring (H?I

Full text of DOI:10.1016/S0040-4039(01)01189-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6251–6253
Regioselectivity of Pictet–Spengler cyclization: synthesis of
halotetrahydroisoquinolines
Su-Dong Cho,a,* Sang-Yong Song,a Eun-Joo Hur,a Ma Chen,a Woo-Hong Joo,a J. R. Falck,b
Yong-Jin Yoonc and Dong-Soo Shina,*
aDepartment of Chemistry, Changwon National University, Changwon, 641-773, South Korea
bDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
cDepartment of Chemistry, Gyeongsang National University, Chinju 660-701, South Korea
Received 24 May 2001; revised 29 June 2001; accepted 2 July 2001
Abstract—The regioselectivity of the Pictet–Spengler cyclization for the synthesis of isoquinolines depends on the aryl substituent
at C-2. The ratio of halotetrahydroisoquinoline 4 to isoquinoline 3 increases with increasing electrophilicity of the aromatic ring
(HꢀI<Br<Cl). © 2001 Elsevier Science Ltd. All rights reserved.
The Pictet–Spengler condensation of N-protected
phenethylamines with aldehydes is a well known syn-
thetic method for the construction of isoquinolines.
This condensation proceeds most smoothly when the
phenethyl aromatic ring is activated by electron
donating substituents. However, a-phenethylamines
bearing an electron withdrawing aryl substituent like
acyl1a–d or sulfonyl2a–d are still amenable to Pictet–
Spengler cyclization, although yields are variable.
Generally, the least sterically hindered ortho position
is the predominant site of cyclization unless blocked
by a substituent at C-2 (Scheme 1). The latter is often
a halogen that is subsequently removed in order to
obtain a 7,8-disubstitution pattern.
group as the N-substituent for a Pictet–Spengler con-
densation. Also, Kohno et al.3a–b reported the reac-
tion of N-benzenesulfonyl-a-phenethylamines with
ethyl chloro(methylthio)acetate in the presence of
SnCl4 affords isoquinolines. Silveira et al.4 carried out
similar cyclizations using b-halo-a-phenylselenyl
esters. Notably, few examples of asymmetric Pictet–
Spengler condensations have been published. For
instance, Piper et al.5 reported the addition of
dopamine hydrochloride with
D-glucose in aqueous
solution gave a chiral tetrahydroisoquinoline in excel-
lent yield. Similarly, Czarnocki et al.6 observed that
the treatment of N-glyoxyoly-(2R)-bornane-10,2-sul-
tam with dopamine hydrochloride furnished a chiral
isoquinoline.
Orazi et al.2a was one of the first to exploit a sulfonyl
X
MeO
MeO
MeO
MeO
L.A.
Aldehyde
HN
N
N
Ms
(or Acetal)
Ms
MeO
Ms
X
R
MeO
R
1a-d
2a-e
3a-e
4a-t
a
c
1
b
d
I
R = -CH2Br, -H, -CO2-(l)-menthyl,
X
H Cl Br
-CH2C6H5, -Ch2CH2C6H5
Scheme 1.
Keywords: Pictet–Spengler; condensation; cyclization; halotetrahydroisoquinoline.
* Corresponding authors. Tel.: (+82)-55-279-7433; e-mail: dsshin@sarim.changwon.ac.kr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01189-3

6252
S.-D. Cho et al. / Tetrahedron Letters 42 (2001) 6251–6253
During the course of our studies directed at the synthe-
sis of substituted 5-halotetrahydroisoquinolines 4, we
turned our attention to the regioselectivity of 2-
halophenethylamines 1a–d in Pictet–Spengler condensa-
tions with acetals or aldehydes under Lewis acidic
conditions (Scheme 1).
As anticipated, condensation of sulfonamide 1a with
bromoacetaldehyde diethyl acetal (2a) in CH2Cl2 and
cyclization of the adduct using boron trifluoride diethyl
etherate complex or conc. H2SO4 at room temperature
for 1 hour afforded 3a as the sole product in excellent
yield (Table 1). Following literature precedent, intro-
duction of a chloride at C-2 as in 1b, completely altered
the regiochemical selectivity to give 4b in 90% yield
accompanied by a trace of 3a (0.2%). On the other
hand, Pictet–Spengler cyclization of 1c with 2a resulted
in a mixture of 3a and 4c, although the latter cycliza-
tion mode still predominates. In contrast, iodo deriva-
tive 1d was the least regioselective and produced a
virtually equimolar mixture of 3a and 4d. Replacement
of BF3·Et2O with mineral acids (H2SO4, HCl) and
various other Lewis acids did not influence the cycliza-
tion yield.
The starting material, sulfonamide7 1a (X=H), was
easily prepared from the corresponding phenethylamine
by addition of methanesulfonyl chloride. Halogenation
of 1a according to literature procedures gave rise to
2-halosulfonamides 1b–d in good yields (Scheme 2).
Specifically, chlorosulfonamide 1b (X=Cl) was readily
prepared via reaction of 1a with CuCl2/Al2O3/
chlorobenzene8 (91%), bromosulfonamide 1c (X=Br)
using NBS/DMF9 (93%), and iodosulfoamide 1d (X=I)
(88%) utilizing CuCl2/Al2O3/I2.10
MeO
MeO
NBS/DMF
CuCl2/Al2O3
1a
HN
Cl
HN
MeO
Ms
MeO
Ms
Br
CuCl2/Al2O3/I2
1b
1c
MeO
MeO
HN
Ms
I
1d
Scheme 2.
Table 1. The yields and ratio of 3/4 by Pictet–Spengler condensation of 1 and 2

S.-D. Cho et al. / Tetrahedron Letters 42 (2001) 6251–6253
6253
3.24–3.26 (m, 1H), 3.07 (s, 3H), 2.72–2.90 (m, 1H); MS
(m/z) 443.
Inspection of Table 1 reveals a similar reactivity pattern
for dimethylacetal 2b. Total yields for aldehydes 2c–e
are somewhat reduced, but they still reflect the same
regioselectivity pattern. In general, the ratio of iso-
quinoline 3 to halotetrahydroisoquinoline 4 depends on
the identity of the halo-substituent at C-2 on the aro-
matic moiety, regardless of the reaction conditions and
condensation partner. The percentage of halotetra-
hydroisoquinoline 4 increased in the order HꢀI<Br<
Cl, i.e. with increasing electrophilicity.
Acknowledgements
The authors thank the Korea Research Foundation
(KRF), the Institute of Basic Science of Changwon
National University for a postdoctoral fellowship, the
Robert A. Welch Foundation, and NIH (GM31278).
In conclusion, we have described a Pictet–Spengler
cyclization strategy to prepare halotetrahydroiso-
quinolines 4 based upon the C-2 halogen substituent.
Applications of this strategy to the syntheses of biolog-
ically active compounds are under investigation and
will be reported in due course.
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