Stereoselectivity of superacid-catalyzed Pictet-Spengler cyclization reactions

Article abstract of DOI:10.1021/ol034526a

(Matrix presented) High stereoselectivities were found in a wide range of superacid-catalyzed Pictet-Spengler cyclization reactions. Particularly in the cases of 2-alkyl-N-benzylidene-2-phenethylamines, an enhanced stereoselectivity was observed under the

Full text of DOI:10.1021/ol034526a

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2087-2090
Stereoselectivity of Superacid-Catalyzed
Pictet−Spengler Cyclization Reactions
Satoshi Nakamura,† Masaru Tanaka,‡ Tooru Taniguchi,‡
,†
Masanobu Uchiyama,† and Tomohiko Ohwada*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and Faculty of Pharmaceutical Sciences,
Nagoya City UniVersity, Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan
ohwada@mol.f.u-tokyo.ac.jp
Received March 26, 2003 (Revised Manuscript Received May 1, 2003)
ABSTRACT
High stereoselectivities were found in a wide range of superacid-catalyzed Pictet−Spengler cyclization reactions. Particularly in the cases of
2-alkyl-N-benzylidene-2-phenethylamines, an enhanced stereoselectivity was observed under the superacid conditions as compared with the
corresponding weak acid (TFA)-catalyzed (monocationic) cyclization reaction of the N-benzylidene-2-(3′,4′-dimethoxy)phenethylamines that
bear electron-donating groups on the cyclizing aromatic ring. The computational study also supported the energetic favorability of the cyclization
of the N,N-diprotonated imine and revealed a significantly early transition-state structure.
The Pictet-Spengler reaction is an acid-catalyzed intramo-
lecular cyclization of the intermediate imine of 2-arylethy-
lamine, formed by condensation with a carbonyl compound,
to give 1,2,3,4-tetrahydroisoquinoline derivatives.1-3 The
Pictet-Spengler reaction, like the Bischler-Napieralski
reaction, is one of the key reactions for construction of the
isoquinoline skeleton, which constitutes an important motif
of naturally occurring bioactive compounds.4,5 Although the
Pictet-Spengler reaction has long been believed to require
electron-rich aromatics such as indoles and benzenes sub-
stituted with strongly electron-donating groups such as a
hydroxy or alkoxy group, superacid catalysts enabled the
cyclization reactions of imines (e.g., 1, X1 ) X2 ) H) of
2-phenethylamine to give 1-substituted 1,2,3,4-tetrahydroiso-
quinoline (e.g., 2, X1 ) X2 ) H) in moderate to high yields
1
(Scheme 1).6 In the H NMR spectrum of a related imine
† The University of Tokyo.
(4) Relevance of unsubstituted 1,2,3,4-tetrahydroisoquinoline derivatives
to Parkinson’s disease: (a) Tasaki, Y.; Makino, Y.; Ohta, S.; Hirobe, M. J.
Neurochem. 1991, 57, 1940-1943. (b) Manini, P.; d’Ischia, M.; Prota, G.
J. Org. Chem. 2001, 66, 5048-5053. (c) Ishiwata, K.; Koyanagi, Y.; Abe,
K.; Kawamura, K.; Taguchi, K.; Saitoh, T.; Toda, J.; Senda, M.; Sano, T.
J. Neurochem. 2001, 79, 868-876. (d) Absi, E.; Parrado, J.; Ayala, A.;
Machado, A. Brain Res. 2002, 955, 161-163. Pharmaceutical interests on
the stereoisomers of substituents of the 1,2,3,4-tetrahydroisoquinoline
derivatives: (e) Gray, N. M.; Cheng, B. K.; Mick, S. J.; Lair, C. M.;
Contrras, P. C. J. Med. Chem. 1989, 32, 1242-1248. (f) Ohkubo, M.; Kuno,
A.; Katsuta, K.; Ueda, Y.; Shirakawa, K.; Nakanishi, H.; Nakanishi, I.;
Kinoshita, T.; Takasugi, H. Chem. Pharm. Bull. 1996, 44, 95-102. (g) Anan,
H.; Tanaka, A.; Tsuzuki, R.; Yokota, M.; Yatsu, T.; Fujiwara, T. Chem.
Pharm. Bull. 1996, 44, 1865-1870.
‡ Nagoya City University.
(1) For reviews, see: (a) Czerwinski, K. M.; Cook, J. M. AdV. Heterocycl.
Nat. Prod. Synth. 1996, 3, 217-277. (b) Cox, E. D.; Cook, J. M. Chem.
ReV. 1995, 5 (6), 1797-1842. (c) Waldmann, H. Synlett 1995, 133-141.
(d) Rozwadowska, M. D. Heterocycles 1994, 39 (2), 903-931. (e) Badia,
D.; Dominguez, E.; Lete, E.; Villa, M. J. Trends Heterocycl. Chem. 1991,
2, 1-11. (f) Ungemach, F.; Cook, J. M. Heterocycles 1978, 9, 1089-1119.
(g) Claret, P. A. In ComprehensiVe Organic Chemistry; Barton, D., Ollis,
W. D., Ed.; Pergamon: Oxford, 1979; Vol. 4, pp 209-211. (h) Gensler,
W. J. In Heterocyclic Compounds; Elderfield, R. C., Ed.; Wiley: New York,
1952; Vol. 4, pp 353-361. (i) Whaley, W. M.; Govindachari, T. R. Org.
React. 1951, 6, 151-190.
(2) (a) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030-
2036.
(3) Decker, H.; Becker, P. Justus Liebigs Ann. Chem. 1913, 395, 342-
362.
(5) Bringmann, G.; Ewers, C. T.; Walter, R. ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 6, Chapter 4.2.
10.1021/ol034526a CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/22/2003

In this paper, we characterized the differences of the
monocationic and dicationic cyclizations of the imines
theoretically and experimentally. First we evaluated theoreti-
cally the dicationic cyclization catalyzed by the superacid
with the aid of ab initio calculation. We also compared the
experimental stereoselectivity of the superacid-catalyzed
cyclization reaction of 1-substituted and 2-substituted N-ben-
zylidene-2-phenethylamines 1b-f with that found in the
TFA-catalyzed cyclization reaction of the corresponding
N-benzylidene-2-(3′,4′-dimethoxy)phenethylamines 5b-f (see
Scheme 2). The different stereoselectivity was consistent with
the postulate that the activation mechanism and the transition-
state structures are different in the dicationic cyclization from
those in the monocationic cyclization.
Scheme 1. Cationic Reactive Species Involved in the
Pictet-Spengler Reaction
(1, X1 ) X2 ) R ) H), N-methylene-2-phenethylamine,
prepared from 2-phenethylamine and paraformaldehyde in
TFA at -18 °C, an NH proton was observed at 12.29 ppm,
and two methylene signals were coupled with the NH
signals.6 This supported practically complete N-protonation
of the imine nitrogen atom to form the monocation 3 in TFA.
However, the cyclization of 1 (X1 ) X2 ) H, and, e.g., R )
Ph, 1a, see Table 1) did not proceed in TFA. Superelectro-
The transition-state (TS) structures for the monocationic
(through 3a) and the dicationic (through 4a) cyclization of
the N-benzylidene-2-phenethylamine (1a, see Scheme 2)
were optimized at the RHF/6-31G* level of calculation (TS1
and TS2, Figure 1).9 The enthalpy of activation of the
Table 1. Stereoselection in the Pictet-Spengler Reaction
conditions
imines
(T (°C), yield
X1 ) X2 X3 R2
R1
acida time (h)) (%) trans/cisb
1a c
1a c
1b
1c
1d
1e
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
Me
Et
n-Bu
H
H
H
Me
Et
n-Bu
H
H
H
H
H
H
H
TFSA 120, 15
TFA 90, 14
TFSA 120, 20
TFSA 120, 17
TFSA 120, 19
90
0
76
81
95
77
74
89
91
100
96
79
73
94
81
67
88:12
81:19
82:18
8:92
Et TFSA 120, 16
n-Bu TFSA 120, 16
H
H
H
H
Et TFA
n-Bu TFA
H
H
H
1f
5:95
5a c OMe
TFA
TFA
TFA
TFA
120, 12
90, 3
90, 3
90, 3
90, 3
90, 3
5b
5c
5d
5e
5f
8a c
8b
8c
OMe
OMe
OMe
OMe
OMe
H
80:20
61:39
60:40
6:94
Figure 1. Calculated transition structures for cationic cyclization
of imines (the out-of-plane angle between the bending aromatic
C-H bond and the aromatic plane is shown in parentheses).
6:94
H
TFSA 120, 15
TFSA 120, 20
TFSA 120, 6
H
H
Cl Me
Cl Et
85:15
80:20
cyclization of the monocation 3a is 32.0 kcal/mol.10 This
high activation barrier strongly indicates that the monoca-
tionic imine (3a) is not the reactive species in the Pictet-
Spengler reaction of N-benzylidene-2-phenethylamine (1a).
The enthalpy of activation of the corresponding cyclization
a 100 equiv. b Ratios of trans/cis isomers were determined in terms of
1H NMR signals. c Reference 6.
philes,7 N,N-diprotonated imines (4), were proposed to be
involved in this cyclization on the basis of kinetic measure-
ments of the acidity-dependence of the reaction (Scheme 1).8
(9) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.;
Salvador, P.; Dannenberg, J. J.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle,
E. S.; Pople, J. A. Gaussian 98, Revision A.11; Gaussian, Inc.: Pittsburgh,
PA, 2001.
(6) Yokoyama, A.; Ohwada, T.; Shudo, K. J. Org. Chem. 1999, 64, 611-
617.
(7) (a) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 767-788.
(b) Ohwada, T.; Yamagata, N.; Shudo, K. J. Am. Chem. Soc. 1991, 113,
1364-1373.
(8) (a) Zucker, L.; Hammett, L. P. J. Am. Chem. Soc. 1939, 61, 2791-
2798. (b) Bonner, T. G.; Thorne, M. P.; Wilkins, J. M. J. Chem. Soc. 1955,
2351-2358. (c) Bonner, T. G.; Barnard, M. J. Chem. Soc. 1958, 4181-
4186. (d) Long, F. A.; Paul, M. A. Chem. ReV. 1957, 57, 935-1010. (e)
Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.; Shudo, K. J. Am. Chem. Soc.
1995, 117, 3037-3043.
2088
Org. Lett., Vol. 5, No. 12, 2003

of the monocation 7a, derived from the electron-rich substrate
(5a) bearing dimethoxy groups on the benzene ring, through
the transition state TS3 (Figure 1) is 25.8 kcal/mol,10 much
smaller than that of the monocationic cyclization of the
inactivated case (TS1).11 The enthalpy of activation of the
cyclization of the dication 4a, the N-protonated form of the
monocation 3a, is calculated to be 9.2 kcal/mol (TS2).12
These differences of activation barriers are consistent with
the observation that the cyclization of N-benzylidene-2-
phenethylamine (1a) requires a strong acid (TFSA) while
the corresponding cyclization of N-benzylidene-2-(3′,4′-
dimethoxy)phenethylamine (5a) is catalyzed by TFA.
The activation energy for the cyclization of 1a in TFSA
was evaluated experimentally from the rate constants of the
cyclization at three different temperatures. The enthalpy of
activation (∆Hq) of the cyclization of 1a in TFSA was found
to be 17.7 kcal/mol.6 Other experimentally evaluated en-
thalpies of activation (∆Hq) are 11.5 kcal/mol (N-p-meth-
ylbenzylidene-2-phenethylamine) and 18.0 kcal/mol (N-p-
chlorobenzylidene-2-phenethylamine 8a), respectively. Thus,
these values are consistent with the calculated enthalpy of
activation of the dicationic cyclization of 4a (9.2 kcal/mol),
rather than that of the monocationic cyclization of 3a (32.0
kcal/mol). The transition-state structures of the monocationic
and dicationic cyclizations are significantly different, par-
ticularly in the distances of the forming C-C bond: TS1,
1.930 Å; TS2, 2.327 Å; TS3, 1.931 Å. Thus, the structural
distortion in the dicationic cyclization (TS2) is less pro-
gressed than in the monocationic cyclization (TS1). The
transition structure (TS3) of the monocationic cyclization
of the electron-rich substrate is more distorted as compared
with that (TS1) of the unreactive substrate. The magnitudes
of the out-of-plane angle of the aromatic hydrogen atoms at
the reaction center, i.e., the angle between the C-H bond
and the aromatic plane, supported this trend (Figure 1).13
The out-of-plane angle of the aromatic bending hydrogen
atom of TS3 is 31.9° and that of TS1 is 15.7°, which is
comparable to that of dicationic TS2 (15.6°). However,
generally the magnitudes of the structural changes, particu-
larly the forming C-C bond lengths in the TSs, are consistent
with the height of the activation barriers: the earlier a
transition structure is, the less endothermic the activation
barrier is.
The present computational results are consistent with the
postulated involvement of the dicationic reactive species (4a)
in the superacid-catalyzed reactions of the N-benzylidene-
2-phenethylamine (1a).
Scheme 2. Stereoselectivity of the Cyclization
Our interest focus was next directed to the experimental
differences between the dicationic and monocationic mech-
anisms, apart from substituent effects of the cyclizing
aromatic rings, which may be reflected in the magnitude of
the stereoselectivity at the stereogenic center of the cycliza-
tion. There is little knowledge about the stereoselectivity of
superacid-catalyzed Pictet-Spengler reactions. Thus, we
studied here the stereoselectivity of the superacid-catalyzed
cyclizations of 1-substituted and 2-substituted N-benzylidene-
2-arylethylamines (Scheme 2).
While the cyclization of 2-alkyl-substituted N-benzylidene-
2-phenethylamine 1b-d (as well as 1a) did not proceed at
all in TFA, the cyclization proceeded in TFSA and gave a
mixture of trans and cis isomers of the tetrahydroisoquino-
lines. These cyclization reactions were stereoselective, and
the trans isomer (2b-d) is predominant over the cis isomer
(2′b-d). The ratios are consistent among methyl (1b; trans/
cis 88:12), ethyl (1c; 81:19) and n-butyl (1d; 82:18) groups
as the R2 substituent (Table 1). Acid-catalyzed isomerization
of cis-1,3-disubstituted 1,2,3,4-tetrahydro-â-carbolines to the
trans isomers has been studied.14 The stereoselectivity of the
cyclization was, however, determined kinetically in the
present cases because a fraction of the minor product did
not isomerize to the corresponding major isomer upon
heating in the presence of TFSA (Supporting Information,
Table 1S). A similar magnitude of the trans selectivity was
also found in the imines 8b,c where the substituent on the
1-phenyl group of the N-benzylidene moiety (X3) was a
chloro group.
(10) This value is the sum of electronic and thermal enthalpies (at 298.15
K) with a scaled thermal correction (a scale factor 0.8929, on the basis of
the RHF/6-31G* frequency calculation): (a) Pople, J. A.; Scott, A. P.; Wong,
M. W.; Radom, L. Isr. J. Chem. 1993, 33, 345. (b) Scott, A.; Radom, L. J.
Phys. Chem. 1996, 100, 16502. (c) Foresman, J. B.; Frish, Æ. Exploring
Chemistry with Electronic Structure Methods, 2nd ed.; Gaussian, Inc.:
Pittsburgh, 1996.
(11) The most stable conformer with respect to the conformations of
the dimethoxy groups of 5a was used. Another structure, e.g., with anti
and all-in-plane conformation of the methoxy groups of 5a, is higher in
energy than the present conformer (in Figure 1) by 2.2 kcal/mol (RHF/6-
31G*, after scaled ZPE correction).
(12) Single-point energy calculations with B3LYP/6-31G* levels on the
basis of the RHF/6-31G*-optimized geometries were carried out. The
enthalpies of activation (at 298.15 K, after the scaled thermal correction,
based on RHF/6-31G* frequency calculations) are as follows: TS1
(monocationic cyclization), 21.1 kcal/mol; TS2 (dicationic cyclization), -0.3
kcal/mol; TS3 (monocationic cyclization), 16.0 kcal/mol, respectively. The
energy differences of the enthalpies of activation through these relevant
TS structures are of similar magnitude as in the RHF calculations, while
the dicationic cycliztion through TS2 became a nonactivation barrier process.
This might be partially because of the incomplete estimation of electron
correlations in this type of reactions (see ref 10c).
(13) The dihedral angle between the bending aromatic C-H bond and
the neighoring aromatic C-H bond is also a descriptor of the strurural
distortion (in the reactant cations, these values are less than 0.9°): TS1,
23.3°; TS2, 13.5°; TS3, 28.1°.
(14) Cox, E. D.; Li, J.; Hamaker, L. K.; Yu, P.; Cook, J. M. Chem.
Commun 1996 2477-2478.
Org. Lett., Vol. 5, No. 12, 2003
2089

The stereoselectivity of the TFA-catalyzed reaction of the
electron-rich substrates was also studied (Table 1). The imine
5b, bearing a methyl substituent as the R2 substituent, showed
stereoselectivity (trans/cis 80:20) as high as that observed
in the case of superacid-catalyzed cyclization of 1b. The
magnitude of the selectivity of 5b was slightly decreased as
compared with that of 1b. In the cases of the sterically
demanding ethyl (5c) and n-butyl (5d) groups, the stereo-
selectivity decreased significantly under similar reaction
conditions (5c: trans/cis 61:39; 5d: trans/cis 60:40) (see
Table 1). Because the two methoxy groups on the benzene
ring are remote from the cyclizing reaction centers, the
stereoselection should be free from the steric effect of these
groups. Therefore, the results support the postulate that a
higher stereoselectivity can be realized under superacid
conditions. These differences in stereoselectivity presumably
arise from the different transition state (TS) structures of the
cyclization, although the relevance of this is not clear at
present.15 In all cases of cyclization of 2-alkyl-substituted
imines, the trans-cyclization was favored because of the 1,4-
diequatorial positions of the substituents (an alkyl and phenyl
group) in the transition state of a chairlike conformation (see
Figure 1).
and 1f (R1 ) n-butyl) are as high as trans/cis 8:92 and 5:95,
respectively (Table 1). In the cases of the cyclization reaction
of the corresponding electron-rich substrates (5e and 5f),
catalyzed by TFA, the stereoselectivities are as high as those
observed in the superacid-catalyzed cases (1e and 1f) (Table
1). The minor trans isomers do not isomerize to the
corresponding cis isomer under these reaction conditions
(Supporting Information, Table 1S).16 The present high cis
preferences in the reactions of 1e,f and 5e,f can be rational-
ized in terms of the overwhelmingly more stable cis-1,2-
diequatorial positions of the substituents of the TSs in a chair-
like conformation.
In summary, high stereoselectivities were found in a wide
range of superacid-catalyzed Pictet-Spengler cyclization
reactions. Particularly in the cases of 2-alkyl-N-benzylidene-
2-phenethylamines, an enhanced stereoselectivity was ob-
served as compared with the corresponding monocationic
cyclization. The present computational study also supported
the energetic favorability of the cyclization of the N,N-
diprotonated imine (4) and revealed a significantly early
TS structure. Further investigation of stereoselectivity in
superacid media and a detailed computational study are under
way.
On the other hand, in the cases of the cyclizations of
1-alkyl-N-benzylidene-2-phenethylamines, the stereoselec-
tivities in the superacid-catalyzed reactions of 1e (R1 ) ethyl)
Acknowledgment. This work was supported in part by
a Grant-in-Aid from the Ministry of Education, Science,
Sports, Culture and Technology, Japan, Uehara Memorial
Foundation, and Tokuyama Science Foundation. Part of the
calculations were carried out at the Computer Center, the
Institute for Molecular Science, and the Computer Center
of the University of Tokyo. We thank these computational
facilities for generous allotments of computer time.
(15) Our preliminary calculations suggested that the enhanced stereo-
selectivity in the cases of 2-alkyl-substituted imines under superacid
conditions can be rationalized in terms of the difference in the structures
and energies of the TSs of the cyclizations. The TSs for trans and cis
cyclization of the N-monoprotonated cation (7c) of 2-ethyl-N-benzylidene-
2-(3′,4′-dimethoxy)phenethylamine (5c) were obtained (TS4 and TS5,
Scheme S1, Supporting Information). The structural features are similar to
those of TS3. The TSs for the trans and cis cyclization of the N,N-
diprotonated imine (4c) of 2-ethyl-N-benzylidene-2-phenethylamine (1c)
were also obtained (TS6 and TS7, Scheme S1, Supporting Information).
The structural features are similar to those of TS2. The activation energies
for cyclization are 25.6 kcal/mol (for trans cyclization through TS4) and
25.8 kcal/mol (for cis cyclization through TS5), respectively. The TS for
the trans cyclization of the monocation 3c is lower in energy than that for
the cis cyclization by 0.25 kcal/mol. The energy difference between the
TSs for trans (TS5) and cis (TS6) cyclizations of the dication 4c is increased
0.37 kcal/mol. Thus, the gap is larger than that of the monocationic
cyclization of the dimethoxyphenyl substrate (5c). This increased gap
between the energies of the TSs for the trans and cis cyclizations seems to
be consistent with the enhanced stereoselection.
Supporting Information Available: Experimental pro-
cedures and characterizations, Table 1S, and Scheme 1S. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL034526A
(16) The trans preference was observed in the Pictet-Spengler cyclization
product of the indole imines, 1,3-disubstituted Na-methyl-Nb-benzyltryp-
tophan methyl ester. See ref 14.
2090
Org. Lett., Vol. 5, No. 12, 2003