Super acid-induced pummerer-type cyclization reaction: Improvement in the synthesis of chiral 1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1248/cpb.51.667

Improved synthesis of four stereoisomeric chiral 1,3-dimethyl-1,2,3,4- tetrahydroisoquinolines (1a, b, ent-1a, b) was achieved via the super acid-induced cyclization of chiral N-[1-methyl-2-(phenylsulfinyl)ethyl]-N-(1- phenylethyl)formamides (4a, b, ent-4a, b) using the Pummerer-type cyclization reaction as a key step. The cyclization leading to the isoquinoline ring proceeded in a quantitative manner when trifluoromethane sulfonic acid (TFSA) was used as the super acid, although Friedel-Crafts-type alkylation of 4-phenylsulfanyl TIQ derivatives (5) with benzene used as the solvent accompanied cyclization to yield the 4-phenyl-TIQs (7). The byproduct (7) was exclusively formed when a large excess amount of TFSA was used.

Full text of DOI:10.1248/cpb.51.667

June 2003
Chem. Pharm. Bull. 51(6) 667—672 (2003)
667
Super Acid-Induced Pummerer-Type Cyclization Reaction: Improvement
in the Synthesis of Chiral 1,3-Dimethyl-1,2,3,4-tetrahydroisoquinolines
*
Toshiaki SAITOH, Kentaro SHIKIYA, Yoshie HORIGUCHI, and Takehiro SANO
Showa Pharmaceutical University; 3–3165 Higashi-tamagawagakuen, Machida, Tokyo 194–8543, Japan.
Received January 30, 2003; accepted March 18, 2003
Improved synthesis of four stereoisomeric chiral 1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines (1a, b, ent-
1a, b) was achieved via the super acid-induced cyclization of chiral N-[1-methyl-2-(phenylsulfinyl)ethyl]-N-(1-
phenylethyl)formamides (4a, b, ent-4a, b) using the Pummerer-type cyclization reaction as a key step. The cy-
clization leading to the isoquinoline ring proceeded in a quantitative manner when trifluoromethane sulfonic
acid (TFSA) was used as the super acid, although Friedel–Crafts-type alkylation of 4-phenylsulfanyl TIQ deriva-
tives (5) with benzene used as the solvent accompanied cyclization to yield the 4-phenyl-TIQs (7). The byproduct
(7) was exclusively formed when a large excess amount of TFSA was used.
Key words super acid; Pummerer reaction; 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline; trifluoromethane sulfonic acid; chiral
synthesis; parkinsonism
It is well known that the sulfonium ion formed in situ from carried out as follows (Chart 3). A solution of 4a in benzene
a sulfoxide by the action of anhydrides such as trifluoroacetic was treated with 5 molar equivalent of TFAA at room tem-
anhydride (TFAA) is a powerful electrophile reacting with perature for 1 h under an argon atmosphere, and then to this
nucleophilic carbon species (Pummerer reaction).1) Recently, solution 5 molar equivalent of TFSA was added. The reac-
we explored the Pummerer-type cyclization reaction of sim- tion mixture was allowed to react at room temperature for a
ple alkyl sulfoxides and developed an efficient method for further 1 h. Separation of crude products with medium-pres-
the preparation of N-heterocycles with isoquinoline, quino- sure liquid chromatography over silica gel yielded two 2-
line, and benzazepine ring systems.2) During the study, we formyl-4-phenylsulfanyl-1,3-DiMeTIQs (5aA) (66%) and
discovered that boron trifluoride diethyl etherate (BF3·Et2O), (5aB) (19%), and 2-formyl-4-phenyl-1,3-DiMeTIQ (7aA)
when used together with TFAA, dramatically facilitated the (10%). The spectral and analytical data of 5aA and 5aB indi-
cyclization reaction.3—9) The high efficiency of this reaction cated that they are epimers in terms of the stereochemistry of
was encountered particularly in the cyclization for substrates the phenylsulfanyl group at the C4-position, although the
with a weak nucleophilic aromatic p-bond, which in the ab- stereochemistries could not be determined since the coupling
sence of the Lewis acid undergoes no cyclization.3)
constants between C4-H and C3-H of 5aA and 5bB showed
Recently, we succeeded in the syntheses of four stereo- similar values (Jϭ2 Hz). The structure of 7aA was deduced
isomeric chiral 1,3-dimethyl-1,2,3,4-tetrahydroisoquinolines from the mass spectroscopic, 1H- and 13C-NMR data, and the
(1,3-DiMeTIQs) (1a, ent-1a, 1b, ent-1b).10) 1,3-DiMeTIQ stereochemistry of the phenyl group at the C4 position was
was detected in the brain of chronic ethanol-intoxicated rats determined to be trans to the C3-methyl group from the cou-
subjected to repeated amphetamine administrations and con- pling constant (Jϭ8 Hz) between C3-H and C4-H.
firmed to cause behavior abnormalities similar to parkinson-
To simplify the product analysis, the Pummerer products
ism.11) In the syntheses, we used the BF3·Et2O-catalyzed were purified after reductive elimination of the phenylsul-
Pummerer reaction of the sulfoxide (4) as a key step, which, fanyl group. The benzene solution of 4a was treated with
however, gave a poor result, producing the corresponding TFAA (5 mol eq) and TFSA (5 mol eq) followed by reduction
TIQ (5) in low yields (Chart 1).10) In this paper, we report the with NaBH4–NiCl2 to yield 2-formyl-1,3-DiMeTIQ (6a) and
Pummerer-type cyclization reaction of 4 promoted by trifluo- 7aA in yields of 79% and 5%, respectively, as shown in
romethane sulfonic acid (TFSA), a super strong acid, which Table 1 (entry 1). This result demonstrated that the TFSA-
may improve the cyclization reaction leading to 1,3-DiMe- promoted Pummerer reaction of 4a induced the cyclization
TIQ (1).
leading to the isoquinoline ring in a highly effective manner,
although the 4-phenyl-TIQ derivative (7aA) was a byproduct.
A similar reaction of 4a on using 7 molar equivalent of
Results and Discussion
Chiral sulfoxides, substrates of the Pummerer reactions, TFSA decreased the formation of 6a (68%) and increased
were prepared starting from (R)- and (S)-1-phenylethyl- that of 7aA (16%) (Table 1, entry 2). On the reaction of 4a
amines (2, ent-2) according to the methods reported in the using a large excess amount of TFSA (21 mol eq), 6a was not
previous paper (Chart 2).10) Condensation of 2 and ent-2 obtained, but instead 4-phenylTIQ (7aA) and its stereoisomer
with phenylsulfanylacetone in titanium(IV) isopropoxide fol- (7aB) were obtained in yields of 87% and 9%, respectively
lowed by reduction with NaBH4 gave four stereoisomeric (Table 1, entry 3). The results clearly demonstrate that the 4-
sulfides (3a, ent-3a, 3b, ent-3b) in an optically pure form, as phenylsulfanyl TIQ derivative initially formed by the Pum-
shown in Chart 2. Formylation of the sulfides followed by ox- merer reaction undergoes an intermolecular alkylation reac-
idation with NaIO4 yielded the sulfoxides (4a, ent-4a, 4b, tion (Friedel–Crafts reaction) with benzene used as the sol-
ent-4b).
vent to give 4-phenylTIQ, and that the increasing acidity in
The super acid-promoted Pummerer reaction of 4a was the reaction medium facilitates this undesirable reaction.
* To whom correspondence should be addressed. e-mail: saitoh-t@ac.shoyaku.ac.jp
© 2003 Pharmaceutical Society of Japan

668
Vol. 51, No. 6
Chart 1
Chart 2
Chart 3

June 2003
669
Several attempts to avoid this alkylation reaction using other reactions gave similar results to those of the enantiomer (4b),
solvents such as tetrahydrofuran (THF) and dichloromethane thus producing the corresponding 1,3-DiMeTIQ (ent-6b)
failed, and no characterizable products were obtained.
and 4-Ph-1,3-DiMeTIQ (ent-7bA), as shown in Table 1 (en-
The sulfoxide (ent-4a), an enantiomer of 4a, in the TFSA- tries 10, 11, 12).
promoted Pummerer reaction, gave similar results to those of
Alkaline hydrolysis of the N-formyl-1,3-DiMeTIQs (6a,
4a, as shown in Table 1 (entries 4, 5, 6), (Chart 4). The reac- ent-6a, 6b, ent-6b) yielded the corresponding chiral 1,3-
tion of the sulfoxide (4b), a diastereoisomer of 4a, yielded DiMeTIQs (1a, ent-1a, 1b, ent-1b). Similarly, N-formyl-4-
the 2-formyl-1,3-DiMeTIQ (6b) and the 4-phenyl-DiMeTIQ Ph-1,3-DiMeTIQs (7aA, ent-7aB, 7bB, ent-7bA) yielded
(7bB). In the reaction using 5 molar equivalent of TFSA, 6b the 4-Ph-1,3-DiMeTIQs (8aA, ent-8aB, 8bB, ent-8bA).
was obtained as the major product (53% yield) and 7bB as
These results demonstrated that the super acid TFSA
the minor one (9%) (Table 1, entry 7). The reaction with 7 greatly facilitates the Pummerer-type cyclization reaction
molar equivalent of TFSA increased both the formation of leading to the isoquinoline ring system, although the
6b (56% yield) and 7bB (23% yield) (Table 1, entry 8). The Friedel–Crafts reaction of the Pummerer product with ben-
reaction using 21 molar equivalent of TFSA also enhanced zene occurred. The fact that the increased acidity of the reac-
the Friedel–Crafts reaction to yield 7bB in an exclusive man- tion medium dramatically enhanced the cationic cyclization
ner (91%) (Table 1, entry 9). The sulfoxide (ent-4b) in the in the Pummerer reaction suggested that the reaction can in-
volve a dicationic intermediate like the super acid-catalyzed
Pictet–Spengler reaction reported by Yokoyama and collabo-
rators.12) For example, as shown in Chart 5, the sulfonium–
carbenium dication (10) can be generated by the protonation
to the cationic sulfur atom of the sulfonium ion (9). The di-
cationic species may be a true electrophile in this cyclization
reaction. Mechanistic studies are now under way.
Table 1. TFSA-Promoted Pummerer-Type Cyclization Reaction of the
Chiral Sulfoxides (4)
Reagents
Entry Sulfoxide (mol eq)
(4)
Yield (%) of
products
TFAA TFSA 1,3-diMeTIQ (6)
4-Ph-1,3-diMeTIQ (7)
Experimental
1
2
3
4
5
6
7
8
9
4a
4a
4a
ent-4a
ent-4a
ent-4a
4b
4b
4b
ent-4b
ent-4b
ent-4b
5
5
5
5
5
5
5
5
5
5
5
5
5
7
21
5
7
21
5
7
21
5
7
21
79 (6a)
68 (6a)
—
76 (ent-6a)
67 (ent-6a) 17 (ent-7aB)
5 (7aA)
16 (7aA)
87 (7aA), 9 (7aB)
5 (ent-7aB)
Unless otherwise noted, the following procedures were adopted. Melting
points were recorded on a Yanagimoto SP-M1 hot-stage melting point appa-
ratus and are uncorrected. IR spectra were measured as films for oils and
gums, and KBr disks for solids with a HORIBA FT-710 spectrophotometer,
and the values are given in cmϪ1. NMR spectra were measured on a JEOL
JNM-AL300 (1H-NMR: 300 MHz, 13C-NMR: 75 MHz) NMR spectrometer
in CDCl3 with tetramethylsilane as an internal standard and the chemical
shifts are given in d values. Low-resolution electron-impact ionization mass
spectra (LR-EIMS) were recorded on JEOL JMS-AM20 mass spectrometer
at 70 eV using direct inlet probe. High-resolution EIMS (HR-EIMS) and
low-resolution chemical ionization mass spectra (LR-CIMS) were measured
on a JEOL JMS-D300 mass spectrometer at 70 eV (EIMS) or at 270 eV
7 (ent-6a) 73 (ent-7aB), 12 (ent-7aA)
53 (6b)
56 (6b)
4 (6b)
54 (ent-6b)
56 (ent-6b) 36 (ent-7bA)
4 (ent-6b) 95 (ent-7bA)
9 (7bB)
23 (7bB)
91 (7bB)
5 (ent-7bA)
10
11
12
Chart 4
Chart 5

670
Vol. 51, No. 6
[CIMS, reactant gas: iso-butane] using a direct inlet probe. Elemental analy-
sis were recorded on a Yanaco CHN-corder MT-3. Optical rotations were de-
termined using a JASCO DIP-1000 digital polarimeter in MeOH. CD spec-
tra were measured on a JASCO J-600 spectrometer in MeOH. TLC was per-
formed on Merck precoated Silica gel 60 F254 plates. Column chromatogra-
phy was carried out with silica gel (Wakogel C-200) or aluminium oxide
(Alumium oxide 90, Merck). Medium-pressure liquid chromatography
(MPLC) was performed on a Kusano CIG prepacked column. The chiral
HPLC analysis were performed on a chiral column of Sumichiral OA 4700
[25 cmϫ4 mm i.d., room temperature, mobile phase, hexane–EtOH–trifluo-
roacetic acid (960 : 40 : 4); flow rate, 1.5 ml/min]. The organic extract from
each reaction mixture was washed with brine, dried over anhydrous Na2SO4,
and concentrated in vacuo to dryness.
each d, Jϭ6 Hz, C1Ј-CH3), 1.65, 1.83 (total 3H, each d, Jϭ7 Hz, C1-CH3),
2.8—3.0, 3.5—4.1 (total 3H, m, C1Ј-H, C2Ј-H), 4.8—4.9 (1H, m, C1-H),
7.3—7.6 (10H, m, 2ϫPh-H), 8.31, 8.44 (total 1H, each s, CHO). LR-CIMS
m/z: 316 (MHϩ), 190 (base peak).
Pummerer Reaction of N-[(1R)-1-Methyl-2-(phenylsulfinyl)ethyl]-N-
[(1R)-1-phenylethyl]formamides (4a) TFAA (1.665 g, 7.93 mmol) was
added to a solution of 4a (500 mg, 1.59 mmol) in benzene (50 ml) at root
temperature, and the mixture was stirred under an argon atmosphere. After
the mixture was stirred for 1 h, TFSA (1.190 g, 7.93 mmol) was added, and
the reaction mixture was further stirred at the same temperature for 1 h.
To this reaction mixture, 5% NaOH solution (50 ml) was added and the mix-
ture was extracted with benzene. The residue was purified by MPLC (ben-
zene : acetoneϭ5 : 1) to give 5aA (312 mg, 66%), 5aB (76 mg, 19%), and
7aA (42 mg, 10%).
(1R,3R)-2-Formyl-1,3-dimethyl-4-phenylsulfanyl-1,2,3,4-tetrahydroiso-
quinoline (5aA): Colorless prisms, recrystallized from AcOEt–hexane, mp
101—103 °C. IR: 1676. 1H-NMR: 0.98, 1.10 (total 3H, each d, Jϭ7 Hz, C3-
CH3), 1.74, 1.85 (total 3H, each d, Jϭ7 Hz, C1-CH3), 4.05, 4.89 (total 1H,
each dd, Jϭ2, 7 Hz, C3-H), 4.17, 4.23 (total 1H, each d, Jϭ2 Hz, C4-H),
4.85, 5.05 (total 1H, q, Jϭ7 Hz, C1-H), 7.2—7.5 (9H, m, Ph-H, SPh-H).
8.18, 8.57 (total 1H, each s, CHO). LR-EIMS m/z: 297 (Mϩ), 188 (base
peak). HR-EIMS m/z (Mϩ): Calcd for C18H19NOS: 297.1188. Found:
297.1187.
(1R,3R)-2-Formyl-1,3-dimethyl-4-phenylsulfanyl-1,2,3,4-tetrahydroiso-
quinoline (5aB): A colorless gum. IR: 1655. 1H-NMR: 1.43 (3H, d, Jϭ7 Hz,
C1-CH3), 1.55 (3H, d, Jϭ7 Hz, C3-CH3), 4.18 (1H, dq, Jϭ2, 7 Hz, C3-H),
4.35 (1H, d, Jϭ2 Hz, C4-H), 5.37 (1H, q, Jϭ7 Hz, C1-H), 7.2—7.5 (9H, m,
Ph-H, SPh-H). 8.35 (1H, s, CHO). LR-CIMS m/z: 298 (MHϩ, base peak).
(1R,3R,4S)-2-Formyl-1,3-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquino-
line (7aA): Colorless prisms, recrystallized from AcOEt–hexane, mp 109—
111 °C. IR: 1654. 1H-NMR: 1.20, 1.31 (total 3H, each d, Jϭ7 Hz, C3-CH3),
1.45, 1.56 (total 3H, each d, Jϭ7 Hz, C1-CH3), 3.83 (1H, d, Jϭ8 Hz, C4-H),
3.9—4.1, 5.1 (total 1H, each m, C3-H), 4.77, 5.70 (total 1H, each q,
Jϭ7 Hz, C1-H), 6.7—7.5 (9H, m, 2ϫPh-H). 8.37, 8.40 (total 1H, each s,
CHO). LR-EIMS m/z: 265 (Mϩ), 177 (base peak). HR-EIMS m/z (Mϩ):
Calcd for C18H19N2O: 265.1467. Found: 265.1467. [a]D25ϭϪ56.7° (cϭ
1.01%).
Pummerer Reaction and Reductive Desulfurization of Pummerer
Products: Typical Procedure i) TFAA (1.665 g, 7.93 mmol) was added to
a solution of 4a (500 mg, 1.59 mmol) in benzene (50 ml) at room tempera-
ture, and the mixture was stirred under an argon atmosphere for 1 h. To this
reaction mixture TFSA (1.190 g, 7.93 mmol) was added, and the mixture
was further stirred at the same temperature for 1 h. To this reaction mixture,
5% NaOH aqueous solution (50 ml) was added and the mixture was ex-
tracted with benzene. The residue was dissolved in EtOH (200 ml) and
NiCl2·6H2O (1.13 g, 7 mmol) in EtOH (200 ml) solution was added to this
solution under ice cooling. NaBH4 (1.7 g, 21 mol) was added in small por-
tions to stirred mixture at 0 °C, and the mixture was stirred at room tempera-
ture for 2 h. Ice water was added to the reaction mixture and then the precip-
itate was removed by filtration. The filtrate was concentrated in vacuo. The
residue was extracted with CHCl3. The residue was purified by MPLC (ben-
zene–acetone 5 : 1) to give 6a (237 mg, 79%) and 7aA (21 mg, 5%) (Table 1,
entry 1).
Spectral Data of 3, ent-3, 4 and ent-413) (1R)-N-[(1R)-1-Methyl-2-
(phenylsulfanyl)ethyl]-1-phenylethylamine (3a): A colorless oil. HCl salt,
colorless needles recrystallized from Et2O–EtOH, mp 165 °C (sublimation).
IR: 2962, 1583. 1H-NMR: 1.07 (3H, d, Jϭ6 Hz, C1Ј-CH3), 1.27 (3H, d,
Jϭ6 Hz, C1-CH3), 2.7—2.9 (1H, m, C1Ј-H), 2.94 (1H, dd, Jϭ6, 13 Hz, C2Ј-
H), 3.04 (1H, dd, Jϭ5, 13 Hz, C2Ј-H), 3.82 (1H, q, Jϭ7 Hz, C1-H), 7.1—
7.3 (10H, m, Ph-Hϫ2). 13C-NMR: 21.1 (C1Ј-CH3), 24.7 (C1-CH3), 40.3
(C2Ј), 49.7 (C1Ј), 55.3 (C1), 125.9 (Ph-CH), 126.5 (2ϫPh-CH), 126.8 (Ph-
CH), 128.4 (2ϫPh-CH), 128.8 (2ϫPh-CH), 129.3 (2ϫPh-CH), 136.8 (Ph-
C), 145.9 (Ph-C). LR-CIMS m/z: 272 (MHϩ, base peak. [a]D24ϭϩ76.4°
(cϭ1.04%). Chiral-HPLC: 17.4 min.
(1R)-N-[(1S)-1-Methyl-2-(phenylsulfanyl)ethyl]-1-phenylethylamine
(3b): A colorless oil. HCl salt recrystallized from Et2O–EtOH, mp 167—
170 °C. IR: 2962, 1583. 1H-NMR: 1.09 (3H, d, Jϭ6 Hz, C1Ј-CH3), 1.35 (3H,
d, Jϭ7 Hz, C1-CH3), 2.6—2.7 (1H, m, C1Ј-H), 2.83 (1H, dd, Jϭ7, 13 Hz,
C2Ј-H), 2.93 (1H, dd, Jϭ5, 13 Hz, C2Ј-H), 3.87 (1H, q, Jϭ7 Hz, C1-H),
7.1—7.3 (10H, m, Ph-Hϫ2). 13C-NMR: 19.8 (C1Ј-CH3), 24.9 (C1-CH3),
41.7 (C2Ј), 48.4 (C1Ј), 55.0 (C1), 125.9 (Ph-CH), 126.4 (2ϫPh-CH), 126.8
(Ph-CH), 128.4 (2ϫPh-CH), 128.8 (2ϫPh-CH), 129.3 (2ϫPh-CH), 136.2
(Ph-C), 145.2 (Ph-C). LR-CIMS m/z: 272 (MHϩ, base peak). [a]D24ϭϩ79.6°
(cϭ0.87%). Chiral-HPLC: 12.5 min.
(1S)-N-[(1S)-1-Methyl-2-(phenylsulfanyl)ethyl]-1-phenylethylamine
(ent-3a): A colorless oil. IR: 2962, 1583. 1H-NMR: 1.07 (3H, d, Jϭ6 Hz,
C1Ј-CH3), 1.27 (3H, d, Jϭ6 Hz, C1-CH3), 2.7—2.9 (1H, m, C1Ј-H), 2.94
(1H, dd, Jϭ6, 13 Hz, C2Ј-H), 3.04 (1H, dd, Jϭ5, 13 Hz, C2Ј-H), 3.82 (1H,
q, Jϭ7 Hz, C1-H), 7.1—7.3 (10H, m, Ph-Hϫ2). 13C-NMR: 21.1 (C1Ј-CH3),
24.7 (C1-CH3), 40.3 (C2Ј), 49.7 (C1Ј), 55.3 (C1), 125.9 (Ph-CH), 126.5
(2ϫPh-CH), 126.8 (Ph-CH), 128.4 (2ϫPh-CH), 128.8 (2ϫPh-CH), 129.3
(2ϫPh-CH), 136.8 (Ph-C), 145.9 (Ph-C). LR-EIMS m/z: 271 (Mϩ), 113
(base peak). HR-EIMS m/z (Mϩ): Calcd for C17H21NS: 271.1343. Found:
271.1388. [a]D24ϭϪ77.0° (cϭ0.80%). Chiral-HPLC: 6.8 min.
(S)-N-[(1R)-1-Methyl-2-(phenylsulfanyl)ethyl]-1-phenylethylamine (ent-
1
3b): A colorless oil. IR: 2964, 1583. H-NMR: 1.09 (3H, d, Jϭ6 Hz, C1Ј-
CH3), 1.35 (3H, d, Jϭ7 Hz, C1-CH3), 2.6—2.7 (1H, m, C1Ј-H), 2.83 (1H,
dd, Jϭ7, 13 Hz, C2Ј-H), 2.93 (1H, dd, Jϭ5, 13 Hz, C2Ј-H), 3.87 (1H, q,
Jϭ7 Hz, C1-H), 7.1—7.3 (10H, m, Ph-Hϫ2). 13C-NMR: 19.8 (C1Ј-CH3),
24.9 (C1-CH3), 41.7 (C2Ј), 48.4 (C1Ј), 55.0 (C1), 125.9 (Ph-CH), 126.4
(2ϫPh-CH), 126.8 (Ph-CH), 128.4 (2ϫPh-CH), 128.8 (2ϫPh-CH), 129.3
(2ϫPh-CH), 136.2 (Ph-C), 145.2 (Ph-C). LR-CIMS m/z: 272 (MHϩ, base
peak). [a]D24ϭϪ77.5° (cϭ0.97%). Chiral-HPLC: 7.3 min.
N-[(1R)-1-Methyl-2-(phenylsulfinyl)ethyl]-N-[(1R)-1-phenylethyl]form-
amide (4a): Colorless needles recrystallized from AcOEt–hexane, mp 91—
93 °C. IR: 1664. 1H-NMR: 1.3—1.8 (6H, m, 2ϫCH3), 2.5—2.9 (1H, m,
C2Ј-H), 3.3—3.9 (2H, m, C1Ј-H, C2Ј-H), 4.76 (1H, q, Jϭ7 Hz, C1-H),
7.1—7.3 (10H, m, 2ϫPh-H), 8.31 (1H, s, CHO). LR-CIMS m/z: 316 (MHϩ,
base peak). Anal. Calcd for C18H21NO2S: C, 68.54; H, 6.71; N, 4.44. Found:
C, 68.61; H, 6.85; N, 4.41.
N-[(1S)-1-Methyl-2-(phenylsulfinyl)ethyl]-N-[(1R)-1-phenylethyl]form-
amide (4b): A colorless gum. IR: 1664. 1H-NMR: 0.90, 1.24 (total 3H, each
d, Jϭ6 Hz, C1Ј-CH3), 1.65, 1.83 (total 3H, each d, Jϭ7 Hz, C1-CH3), 2.8—
3.0, 3.5—4.1 (total 3H, m, C1Ј-H, C2Ј-H), 4.8—4.9 (1H, m, C1-H), 7.3—
7.6 (10H, m, 2ϫPh-H), 8.31, 8.44 (total 1H, each s, CHO). LR-CIMS m/z:
316 (MHϩ), 190 (base peak).
N-[(1S)-1-Methyl-2-(phenylsulfinyl)ethyl]-N-[(1S)-1-phenylethyl]form-
amide (ent-4a): Colorless needles recrystallized from AcOEt–hexane, mp
93—95 °C. IR: 1664. 1H-NMR: 1.3—1.8 (6H, m, 2ϫCH3), 2.5—2.9 (1H, m,
C2Ј-H), 3.3—3.9 (2H, m, C1Ј-H, C2Ј-H), 4.76 (1H, q, Jϭ7 Hz, C1-H),
7.1—7.3 (10H, m, 2ϫPh-H), 8.31 (1H, s, CHO). LR-CIMS m/z: 316 (MHϩ,
base peak).
(1R,3R)-2-Formyl-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (6a): Col-
orless prisms, recrystallized from AcOEt–hexane, mp 67—70 °C. IR: 1660.
1H-NMR: 1.0—1.5 (6H, m, C1-CH3, C3-CH3), 2.6—2.7 (1H, m, C4-H),
3.1—3.2 (1H, m, C4-H), 4.0—4.1, 4.6—4.7 (total 1H, each m, C3-H), 4.75,
5.37 (total 1H, each q, Jϭ7 Hz, C1-H), 7.1—7.3 (4H, m, Ph-H), 8.32, 8.35
(total 1H, each s, CHO). LR-EIMS m/z: 189 (Mϩ), 91 (base peak). HR-
EIMS m/z (Mϩ): Calcd for C12H15NO: 189.1154. Found: 189.1157. Anal.
Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.17; H, 8.15;
N, 7.36. [a]D25ϭ24.1° (cϭ0.82%).
ii) The reaction was proceeded under using excess amount of TFSA
(5.1 g, 33.3 mmol) to give 7aA (367 mg, 87%) and 7aB (38 mg, 9%) (Table
1, entry 3).
(1R,3R,4R)-2-Formyl-1,3-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquino-
line (7aB): Colorless prisms, recrystallized from AcOEt–hexane, mp 135—
138 °C. IR: 1658. 1H-NMR: 1.26 (3H, d, Jϭ7 Hz, C3-CH3), 1.56 (3H, d,
Jϭ7 Hz, C1-CH3), 4.00 (1H, d, Jϭ3 Hz, C4-H), 4.16 (1H, dq, Jϭ3, 7 Hz,
C3-H), 5.84 (1H, q, Jϭ7 Hz, C1-H), 6.9—7.3 (9H, m, 2ϫPh-H) 7.76 (1H, s,
CHO). 13C-NMR: 16.4 (C3-CH3), 21.5 (C1-CH3), 47.9 (C1), 49.0 (C3), 51.2
(C4), 126.8 (Ph-CH), 128.1 (3ϫPh-CH), 128.2 (2ϫPh-CH), 129.9 (3ϫPh-
CH), 136.8 (Ph-C), 137.1 (Ph-C), 139.2 (Ph-C), 159.9 (CHO). LR-EIMS
m/z: 265 (Mϩ), 177 (base peak). HR-EIMS m/z (Mϩ): Calcd for C18H19N2O:
N-[(1R)-1-Methyl-2-(phenylsulfinyl)ethyl]-N-[(1S)-1-phenylethyl]form-
1
amide (ent-4b): A colorless gum. IR: 1664. H-NMR: 0.90, 1.24 (total 3H,

June 2003
671
265.1467. Found: 265.1461. [a]D25ϭϪ208.4° (cϭ0.32%).
265.1467. Found: 265.1484. Anal. Calcd for C18H19N2O: C, 91.47; H, 7.22;
N, 5.28. Found: C, 81.65; H, 7.31; N, 5.50. [a]D25ϭ157.3° (cϭ1.00%).
Hydrolysis of 2-Formyl-1,3-DiMeTIQs (6a, ent-6a, 6b, ent-6b): Typi-
cal Procedure A solution of 6a (426 mg, 2.25 mmol) in EtOH (40 ml) and
20% NaOH aqueous solution (40 ml) was refluxed for 17 h under an argon
atmosphere. The reaction mixture was diluted with water and extracted with
CHCl3. The residue was purified by column chromatography over aluminum
oxide with AcOEt–hexane (1 : 2) to give 1 (265 mg, 73%) as a pale yellow
oil. Similarly, the isomers (6b—d) gave 1,3-DiMeTIQs (ent-1, 2, ent-2), re-
spectively.
(1R,3R)-1,3-Dimethyl-1,2,3,4-tetrahydroisoquinoline (1a): A pale yellow
oil. HCl salt, colorless prisms, recrystallized from EtOH, mp 249 °C (subli-
mation). 1H-NMR: 1.21 (3H, d, Jϭ7 Hz, C3-CH3), 1.45 (3H, d, Jϭ7 Hz, C1-
CH3), 2.46 (1H, dd, Jϭ10, 16 Hz, C4-H), 2.79 (1H, dd, Jϭ4, 16 Hz, C4-H),
3.3 (1H, m, C3-H), 4.23 (1H, q, Jϭ7 Hz, C1-H), 7.0—7.2 (4H, m, Ph-H).
13C-NMR: 22.4 (C3-CH3), 24.2 (C1-CH3), 37.5 (C4), 42.7 (C3), 50.8 (C1),
125.6 (C6), 125.9 (C7), 126.7 (C5), 129.1 (C8), 134.4 (C4a), 134.0 (C8a).
HR-EIMS m/z (Mϩ): Calcd for C11H15N: 161.1202. Found: 161.1195. Anal.
Calcd for C11H16ClN (HCl salt): C, 66.83; H, 8.16; N, 7.08. Found: C, 66.68;
H, 8.26; N, 7.03. [a]D26ϭϪ45.9° (HCl salt, cϭ1.00%). CD (HCl salt,
cϭ2.54ϫ10Ϫ3 M) [q]25 (nm): Ϫ300 (269), Ϫ310 (263).
(1S,3S)-1,3-Dimethyl-1,2,3,4-tetrahydroisoquinoline (ent-1a): Yield 70%.
A pale yellow oil. HCl salt, colorless prisms, recrystallized from EtOH, mp
252 °C (sublimation). 1H-NMR: 1.21 (3H, d, Jϭ7 Hz, C3-CH3), 1.45 (3H, d,
Jϭ7 Hz, C1-CH3), 2.46 (1H, dd, Jϭ10, 16 Hz, C4-H), 2.79 (1H, dd, Jϭ4,
16 Hz, C4-H), 3.3 (1H, m, C3-H), 4.23 (1H, q, Jϭ7 Hz, C1-H), 7.0—7.2
(4H, m, Ph-H). 13C-NMR: 22.4 (C3-CH3), 24.2 (C1-CH3), 37.5 (C4), 42.7
(C3), 50.8 (C1), 125.6 (C6), 125.9 (C7), 126.7 (C5), 129.1 (C8), 134.4
(C4a), 134.0 (C8a). HR-EIMS m/z (Mϩ): Calcd for C11H15N: 161.1202.
Found: 161.1184. Anal. Calcd for C11H16ClN (HCl salt): C, 66.83; H, 8.16;
N, 7.08. Found: C, 66.73; H, 8.21; N, 7.04. [a]D28ϭϩ49.2° (HCl salt,
cϭ1.03%). CD (HCl salt, cϭ2.64ϫ10Ϫ3 M) [q]25 (nm): 293 (270), 316
(263).
(1R,3S)-1,3-Dimethyl-1,2,3,4-tetrahydroisoquinoline (1b): Yield 72%. A
pale yellow oil. HCl salt, colorless needles, recrystallized from EtOH, mp
248 °C (sublimation). 1H-NMR: 1.24 (3H, d, Jϭ7 Hz, C3-CH3), 1.48 (3H, d,
Jϭ7 Hz, C1-CH3), 2.56 (1H, dd, Jϭ10, 16 Hz, C4-H), 2.75 (1H, dd, Jϭ4,
16 Hz, C4-H), 3.0—3.1 (1H, m, C3-H), 4.16 (1H, q, Jϭ7 Hz, C1-H), 7.1—
7.2 (4H, m, Ph-H). 13C-NMR: 22.3 (C3-CH3), 22.7 (C1-CH3), 38.4 (C4),
49.0 (C3), 52.6 (C1), 125.2 (C6), 125.9 (C7), 125.9 (C5), 128.9 (C8), 135.1
(C4a), 139.9 (C8a). HR-EIMS m/z (Mϩ): Calcd for C11H15N: 161.1202.
Found: 161.1188. Anal. Calcd for C11H16ClN (HCl salt): C, 66.83; H, 8.16;
N, 7.08. Found: C, 66.75; H, 8.21; N, 7.06. [a]D26ϭϩ129.9° (HCl salt,
cϭ1.02%). CD (HCl salt, cϭ2.48ϫ10Ϫ3 M) [q]25 (nm): Ϫ230 (272), Ϫ200
(263).
(1S,3R)-1,3-Dimethyl-1,2,3,4-tetrahydroisoquinoline (ent-1b): Yield 72%.
A pale yellow oil. HCl salt, colorless needles, recrystallized from EtOH, mp
247 °C (sublimation). 1H-NMR: 1.24 (3H, d, Jϭ7 Hz, C3-CH3), 1.48 (3H, d,
Jϭ7 Hz, C1-CH3), 2.56 (1H, dd, Jϭ10, 16 Hz, C4-H), 2.75 (1H, dd, Jϭ4,
16 Hz, C4-H), 3.0—3.1 (1H, m, C3-H), 4.16 (1H, q, Jϭ7 Hz, C1-H), 7.1—
7.2 (4H, m, Ph-H). 13C-NMR: 22.3 (C3-CH3), 22.7 (C1-CH3), 38.4 (C4),
49.0 (C3), 52.6 (C1), 125.2 (C6), 125.9 (C7), 125.9 (C5), 128.9 (C8), 135.1
(C4a), 139.9 (C8a). LR-CIMS m/z: 162 (MHϩ, base peak). Anal. Calcd for
C11H16ClN (HCl salt): C, 66.83; H, 8.16; N, 7.08. Found: C, 66.89; H, 8.24;
N, 7.11. [a]D24ϭϪ119.3° (HCl salt, cϭ0.99%). CD (HCl salt, cϭ
2.49ϫ10Ϫ3 M) [q]25 (nm): 230 (272), 200 (263).
Hydrolysis of 2-Formyl-4-Phenyl-1,3-DiMeTIQs (7aA, ent-7aB, 7bB,
ent-7bA): Typical Procedure A solution of 7aA (235 mg, 0.887 mmol) in
EtOH (20 ml) and 20% NaOH aqueous solution (20 ml) was refluxed for
17 h under an argon atmosphere. The reaction mixture was diluted with
water and extracted with CHCl3. The residue was purified by column chro-
matography over aluminum oxide with AcOEt–hexane (1 : 2) to give 8aA
(207 mg, 99%) as a pale yellow oil. Similarly, the isomers (ent-7aB, 7bB,
ent-7bA) gave 4-phenyl-1,3-DiMeTIQs (ent-8aB, 8bB, ent-8bA), respec-
tively.
Similarly, ent-4a (3.0 g, 9.52 mmol) was treated with TFAA (9.99 g,
47.6 mol) and TFSA (30.6 g, 0.2 mol) under similar condition described
above. The reduction of this reaction mixture in EtOH with NiCl2·6H2O
(1.13 g, 7 mmol) and NaBH4 (1.7 g, 21 mol) gave ent-6a (128 mg, 7%), ent-
7aA (293 mg, 12%), and ent-7aB (1.832 g, 73%) (Table 1, entry 6).
(1S,3S)-2-Formyl-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (ent-6a):
Colorless prisms, recrystallized from AcOEt–hexane, mp 74—76 °C. IR:
1
1660. H-NMR: 1.0—1.5 (6H, m, C1-CH3, C3-CH3), 2.6—2.7 (1H, m, C4-
H), 3.1—3.2 (1H, m, C4-H), 4.0—4.1, 4.6—4.7 (total 1H, each m, C3-H)
4.75, 5.37 (total 1H, each q, Jϭ7 Hz, C1-H), 7.1—7.3 (4H, m, Ph-H) 8.32,
8.35 (total 1H, each s, CHO). LR-EIMS m/z: 189 (Mϩ), 91 (base peak). HR-
EIMS m/z (Mϩ): Calcd for C12H15NO: 189.1154. Found: 189.1157. Anal.
Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.17; H, 8.15;
N, 7.36. [a]D25ϭϪ23.5° (cϭ1.00%).
(1S,3S,4S)-2-Formyl-1,3-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquino-
line (ent-7aA): Colorless prisms, recrystallized from AcOEt–hexane, mp
154—156 °C. IR: 1662. 1H-NMR: 1.26, (3H, d, Jϭ7 Hz, C3-CH3), 1.56 (3H,
d, Jϭ7 Hz, C1-CH3), 4.00 (1H, d, Jϭ3 Hz, C4-H), 4.16 (1H, dq, Jϭ3, 7 Hz,
C3-H), 5.84 (1H, q, Jϭ7 Hz, C1-H), 6.9—7.3 (9H, m, 2ϫPh-H) 7.76 (1H, s,
CHO). LR-EIMS m/z: 265 (Mϩ), 179 (base peak). HR-EIMS m/z
(Mϩ): Calcd for C18H19N2O: 265.1467. Found: 265.1476. [a]D25ϭ212.6°
(cϭ1.00%).
(1S,3S,4R)-2-Formyl-1,3-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquino-
line (ent-7aB): Colorless prisms, recrystallized from AcOEt–hexane, mp
108—110 °C. IR: 1655. 1H-NMR: 1.20, 1.31 (total 3H, each d, Jϭ7 Hz, C3-
CH3), 1.45, 1.56 (total 3H, each d, Jϭ7 Hz, C1-CH3), 3.83 (1H, d, Jϭ8 Hz,
C4-H), 3.9—4.1, 5.1 (total 1H, each m, C3-H), 4.77, 5.70 (total 1H, each q,
Jϭ7 Hz, C1-H), 6.7—7.5 (9H, m, 2ϫPh-H). 8.37, 8.40 (total 1H, each s,
CHO). LR-EIMS m/z: 265 (Mϩ), 177 (base peak). HR-EIMS m/z (Mϩ):
Calcd for C18H19N2O: 265.1467. Found: 265.1479. [a]D25ϭϪ91.0° (cϭ
1.00%).
Similarly, 4b (8.0 g, 25 mmol) was treated with TFAA (26.7 g, 0.125 mol)
and TFSA (27.2 g, 0.175 mol) under similar conditions as described above.
The reduction of this reaction mixture in EtOH with NiCl2·6H2O (1.13 g,
7 mmol) and NaBH4 (1.7 g, 21 mol) gave 6b (2.65 g, 56%), 7bB (1.55 g,
23%) (Table 1, entry 8).
(1R,3S)-2-Formyl-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (6b): Col-
orless prisms, recrystallized from AcOEt–hexane, mp 59—61 °C. IR: 1660.
1H-NMR: 1.33, 1.36 (total 3H, each d, Jϭ7 Hz, C3-CH3) 1.59, 1.60 (total
3H, each d, Jϭ7 Hz, C1-CH3), 2.7—2.8 (1H, m, C4-H), 3.1—3.2 (1H, m,
C4-H), 4.1—4.2, 4.6—4.7 (total 1H, each m, C3-H), 4.78, 5.38 (total 1H,
each q, Jϭ7 Hz, C1-H), 7.1—7.3 (4H, m, Ph-H) 8.23, 8.29 (total 1H, each s,
CHO). LR-EIMS m/z: 189(Mϩ), 174 (base peak). HR-EIMS m/z (Mϩ):
Calcd for C12H15NO: 189.1154. Found: 189.1154. [a]D25ϭϪ80.8° (cϭ
0.65%).
(1R,3S,4R)-2-Formyl-1,3-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquino-
line (7bB): Colorless prisms, recrystallized from AcOEt–hexane, mp 97—
100 °C. IR: 1668. 1H-NMR: 1.37, 1.44 (total 3H, each d, Jϭ7 Hz, C3-CH3),
1.6—1.7 (3H, m, C1-CH3), 3.9—4.0, 4.8—4.9 (total 1H, each m, C3-H),
4.08 (1H, s, C4-H), 4.90, 5.48 (total 1H, each q, Jϭ7 Hz, C1-H), 6.8—7.4
(9H, m, 2ϫPh-H), 7.62, 8.25 (total 1H, each s, CHO). LR-EIMS m/z: 265
(Mϩ), 179 (base peak). HR-EIMS m/z (Mϩ): Calcd for C18H19N2O:
265.1467. Found: 265.1484. [a]D25ϭϪ160.0° (cϭ1.00%).
Similarly, ent-4b (500 mg, 1.59 mmol) was treated with TFAA (1.66 g,
11.13 mmol) and TFSA (27.2 g, 0.175 mol) under similar conditions as de-
scribed above. The reduction of this reaction mixture in EtOH with
NiCl2·6H2O (1.13 g, 7 mmol) and NaBH4 (1.7 g, 21 mol) gave ent-6b
(167 mg, 56%), and ent-7bA (152 mg, 36%) (Table 1, entry 11).
(1S,3R)-2-Formyl-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (ent-6b):
Colorless prisms, recrystallized from AcOEt–hexane, mp 62—65 °C. IR:
1
1660. H-NMR: 1.33, 1.36 (total 3H, each d, Jϭ7 Hz, C3-CH3) 1.59, 1.60
(total 3H, each d, Jϭ7 Hz, C1-CH3), 2.7—2.8 (1H, m, C4-H), 3.1—3.2 (1H,
m, C4-H), 4.1—4.2, 4.6—4.7 (total 1H, each m, C3-H), 4.78, 5.38 (total 1H,
each q, Jϭ7 Hz, C1-H), 7.1—7.3 (4H, m, Ph-H) 8.23, 8.29 (total 1H, each s,
CHO). LR-EIMS m/z: 189 (Mϩ), 174 (base peak). HR-EIMS m/z (Mϩ):
Calcd for C12H15NO: 189.1154. Found: 189.1157. [a]D25ϭ83.2° (cϭ1.00%).
(1S,3R,4S)-2-Formyl-1,3-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquino-
line (ent-7bA): Colorless prisms, recrystallized from AcOEt–ether, mp 98—
101 °C. IR: 1670. 1H-NMR: 1.21, 1.44 (total 3H, each d, Jϭ7 Hz, C3-CH3),
1.6—1.7 (3H, m, C1-CH3), 3.9—4.0, 4.8—4.9 (total 1H, each m, C3-H),
4.08 (1H, s, C4-H), 4.90, 5.48 (total 1H, each q, Jϭ7 Hz, C1-H), 6.8—7.4
(9H, m, 2ϫPh-H). 7.62, 8.25 (total 1H, each s, CHO). LR-EIMS m/z: 265
(Mϩ), 179 (base peak). HR-EIMS m/z (Mϩ): Calcd for C18H19N2O:
(1R,3R,4S)-1,3-Dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (8aA):
HCl salt, pale yellow prisms, recrystallized from AcOEt–hexane, mp 127—
1
129 °C. H-NMR: 1.11 (3H, d, Jϭ6 Hz, C3-CH3), 1.58 (3H, d, Jϭ7 Hz, C1-
CH3), 3.3—3.4 (1H, m, C3-H), 3.64 (1H, d, Jϭ8 Hz, C4-H), 4.27 (1H, q,
Jϭ7 Hz, C1-H), 6.7—7.3 (9H, m, Ar-H, Ph-H). 13C-NMR: 20.6 (C3-CH3),
24.1 (C1-CH3), 50.4 (C4), 50.7 (C1), 53.2 (C3), 125.9 (C6), 126.1 (C7),
126.2 (C5), 126.4 (C8), 128.4 (2ϫPhCH), 129.4 (2ϫPhCH), 130.3 (PhCH),
137.5 (C4a), 140.4 (C8a), 144.7 (PhC). LR-EIMS m/z: 237 (Mϩ), 179 (base
peak). HR-EIMS m/z (Mϩ): Calcd for C17H19N: 237.1516. Found: 237.1516.

672
Vol. 51, No. 6
[a]D24ϭϩ53.1° (HCl salt, cϭ0.86%). CD (HCl salt, cϭ7.91ϫ10Ϫ4 M) [q]25
(nm): 1500 (268), 1900 (263), Ϫ25000 (224).
126.4 (C8), 128.4 (2ϫPhCH), 129.7 (2ϫPhCH), 129.9 (PhCH), 139.1
(C4a), 140.2 (C8a), 144.2 (PhC). LR-EIMS m/z: 237 (Mϩ), 179 (base peak).
(1S,3S,4R)-1,3-Dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (ent- HR-EIMS m/z (Mϩ): Calcd for C17H19N: 237.1516. Found: 237.1499.
8aB): 177 mg (99%) was obtained from ent-7aB (200 mg, 0.755 mmol) as [a]D28ϭϩ34.32° (HCl salt cϭ1.00%). CD (HCl salt cϭ1.82ϫ10Ϫ3 M) [q]25
a pale yellow oil, HCl salt, pale yellow prisms, recrystallized from (nm): 2400 (269), 3000 (261), Ϫ15000 (227).
AcOEt–hexane, mp 127—129 °C. 1H-NMR: 1.11 (3H, d, Jϭ6 Hz, C3-CH3),
References and Notes
1) Padwa A., Gunn D. E., Jr., Osterhout M. H., Synthesis, 1997, 1353—
1377 (1997).
2) Sano T., Trends Heterocycl. Chem., 7, 117—142 (2001).
3) Shinohara T., Toda J., Sano T., Chem. Pharm. Bull., 45, 813—819
(1997).
4) Shinohara T., Takeda A., Toda J., Terasawa N., Sano T., Heterocycles,
46, 555—565 (1997).
5) Shinohara T., Takeda A., Toda J., Ueda Y., Kohno M., Sano T., Chem.
Pharm. Bull., 46, 918—927 (1998).
6) Shinohara T., Takeda A., Toda J., Sano T., Chem. Pharm. Bull., 46,
430—433 (1998).
7) Toda J., Sakagami M., Sano T., Chem. Pharm. Bull., 47, 1269—1275
(1999).
8) Toda J., Ichikawa T., Saitoh T., Horiguchi Y., Sano T., Heterocycles,
52, 2009—2018 (2000).
9) Horiguchi Y., Saitoh T., Terakado S., Honda K., Kimura T., Toda J.,
Heterocycles, 54, 967—984 (2001).
10) Toda J., Matsumoto S., Saitoh T., Sano T., Chem. Pharm. Bull., 48,
91—98 (2000).
11) Makino Y., Ohta S., Tasaki Y., Tachikawa O., Kashiwasaki M., Hirobe
M., J. Neurochem., 55, 963—969 (1990).
12) Yokoyama A., Ohwada T., Shudo K., J. Org. Chem., 64, 611—617
(1999).
13) The spectral data including the [a]D values of the compounds (1a, ent-
1a, 1b, ent-1b, 3a, ent-3a, 3b, ent-3b, 4a, ent-4a, 4b, ent-4b) and the
CD values of the TIQs (1a, ent-1a, 1b, ent-1b) reported in ref. 4 are
found have errors in the description and therefore should be discarded.
[Errata: Chem. Pharm. Bull., 50, 1641—1642 (2002)].
1.58 (3H, d, Jϭ7 Hz, C1-CH3), 3.3—3.4 (1H, m, C3-H), 3.64 (1H, d,
Jϭ8 Hz, C4-H), 4.27 (1H, q, Jϭ7 Hz, C1-H), 6.7—7.3 (9H, m, Ar-H, Ph-H).
13C-NMR: 20.6 (C3-CH3), 24.1 (C1-CH3), 50.4 (C4), 50.7 (C1), 53.2 (C3),
125.9 (C6), 126.1 (C7), 126.2 (C5), 126.4(C8), 128.4 (2ϫPhCH), 129.4
(2ϫPhCH), 130.3 (PhCH), 137.5 (C4a), 140.4 (C8a), 144.7 (PhC). LR-EI-
MS m/z: 237 (Mϩ), 179 (base peak). HR-EIMS m/z (Mϩ): Calcd for
C17H19N: 237.1516. Found: 237.1516. [a]D24ϭϪ62.1° (HCl salt, cϭ0.86%).
CD (HCl salt cϭ7.17ϫ10Ϫ4 M) [q]25 (nm): Ϫ1100 (268), Ϫ1800 (261),
28600 (224).
(1R,3S,4R)-1,3-Dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (8bB):
561 mg (48%) was obtained from 7bB (1.3 g, 4.95 mmol) as colorless
prisms, recrystallized from AcOEt–hexane, mp 57—59 °C, HCl salt, pale
yellow prisms, recrystallized from AcOEt–hexane, mp 253—256 °C. 1H-
NMR: 1.07 (3H, d, Jϭ6 Hz, C3-CH3), 1.53 (3H, d, Jϭ7 Hz, C1-CH3), 3.1—
3.2 (1H, m, C3-H), 3.70 (1H, d, Jϭ8 Hz, C4-H), 4.33 (1H, q, Jϭ7 Hz, C1-
H), 6.7—7.3 (9H, m, Ar-H, Ph-H). 13C-NMR: 20.9 (C3-CH3), 22.4
(C1-CH3), 52.6 (C4), 54.7 (C1), 56.5 (C3), 124.5 (C6), 125.9 (C7), 126.1
(C5), 126.4 (C8), 128.4 (2ϫPhCH), 129.7 (2ϫPhCH), 129.9 (PhCH),
139.1 (C4a), 140.2 (C8a), 144.2 (PhC). LR-EIMS m/z: 237 (Mϩ),
179 (base peak). HR-EIMS m/z (Mϩ): Calcd for C17H19N: 237.1516. Found:
237.1499. [a]D28ϭϪ30.84° (HCl salt, cϭ1.00%). CD (HCl salt cϭ7.50ϫ
10Ϫ4 M) [q]25 (nm): Ϫ3000 (268), Ϫ3400 (261), 22600 (226).
(1S,3R,4S)-1,3-Dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (ent-
8bA): 97 mg (48%) was obtained from ent-7bA (233 mg, 0.88 mmol) as col-
orless prisms, recrystallized from AcOEt–hexane, mp 57—59 °C, HCl salt,
pale yellow prisms, recrystallized from AcOEt–hexane, mp 253—256 °C.
1H-NMR: 1.07 (3H, d, Jϭ6 Hz, C3-CH3), 1.53 (3H, d, Jϭ7 Hz, C1-CH3),
3.1—3.2 (1H, m, C3-H), 3.70 (1H, d, Jϭ8 Hz, C4-H), 4.33 (1H, q, Jϭ7 Hz,
C1-H), 6.7—7.3 (9H, m, Ar-H, Ph-H). 13C-NMR: 20.9 (C3-CH3), 22.4 (C1-
CH3), 52.6 (C4), 54.7 (C1), 56.5 (C3), 124.5 (C6), 125.9 (C7), 126.1 (C5),