Asymmetric acyl-Strecker reaction promoted by novel thiourea organocatalyst

Article abstract of DOI:10.3987/COM-10-12055

Asymmetric acyl-Strecker reaction using novel thiourea organocatalyst is described. Screening experiments of the catalysts revealed that a bifunctional organocatalyst afforded an enantio-enriched product via an unique mechanism. That is, dihydroisoquinoli

Full text of DOI:10.3987/COM-10-12055

HETEROCYCLES, Vol. 81, No. 12, 2010
2781
HETEROCYCLES, Vol. 81, No. 12, 2010, pp. 2781 - 2792. © The Japan Institute of Heterocyclic Chemistry
Received, 28th August, 2010, Accepted, 15th October, 2010, Published online, 25th October, 2010
DOI: 10.3987/COM-10-12055
ASYMMETRIC ACYL-STRECKER REACTION PROMOTED BY
NOVEL THIOUREA ORGANOCATALYST
Takuya Kanemitsu, Eisuke Toyoshima, Michiko Miyazaki, Kazuhiro Nagata,
and Takashi Itoh*
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai,
Shinagawa-ku, Tokyo 142-8555, Japan; e-mail: itoh-t@pharm.showa-u.ac.jp
Abstract – Asymmetric acyl-Strecker reaction using novel thiourea
organocatalyst is described. Screening experiments of the catalysts revealed that a
bifunctional organocatalyst afforded an enantio-enriched product via an unique
mechanism. That is, dihydroisoquinoline derivatives were converted to a
corresponding 1-cyano-1,2,3,4-tetrahydroisoquinolines using the bifunctional
thiourea catalystꢀderived from Betti base in moderate yield and enantioselectivity.
INTRODUCTION
Strecker reaction is a powerful method for the preparation of !-amino acids.1 Thus, development of
asymmetric Strecker reaction has recently received much attention for the synthesis of optically active
!-amino acids or their derivatives.2 Especially, organocatalytic approaches to the asymmetric reaction
have been widely acknowledged.3,4 Jacobsen and co-workers described an asymmetric Strecker reaction
catalyzed by a thiourea organocatalyst with excellent enantioselectivity.5 Recently, thiourea
organocatalysts have been widely used in asymmetric reaction6 owing to their strong activation of imino,
carbonyl or nitro groups through efficient hydrogen bonding interactions.7 We previously reported an
asymmetric Strecker reaction using the Jacobsen’s catalyst for the synthesis of tetrahydroisoquinoline
alkaloids.8 The Strecker reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline was succeeded in high yield
and high enantiomeric excess, and a 1-cyano-1,2,3,4-tetrahydroisoquinoline derivative thus obtained
could be readily converted to a variety of alkaloids. One of the drawbacks of the reaction was that the
Jacobsen catalyst was expensive because synthesis of the compound proceeded in multi-steps using rare
L-t-leucine as a chiral source. Therefore, it was thought that more readily prepared catalyst was necessary
for the present asymmetric reaction. In addition, List’s recent works described an asymmetric
acyl-Strecker reaction using less toxic acetyl cyanide as a cyanide source catalyzed by thiourea catalysts.9

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HETEROCYCLES, Vol. 81, No. 12, 2010
The result prompted us to carry out the study of asymmetric acyl-Strecker reaction of dihydroisoquinoline
catalyzed by novel thiourea organocatalysts. In this paper, we report readily accessible thiourea
organocatalysts, which are prepared from commercially available simple chiral amines or Betti base, and
efforts to accomplish an asymmetric acyl-Strecker reaction.ꢀ
RESULTS AND DISCUSSION
The study was commenced with the synthesis of new catalysts. We have designed a series of
asymmetrical chiral catalysts 3a-i (Scheme 1). We planned to make thiourea catalysts bearing a
bis(trifluoromethyl)phenyl group, because the substituent was reported to enhance the catalytic activity
due to higher acidity of N-H group in the thiourea.10 Moreover, we decided to use chiral amines 1a-i in
hope of their steric effects. Since commercially available chiral amines, (–)-1-phenylethylamine (1a),
(+)-1-(1-naphthyl)ethylamine (1b), (–)-isopinocamphenylamine (1c), and (–)-cis-myrtanylamine (1d)
have been used as chiral auxiliaries, they were expected to function as chirality sources of the thiourea
catalyst. Betti base 1e, which can be readily prepared as an enantiopure product,11 have a phenolic
hydroxyl group, which was expected to play an effective role in an asymmetric reaction. To confirm the
role of the phenolic hydroxyl group, we prepared amines 1f-i derived from Betti base 1e, L-tyrosine, and
L-phenylalanine, respectively. The coupling reaction of 3,5-bis(trifluoromethyl)phenyl isothiocyanate 2
and chiral amines 1a-i was carried out in CH2Cl2 at room temperature to afford corresponding chiral
thiourea catalysts 3a-i in moderate to good yields (Scheme 1).
CF3
CF3
S
+
R
NH2
S
R
CH2Cl2
rt, 2-48 h
C
N
N
CF3
N
CF3
Me
1a-i
H
H
2
3a-i
50-95%
Me
R =
d
a
c
b
OH
Me
N
Me
N
Bn
Bn
O
OMe
OH
OTBDMS
O
e
h
g
i
f
Scheme 1. Preparation of catalysts

HETEROCYCLES, Vol. 81, No. 12, 2010
2783
Next, the catalytic properties of a series of thiourea catalysts were examined using conditions shown in
Table 1. An acyl-Strecker reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline 4 with acetyl cyanide 5 was
used for the screening process. The reaction was carried out by using 10 mol% of the chiral catalyst at
–40 ˚C in CH2Cl2. A reaction hardly proceeded in the absence of the catalyst (Table 1, entry 1). In the
cases of the thiourea catalysts 3a-d derived from commercially available chiral amines, nearly racemic
products were obtained (Table 1, entries 2-5). On the other hand, catalyst 3e bearing Betti base exhibited
improved enantioselectivity (Table 1, entry 6). Thus, Betti base was found to act as a chiral source of the
catalytic acyl-Strecker reaction. In addition, TBDMS protection (3f) or methylation (3g) of the phenolic
hydroxyl group resulted in disappearance of enantioselectivity (Table 1, entries 7 and 8). These results
suggested that the phenolic hydroxyl group of the catalyst took part in the enantioselective mechanism in
this reaction. Thus, the catalyst 3e was considered to be a bifunctional organocatalyst. On the contrary,
neither L-tyrosine nor L-phenylalanine derivatives did afford the enantioselective product (Table 1, entries
9 and 10). These results indicated that the importance of a distance and/or an angle between thiourea and
phenolic hydroxyl group for the enantioselectivity.
Table 1. Screening studies of organocatalytic acyl-Strecker reaction of 6,7-dimethoxy-3,4-dihydro-
isoquinoline 4 and acetyl cyanide 5a
catalyst
MeO
MeO
MeO
MeO
(10 mol%)
O
Me CN
5
+
Me
N
N
CH2Cl2
-40 oC, 48 h
O
CN
4
6
entry
catalyst
none
3a
yieldb (%)
eec (%)
1
2
-
2
3
46
42
46
48
45
39
34
41
45
3
1
3b
4
3
3c
5
0
3d
6
46
1
3e
7
3f
8
7
3g
9
2
3h
10
3
3i
a
The reaction was carried out with 4 (0.25 mmol), 5 (0.38 mmol), and catalyst (0.025 mmol) in CH2Cl2
(0.5 mL) at –40 ˚C.
b Yield of isolated product.
c Determined by HPLC analysis with a chiral column.

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HETEROCYCLES, Vol. 81, No. 12, 2010
Although all the thiourea compounds 3a-i could be employed with comparable efficiency as catalyst, only
the compound 3e did exhibit stereoselectivity. The thiourea catalyst 3e might form two hydrogen bonds
with the substrates, thereby activating or coordinating the substrates in a synergistic manner (Figure 1).
Namely, the asymmetric reaction was accelerated presumably through hydrogen bonds between the imine
nitrogen and two thiourea hydrogensꢀ and a hydrogen bond between oxygen of acetyl cyanide and
hydrogen of phenolic hydroxyl group. Recently, Takemoto et al reported a practical result of asymmetric
Michael addition of organoboronic acid using a bifunctional thiourea catalyst bearing a phenolic hydroxyl
group on (1R)-trans-cyclohexanediamine, which is often used as a chiral scaffold of various thiourea
catalyst.6(c) Here we described another type of chiral scaffold between a thiourea moiety and a phenolic
hydroxyl group.
CF3
S
N
H
O
CF3
N
H
N
H
H
O
CN
Me
MeO
OMe
Figure 1
Encouraged by the results, we next investigated the solvent effect using 10 mol% of catalyst 3e and 1.5
equiv of acetyl cyanide 5. As shown in Table 2, all the tested solvents except for methanol, afforded the
desired 1-cyanoisoquinoline 6 in low to moderate yields. Among the solvents examined, toluene was
found to be the best one in term of enantioselectivity (Table 2, entry 3), whereas other aromatic solvents
such as xylene and mesitylene obtained low enantioselectivity (Table 2, entries 4 and 5). Using CH Cl
2
2
as a solvent, the enantioselectivity of 6 dropped slightly (Table 2, entry 1). Weakly coordinating solvents,
THF and Et2O gave 6 with low yields and enantioselectivity (Table 2, entries 6 and 7). Based on these
results, we chose toluene as the solvent for the present reaction.

HETEROCYCLES, Vol. 81, No. 12, 2010
2785
Table 2. Screening studies of organocatalytic acyl-Strecker reaction of 6,7-dimethoxy-3,4-dihydro-
isoquinoline 4 and acetyl cyanide 5a
catalyst 3e
MeO
MeO
MeO
MeO
O
Me CN
5
(10 mol%)
+
Me
N
N
solvent
O
CN
temp., 48 h
4
6
entry
solvent
CH2Cl2
CHCl3
toluene
xylene
mesitylene
THF
temp. (oC)
-40
yieldb (%)
45
eec (%)
46
1
2
20
-40
44
3
53
-40
39
4
8
-40
32
5
4
-40
40
6
13
-40
11
7
10
Et2O
-40
10
8
-18
ndd
31
CH3CN
MeOH
CH2Cl2
DCE
-40
14
9
-40
trace
50
10
11
12
13
-20
19
-20
65
18
CCl4
-20
46
23
CF3C6H5
-20
58
a
The reaction was carried out with 4 (0.25 mmol), 5 (0.38 mmol), and catalyst (0.025 mmol) in CH2Cl2
(0.5 mL) at –40 ˚C.
b Yield of isolated product.
c Determined by HPLC analysis with a chiral column.
d not determined.
In order to improve the enantioselectivity, various additives were screened, and the results were
summarized in Table 3. With trifluoroacetic acid as an additive, the enantioselectivity was improved
(Table 3, entries 5-8). When 10 mol% of TFA was used, the enantioselectivity was slightly better with
similar reaction yield (Table 3, entry 6). Further increase of TFA amount did not raise enantioselectivity
(Table 3, entries 7 and 8). Thus, the best result was obtained when the reaction was conducted with 10
mol% of TFA in toluene using 30 mol% of catalyst 3e, giving 46% isolated yield and 67% eeꢁꢀ

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HETEROCYCLES, Vol. 81, No. 12, 2010
Table 3. Additive screening for the asymmetric acyl-Strecker reactiona
catalyst 3e
MeO
MeO
MeO
MeO
O
Me CN
5
additive
+
Me
N
N
toluene
-40 oC, 72 h
O
CN
4
6
yieldb (%)
eec (%)
57
additive (mol%)
none
entry
1
2
3
4
5
6
7
8
48
47
54
38
46
46
46
42
63
CH3SO3H (10)
CF3SO3H (10)
TCA (10)
57
49
63
TFA (5)
67
TFA (10)
62
TFA (20)
52
TFA (30)
a
The reaction was carried out with 4 (0.25 mmol), 5 (0.75 mmol), and catalyst 3e (0.075 mmol) in
toluene (0.5 mL) at –40 ˚C.
b Yield of isolated product.
c Determined by HPLC analysis with a chiral column.
Finally, several isoquinoline derivatives were used as substrates under the optimized reaction conditions.
Results using catalyst 3e are summarized in Table 4. 3,4-dihydroisoquinoline (7) was converted into
corresponding 1-cyanoisoquinoline 9 in moderate yield and enantioselectivity (Table 4, entry 3).
Decrease of enantioselectivity was observed when using TFA as an additive (Table 4, entry 4). The
reactions of 6,8-dimethoxy-3,4-dihydroisoquinoline 8 provided product 10 in good yields, but the
enantioselectivities were low (Table 4, entries 5 and 6).
In summary, we have discovered a novel class of organocatalyst and developed an enantioselective
acyl-Strecker reaction of isoquinolines. The new thiourea catalyst which has a phenolic hydroxyl group
was simple in structure and prepared easily from a chiral amine, Betti base. The phenolic hydroxyl group
played an important role for the enantioselectivity. This is the first example of acyl-cyanayion of cyclic
imines. The results indicated that simple and practical thiourea catalysts might be found by the
combination with chiral amines which have phenolic hydroxyl group. Further study on the mechanistic
aspect and the improvement of the ees are currently under investigation.

HETEROCYCLES, Vol. 81, No. 12, 2010
2787
Table 4. Thiourea 3e catalyzed asymmetric acyl-Strecker reaction of isoquinolinesa
R1
R2
R1
R2
catalyst 3e
O
Me CN
5
additive
Me
N
N
+
toluene
R3
O
CN
R3
4, 7, 8
-40 oC, 72 h
6, 9, 10
entry
R1
R2
OMe
OMe
H
R3
H
additive (mol%)
none
product
substrate
yieldb (%) eec (%)
57
48
1
2
3
4
5
6
4
4
7
7
8
8
OMe
OMe
H
6
6
67
46
H
TFA (10)
none
62
46
H
9
50
54
H
H
H
TFA (10)
none
9
29
82
OMe
OMe
H
OMe
OMe
10
10
29
66
H
TFA (10)
a
The reaction was carried out with 4 (0.25 mmol), 5 (0.75 mmol), and catalyst 3e (0.075 mmol) in
toluene (0.5 mL) at –40 ˚C.
b Yield of isolated product.
c Determined by HPLC analysis with a chiral column.
EXPERIMENTAL
Unless otherwise noted, materials were purchased from commercial suppliers and used without further
purification. Progress of the reactions was monitored by thin layer chromatography (TLC) performed on
Merck Art. 5715 Kieselgel 60 F254/0.25 mm thickness plates. Visualization was accomplished with UV
light and cerium sulfate-ammonium molybdate solution followed by heating. Column chromatography
was performed using forced flow of the indicated solvent on Sigma H-type silica Gel 60N (100-210 µm).
13
1
1H- and C-NMR spectra were recorded with JEOL JNM AL-400 instrument (400 MHz for H and 100
MHz for 13C) in deuterated solvent, using tetramethylsilane (" = 0.0 ppm in 1H-NMR spectra) and CDCl3
(" = 77.0 ppm in 13C-NMR spectra) as internal standards. 1H data were reported as follows: chemical shift
(" in ppm), multiplicity (s = singlet, d = doublet, t = triplet, dd = doublet of doublets, m = multiplet) and
coupling costant (J in Hz). Optical rotations were measured on a JASCO P1020 polarimeter operating at
the sodium D line at room temperature. Concentration is given in g/100 mL. The HPLC analyses were
performed with Shimadzu equipment (254 # absorbance Detector) using Daicel Chemical Industries,
LTD. CHIRALPAK IA column with hexane/ethyl acetate mixtures (composition and flow rate as
indicated). HPLC methods were calibrated with the corresponding racemic mixtures. High-resolution
mass spectra (HR-FAB MS) were measured with JEOL JMS-MS700V using p-nitrobenzyl alcohol as a
matrix. The known compounds have been identified by comparison of spectral data with those reported.

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HETEROCYCLES, Vol. 81, No. 12, 2010
The absolute configuration of the optically active compound 6 was determined after conversion into
methyl ester through acid-mediated hydrolysis and hydrogenolysis9(c) on the basis of the measured optical
rotation compared with literature values.8(a) In the case of compound 9 and 10, the absolute configurations
were not determined.ꢀ
Typical procedure for the synthesis of catalysts 3. To a solution of chiral amine (1.0 mmol) in CH2Cl2
(3 mL) was added dropwise 3,5-bis(trifluoromethyl)phenyl isothiocyanate (1.0 mmol) at rt under an
argon atmosphere. After stirring the reaction mixture for 24 h at rt, the solvent was removed under
reduced pressure and the resulting residue was recrystallized from CH2Cl2/hexane to provide 3.
Thiourea catalyst 3a: 83% yield; white crystals; mp 136-137!; ["]18D +14.0 (c 0.70, CHCl3); 1H-NMR
(400 MHz, CDCl3, 24.5!) # 7.86 (bs, 1H), 7.65 (s, 3H), 7.42-7.35 (m, 5H), 6.57 (bs, 1H), 5.39 (bs, 1H),
1.60 (d, J = 6.8 Hz, 3H); 13C-NMR (100 MHz, CDCl3, 24.5!) # 179.9, 141.3, 139.1,132.7 (q, JCF = 34.6
Hz), 129.3, 128.4, 126.1, 123.9, 122.8 (q, JCF = 271.7 Hz), 119.4, 54.8, 22.2; HR-FAB MS: Calcd for
C17H15F6N2S [M+H]+: 393.0860. Found 393.0872.
Thiourea catalyst 3b: 82% yield; white crystals; mp 130-131!; ["]18D –46.1 (c 0.69, CHCl3); 1H-NMR
(400 MHz, CDCl3, 23.8!) # 8.15 (d, J = 8.4 Hz, 1H), 7.92-7.84 (bs, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.85
13
(d, J = 8.0 Hz, 1H), 7.63-7.45 (m, 7H), 6.24 (bs, 2H), 1.80 (d, J = 6.8 Hz, 3H); C-NMR (100 MHz,
CDCl3, 23.7!) # 138.8, 136.3, 134.1, 132.8 (q, JCF = 31.4 Hz), 130.8, 129.2, 127.2, 126.3, 125.3, 123.8,
123.8, 123.8, 122.9, 122.6 (q, JCF = 271.4 Hz), 119.3, 51.0, 19.0; HR-FAB MS: Calcd for C21H17F6N2S
[M+H]+: 443.1017. Found 443.0986.
Thiourea catalyst 3c: 70% yield; colorless needles; mp 137-138!; ["]18 –17.5 (c 0.69, CHCl3);
D
1H-NMR (400 MHz, CDCl3) # 8.64 (s, 1H), 7.76 (s, 2H), 7.71 (s, 1H), 6.22 (s, 1H), 3.62 (s, 2H),
2.42-2.29 (m, 2H), 2.00-1.85 (m, 5H), 1.56-1.48 (m, 1H), 1.19 (s, 3H), 1.04 (s, 3H), 0.91 (d, J = 9.8 Hz,
13
1H); C-NMR (100 MHz, CDCl3) # 180.4, 138.8, 133.2 (q, JCF = 38.1 Hz), 123.9, 122.7 (q, JCF = 273.1
Hz), 119.4, 51.0, 43.8, 41.2, 40.7, 38.6, 33.1, 27.8, 25.8, 23.1, 19.7; HR-FAB MS: Calcd for C19H23F6N2S
[M+H]+: 425.1486. Found 425.1488.
Thiourea catalyst 3d: 71% yield; colorless needles; mp 197-198!; ["]18 –20.3 (c 0.67, CHCl3);
D
1H-NMR (400 MHz, CDCl3) # 8.53 (s, 1H), 7.77 (s, 2H), 7.69 (s, 1H), 6.15 (s, 1H), 4.79 (s, 1H), 2.78 (t, J

HETEROCYCLES, Vol. 81, No. 12, 2010
2789
= 12.0 Hz, 1H), 2.46-2.40 (m, 1H), 2.00-1.99 (m, 1H), 1.85 (t, J = 5.6 Hz, 1H), 1.79 (s, 1H), 1.57 (s, 1H),
1.24 (s, 3H), 1.19 (d, J = 7.1 Hz, 3H), 1.06 (s, 3H), 0.77 (d, J = 9.5 Hz, 1H); 13C-NMR (100 MHz, CDCl3)
# 179.9, 139.0, 133.0 (q, JCF = 31.4 Hz), 123.7, 122.7 (q, JCF = 273.1 Hz), 119.2, 54.1, 47.5, 46.0, 41.3,
38.4, 36.4, 35.3, 27.8, 23.3, 20.6; HR-FAB MS: Calcd for C19H23F6N2S [M+H]+: 425.1486. Found
425.1462.
Thiourea catalyst 3e: 84% yield; white crystals; mp 139-140!, ["]18D +14.4 (c 0.71, CHCl3); 1H-NMR
(500 MHz, CD2Cl2) # 8.29 (d, J = 5.8 Hz, 1H), 8.17 (s, 1H), 8.14 (bs, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.84
(d, J = 6.9 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.72 (s, 2H), 7.71 (s, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.39 (t, J
= 7.2 Hz, 1H), 7.23-7.18 (m, 5H), 7.07 (d, J = 8.6 Hz, 1H), 5.76 (bs, 1H); 13C-NMR (125 MHz, CD2Cl2) #
180.7, 151.5, 140.6, 139.0, 133.1 (q, JCF = 33.6 Hz), 132.8, 130.9, 130.1, 129.2, 128.9, 128.1, 127.7,
126.6, 124.5, 124.3, 123.3 (q, JCF = 271.0 Hz), 123.3, 119.8, 119.2, 118.6, 54.0; HR-FAB MS: Calcd for
C26H19F6N2OS [M+H]+: 521.1122. Found 521.1116.
Thiourea catalyst 3f: 50% yield; yellow amorphous; mp 85-87!; ["]18 +40.6 (c 0.69, CHCl3);
D
1H-NMR (400 MHz, CD3OD, 24.8!) # 7.96 (s, 2H), 7.72 (s, 1H), 7.60-7.50 (m, 4H), 7.36 (s, 1H),
7.11-6.92 (m, 9H), 0.90 (s, 9H), 0.25 (s, 3H), 0.21 (s, 3H); HR-FAB MS: Calcd for C32H33F6N2OSSi
[M+H]+: 635.1987. Found 635.2012.
Thiourea catalyst 3g: 95% yield; yellow amorphous; mp 88-90!; ["]18 –34.0 (c 0.69, CHCl3);
D
1H-NMR (400 MHz, CDCl3, 22.8!) # 8.83 (bs, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.35 (bs, 1H), 8.06 (d, J =
9.2 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz,
1H), 7.25-7.15 (m, 6H), 3.47 (s, 3H); 13C-NMR (100 MHz, CDCl3, 22.8!) # 179.9, 155.0, 140.9, 138.5,
133.1 (q, JCF = 34.6 Hz), 132.3, 130.5, 129.6, 128.6, 128.3, 127.8, 127.0, 125.8, 124.4, 123.6, 123.2,
122.8 (q, JCF = 271.7 Hz), 122.1, 119.3, 114.2, 56.5, 55.7; HR-FAB MS: Calcd for C27H21F6N2OS
[M+H]+: 535.1279. Found 535.1252.
Thiourea catalyst 3h: 50% yield; colorless amorphous; mp 95-97!; ["]18 +18.6 (c 0.69, CHCl3);
D
1H-NMR (400 MHz, CDCl3, 22.8!) # 9.04 (s, 1H), 8.79 (s, 1H), 7.91 (s, 2H), 7.43 (s, 1H), 7.17-7.11 (m,
7H), 6.76-6.70 (m, 2H), 5.61 (bs, 1H), 5.50 (q, J = 7.2 Hz, 1H), 4.84 (d, J = 15.2 Hz, 1H), 4.32 (d, J =
14.8 Hz, 1H), 3.15 (ddd, J = 4.6, 13.6, 21.0 Hz, 2H), 2.94 (s, 3H); 13C-NMR (100 MHz, CDCl3, 23.1!) #
181.4, 174.6, 155.1, 139.8, 135.3, 131.1 (q, JCF = 33.3 Hz), 130.5, 128.7, 127.5, 127.4, 127.3, 124.1,

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HETEROCYCLES, Vol. 81, No. 12, 2010
123.0 (q, JCF = 271.4 Hz), 118.0, 115.7, 56.6, 52.2, 37.7, 35.3; HR-FAB MS: Calcd for C26H24F6N3O2S
[M+H]+: 556.1493. Found 556.1524.
Thiourea catalyst 3i: 69% yield; colorless amorphous; mp 60-62!; ["]18 +13.5 (c 0.67, CHCl3);
D
1H-NMR (400 MHz, CDCl3, 22.9!) # 9.28 (s, 1H), 8.80 (s, 1H), 7.96 (s, 2H), 7.41 (s, 1H), 7.36-7.29 (m,
5H), 7.15-7.10 (m, 5H), 5.55 (q, J = 7.1 Hz, 1H), 4.88 (d, J = 14.4 Hz, 1H), 4.30 (d, J = 15.2 Hz, 1H),
3.26 (ddd, J = 7.7, 13.3, 24.3 Hz, 2H), 2.92 (s, 3H); 13C-NMR (100 MHz, CDCl3, 23.6!) # 181.6, 174.8,
139.9, 135.4, 135.3, 131.0 (q, JCF = 33.5 Hz), 129.3, 128.9, 128.7, 127.7, 127.6, 127.5, 124.1, 123.1 (q,
JCF = 271.7 Hz), 117.9, 56.6, 52.3, 38.7, 35.2; HR-FAB MS: Calcd for C26H24F6N3OS [M+H]+: 540.1544.
Found 540.1560.
General
procedure
for
the
acyl-Strecker
reaction.
To
a
solution
of
6,7-dimethoxy-3,4-dihydroisoquinoline (1 mmol) and catalyst 3 in CH2Cl2 (10 mL) was added dropwise
acetyl cyanide (1 mmol) at –40˚C under an argon atmosphere. After stirring the reaction mixture for 48 h
at –40˚C, the reaction mixture was directly purified though column chromatography on silica gel
(hexane-ethyl acetate, 6:4) to provide 6.
Compound 6: white solid; mp 204-205!, ["]24 –101.3 (c 0.45, CHCl3, 67% ee); HPLC tR (minor: R):
D
16.8 min; tR (major: S): 19.5 min [Chiralpak IA (0.46 cm x 25 cm, Daicel Chemical Ind., Ltd.), ethyl
acetate/hexane, 2/3, 0.5 mL/min]; 1H NMR (CDCl3) " 6.77 (s, 1 H), 6.65 (s, 1 H), 6.41 (s, 1 H), 3.96 (ddd,
1 H, J = 4.3, 4.3, 13.5 Hz), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.67 (ddd, 1 H, J = 4.3, 10.7, 13.7 Hz), 2.95 (ddd,
13
1 H, J = 5.4, 10.6, 16.0 Hz), 2.86 (ddd, 1 H, J = 3.8, 3.8, 15.8 Hz), 2.23 (s, 3 H); C NMR (CDCl3) "
169.5, 149.5, 148.6, 125.9, 120.1, 118.0, 111.4, 109.5, 56.1, 56.0, 43.2, 42.1, 28.1, 21.3; HR-FAB MS:
Calcd for C14H17N2O3 [M+H]+: 261.1239. Found 261.1227.
Compound 9: white solid; mp 112-114!, ["]24 –96.6 (c 0.1, CHCl3, 62% ee); HPLC tR (minor): 24.9
D
min; tR (major): 26.8 min [Chiralpak IA (0.46 cm x 25 cm, Daicel Chemical Ind., Ltd.), ethyl
acetate/hexane, 1/3, 0.5 mL/min]; 1H NMR (CDCl3) " 7.33-7.21 (m, 4 H), 6.48 (s, 1 H), 3.96 (dt, 1 H, J =
4.7, 13.3 Hz), 3.72 (ddd, 1 H, J = 5.5, 9.6, 12.4 Hz), 3.02-2.99 (m, 2 H), 2.23 (s, 3 H); 13C NMR (CDCl3)
" 169.6, 133.8, 129.2, 129.0, 128.6, 127.6, 127.4, 117.8, 43.5, 42.2, 28.5, 21.3; HR-FAB MS: Calcd for
C28H31N2OS [M+H]+: 201.1028. Found 201.1037.

HETEROCYCLES, Vol. 81, No. 12, 2010
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Compound 10: white solid; mp 107-109!, ["]24 –27.1 (c 0.1, CHCl3, 29% ee); HPLC tR (minor): 25.8
D
min; tR (major): 33.4 min [Chiralpak IA (0.46 cm x 25 cm, Daicel Chemical Ind., Ltd.), ethyl
acetate/hexane, 1/3, 0.5 mL/min]; 1H NMR (CDCl3) " 6.48 (s, 1 H), 6.36 (d, 1 H, J = 2.4 Hz), 6.29 (d, 1 H
J = 1.6 Hz), 3.96 (dt, 1 H, J = 4.6, 13.7 Hz), 3.88 (s, 3 H), 3.80 (s, 3 H), 3.67 (ddd, 1 H, J = 4.6, 10.6, 14.0
13
Hz), 2.95 (ddd, 1 H, J = 5.4, 10.6, 16.2 Hz), 2.87 (dt, 1 H, J = 3.8, 12.7 Hz), 2.21 (s, 3H); C NMR
(CDCl3) " 169.3, 161.0, 157.4, 135.7, 117.8, 109.9, 104.5, 97.0, 55.7, 55.4, 41.9, 39.5, 28.7, 21.3;
HR-FAB MS: Calcd for C14H17N2O3 [M+H]+: 261.1239. Found 261.1210.
ACKNOWLEDGEMENTS
This work was supported in part by a Grant for the High-Tech Research Center Project from the Ministry
of Education, Culture, Sports, Science and Technology of Japan.
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