Asymmetric intramolecular aza-Michael reaction using environmentally friendly organocatalysis

Article abstract of DOI:10.3987/com-02-s9

This communication describes enantioselective intramolecular aza-Michael reaction to prepare 1,2,3,4-tetrahydroisoquinolines by using organocatalysts. The organocatalytic reaction offers new green chemical process in heterocyclic chemistry. Additional not

Full text of DOI:10.3987/com-02-s9

HETEROCYCLES, Vol. 59, No. 1, 2003, pp. 51 - 55, Received, 13th May, 2002
ASYMMETRIC
REACTION
INTRAMOLECULAR
AZA-MICHAEL
FRIENDLY
USING ENVIRONMENTALLY
ORGANOCATALYSIS†
Kiyosei Takasu,* Soumen Maiti, and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, Aobayama, Sendai 980-8578, Japan
E-mail: mihara@mail.pharm.tohoku.ac.jp
Abstract – This communication describes enantioselective intramolecular aza-
Michael reaction to prepare 1,2,3,4-tetrahydroisoquinolines by using
organocatalysts. The organocatalytic reaction offers new green chemical process
in heterocyclic chemistry. Additional noting, both enantiomers of the product
were easily synthesized by using two types of organocatalysts prepared from the
same amino acid.
Aza-Michael reaction has been intensely investigated as an important C–N bond formation reaction in
the synthesis of heterocyclic compounds.1 Most of the cases a nitrogen nucleophile reacts with α,β-
unsaturated carbonyl function as either a neutral nitrogen or an anionic nitrogen such as metal amide
base. However, due to the strong Lewis basicity of the neutral or anionic nitrogen, catalytic aza-Michael
reaction utilizing Lewis acid catalysis must be a difficult task. We have supposed that utilization of
organocatalysts can solve the inherent problems. During the past few years, asymmetric organocatalysis2
(only small organic molecule used as a reaction catalyst) has received intensive interests from the
viewpoint of green chemistry as well as bioorganic chemistry. Recently, MacMillan and co-workers
have revealed that organocatalysts (1a) and/or (1b) are significantly effective in enantioselective
reactions with α,β-unsaturated carbonyl compounds, such as Diels-Alder reaction,3 1,3-dipolar addition4
and Friedel-Crafts alkylation5 (Figure 1). Through the asymmetric reactions the organocatalysts serves to
activate the achiral Michael acceptor via formation of a chiral iminium species. It is noteworthy that
MacMillan’s process is very ecological; the reaction proceeds without metallic reagents/catalysts in
† Dedicated to Prof. Y. Kanaoka on the occasion of his 75th birthday.

alcohol and/or aqueous solution. In this communication, we report the first enantioselective
organocatalytic intramolecular aza-Michael reaction to prepare nonracemic 1,2,3,4-
tetrahydroisoquinolines under environmentally friendly conditions.6,7
We have designed dopamine derivatives (2) as reaction substrates, which possess α,β-unsaturated
aldehyde and amide functions at each ends. Compounds (2a-f) were synthesized from 3,4-dihydro-6,7-
Figure 1. Asymmetric aminocatalysts
O
O
Me
Me
O
Me
O
O
Me
Me
N
N
N
N
N
NH
NH
Ph
Ph
N
N
N
N
N
H •HCl
H •HCl
H •HCl
H •HCl
H •HCl
1a
1b
1c
1d
1e
dimethoxyisoquinoline hydrochloride (3) in a short sequence (Scheme 1). Namely, the reaction of 3 with
acid chlorides in a mixture of dichloromethane and saturated aqueous sodium bicarbonate at room
temperature afforded aldehydes (4a-f).8 Wittig olefination of 4a-f with 1,3-dioxolan-2-ylmethyltributyl-
phosphonium bromide in the presence of potassium t-butoxide and catalytic amount of 18-crown-6
produced (E)-alkenyldioxolanes (5a-f) in good yields. Deacetalization of 5a-f was achieved under
neutral condition to furnish (E)-α,β-unsaturated aldehydes (2a-f) as key substrates. Novel MacMillan-
type of asymmetric catalysts (1c-e)9 were also prepared from the corresponding L-amino acid methyl
esters by the same strategies as the syntheses of 1a and 1b.3,5
MeO
MeO
NHCOR
MeO
MeO
b
a
N•HCl
CHO
4a-f
3
a : R = CH=CH2
b : R = t-Bu
c : R = Ph
d : R = (E)-CH=CHCH3
e : R = CF3
f : R = Me
MeO
MeO
NHCOR
MeO
MeO
NHCOR
c
O
CHO
2a-f
O
5a-f
Scheme 1. conditions; (a) RCOCl, NaHCO3, CH2Cl2, rt; (b) 1,3-dioxolan-2-ylmethyltributylphosphonium
bromide, t-BuOK, 18-crown-6, CH2Cl2, rt; (c) SiO2, CH2Cl2–EtOH–H2O, rt.
First, we evaluated the chiral organocatalysts (1a-e) for the intramolecular aza-Michael reaction of 2a
(Scheme 2, Table 1). The catalytic reaction was typically performed as follows. To a solution of the
catalyst (1) (20 mol%) in MeOH/H2O (95:5 v/v)10 was added the substrate (2), and the reaction mixture

was stirred for 10 days at ambient temperature. After usual work up, the intramolecular aza-Michael
product (6) was purified by column chromatography (silica gel). The enantiomeric excess (ee) of 6 was
determined by HPLC analysis using a chiral column. Although no cyclized product was observed
without catalyst but with HCl (run 1), the reaction in the presence of organocatalyst (1a) provided
tetrahydroisoquinoline (+)-(6a) with 34% ee in 87% yield (run 2). Whereas alkenylacetal (5a) also
furnished (+)-6a in good yield, its stereoselectivity decreased to 30% ee (run 3). Among various
catalysts tested, catalyst (1d) derived from L-tryptophan was found to be the most effective in the
asymmetric reaction of 2a (run 6). Interestingly, we found that catalysts (1a) and (1b), which were both
prepared from L-phenylalanine, gave raise to different enantiomers (+)-(6a) and (–)-(6a), respectively
(runs 2 and 4). The similar phenomenon was observed in the reaction with 1d and 1e (runs 6 and 7). This
result indicates that both enantiomers can be easily prepared using secondary amine catalysts derived
from natural amino acids. The absolute configuration of (+)-6a was determined by comparison with the
authentic sample after transformation into (+)-(R)-7.11
Results of asymmetric aza-Michael reaction of other substrates having various N-acyl function are
Scheme 2
MeO
MeO
NHCOR
H
MeO
MeO
N
R
1 (20 mol%)
*
2
MeO
O
MeOH-H2O, rt
N
OMe
*
6
Table 1. Catalytic asymmeytic intramolecular aza-Michael
reactions of 2a.a
run catalyst
product
% ee (config)
substrate
% yield
—
MeO
MeO
HCl
1a
1a
1b
1c
6a
0
1
2
3
4
5
6
7
2a
2a
5a
2a
2a
2a
2a
34 (R)
30 (R)
18 (S)
30 (R)
46 (R)
25 (S)
(+)-6a
(+)-6a
(–)-6a
(+)-6a
(+)-6a
(–)-6a
87
89
85
88
90
85
N
O
(R)-7
1d
1e
a
All reactions were performed by treatment of substrate with 20 mol% of
catalyst in MeOH/H O (19 : 1) at room temperature for 10 days.
2
summarized in Table 2. From this study, it is found that reaction of 2 possessing less bulky N-acyl
moiety tends to achieve 6 with higher enantioselectivity (runs 2, 3 and 5 in Table 2, and run 6 in Table 1).

Although the enantioselectivity was not satisfactory, highest asymmetric induction (53 %ee) was
achieved in the reaction of acetamide (2f) (run 5 in Table 2). On the contrary, no cyclization was
observed in the reaction of 2b and 2e (runs 1 and 4).
Table 2. Catalytic asymmeytic aza-Michael reactions with (S)-1d.
run substrate
product % yield
% ee
2b (R = tBu)
6b
0
—
34
43
—
53
1
2
3
4
5
2c (R = Ph)
(+)-6c
(+)-6d
6e
70
88
0
2d (R = (E)-CH=CHCH3)
2e (R = CF3)
2f (R = Me)
(+)-6f
85
a All reactions were performed by treatment of 2 with 20 mol% of (S)-1d
in MeOH/H2O (19 : 1) at room temperature until 2 was fully comsumed.
In conclusion, we demonstrated a new strategy for enantioselective intramolecular aza-Michael reaction
by using MacMillan-type organocatalysts, although there still stands improvement in enantioselectivity
and reaction rate. Both enantiomers of 1-substituted 1,2,3,4-tetrahydroisoquinolines can be easily
synthesized by using two types of organocatalysts prepared from the same amino acid. We believe the
further studies will pave way for a new synthetic method towards various chiral heterocycles.
ACKNOWLEDGEMENT
This work was supported in part by Fujisawa Pharmaceutical Company Award in Synthetic Organic
Chemistry, Japan, and a Grant-In-Aid for Scientific Research on Priority Areas (A) “Exploitation of
Multi Element Cyclic Molecules” and JSPS Postdoctoral Fellowship (for S.M.) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
REFERENCES AND NOTES
1. (a) M. Schafer, K. Drauz, and M. Schwarm, ‘Methoden der Organischen Chemie (Houben–Weyl),
4thedition,’ ed. by G. Helmchen, R. W. Hoffmann, J. Mulzer, and E. Schaumann, Thieme, Stuttgart,
1995, Vol. E21/5, pp. 5588–5642. (b) P. Perimutter, ‘Conjugate Addition Reactions in Organic
synthesis,’ Pergamon, Oxford, 1992.
2. For reviews. See, (a) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2001, 40, 3727. (b) B. List,
Synlett, 2001, 1675.
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B. Northrup and D. W. C. MacMillan, J. Am. Chem. Soc., 2002, 124, 2458.
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W. C. MacMillan, J. Am. Chem. Soc., 2002, 124, 1172.
6. Racemic version of organocatalytic intermolecular aza-Michael reaction was recently reported; see
K. Nagasawa, A. Georgieva, H. Takahashi, and T. Nakata, Tetrahedron, 2001, 57, 8959.
7. Asymmetric catalytic Michael reactions via iminium species. (a) M. Ymaguchi, T. Shiraishi, and M.
Hirama, Angew. Chem., Int. Ed., 1993, 32, 1176. (b) M. Ymaguchi, T. Shiraishi, and M. Hirama, J.
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Perkin Trans. 1, 1987, 1719.
23
9. Selected spectral data; (S)-1d (as HCl salt): colorless solids, mp 237-238 °C (decomp); [α]D
1
–101.1° (c 1.43, MeOH); IR (KBr): ν 3370, 1725, 1647 cm–1; H NMR (400 MHz, CD3OD): δ
7.62-7.64 (m, 1H), 7.35-7.40 (m, 2H), 7.05-7.17 (m, 2H), 4.65 (dd, J = 10.5, 3.4 Hz, 1H), 3.62-3.67
(m, 1H), 3.22-3.31 (m, 2H), 2.90 (s, 3H), 1.67 (s, 3H), 1.55 (s, 3H); 13C NMR (100 MHz, CD3OD):
δ 168.0, 138.2, 127.7, 125.5, 122.9, 120.2, 119.0, 112.6, 108.3, 79.0, 58.7, 25.7, 25.6, 24.4, 22.4;
HRMS (as free amine) m/z calcd for C15H19N3O (M+) 257.1528, found 257.1512.
10. Other reaction solvent systems such as THF–H2O, t-BuOH–H2O, DMSO–H2O resulted in lower
asymmetric induction.
11. M. Nakamura, A. Hirai, and E. Nakamura, J. Am. Chem. Soc., 1996, 118, 8489.