Phase-transfer-catalyzed asymmetric synthesis of 1,1-disubstituted tetrahydroisoquinolines

Article abstract of DOI:10.1002/adsc.201100269

A highly efficient catalytic asymmetric synthesis of 1,1-disubstituted tetrahydroisoquinolines has been achieved via asymmetric alkylation or Michael addition of 1-cyanotetrahydroisoquinolines using binaphthyl-modified N-spiro-type chiral phase-transfer c

Full text of DOI:10.1002/adsc.201100269

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DOI: 10.1002/adsc.201100269
Phase-Transfer-Catalyzed Asymmetric Synthesis of
1,1-Disubstituted Tetrahydroisoquinolines
Seiji Shirakawa,a Kun Liu,a Hironobu Ito,a Thanh Nguyen Le,a
and Keiji Maruokaa,*
a
Laboratory of Synthetic Organic Chemistry and Special Laboratory of Organocatalytic Chemistry, Department of
Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Fax : (+81)-75-753-4041; phone: (+81)-75-753-4041; e-mail: maruoka@kuchem.kyoto-u.ac.jp
Received: April 11, 2011; Revised: May 27, 2011; Published online: October 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100269.
Abstract: A highly efficient catalytic asymmetric
synthesis of 1,1-disubstituted tetrahydroisoquino-
lines has been achieved via asymmetric alkylation
or Michael addition of 1-cyanotetrahydroisoquino-
lines using binaphthyl-modified N-spiro-type chiral
phase-transfer catalysts.
Figure 1. Biologically active 1,1-disubstituted tetrahydroiso-
quinolines.
Keywords: alkylation; asymmetric synthesis; Mi-
chael addition; organocatalysis; phase-transfer cat-
alysis
stituted tetrahydro-b-carbolines,[12] which are recog-
nized as compounds related to tetrahydroisoquino-
lines.[2] In this context, we became interested in the
extension of this practical synthetic method to the
asymmetric synthesis of 1,1-disubstituted tetrahydro-
The structure of 1-substituted tetrahydroisoquinolines
ACHTUNGTRENiNGNU soquinolines. Here we wish to report a valuable ex-
is found in a variety of biologically active natural ample of the highly efficient catalytic asymmetric syn-
products,[1] and hence these heterocyclic compounds thesis of 1,1-disubstituted tetrahydroisoquinolines via
are important targets for organic synthesis. Numerous phase-transfer-catalyzed asymmetric alkylation of 1-
synthetic efforts have been devoted to building up cyanotetrahydroisoquinolines. Furthermore, this syn-
this structure in an especially stereoselective thetic method can be applied to asymmetric Michael
manner,[2] and various efficient catalytic asymmetric additions for the synthesis of other types of 1,1-disub-
methods have been developed to synthesize chiral tet- stituted tetrahydroisoquinolines.
rahydroisoquinolines.[3] Among them, the catalytic
We first examined the screening of the N-spiro-type
asymmetric synthesis of 1,1-disubstituted tetrahydro- chiral phase-transfer catalysts (S,S)-1[13] for asymmet-
ACHTUNGTRENNUNGisoquinolines possessing a chiral quaternary carbon ric alkylation of 1-cyanotetrahydroisoquinolines 2. An
center[4] is a formidable challenge in organic synthesis. attempted reaction of 1-cyanotetrahydroisoquinoline
Although a few examples of the catalytic asymmetric 2a with benzyl bromide (1.2 equiv.) in aqueous KOH/
synthesis of 1,1-disubstituted dihydroisoquinolines toluene under the influence of N-spiro-type phase-
have been reported,[5] a direct catalytic asymmetric transfer catalyst (S,S)-1a (1 mol%) at 08C for 24 h af-
method for the synthesis of 1,1-disubstituted tetrahy- forded the benzylation product 3a with 64% ee
droisoquinolines is still unknown,[6] despite the impor- (Table 1, entry 1). Switching the 3,3’-aromatic sub-
tance of these compounds in natural product chemis- stituents (Ar) of the catalyst to 3,5-di-tert-butylphenyl
try[1,7] and medicinal chemistry (Figure 1).[8,9]
groups (1b) resulted in improved enantioselectivity
In the course of our study on the asymmetric con- (75% ee, entry 2). The reaction using catalyst (S,S)-1c
struction of a chiral quaternary carbon center under which possessed 3,5-bis(trifluoromethyl)phenyl groups
phase-transfer conditions,[10,11] we have recently re- further improved the enantioselectivity, and the prod-
ported the catalytic asymmetric alkylation of 1-cyano- uct 3a was obtained with good enantioselectivity
tetrahydro-b-carbolines for the synthesis of 1,1-disub- (88% ee, entry 3). Finally, we found that introduction
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Phase-Transfer-Catalyzed Asymmetric Synthesis of 1,1-Disubstituted Tetrahydroisoquinolines
Table 1. Screening of chiral phase-transfer catalysts.[a]
Table 2. Asymmetric alkylation of 1-cyanotetrahydroisoqui-
nolines 2.[a]
Entry Y
RBr
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
H (2a)
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
73 (3a)
75 (3b)
68 (3c)
58 (3d)
89 (3e)
66 (3f)
93
94
87
84
87
90
5-Cl (2b)
7-Cl (2c)
7-F (2d)
7-Me (2e) PhCH2Br
5,7-Cl2
PhCH2Br
(2f)
Entry
PTC
Yield [%][b]
ee [%][c]
1
2
3
U
73
65
83
74
73
64
75
88
90
93
7
8
9
H (2a)
H (2a)
H (2a)
Z=Br
Z=F
Z=Me
73 (3g)
76 (3h)
74 (3i)
90
93
90
4
5[d]
[a]
10
5-Cl (2b)
70 (3j)
92
Reaction conditions: 2a (0.050 mmol) and benzyl bromide
(0.060 mmol) in the presence of 1 mol% of chiral phase-
transfer catalyst (PTC) in 50% aqueous KOH (0.25 mL)/
toluene (0.50 mL) at 08C for 24 h.
Yield of isolated products.
Determined by chiral HPLC analysis.
11
12
5-Cl (2b)
5-Cl (2b)
64 (3k)
71 (3l)
94
92
[b]
[c]
[d]
The reaction was performed at À208C.
of trifluoromethyl groups onto the 6,6’-positions of
one binaphthyl unit of the catalyst (1d) even further
improved the enantioselectivity (90% ee, entry 4).
The highest enantioselectivity was attained when a
lower temperature (À208C) was employed with cata-
lyst (S,S)-1d (93% ee, entry 5).
With these optimum reaction conditions in hand,
we studied the substrate generality of asymmetric alk-
ACHTUNGTRENNUNGylation of 1-cyanotetrahydroisoquinolines 2 under the
13
5-Cl (2b)
5-Cl (2b)
65 (3m)
46 (3n)
93
66
14
[a]
Reaction conditions: 2 (0.050 mmol) and alkyl halide
(0.060 mmol) in the presence of 1 mol% of (S,S)-1d in
50% aqueous KOH (0.25 mL)/toluene (0.50 mL) at
À208C for 24 h.
[b]
[c]
Yield of isolated products.
influence of chiral phase-transfer catalyst (S,S)-1d, as
shown in Table 2. The introduction of electron-with-
drawing and electron-donating substituents on the ar-
Determined by chiral HPLC analysis.
omatic ring of the tetrahydroisoquinoline core gave tivity (66% ee, entry 14). The absolute configuration
the benzylation products 3b–3f in good to high enan- of alkylation products 3 was determined by an X-ray
tioselectivities (84–94% ee, entries 2–6). Furthermore, diffraction analysis of 3l.[14]
a series of benzylic bromides with different steric and
To expand the utility of this synthetic method, we
electronic properties was tolerated in this reaction, were also interested in the development of an asym-
thus allowing the preparation of structurally diverse, metric Michael addition of 1-cyanotetrahydroisoqui-
enantioenriched
1,1-disubstituted
tetrahydro- nolines 2 under the phase-transfer conditions. As a
ACHTUNGTRENNUNGisoquinolines (90–94% ee, entries 7–12). The alkyl Michael acceptor for the reaction, phenyl vinyl sul-
halide containing a heteroaromatic ring could also be fone was selected to obtain synthetically useful prod-
applied to the reaction with high enantioselectivity ucts. The sulfonyl group of the product is a versatile
(93% ee, entry 13). The reaction with cinnamyl bro- building block for further transformations.[15] An at-
mide gave the product 3n in moderate enantioselec- tempted reaction of 1-cyanotetrahydroisoquinoline 2a
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Seiji Shirakawa et al.
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Table 3. Asymmetric Michael addition of 1-cyanotetrahy-
droisoquinolines 2 with vinyl sulfone.[a]
Scheme 1. Transformations of the product 3a.
the optically active alkylation product 3a was subject-
ed to alkaline hydrolysis or reduction to furnish
amide derivative 5 and amine derivative 6, respective-
ly, which possessed tricyclic structures (Scheme 1).
These tricyclic structures have been observed in bio-
logically active compounds.[9,19]
In summary, we have successfully developed the
highly enantioselective alkylation and Michael addi-
tion of 1-cyanotetrahydroisoquinolines for the synthe-
sis of 1,1-disubstituted tetrahydroisoquinolines under
mild phase-transfer conditions. The cyano group of
the products was easily transformed to other function-
al groups to obtain biologically interesting com-
pounds.
Entry
PTC
Y
Yield [%][b]
ee [%][c]
1[d]
2[e]
3[f]
4[f]
5
A
E
T
ACHTUNGTRENNUNG
H (2a)
H (2a)
5-Cl (2b)
7-Cl (2c)
7-F (2d)
7-Me (2e)
5,7-Cl2 (2f)
74 (4a)
67 (4a)
73 (4b)
64 (4c)
73 (4d)
47 (4e)
59 (4f)
53
84
93
95
91
88
95
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
6
7[f]
[a]
Reaction conditions: 2 (0.050 mmol) and phenyl vinyl sul-
fone (0.060 mmol) in the presence of 1 mol% of chiral
phase-transfer catalyst (PTC) in 50% aqueous Cs2CO3
(0.25 mL)/toluene (0.50 mL) at 08C for 72 h.
Yield of isolated products.
Determined by chiral HPLC analysis.
The reaction was performed for 24 h.
The reaction was performed for 48 h.
The reaction was performed at À208C.
[b]
[c]
[d]
[e]
[f]
Experimental Section
General Procedure for the Asymmetric Alkylation of
1-Cyanotetrahydroisoquinolines 2
To
a
solution of 1-cyanotetrahydroisoquinoline
2
with phenyl vinyl sulfone (1.2 equiv.) in aqueous
Cs2CO3/toluene under the influence of phase-transfer
catalyst (S,S)-1c, which was an effective catalyst for
the alkylation of 2a, afforded Michael adduct 4a with
moderate enantioselectivity (Table 3, entry 1).[16]
Switching the catalyst to (S,S)-1e possessing a radially
extended aromatic substituent (Ar) improved the
enantioselectivity, and the product 4a was obtained
with good enantioselectivity (84% ee, entry 2). Other
types of 1-cyanotetrahydroisoquinolines 2 possessing
electron-withdrawing and electron-donating substitu-
ents were found to be employable for the highly
enantioselective Michael addition with catalyst (S,S)-
1e (88–95% ee, entries 3–7). The absolute configura-
tion of Michael adducts 4 was determined by an X-
ray diffraction analysis of 4c,[17] and interestingly, the
observed configuration was the opposite of that of the
alkylation products 3.[18]
(0.050 mmol) and PTC (S,S)-1d (0.0005 mmol, 1 mol%) in
50% aqueous KOH (0.25 mL)/toluene (0.50 mL) was added
alkyl halide (0.060 mmol) at À208C under an argon atmos-
phere. The reaction mixture was vigorously stirred at À208C
for 24 h and quenched with saturated aqueous NH4Cl. The
organic phase was separated, and the aqueous phase was ex-
tracted with CH2Cl2. The combined extracts were washed
with brine and dried over Na2SO4. After evaporation of sol-
vents, the residue was purified by preparative thin layer
chromatography or column chromatography on silica gel
(CH2Cl2/hexane as eluent) to afford the alkylation product
3. The enantiomeric excess of the product was determined
by chiral HPLC analysis.
General Procedure for the Asymmetric Michael
Addition of 1-Cyanotetrahydroisoquinolines 2 to
Phenyl Vinyl Sulfone
To
a
solution of 1-cyanotetrahydroisoquinoline
2
The cyano group of the products can be readily
(0.050 mmol) and PTC (S,S)-1e (0.0005 mmol, 1 mol%) in
transformed to other functional groups. For example, 50% aqueous Cs2CO3 (0.25 mL)/toluene (0.50 mL) was
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Phase-Transfer-Catalyzed Asymmetric Synthesis of 1,1-Disubstituted Tetrahydroisoquinolines
added phenyl vinyl sulfone (0.060 mmol) at 08C under an
argon atmosphere. The reaction mixture was vigorously
stirred for 72 h and quenched with saturated aqueous
NH4Cl. The organic phase was separated, and the aqueous
phase was extracted with CH2Cl2. The combined extracts
were washed with brine and dried over Na2SO4. After evap-
oration of solvents, the residue was purified by preparative
thin layer chromatography or column chromatography on
silica gel (AcOEt/hexane as eluent) to afford the Michael
adduct 4. The enantiomeric excess of the product was deter-
mined by chiral HPLC analysis.
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[17] The crystal structure of 4c has been deposited at the
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from The Cambridge Crystallographic Data Centre via
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