Solvent-free direct aza-Friedel-Crafts reactions between 3,4-dihydroisoquinoline and 1- or 2-naphthols

Article abstract of DOI:10.1016/j.tetlet.2006.07.066

A self-catalytic aza-Friedel-Crafts method was employed to generate 1-naphtholyl tetrahydroisoquinoline products under neat conditions. In addition, a derivative was prepared in its enantiomerically pure form and has shown moderate activity for asymmetric catalysis in the asymmetric diethylzinc addition to aldehydes.

Full text of DOI:10.1016/j.tetlet.2006.07.066

Tetrahedron Letters 47 (2006) 6791–6794
Solvent-free direct aza-Friedel–Crafts reactions between
3
,4-dihydroisoquinoline and 1- or 2-naphthols
Patricia D. MacLeod, Zhiping Li, Jianqing Feng and Chao-Jun Li*
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Que., Canada H3A 2K6
Received 19 June 2006; revised 12 July 2006; accepted 14 July 2006
Available online 8 August 2006
Abstract—A self-catalytic aza-Friedel–Crafts method was employed to generate 1-naphtholyl tetrahydroisoquinoline products
under neat conditions. In addition, a derivative was prepared in its enantiomerically pure form and has shown moderate activity
for asymmetric catalysis in the asymmetric diethylzinc addition to aldehydes.
Ó 2006 Elsevier Ltd. All rights reserved.
The Friedel–Crafts reaction is an important reaction for
C–C bond formation. After over a century of develop-
ment, it still attracts much research interest in both
academia and industry. Brønsted acid- or Lewis
acid-catalyzed imine or iminium Friedel–Crafts
reactions (aza-Friedel–Crafts reactions) are important
methods to construct a variety of nitrogen containing
compounds.
1
2
a
Table 1. Optimization of reaction conditions
NH
OH
OH
NH
OH
+
N
1
6 h
R
1
2a R=H
R=OMe
R
2
b
3
a or 3b
Figure 1. THIQNOL.
b
c
Entry
2
Solvent
Temperature (°C) Yields (%)
1
2
3
4
5
6
7
8
9
2a Neat
2a Neat
2a Neat
2a Toluene
2a THF
2a Dichloroethane
2b Neat
2b Neat
60
90
90
60
60
60
25
60
90
92 (87)
83
66
41
6
20
NR
62
H
H
O
O
N
d
N
+
2b Neat
84
1
1
1
1
1
1
0
1
2
3
4
5
2b Neat
2b Methanol
2b Acetonitrile
2b Dichloromethane Reflux
2b Diethyl ether
2b Nitromethane
120
60
60
Decomp’n
12
16
NR
NR
9
OH HN
Reflux
60
a
b
c
3
,4-Dihydroisoquinoline (1.0 mmol) and naphthol (1.0 mmol).
Scheme 1. Self-catalytic reaction between hydroxyl and imine.
When solvent was used, 3 mL solvent was used.
HNMR yields were determined by HNMR by using an internal
standard; isolated yield is given in parentheses.
Under microwave conditions.
*
Corresponding author. Tel.: +1 514 398 8457; fax: +1 514 398
797; e-mail: cj.li@mcgill.ca
d
3
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.066

6792
P. D. MacLeod et al. / Tetrahedron Letters 47 (2006) 6791–6794
Recently, we have designed and synthesized a new class
OH
o
NH
OH
of chiral compounds, 1-naphtholyl tetrahydroisoquino-
lines, including the lead compound 1-(1,2,3,4-tetra-
9
0 C
+
N
NMR yield: 92%
hydroisoquinolin-1-yl)-naphthalen-2-ol
(THIQNOL)
3
,4
1
2
g
(Fig. 1), as potential chiral ligands for asymmetric
synthesis and other applications.
3g
3
In our initial report, a cross-dehydrogenative-coupling
N
H
5
(CDC) was used to generate the corresponding chiral
ligands. Alternatively, we also expected that the
4
O
compound could be formed through a Friedel–Crafts
6
reaction. We postulated that the hydroxyl group on
2
-naphthol might act as a catalyst to bind the nitrogen
4
in an imine and catalyze the reaction. In other words,
the whole reaction is self-catalytic (Scheme 1). There-
Scheme 2. The reaction of 3,4-dihydroisoquinoline and 1-napthol.
a
Table 2. Self-catalytic reactions of 3,4-dihydroisoquinoline with 2-naphthols
b
Entry
2
Product
Yield (%)
NH
OH
OH
1
2
3
2b
62
c
MeO
84
d
66
3b
MeO
NH
OH
OH
4
5
2c
81
60
e
OMe
3c
OMe
NH
MeO
OH
6
7
2d
91
97
MeO
OH
3
c
d
NH
OH
3e
OH
2e
8
9
Ph
54
12
c
Ph
O
O
NH
OH
OH
1
1
0
1
2f
32
45
e
Br
3
f
Br
NH
OH
OH
1
1
2
3
2g
73
92
c
3
g
a
b
c
Conditions: 3,4-dihydroisoquinoline (1.0 mmol), naphthol (1.0 mmol), at 60 °C; otherwise noted.
Determined by NMR spectroscopy by using an internal standard.
At 90 °C.
Water was used as solvent.
At 90 °C; isolated yield after crystallization.
d
e

P. D. MacLeod et al. / Tetrahedron Letters 47 (2006) 6791–6794
6793
fore, the reaction might occur without any extra cata-
lyst. Herein, we wish to report the synthesis of 1-naph-
tholyl tetrahydroisoquinolines directly by mixing the two
starting materials in situ without any catalyst or solvent.
the absence of any catalyst. After a series of experiments
(Table 1), the reaction was found to proceed smoothly
under neat conditions at 60 °C (Table 1, entry 1). The
reaction could also be performed in air without a large
reduction in yield. With 6-methoxy-2-naphthol (2b)
being used as the substrate, the reaction gave a higher
yield under neat conditions at 90 °C instead of 60 °C
(Table 1, entry 9). The reaction of 2-naphthol and 6-
methoxy-2-naphthol in various solvents all resulted in
much lower yields (Table 1, entries 4–6 and 11–15).
7
The reaction proceeded with 100% ‘atom economy’.
To begin our study, 3,4-dihydroisoquinoline (1) was re-
acted with 2-naphthol (2a) under various conditions in
MeI, KHCO3
DMF, rt
When 1-naphthol (2g) was reacted with 3,4-dihydroiso-
quinoline (1) under neat conditions, the desired product
NH
OH
N
CH3
OH
3g was obtained in 92% yield as a single regio-isomer.
87%
The regio-selectivity of the reaction was most likely
the result of a 6-membered cyclic transition state 4,
which then gives the desired product 3g after re-aroma-
tization (Scheme 2). This experiment also provided an
indirect validation of our initial hypothesis in Scheme 1.
3
a
4a
N
N
*
*
CH3
OH
CH
OH
3
L-tartaric acid
CH Cl , EtOH
+
With the optimized conditions in hand, various naph-
thols were subjected to the reaction to give a series of
THIQNOL analogs. Representative results are listed in
Table 2. A marked electronic effect was observed in
the reaction: 2-naphthols with electron-donating substit-
uents gave excellent yields (Table 2, entries 1–7, 12–13);
2
2
(
-)-4a
(+)-4a
92%ee
>
99%ee
Scheme 3. Preparation of (À)-4a.
Table 3. Asymmetric addition of diethylzinc to aldehydes
OH
CHO
Et Zn / Heptane
2
R
R
8
mol% (-)4a/Toluene
O
0
C, 72h
a
b
c
Entry
1
2
Product
OH
Yield (%)
ee (%)
Config
CHO
72
85
69
R
5
a
OH
CHO
d
2
3
53
R
R
H C
3
5b
H C
3
OH
CHO
66
38
H CO
3
5c
H CO
3
OH
CHO
4
66
55
62
70
R
R
5
d
OMe
OMe
OH
CHO
5
5e
Cl
Cl
a
b
c
Isolated yields.
Determined by chiral HPLC.
Configuration of the predominant enantiomer of the product.
Run at room temperature for 24 h.
d

6794
P. D. MacLeod et al. / Tetrahedron Letters 47 (2006) 6791–6794
whereas 2-naphthols with electron-withdrawing substit-
uents gave lower yields (Table 2, entries 8–11). These
results are consistent with the proposed Friedel–
Crafts-type mechanism of the reaction.
The reaction generates various chiral THIQNOL
derivatives. A method was developed to resolve the
two enantiomers of a THIQNOL derivative. The enan-
tiomerically pure derivative showed moderate catalytic
activity and enantioselectivity in the asymmetric diethyl-
zinc addition to aldehydes.
With the efficient method in hand, we attempted to syn-
thesize THIQNOL derivatives asymmetrically. Initially,
many catalytic systems were screened in an attempt to
produce 3a enantioselectively. Unfortunately, all these
attempts failed to generate significant enantioselectivi-
ties. Consequently, various resolution methods were ex-
plored. A moderate enantiomeric excess (up to 58% ee)
was obtained when using L-tartaric acid in dichloro-
methane as the resolution method. Unfortunately, it
was found that enantiomerically enriched product 3a
Acknowledgments
We are grateful to the Canada Research Chair (Tier I)
foundation (to C.J.L.), the CFI, NSERC, Merck Frosst
and McGill University for support of our research.
8
References and notes
racemized rapidly under weakly basic conditions.
1
. (a) Olah, G. A. In Friedel–Crafts and Related Reactions;
Wiley: New York, 1963; (b) Olah, G. A. In Friedel–Crafts
Chemistry; Wiley: New York, 1973; (c) Bandini, M.;
Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed.
Subsequently, an attempt was made to obtain an opti-
cally active tertiary amine derivative of THIQNOL
instead of the corresponding secondary amine present
in the original THIQNOL. Compound 3a was methyl-
2
004, 43, 550–556, and references therein.
2. For an overview, please see: Noyori, R. Adv. Synth. Catal.
003, 345, 15–32.
3. Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. (USA)
2006, 103, 8928–8933.
ated with CH I in the presence of KHCO to give 4a
3
3
in high yield. Fortunately, by using 0.5 equiv of L-tar-
taric acid in dichloromethane and ethanol, resolution
of the two enantiomers of 4a was achieved readily by
filtering the diastereoisomeric tartaric acid salt. The less
soluble salt was found to precipitate in an almost pure
form. Then, hydrolysis of the less soluble salt gave
2
4. MacLeod, P. D.; Li, Z.; Li, C.-J. U.S. Patent Appl., Feb.
2
006.
5
. For other refs on CDC reactions, see: (a) Li, Z.; Li, C.-J.
Eur. J. Org. Chem. 2005, 3173–3176; (b) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2005, 127, 6968–6969; (c) Li, Z.; Li,
C.-J. J. Am. Chem. Soc. 2005, 127, 3672–3673; (d) Li, Z.;
Li, C.-J. J. Org. Lett. 2004, 6, 4997–4999; (e) Li, Z.; Li,
C.-J. J. Am. Chem. Soc. 2004, 126, 11810–11811; (f) Li,
Z.; MacLeod, P. D.; Li, C.-J. Tetrahedron: Asymmetry
2006, 17, 590–597.
(
3
(
À)-4a in more than 99% enantiomeric excess (Scheme
). On the other hand, workup of the solution generated
+)-4a in 92% ee.
With the optically-pure THIQNOL derivative in hand,
its use as a chiral ligand for asymmetric reactions was
examined briefly. THIQNOL (À)-4a was tested as a chi-
ral catalyst in the addition of diethylzinc towards vari-
ous aldehydes. The reaction gave the corresponding
products in moderate yield and enantiomeric excess
6. Very recently a similar reaction was reported, see: Szatmari,
I.; Lazar, L.; Fulop, F. Tetrahedron Lett. 2006, 47, 3881–
3
883.
7
. (a) Trost, B. M. Science 1991, 254, 1471–1477; (b) Trost, B.
M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259–281; (c)
Sheldon, R. A. Chem. Rev. 1999, 9, 10.
(
Table 3). The R configuration was assigned by compar-
ing the retention time of the major enantiomer with
8
9
. For similar example, see: Dong, Y.; Li, R.; Lu, J.; Xu, X.;
Wang, X.; Hu, Y. J. Org. Chem. 2005, 70, 8617–8620.
. (a) Dai, W.-M.; Zhu, H.-J.; Hao, X.-J. Tetrahedron:
Asymmetry 2000, 11, 2315–2337; (b) Nakamura, Y.;
Takeuchi, S.; Okumura, K.; Ohgo, Y. Tetrahedron 2001,
57, 5565–5571.
9
literature reports.
In conclusion, we report here an efficient self-catalytic
aza-Friedel–Crafts reaction between 3,4-dihydroiso-
quinoline and naphthols without any solvent or catalyst.