Self-catalytic, solvent-free or in/on water protocol: aza-Friedel-Crafts reactions between 3,4-dihydroisoquinoline and 1- or 2-naphthols

Article abstract of DOI:10.1016/j.tet.2009.11.008

A self-catalytic protocol was developed using an aza-Friedel-Crafts method to generate 1-naphthoyl tetrahydroisoquinoline products under solvent-free conditions or in/on water. Yields were increased with the use of water. The reaction proceeded with 100%

Full text of DOI:10.1016/j.tet.2009.11.008

Tetrahedron 66 (2010) 1045–1050
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Self-catalytic, solvent-free or in/on water protocol: aza-Friedel–Crafts reactions
between 3,4-dihydroisoquinoline and 1- or 2-naphthols
*
Patricia D. MacLeod, Zhiping Li, Chao-Jun Li
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montre´al, QC, Canada H3A 2K6
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 May 2009
Accepted 29 September 2009
Available online 6 November 2009
A self-catalytic protocol was developed using an aza-Friedel–Crafts method to generate 1-naphthoyl
tetrahydroisoquinoline products under solvent-free conditions or in/on water. Yields were increased
with the use of water. The reaction proceeded with 100% atom economy in the absence of any additional
catalyst.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
for biological applications. In our earliest report,7a a cross-dehy-
drogenative-coupling (CDC) reaction8 was utilized in the synthesis
With the advent of green chemistry, chemists are searching for
innovative new approaches for the generation, purification, and use
of chemical products, which adhere to the 12 principles laid out by
Anastas and Warner.1 For synthetic purposes, innovations to be
sought involve the minimization of derivatizations, the minimiza-
tion of auxiliary substances, the minimization of the number of
steps, and the maximization of incorporation of starting materials
and reagents. Minimizing solvent involves either making solvent
completely unnecessary or if one must be used, then an innocuous
solvent is preferable. It is even more desirable, reactions, which
take place either neat,2 or in an alternative media such as water3 or
others4 can impart improved selectivity, enhance reactivity or
ameliorate the ease of separation or purification. The concepts of
atom economy5 and step economy6 provide the guiding principles
to design more efficient synthesis.
of the corresponding chiral ligands. We envisaged that similar
structures could be generated in a simple fashion by designing
a reaction that could be self-catalytic. This idea goes beyond simply
avoiding unnecessary stoichiometric reagents; it also eliminates
the added catalyst, which in turn, eliminates the need for additional
separation steps. If we successfully design a reaction, which uses
the starting reagents’ intrinsic functionalities to provide the means
to initiate the reaction, we should be able to achieve the following:
ꢀ A self-catalytic reaction: the process would be pseudo-intra-
molecular, which would be entropically favored and allow for
the reaction to occur without added catalyst.
ꢀ A solvent-free reaction: a self-catalytic reaction would require
the starting materials to come within close proximity to each
other. Solvent-free conditions should enhance the yield.
ꢀ Added reactivity in water: the hydrophobic effect of the water
on the starting reagents should lead to further enhanced yields
by decreasing the volume change of activation.
With our continued interest in the synthesis of tetrahy-
droisoquinoline-based structures, we recently designed and syn-
thesized a new class of chiral compounds, including the lead
compound 1-(1,2,3,4-tetrahydroisoquinolin-1-yl)-naphthalen-2-ol
(THIQNOL) (Fig. 1).7 The molecules based on this structure have the
potential to be chiral ligands for asymmetric synthesis and agents
In this case, the reaction could become self-catalytic by allowing
a hydroxyl group on a naphthol to act as a catalyst and bind the
nitrogen in an imine, which would then generate the product
through an aza-Friedel–Crafts reaction in the absence of added
Brønsted or Lewis acid catalyst (Scheme 1).7b,9
The aza-Friedel–Crafts reaction is a popular method used to
synthesize numerous nitrogen-containing molecules. A variation of
the Friedel–Crafts reaction,10 it is generally known as an atom-
economical way to form a carbon–carbon bond through the addi-
tion of an electron-rich arene to an imine and often involves the use
of a stoichiometric or catalytic amount of Brønsted acid,11 Lewis
acid12 or organocatalyst,13 as well as organic solvents. Recent ex-
amples of aza-Friedel–Crafts reactions in literature often involve
NH
OH
Figure 1. THIQNOL.
* Corresponding author.
E-mail address: cj.li@mcgill.ca (C.-J. Li).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.008

1046
P.D. MacLeod et al. / Tetrahedron 66 (2010) 1045–1050
Table 1
Optimization of reaction conditionsa
R
N
R'
R
NH
Catalyst
NH
OH
R'
OH
A)
+
Catalyst
+
N
Nu
16 h
R
Nu
1
2a R=H
R
2b R=OMe
3a or 3b
Entry
2
Solventb
Temperature (ꢁC)
Yieldc (%)
R
N
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
Neat
Neat
Neat
Toluene
THF
Dichloroethane
Water
Neat
Neat
Neat
60
92 (87)
83
66
41
6
20
70
HP
62
84
dec
12
16
NR
NR
9
R
N
R
NH
R'
90
R'
R'
B)
H
H
O
90d
60
Nu
OH
Nu
Nu
O
60
60
60
25
60
90
120
60
60
Scheme 1. Typical Lewis or Brønsted acid catalyzed system (Path A) versus the pro-
posed self-catalytic system (Path B).
9
10
11
12
13
14
15
16
17
Neat
the addition of indoles to imino esters of glyoxylates,14 or other
imines,15 as well as other, more specific reactions.16 These reactions
however, generally take place in organic solvents. Some work on
Friedel–Crafts reactions has been done in water,3e namely the ad-
dition of indoles to glyoxylates17 and alkenes18; however there are
few examples of aza-Friedel–Crafts reactions in water.19 Examples
in literature have also shown that the C]N double bond of 3,4-
dihydroisoquinolines is susceptible to nucleophilic attack by strong
electrophiles,20 and there are also examples of the addition of
naphthol to imines formed in situ.21 Herein, we provide further
details on the synthesis of 1-naphthoyl tetrahydroisoquinolines
under solvent-free conditions, in the absence of added catalyst. In
addition we describe the synthesis and expanded scope of the same
reaction in water. The reaction occurred with 100% atom economy
in the absence of added catalyst.
Methanol
Acetonitrile
Dichloromethane
Diethyl ether
Nitromethane
Water
Reflux
Reflux
60
60
65
a
Condition: 3,4-dihydroisoquinoline (1.0 mmol) and naphthol (1.0 mmol).
When solvent was used, 3 mL solvent was used.
NMR yields were determined by NMR by using an internal standard; isolated
b
c
yields is given in parentheses.
d
Under microwave conditions.
surprisingly, the presence of electron-withdrawing substituents on
the naphthol ring resulted in lower yields (Table 2, entries 7–10) as
compared to the excellent yields naphthols with electron-donating
substituents provided (Table 2, entries 1–6). However, it must be
noted that owing to the heavier molecular weight of the electron-
withdrawing naphthols, there was proportionally more solid
present in the corresponding reactions. This made the reaction
more inefficient because the reactants were not able to be properly
mixed before the solid product, which inhibited the stirring, was
generated.
2. Results and discussion
2.1. Reactions under solvent-free conditions
Our study began with the reaction between 3,4-dihy-
droisoquinoline (1) and 2-naphthol (2a), in the absence of catalyst
under various conditions. Performing the reaction under neat
conditions at 60 ꢁC led to the optimal yield (Table 1, entry 1). In
addition, carrying out the reaction in air did not lead to a sub-
stantial reduction in yield. However, when 6-methoxy-2-naphthol
(2b) was used as a substrate, executing the reaction under neat
conditions at 90 ꢁC, as opposed to 60 ꢁC, led to a higher yield
(Table 1, entry 9). Furthermore, reacting 2-naphthol and
6-methoxy-2-naphthol in a variety of organic solvents consistently
resulted in much lower yields (Table 1, entries 4–6 and 12–16). It
should also be noted that both substrates provided their corre-
sponding products when the reaction took place in degassed
water, albeit in lower yields than under neat conditions (Table 1,
entries 7 and 17). To fully appreciate the scope of the neat con-
ditions however, we continued our investigation into the synthesis
of these molecules by performing the reactions under neat
conditions.
OH
NH
OH
90 o
C
+
N
NMR yield: 92%
2g
1
3g
N
H
O
4
Scheme 2. Hydrogen-bonding assisted C–C bond formation.
2.2. Reactions on water
Reacting 1-naphthol (2g) with 3,4-dihydroisoquinoline (1) un-
der neat conditions resulted in attaining product 3g as a single
regioisomer in 92% yield. We believe that this regioselectivity can
be explained as the result of a six-membered cyclic transition state,
which can re-aromatize to yield product 3g. This result also in-
directly validates our original hypothesis in Scheme 2. The opti-
mized conditions were applied to various naphthols to yield
a series of THIQNOLÒ analogs to evaluate the scope and limitations
of this reaction. These results are illustrated in Table 2. Not
While attempting to expand the scope of this reaction, we found
that 3-hydroxy-2-naphthoic acid (2h) would not react with 3,4-
dihydroisoquinoline (1) under the solvent-free conditions. Initially,
this result was unsurprising due to the strongly electron-with-
drawing nature of the substrate. We then reduced22 the substrate to
obtain the corresponding dialcohol, 3-hydroxymethyl-2-naphthol
(2i) and once again attempted the reaction. Under neat conditions,

P.D. MacLeod et al. / Tetrahedron 66 (2010) 1045–1050
1047
Table 2
Self-catalytic reactions between 3,4-dihydroisoquinoline and naphtholsa
Table 3
Self-catalytic reactions between 3,4-dihydroisoquinoline and naphtholsa
Entry
2
Product
Yieldb (%)
Entry
2
Product
Yieldb (%)
1
62
NH
OH
NH
OH
OH
3b
3b
OH
2b
2b
1
89
MeO
MeO
84c
81
MeO
MeO
2
3
NH
OH
OH
3c
2c
NH
OH
OH
OMe
OMe
3c
60d
91
2c
2
3
100
4
5
OMe
OMe
NH
OH
MeO
OH
2d
3d
MeO
97c
54
NH
OH
6
7
8
9
MeO
OH
3d
3e
3f
95
75
85
96
2d
2e
2f
MeO
NH
OH
OH
2e
3e
Ph
12c
32
Ph
O
NH
OH
OH
O
4
5
6
Ph
Ph
O
NH
OH
OH
3f
2f
O
Br
10
11
45d
73
Br
NH
OH
OH
NH
OH
OH
Br
12
92c
3g
2g
Br
NH
OH
a
Conditions: 3,4-dihydroisoquinoline (1.0 mmol), naphthol (1.0 mmol), at 60 ꢁC;
otherwise noted.
OH
3g
2g
b
Determine by NMR spectroscopy by using an internal standard.
c
At 90 ꢁC.
d
At 90 ꢁC; isolated yield after crystallization.
at both 60 ꢁC and 90 ꢁC, the reaction failed to react and produce the
desired product.
NH
OH
OH
OH
OH
2h
Operating under our previous assumptions about this type of
reaction, we decided to attempt the above reactions in degassed
water, hoping that a hydrophobic effect of the water on the starting
materials would lead to better reactivity. Gratifyingly, we found
that both substrates produced their corresponding products in
excellent yields when the reaction was performed at 80 ꢁC. With
our hypothesis confirmed, we then decided to determine if per-
forming this reaction with water as solvent with the previously
used naphthols would lead to different results, more specifically, if
we could use water to increase the yield of the electron-with-
drawing substituted naphthols.
3h
7
83
O
O
NH
OH
OH
OH
8
90
76
2i
3i
OH
9
We were pleased to discover that water did indeed provide an
increase in the yield of all substrates, resulting in excellent yields as
seen in Table 3. When electron-withdrawing substituents are
present (Table 3, entries 4 and 5), the yields are still somewhat
lower, however they are much higher than when performed neat.
Dihydroxy-substituted naphthalene rings were also used as sub-
strates, yielding good amounts of products (Table 3, entries 9–12).
These substrates previously gave a mixture of products, which we
were unable to separate when they had been used under the neat
conditions. Interestingly, when 2,3-dihydroxynaphthalene (2j) was
reacted with 2 equiv of 3,4-dihydroisoquinoline, the product only
NH
OH
OH
3j
2j
OH
OH
10
89c
NH
OH
HO
OH
11
72
3k
2k
HO
(continued on next page)

1048
Table 3 (continued)
P.D. MacLeod et al. / Tetrahedron 66 (2010) 1045–1050
spectra were recorded by an ABB Bomem MB100 instrument.
Melting points were recorded by Melting Point Apparatus, Gal-
lenkamp. All reagents were weighed and handled in air at room
temperature. All reagents were purchased from Aldrich and were
used without further purification.
Entry
2
Product
Yieldb (%)
NH
OH
OH
3l
2l
12
86
4.1.1. General procedure for reactions under neat conditions. Unless
otherwise noted, the corresponding naphthol derivative (1.0 mmol)
was placed in a flask under nitrogen and to it was added 3,4-
dihydroisoquinoline20c (1.0 mmol). The resulting mixture was
stirred for 16 h at 60 ꢁC, whereupon no liquid remained. The
resulting mixture was recrystallized from chloroform and hexane
and collected to give the desired product 3.
OH
OH
NH
OH
OH
13
71
3m
2m
4.1.2. 1-(1,2,3,4-Tetrahydroisoquinolin-1-yl)-naphthalen-2-ol
a
Conditions: 3,4-dihydroisoquinoline (1.2 mmol), naphthol (1.0 mmol), at 80 ꢁC;
otherwise noted.
(3a). Mp 148–150 ꢁC; IR (KBr pellet): nmax 3289, 3056, 3018, 2954,
2921, 2886, 2834, 1622, 1597, 1462, 1230, 807, 738 cmꢂ1 1H NMR
;
b
Isolated yield.
2 equiv 3,4-dihydroisoquinoline used.
c
(CDCl3, 400 MHz, ppm)
d
8.01 (d, J¼8.8 Hz, 1H), 7.79 (d, J¼7.6 Hz,
1H), 7.49 (t, J¼8.4 Hz, 1H), 7.33 (t, J¼7.6 Hz, 1H), 7.11–7.05 (m, 3H),
6.87–6.83 (m, 1H), 6.61 (d, J¼7.6 Hz, 1H), 6.03 (s, 1H), 3.45–4.40 (m,
1H), 3.30–3.12 (m, 2H), 2.89 (d, J¼14 Hz, 1H); 13C NMR (CDCl3,
75 MHz, ppm) 155.8, 149.7, 136.2, 133.8, 129.6, 128.8, 128.6, 126.9,
126.9, 126.6, 126.2, 122.5, 121.3, 120.2, 55.7, 44.0, 29.4; MS (EI) m/z
(%) 275 (Mþ, 100), 258, 229, 215; HRMS Calcd for C19H17NO:
275.1310; found: 275.1307.
incorporated 1 equiv. There was no evidence of product 3j un-
dergoing further reaction with the second equivalent of 3,4-dihy-
droisoquinoline. In addition, we investigated the effect of a catalytic
amount of external Brønsted acid on the reaction. In the presence of
10 mol % of HCl, H3PO4 or HOAc, the yields as shown by 1H NMR of
the crude reaction mixture were similar to the results that we
obtained in the absence of such protonic acids (Table 3, entry 1).
As neither the starting materials nor products are significantly
soluble in water, a hydrophobic effect is the most likely explanation
for these increased yields23; the nearly insoluble hydrophobic
starting materials are brought closer together by the water, which
increases the efficiency of the reaction by decreasing the volume
change of activation.
4.1.3. 6-Methoxy-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)-naphthalen-
2-ol (3b). Mp 148–151 ꢁC; IR (KBr pellet) nmax 3315, 2963, 2932,
2835, 1601, 1517, 1384, 1366, 1246, 1160, 1034, 866 cmꢂ1 1H NMR
;
(CDCl3, 400 MHz, ppm)
d
7.92 (d, J¼9.6 Hz, 1H), 7.61 (d, J¼9.2 Hz,
1H), 7.17–7.02 (m, 5H), 6.87–6.83 (m, 1H), 6.59 (d, J¼8.0 Hz, 1H),
5.97 (s, 1H), 3.92 (s, 3H), 3.48–3.44 (m, 1H), 3.32–3.15 (m, 2H), 2.89
(d, J¼14.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz, ppm)
d 155.0, 153.9,
136.1, 133.8, 129.0, 128.5, 128.2, 126.8, 126.5, 126.1, 122.9, 120.5,
119.2, 118.5, 107.0, 55.8, 55.3, 43.9, 29.4; MS (EI) m/z (%) 305 (Mþ,
100), 288, 261, 125, 174, 151, 131; HRMS Calcd for C20H19NO2:
305.1416; found: 305.1418.
3. Conclusions
By using an aza-Friedel–Crafts reaction the direct addition of
a variety of naphthols to 3,4-dihydroisoquinoline was achieved to
yield THIQNOL derivatives with 100% atom economy in the absence
of added catalyst. These reactions were first accomplished under
neat conditions with good yields. This reaction was then improved
upon by performing the reaction in water, resulting in excellent
yields and an expanded scope, most likely due to a hydrophobic
effect. Isolation of the products is simple due to the absence of
added catalyst. In essence, we have shown that by using the func-
tionalities of starting materials, we can design a reaction to be self-
catalytic, which in turn is enhanced by the solvent-free conditions
or the use of water as solvent. Such a design provides a prototype
for other potential reactions.
4.1.4. 3-Methoxy-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)-naphthalen-
2-ol (3c). Mp 154–156 ꢁC; IR (KBr pellet) nmax 3284, 3060, 2970,
2933, 2833, 1456, 1423, 1322, 1256, 1119, 745 cmꢂ1; 1H NMR (CDCl3,
400 MHz, ppm)
d
7.95 (d, J¼8.4 Hz), 7.72 (d, J¼8.4 Hz), 7.40–7.30 (m,
2H), 7.11–7.05 (m, 3H), 6.87–6.84 (m, 1H), 6.63 (d, J¼7.6 Hz, 1H),
6.05 (s, 1H), 3.94 (s, 3H), 3.54–3.50 (m, 1H), 3.35–3.20 (m, 2H), 2.90
(d, J¼14.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz, ppm)
d 149.6, 148.1,
142.8, 136.0, 133.9, 128.6, 128.4, 127.5, 127.0, 126.7, 126.2, 124.6,
123.2, 121.2, 119.0, 106.6, 55.7, 55.6, 43.8, 29.3; MS (EI) m/z (%) 305
(Mþ), 288, 174, 159, 131 (100); HRMS Calcd for C20H19NO2:
305.1416; found: 305.1412.
4. Experimental
4.1. General
4.1.5. 7-Methoxy-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)-naphthalen-
2-ol (3d). Mp 126–130 ꢁC; IR (KBr pellet) nmax 3527, 3286, 2990,
2961, 2889, 2837,1622, 1517, 1482, 1387, 1221, 1135, 1032, 829 cmꢂ1
;
1H NMR (CDCl3, 400 MHz, ppm)
d
7.68 (d, J¼8.4 Hz, 1H), 7.62 (d,
1H NMR spectra were recorded on Varian 300 and 400 MHz
spectrometers and the chemical shifts were reported in parts per
million (d) relative to internal standard TMS (0 ppm) for CDCl3 or
J¼8.4 Hz, 1H), 7.27 (d, J¼2 Hz, 1H), 7.10–7.09 (m, 2H), 7.01–6.98 (m,
1H), 6.92–6.87 (m, 2H), 6.67 (d, J¼8.0 Hz, 1H), 5.91 (s, 1H), 3.86 (s,
3H), 3.52–3.49 (m, 1H), 3.31–3.23 (m, 2H), 2.87 (d, J¼14.8 Hz, 1H);
internal solvent signal (2.49 ppm) for DMSO. The peak patterns are
indicated as follows: s, singlet; br s, broad singlet; d, doublet; t,
triplet; dt, doublet of triplet; dq, doublet of quartet; ddd, doublet of
doublet of doublet; dtd, doublet of triplet of doublet; m, multiplet;
q, quartet; dq, doublet of quartet. The coupling constants, J, are
reported in hertz (Hz). 13C NMR spectra were obtained at 75 and
100 MHz spectrometers and referenced to the internal solvent
signals (central peak is 77.0 ppm in CDCl3 or 39.5 ppm in DMSO).
HRMS were obtained by Kratos MS25RFA Mass Spectrometer. IR
13C NMR (CDCl3, 100 MHz, ppm)
d 158.6, 156.4, 136.2, 134.5, 133.8,
130.3, 129.4, 128.6, 126.8, 126.6, 126.2, 123.6, 117.5, 114.5, 100.7, 55.9,
44.0, 29.4; MS (EI) m/z (%) 305 (Mþ), 288, 174, 131 (100); HRMS
Calcd for C20H19NO2: 305.1416; found: 305.1413.
4.1.6. [6-Hydroxy-5-(1,2,3,4-tetrahydroisoquinolin-1-yl)-naph-
thalen-2-yl]-phenyl-methanone (3e). Addition of 6-benzoyl-2-
naphthol (0.2 mmol) to 3,4-dihydroisoquinoline (0.2 mmol). Mp
138–142 ꢁC; IR (KBr pellet) nmax 3034, 1685, 1654, 1609, 1559, 1473,

P.D. MacLeod et al. / Tetrahedron 66 (2010) 1045–1050
1049
1355, 1283, 1243, 1210, 1141, 721 cmꢂ1
ppm)
;
1H NMR (CDCl3, 400 MHz,
6.88–6.84 (m,1H), 6.47 (d, J¼7.6 Hz,1H), 6.00 (s, 1H), 5.09 (s, br, 1H),
d
8.25 (s, 1H) 8.13 (d, J¼8.8 Hz, 1H), 8.04 (d, J¼10.8 Hz, 1H),
4.57–4.47 (m, 2H), 3.37–3.33 (m, 2H), 3.16–3.04 (m, 2H), 2.83 (d,
7.89 (d, J¼8.0 Hz, 2H), 7.80 (d, J¼9.2 Hz, 1H), 7.65–7.61 (m, 1H),
7.60–7.52 (m, 2H), 7.17–7.12 (m, 3H), 6.95–6.91 (m, 1H), 6.62 (d,
J¼8.00 Hz, 1H), 6.10 (s, 1H), 3.59–3.55 (m, 1H), 3.39–3.27 (m, 2H),
2.93 (d, J¼12.8 Hz, 1H), 2.76 (br s, 1H); 13C NMR (CDCl3, 100 MHz,
J¼13.6 Hz, 1H); 13C NMR (DMSO, 75 MHz, ppm)
d 153.8, 137.1, 134.4,
132.5, 132.3, 128.6, 128.3, 127.3, 126.4, 126.2, 126.1, 125.8, 124.9,
122.2, 121.6, 118.1, 58.5, 54.5, 42.5, 28.8; HRMS Calcd for C20H20NO2:
306.1489; found: 306.1491.
ppm)
d 196.2, 158.4, 138.0, 136.0, 133.8, 133.3, 132.0, 131.5, 131.4,
129.8, 128.7,128.2, 126.9, 126.8, 126.3, 121.7, 121.1, 119.0, 118.4, 109.5,
55.7, 43.9, 29.3; MS (EI) m/z (%) 379 (Mþ), 248, 171 (100), 131; HRMS
Calcd for C26H21NO2: 379.1572; found: 379.1563.
4.2.3. 1-(1,2,3,4-Tetrahydroisoquinolin-1-yl)naphthalene-2,3-diol
(3j). Mp 162–166 ꢁC; IR (solid): nmax 3261, 1510, 1455, 1424, 1254,
1243, 1176, 945, 748 cmꢂ1 1H NMR (DMSO, 400 MHz, ppm)
; d 7.97
(d, J¼8.4 Hz, 1H), 7.61 (dd, J¼8.4, 1.2 Hz, 1H), 7.30–7.26 (m, 1H), 7.20
(td, J¼8.0,1.2 Hz,1H), 7.15 (d, J¼6.8 Hz,1H), 7.09–7.06 (m, 2H), 6.90–
6.86 (m, 1H), 6.38 (d, J¼8.0 Hz, 1H), 5.98 (s, 1H), 3.40–3.35 (m, 1H),
3.14–3.09 (m, 2H), 2.90–2.84 (m, 1H); 13C NMR (DMSO, 75 MHz,
ppm) d 148.3, 147.3, 137.0, 134.2, 128.5, 128.0, 127.9, 126.5, 126.4,
126.2, 125.8, 123.4, 122.3, 121.5, 118.8, 109.0, 54.5, 42.3, 28.6; HRMS
Calcd for C19H18NO2: 292.1332; found: 292.1330.
4.1.7. 6-Bromo-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)-naphthalen-2-
ol (3f). Washed with CHCl3 for purification. Mp 168–170 ꢁC; IR (KBr
pellet) nmax 3047, 3018, 2401, 1612, 1586, 1495, 1451, 1362, 1259,
1237, 1212, 1151, 1023, 957, 863 cmꢂ1
ppm)
;
1H NMR (CDCl3, 400 MHz,
d
7.94 (d, J¼2.0 Hz, 1H), 7.88 (d, J¼8.8 Hz, 1H), 7.61 (d,
J¼8.4 Hz, 1H), 7.55 (dd, 1H, J¼2.0, 9.0 Hz), 7.14–7.07 (m, 3H), 6.90–
6.86 (m, 1H), 6.54 (d, J¼7.6 Hz, 1H), 5.98 (s, 1H), 3.56–3.52 (m, 1H),
3.36–3.22 (m, 2H), 2.90 (d, J¼14.4 Hz, 1H), 2.69 (br s, 1H); 13C NMR
4.2.4. 1-(1,2,3,4-Tetrahydroisoquinolin-1-yl)naphthalene-2,7-diol
(CDCl3, 75 MHz, ppm)
d
156.2, 135.8, 133.9, 131.9, 130.6, 130.0, 129.4,
(3k). Mp 150–153 ꢁC; IR (solid): nmax 3293, 3285, 1618, 1471, 1350,
128.8, 128.7, 126.8, 126.7, 126.3, 123.2, 121.4, 118.3, 116.0, 55.8 44.0,
29.3; MS (EI) m/z (%) 353 (Mþ, 100) 324, 309, 257, 228, 132; HRMS
Calcd for C19H16NO79Br: 353.0415; found: 353.0407; HRMS Calcd
for C19H16NO81Br: 355.0395; found: 355.0403.
1220, 1198, 1135, 838 cmꢂ1; 1H NMR (DMSO, 400 MHz, ppm)
d 9.62
(br s, 1H), 7.65 (d, J¼8.8 Hz, 1H), 7.59 (d, J¼8.4 Hz, 1H), 7.30 (s, 1H),
7.14 (d, J¼7.2 Hz, 1H), 7.08 (t, J¼7.2 Hz, 1H), 6.91–6.86 (m, 2H), 6.71
(d, J¼8.4 Hz, 1H), 6.54 (d, J¼8.0 Hz, 1H), 5.74 (s, 1H), 4.28 (br s, 1H),
3.37–3.33 (m, 1H), 3.15–3.00 (m, 2H), 2.82 (d, J¼14.4 Hz, 1H); 13C
4.1.8. 2-(1,2,3,4-Tetrahydroisoquinolin-1-yl)-naphthalen-1-ol
(3g). Mp 117–120 ꢁC; IR (KBr pellet): nmax 3305, 3050, 3015, 2950,
2915, 1577, 1491, 1456, 1390, 1121, 1085, 805 cmꢂ1; 1H NMR (CDCl3,
NMR (DMSO, 75 MHz, ppm) d 156.3, 156.1, 137.2, 135.0, 134.4, 130.1,
128.9, 128.6, 126.3, 126.1, 125.8, 122.5, 117.5, 116.2, 114.6, 103.8, 54.8,
42.9, 28.9; HRMS Calcd for C19H18NO2: 292.1332; found: 292.1331.
400 MHz, ppm)
d
8.18 (d, J¼8.4 Hz, 1H), 7.75 (d, J¼7.6 Hz, 1H), 7.40–
7.33 (m, 2H), 7.29 (d, J¼8.4 Hz, 1H), 7.14–7.11 (m, 1H), 7.08–7.03 (m,
2H), 6.97–6.93 (m, 1H), 6.81 (d, J¼8.0 Hz, 1H), 5.11 (s, 1H), 3.19–3.14
(m, 1H), 3.09–3.01 (m, 1H), 2.96–2.90 (m, 1H), 2.74–2.69 (m, 1H);
4.2.5. 4-(1,2,3,4-Tetrahydroisoquinolin-1-yl)naphthalene-1,3-diol
(3l). Mp 173–175 ꢁC; IR (solid): nmax 2908, 1570, 1502, 343, 1163,
1082, 725 cmꢂ1 1H NMR (DMSO, 400 MHz, ppm)
; d 10.1 (br s, 1H),
13C NMR (CDCl3, MHz, ppm)
d
152.8, 136.0, 133.8, 133.7, 128.8, 127.4,
7.83 (d, J¼8.4 Hz, 1H), 7.53 (d, J¼8.0 Hz, 1H), 7.31–7.27 (m, 1H), 7.13–
7.05 (m, 3H), 6.97 (t, J¼7.2 Hz, 1H), 6.90 (d, J¼8.0 Hz, 1H), 6.72 (s,
1H), 5.68 (s, 1H), 3.37–3.33 (m, 2H), 3.14–3.06 (m, 1H), 2.98–2.91
(m, 1H), 2.79 (d, J¼15.2 Hz, 1H); 13C NMR (DMSO, 75 MHz, ppm)
127.4, 127.1, 126.6, 126.0, 125.8, 125.5, 124.7, 122.1, 119.4, 117.7, 60.8,
42.2, 29.0; MS (EI) m/z (%) 275 (Mþ, 100), 258, 229, 215, 144, 132;
HRMS Calcd for C19H17NO: 275.1310; found: 275.1307.
d
154.4, 154.1, 137.2, 134.2, 134.1, 128.4, 127.0, 126.2, 126.0, 125.8,
4.2. General procedure for reactions in water
125.4, 121.8, 121.2, 120.3, 113.6, 99.5, 53.1, 42.5, 28.8. HRMS Calcd for
C19H18NO2: 292.1332; found: 292.1333.
Unless otherwise noted, 3,4-dihydroisoquinoline (0.2 mmol)
and the corresponding naphthol (0.2 mmol) were placed under
nitrogen atmosphere and degassed water (0.4 mL) was added to
the capped vessel. The reaction mixture was heated to 80 ꢁC and
stirred overnight. The resulting solids were filtered by vacuum,
washed with diethyl ether, and dried in a 60 ꢁC oven.
4.2.6. 3-Phenyl-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)naphthalen-2-
ol (3m). Mp 135–138 ꢁC; IR (solid): nmax 3288, 1623, 1455, 1425,
1259, 1116, 767 cmꢂ1; 1H NMR (DMSO, 400 MHz, ppm)
d 12.40 (br s,
1H), 8.04 (d, J¼8.4 Hz, 1H), 7.84 (d, J¼8.4 Hz, 1H), 7.79 (s, 1H), 7.59
(d, J¼7.6 Hz, 1H), 7.53–7.50 (m, 1H), 7.41–7.29 (m, 4H), 7.12–7.11 (m,
2H), 6.94–6.90 (m, 1H), 6.71 (d, J¼8.0 Hz, 1H), 6.11 (s, 1H), 3.55–3.49
(m,1H), 3.34–3.23 (m, 2H), 2.88 (d, J¼13.6 Hz,1H); 13C NMR (DMSO,
4.2.1. 3-Hydroxy-4-(1,2,3,4-tetrahydroisoquinolin-1-yl)-2-naphthoic
acid (3h). Addition of 3-hydroxy-2-naphthoic acid (0.5 mmol) to
3,4-dihydroisoquinoline (0.5 mmol) in 1.0 mL water. Mp 180–
181 ꢁC; IR (solid): nmax 3019, 1660, 1622, 1592, 1454, 1362, 1336,
75 MHz, ppm) d 154.0, 142.8, 128.4, 136.2, 134.0, 133.0, 132.6, 129.9,
129.6, 129.0, 128.7, 128.1, 127.9, 127.1, 127.1, 126.9, 126.7, 126.2, 122.9,
121.2, 118.6, 55.8, 43.8, 29.3 HRMS Calcd for C25H22NO: 352.1696;
found: 352.1697.
1256, 993, 736 cmꢂ1 1H NMR (CDCl3, 400 MHz, ppm)
; d 9.54 (br s,
1H), 9.09 (br s, 1H), 8.41 (s, 1H), 7.93 (d, J¼8.0 Hz, 1H), 7.52 (m, 1H),
7.27–7.16 (m, 3H), 7.02–6.98 (m, 1H), 6.48 (d, J¼7.6 Hz, 1H), 6.40 (br
s, 1H), 3.63–3.53 (m, 2H), 3.38–3.29 (m, 2H), 3.05 (d, J¼16.4 Hz,1H);
13C NMR (DMSO, 75 MHz, ppm) 169.7, 161.2, 135.3, 134.1, 132.2,
131.9,130.1,128.4,128.3, 126.9, 126.7, 125.4, 125.1,121.6,121.5,120.8,
113.1, 53.3, 41.6, 25.6; HRMS Calcd for C20H18NO3: 320.1281; found:
320.1282.
Acknowledgements
This work was supported by the Canada Research Chair (Tier I)
Foundation (C.-J.L.), the Canada Foundation for Innovation, Natural
Sciences and Engineering Research Council (Canada), the ACS-GCI
Pharmaceutical Roundtable, and McGill University.
4.2.2. 3-(Hydroxymethyl)-1-(1,2,3,4-tetrahydroisoquinolin-1-yl)-
naphthalen-2-ol (3i). Addition of 3-(hydroxymethyl)naphthalen-2-
ol (1.7 mmol) to 3,4-dihydroisoquinoline (1.7 mmol) in 2.5 mL
water. Mp 154–157 ꢁC; IR (solid): nmax 2951, 1622, 1495, 1451, 1410,
1366, 1262, 1251, 1178, 1008, 746 cmꢂ1; 1H NMR (DMSO, 400 MHz,
References and notes
1. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford Uni-
versity: New York, NY, 1998.
2. (a) Tanaka, T. Solvent-free Organic Synthesis; Wiley-VCH: Weinheim, 2003; (b)
Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem. Commun. 2001, 2159–2169.
3. For reviews on chemistry in water: (a) Organic Synthesis in Water; Grieco, P. A.,
Ed.; Blacky Academic and Professional: London, 1998; (b) Li, C.-J.; Chan, T.-H.
ppm)
d
8.10 (d, J¼8.8 Hz, 1H), 7.84–7.80 (m, 2H), 7.49–7.45 (m, 1H),
7.28 (t, J¼7.2 Hz, 1H), 7.14 (d, J¼7.2 Hz, 1H), 7.07 (t, J¼7.2 Hz, 1H),

1050
P.D. MacLeod et al. / Tetrahedron 66 (2010) 1045–1050
Organic Reactions in Aqueous Media; John Wiley: New York, NY, 1997; (c)
13. (a) Dessole, G.; Herrera, R. P.; Ricci, A. Synlett 2004, 2374–2378; (b) To¨ro¨k, B.;
Abid, M.; London, G.; Esquibel, J.; To¨ro¨k, M.; Mhadgut, S. C.; Yan, P.; Prakash, S.
G. K. Angew. Chem., Int. Ed. 2005, 44, 3086–3089.
14. (a) Huang, T.; Li, C.-J. Tetrahedron Lett. 2000, 41, 6715–6719; (b) Zhao, J.-L.; Liu,
L.; Zhang, H.-B.; Wu, Y.-C.; Wang, D.; Chen, Y.-J. Synlett 2006, 96–100; (c) Jiang,
B.; Huang, Z.-G. Synthesis 2005, 2198–2204; (d) Lei, F.; Chen, Y.-J.; Sui, Y.; Liu, L.;
Wang, D. Synlett 2003, 1160–1164.
Lindstrom, U. M. Chem. Rev. 2002, 102, 2751–2772; (d) Li, C.-J. Chem. Rev. 1993,
93, 2023–2035; (e) Li, C.-J. Chem. Rev. 2005, 105, 3095–3166; (f) Herrerı´as, C. I.;
Yao, X.; Li, Z.; Li, C.-J. Chem. Rev. 2007, 107, 2546–2562.
4. (a) Seddon, K. R. J. Chem. Technol. Biotechnol. 1997, 68, 351–356; (b) Holbrey, J.
D.; Seddon, K. R. Clean Technol. Environ. Policy 1999, 1, 223–236; (c) Welton, T.
Chem. Rev. 1999, 99, 2071–2084; (d) Dzyuba, S. V.; Bartsch, R. A. Angew. Chem.,
Int. Ed. 2003, 42, 148–150; (e) Leitner, W. Acc. Chem. Res. 2002, 35, 746–756; (f)
Jessop, P. G.; Ikariya, T.; Noyori, R. Science 1995, 269, 1065–1069.
5. (a) Trost, B. M. Science 1991, 254, 1471–1477; (b) Trost, B. M. Angew. Chem., Int.
Ed. Engl. 1995, 34, 259–281.
15. (a) Enders, D.; Narine, A. A.; Toulgoat, F.; Bisschops, T. Angew. Chem., Int. Ed.
´
2008, 47, 5661–5665; (b) Esquivias, J.; Arrayas, R. G.; Carretero, J. C. Angew.
Chem., Int. Ed. 2006, 45, 629–633; (c) Johannsen, M. Chem. Commun. 1999,
2233–2234; (d) Jia, Y.-X.; Xie, J.-H.; Duan, H.-F.; Wang, L.-X.; Zhou, Q.-L. Org.
Lett. 2006, 8, 1621–1624; (e) Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 8156–8157.
6. Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41,
40–49.
7. (a) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928–8933;
(b) Li, C. -J.; McLeod, P.; Li, Z.; Feng, J. U.S. Patent WO 2007098608, 2007.
8. For other references from our group on CDC reaction, 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. Org. Lett. 2004, 6, 4997–4999; (e) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2006,
128, 56–57; (f) Li, Z.; MacLeod, P. D.; Li, C.-J. Tetrahedron: Asymmetry 2006, 17,
590–597.
9. MacLeod, P. D.; Li, Z.; Feng, J.; Li, C.-J. Tetrahedron Lett. 2006, 47, 6791–6794.
10. For reviews on Friedel–Crafts reaction: (a) Olah, G. A. Friedel–Crafts and Related
Reactions; Wiley: New York, NY, 1963; (b) Olah, G. A. Friedel–Crafts Chemistry;
Wiley: New York, NY, 1973; (c) Bandini, M.; Melloni, A.; Umani-Ronchi, A.
Angew. Chem., Int. Ed. 2004, 43, 550–556 and references therein; (d) Jørgensen,
K. A. Synthesis 2003, 1117–1125.
11. Selected examples: (a) Zeng, M.; Kang, Q.; He, Q.-L.; You, S.-L. Adv. Synth. Catal.
2008, 350, 2169–2173; (b) Wang, B.-Y.; Jiang, R.-S.; Li, J.; Shi, M. Eur. J. Org. Chem.
2005, 4002–4008; (c) Zhou, W.; Xu, L.-W.; Yang, L.; Zhao, P.-Q.; Xia, C.-G. J. Mol.
Catal. A: Chem. 2006, 249, 129–134; (d) Terada, M.; Sorimachi, K. J. Am. Chem.
Soc. 2007, 129, 292–293.
12. Selected examples: (a) Luo, Y.; Li, C.-J. Chem. Commun. 2004, 1930–1931; (b)
Chen, Y. J.; Ge, C.-S.; Wang, D. Synlett 2000, 1429–1432; (c) Yamazaki, S.;
Morikawa, S.; Iwata, Y.; Yamamoto, M.; Kuramoto, K. Org. Biomol. Chem. 2004, 2,
3134–3138; (d) Huang, J.-W.; Shi, M. Tetrahedron Lett. 2003, 44, 9343–9347.
16. (a) Chen, Y.-J.; Ge, C.-S.; Wang, D. Synlett 2000, 1429–1432; (b) Shirakawa, S.;
Berger, R.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 2858–2859; (c) Malassene,
R.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Synlett 2002, 895–898; (d) Sasamoto, N.;
Dubs, C.; Hamashima, Y.; Sodeoka, M. J. Am. Chem. Soc. 2006, 128, 14010–14011.
17. Zhuang, W.; Jørgensen, K. A. Chem. Commun. 2002, 1336–1337.
18. Manabe, K.; Aoyama, N.; Kobayashi, S. Adv. Synth. Catal. 2001, 343, 174–176.
19. Shirakawa, S.; Kobayashi, S. Org. Lett. 2006, 8, 4939–4942.
20. (a) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341–3370; (b)
Chrzanowska, M. Tetrahedron: Asymmetry 2002, 13, 2497–2500; (c) Pelletier,
J. C.; Cava, M. P. Synthesis 1987, 474–477.
21. (a) Betti, M. Org. Synth. 1941, 1, 381–410; (b) Betti, M. Gazz. Chim. Ital. 1907, 36,
392–395; (c) Szatma´ri, I.; Martinek, T. A.; La´za´r, L.; Fu¨lo¨p, F. Tetrahedron 2003,
59, 2877–2884; (d) Szatmari, I.; Martinek, T. A.; Lazar, L.; Koch, A.; Kleinpeter,
E.; Neuvonen, K.; Fulop, F. J. Org. Chem. 2004, 69, 3645–3653; (e) Cardellicchio,
C.; Ciccarella, G.; Naso, F.; Perna, F.; Tortorella, P. Tetrahedron 1999, 55, 14685–
14692; (f) Dong, Y.; Li, R.; Lu, J.; Xu, X.; Wang, X.; Hu, Y. J. Org. Chem. 2005, 70,
8617–8620; (g) Wang, X.; Dong, Y.; Sun, J.; Xu, X.; Li, R.; Hu, Y. J. Org. Chem.
2005, 70, 1897–1900.
22. For reduction: Miller, L. E.; Hanneman, W. W.; John, W. L. S.; Smeby, R. R. J. Am.
Chem. Soc. 1954, 76, 296–297.
23. (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159–164; (b) Fokin, V. V.; Sharpless, K. B.
Angew. Chem. 2001, 113, 3563–3565; (c) Narayan, S.; Muldoon, J.; Finn, M. G.;
Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275–3279.