Calcium-promoted pictet-spengler reactions of ketones and aldehydes

Article abstract of DOI:10.1021/jo1019283

Calcium bis-1,1,1,3,3,3-hexafluoroisopropoxide is shown to be an effective catalyst for Pictet-Spengler reactions of 3-hydroxyphenethylamine and 3-hydroxy-4-methoxyphenethylamine with various aldehydes and ketones. Previous Lewis acid catalyzed Pictet-Spe

Full text of DOI:10.1021/jo1019283

pubs.acs.org/joc
Calcium-Promoted Pictet-Spengler Reactions of Ketones and Aldehydes
Matthew J. Vanden Eynden, Kamala Kunchithapatham, and James P. Stambuli*
Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210,
United States
stambuli@chemistry.ohio-state.edu
Received October 1, 2010
Calcium bis-1,1,1,3,3,3-hexafluoroisopropoxide is shown to be an effective catalyst for Pictet-Spengler
reactions of 3-hydroxyphenethylamine and 3-hydroxy-4-methoxyphenethylamine with various
aldehydes and ketones. Previous Lewis acid catalyzed Pictet-Spengler reactions of unactivated
ketones typically require two separate reactions (imine formation, cyclization) to obtain the same
results. The reactions described within directly provide 1,10-disubstituted tetrahydroisoquinolines
from the corresponding amine and ketone. These rare examples of Pictet-Spengler reactions of
unactivated ketones demonstrate the unique nature of calcium as a Lewis acid catalyst.
Introduction
Calcium salts are highly abundant in nature and have a
wide variety of industrial and commercial uses. Though
calcium salts are often used as drying agents in organic
chemistry, the use of calcium as a Lewis acid in organic
synthesis is slowly gaining widespread attention because of
the interesting reactivity of calcium, along with its low cost
and low toxicity.1 Calcium is a versatile metal as it catalyzes a
FIGURE 1. Classical Pictet-Spengler reaction.
variety of reactions including hydroaminations2 and -phos-
phinations,3 ring-opening polymerizations of lactides,4 asym-
metric epoxidations,5 aldol reactions,6 1,4 additions,7 and C-H
activation reactions.8
(1) Crimmin, M. R.; Casely, I. J.; Hill, M. S. J. Am. Chem. Soc. 2005,
127, 2042. Chisholm, M. H.; Gallucci, J. C.; Phomphrai, K. Inorg. Chem.
2004, 43, 6717. Kumaraswamy, G.; Sastry, M. N. V.; Jena, N.; Kumar, K. R.;
Vairamani, M. Tetrahedron-Asymmetry 2003, 14, 3797. Suzuki, T.;
Yamagiwa, N.; Matsuo, Y.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M.;
Noyori, R. Tetrahedron Lett. 2001, 42, 4669. Tsubogo, T.; Saito, S.; Seki, K.;
Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321. He, X. Y.;
Hurley, E.; Noll, B. C.; Henderson, K. W. Organometallics 2008, 27, 3094.
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2010, 49, 3823. Harder, S. Chem. Rev. 2010, 110, 3852. Niggemann, M.; Meel,
M. J. Angew. Chem., Int. Ed. 2010, 49, 3684.
The Pictet-Spengler reaction is a commonly used syn-
thetic tool for the preparation of tetrahydroisoquinoline and
β-carboline alkaloids (Figure 1).9 This reaction is typically
promoted by stoichiometric amounts of strong Brønsted
acids, which can have obvious functional group compatibility
issues andtypically exhibitpoorregiochemical control. There-
fore, recent investigations of Pictet-Spengler reactions have
(2) Crimmin, M. R.; Arrowsmith, M.; Barrett, A. G. M.; Casely, I. J.;
Hill, M. S.; Procopiou, P. A. J. Am. Chem. Soc. 2009, 131, 9670–9685.
(3) (a) Crimmin, M. R.; Barrett, A. G. M.; Hill, M. S.; Hitchcock, P. B.;
Procopiou, P. A. Organometallics 2007, 26, 2953. (b) Crimmin, M. R.;
Barrett, A. G. M.; Hill, M. S.; Hitchcock, P. B.; Procopiou, P. A. Organo-
metallics 2008, 27, 497.
(6) Suzuki, T.; Yamagiwa, N.; Matsuo, Y.; Sakamoto, S.; Yamaguchi,
K.; Shibasaki, M.; Nyori, R. Tetrahedron Lett. 2001, 42, 4669.
(7) Poisson, T.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2010,
132, 7890. Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.; Kobayashi, S.
J. Am. Chem. Soc. 2008, 130, 13321.
(4) Chisholm, M. H.; Galluchi, J.; Phomphrai, K. Inorg. Chem. 2004, 43,
6717–6725.
(5) (a) Kumaraswamy, G.; Jena, N.; Sastry, M. N. V.; Ramakrishna,
G. ArkiVoc 2005, 15, 53. (b) Kumaraswamy, G.; Sastry, M. N. V.; Jena, N.;
Ravi Kumar, K.; Vairamani, M. Tetrahedron: Asymmetry 2003, 14,
3797.
(8) Harder, S. Angew. Chem., Int. Ed. 2003, 42, 3430. Asadullah, M.;
Kitamura, T.; Fujiwara, Y. Angew. Chem., Int. Ed. 2000, 39, 2475.
(9) For reviews on the Pictet-Spengler Reaction see: Lorenz, M.;
Van Linn, M. L.; Cook, J. M. Curr. Org. Synth. 2010, 7, 189. Cox, E. D.;
Cook, J. M. Chem. Rev. 1995, 95, 1797. Youn, S. W. Org. Prep. Proced. Int.
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8542 J. Org. Chem. 2010, 75, 8542–8549
Published on Web 11/22/2010
DOI: 10.1021/jo1019283
r
2010 American Chemical Society

Vanden Eynden et al.
JOCArticle
SCHEME 1
TABLE 1. Pictet-Spengler Reaction of Phenethylamine (2) and
Aldehydesa
FIGURE 2. Some naturally occurring tetrahydroisoquinolines.
focused on employing Lewis acid catalysts to affect this
transformation.10
Previously, we reported that 1-substituted 1,2,3,4-tetrahy-
droisoquinolines can be prepared regioselectively in excellent
yields by the reaction of a 1:1 mixture of 3-hydroxyphenthy-
lamine and various aldehydes using a catalytic amount of
calcium 1,1,1,3,3,3-hexafluoroisopropoxide (Ca(HFIP)2, 1).11
These reactions were conducted at ambient temperature and
required 24 h or less to proceed to completion, making this a
mild procedure for synthesizing such compounds. The reac-
tion was tolerant of many functional groups and allowed for
the installation of alkyl, aryl and alkenyl groups about the
1-position of the tetrahydroisoquinoline molecule. Herein,
we report an expanded scope of calcium-catalyzed Pictet-
Spengler reactions along with possible mechanistic details
for the reaction.
aYields are an average of two one mmol scale reactions.
(Table 1). All reactions gave the corresponding tetrahydro-
isoquinoline products in 79-91% yield at 23 °C in less than
24 h. The only outlier was 4-formylbenzonitrile, which re-
quired 48 h (entry 4) for the reaction to proceed to completion.
Although the Pictet-Spengler reaction proceeds smoothly
with aldehydes, there are few reported methods that employ
ketones to prepare 1,10-disubstituted tetrahydroisoquinolines.12
Typical ketones employed in the majority of these reactions are
activated β-ketoacids or esters. Low-yielding reactions with
unactivated ketones are likely caused by slow imine formation,
as well as a cyclization step that is inhibited by steric issues
encountered during formation of the tetrasubstituted center.
To avoid these issues, Pictet-Spengler reactions of ketones are
usually separated into multiple steps that involve the synthesis
and activation of the imine, followed by a cyclization step after
purification. For example, Horiguchi and co-workers reported
that the Pictet-Spengler reaction to form 1,1-disubstituted
1,2,3,4-tetrahydroisoquinolines required two steps: titanium
isopropoxide mediated imine formation following by trifluoro-
acetic acid mediated cyclization of the resulting imine.13 One of
Results and Discussion
In an effort to further expand the substrate scope of the
calcium-catalyzed reactions, a series of reactions were carried
out using 3-hydroxy-4-methoxyphenethylamine (2) and various
aldehydes, to provide tetrahydrosioquinolines that contain
the oxygen substitution pattern that mimics some naturally
occurring tetrahydroisoquinolines (Figure 2). The lack of re-
activity of calcium using this type of substrate may be caused
by the potential chelating ability of the 1,2-OH/OCH3 groups.
The ability of the amine substrate (2) to reversibly coordinate
to the calcium complex through the hydroxy and methoxy
functionalities likely causes the catalyst to be bound to this
area of the molecule, making less calcium catalyst available
in the reaction mixture to coordinate to the imine and promote
the cyclization (Scheme 1). The product also contains this
ortho relationship and can therefore coordinate to calcium to
deactivate the catalyst.
To overcome this problem, we increased the catalyst
loading of (1) to 20 mol %, which then allowed the formation
of a variety of THIQ from amine 2 and various aldehydes
(12) Bois-Choussy, M.; Cadet, S.; De Paolis, M.; Zhu, J. P. Tetrahedron
Lett. 2001, 42, 4503. Hegedus, A.; Hell, Z. Tetrahedron Lett. 2004, 45, 8553.
Horiguchi, Y.; Kodama, H.; Nakamura, M.; Yoshimura, T.; Hanezi, K.;
Hamada, H.; Saitoh, T.; Sano, T. Chem. Pharm. Bull. 2002, 50, 253.
Hudlicky, T.; Kutchan, T. M.; Shen, G.; Sutliff, V. E.; Coscia, C. J. J. Org.
Chem. 1981, 46, 1738. Kawai, M.; Deng, Y. L.; Kimura, I.; Yamamura, H.;
Araki, S.; Naoi, M. Tetrahedron-Asymmetry 1997, 8, 1487. Venkov, A. P.;
Angelov, P. A. Synth. Commun. 2003, 33, 3025.
(10) (a) Manabe, K.; Nobutou, D.; Kobayashi, S. Bioorg. Med. Chem.
2005, 13, 5154. (b) Srinivasan, N.; Ganesan, A. Chem. Commun. 2003, 916.
(c) Tsuji, R.; Yamanaka, M.; Nishida, A.; Nakagawa, M. Chem. Lett. 2002,
428. (d) Yamada, H.; Kawate, T.; Matsumizu, M.; Nishida, A.; Yamaguchi,
K.; Nakagawa, M. J. Org. Chem. 1998, 63, 6348. (e) Youn, S. W. J. Org.
Chem. 2006, 71, 2521.
(13) Horiguchi, Y.; Kodama, H.; Nakamura, M.; Yoshimura, T.; Hanezi,
K.; Hamada, H.; Saitoh, T.; Sano, T. Chem. Pharm. Bull. 2002, 50, 253.
(11) Vanden Eynden, M. J.; Stambuli, J. P. Org. Lett. 2008, 10, 5289.
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SCHEME 2
TABLE 2. Initial Screening for Pictet-Spengler Reactions of
Acetophenone
entry catalyst (mol %)
solvent
DCM
DCE
T (°C) time (h) yield (%)a
1
2
3
4
5
6
7
10
10
10
10
10
10
0
23
85
24
24
24
24
24
24
24
18
24
96
96
0
11
0
the most effective approaches for the synthesis of tetrahydroi-
soquinolines containing a quaternary center was developed by
Meyers (Scheme 2).14 However, this method is a lengthy
multistep sequence of reactions producing spirocyclic tetrahy-
droisoquinolines. Because of our previous success in catalyzing
Pictet-Spengler reactions of aldehydes using catalyst (1) and
the fact that a Lewis acid catalyst for Pictet-Spengler reactions
of ketones does not exist, a thorough examination of ketones
was undertaken.
DME
85
80
100
23
100
100
100
100
100
2-MeTHF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
14
71
11
29
87
98
73
99
8
9
10
11
20
20
1
10
aYield determined by 1H NMR spectroscopy
During our previous study of Pictet-Spengler reactions of
aldehydes at ambient temperature reactions with ketones
failed,11 although a rigorous study was not undertaken. A
number of solvents were tested in the reaction of 3-hydro-
xyphenethylamine (9) with acetophenone in the presence of
catalytic Ca(HFIP)2 (1). Reacting 10 mol % of (1) with 1 equiv
of amine (9) and acetophenone in dichloromethane at room
temperature confirmed that prior standard conditions were not
sufficient to promote cyclization to the 1,10-disubstituted tetra-
hydroisoquinoline (10) (Table 2, entry 1). Imine formation was
slow and large amounts of starting ketone and amine were
toluene at 100 °C proved to be the most general reaction
conditions.
With these new reaction conditions in hand, a series of
ketones were screened (Table 3). The initial test substrate
using acetophenone (entry 1) only provided 65% yield of the
corresponding product. This THIQ (10) suffers from severe
solubility issues in common organic solvents, including
DMSO, making workup and isolation problematic even
though the reaction shows high conversions. Simple ketones
work well (entry 2-3) as do ketones that give 1,10-spiroalkane
products (entry 4-6). Substituted acetophenone derivatives
also provide the desired products (entry 7-8). Ethyl pyru-
vate was converted to the corresponding tetrahydroisoqui-
noline in good yield, but was difficult to purify by column
chromatography (entry 9).15 Ketones bearing a tertiary
amine gave a mixture of regioisomers most likely because
of the compound’s ability to serve as a ligand (vide infra) for
the calcium catalyst (entry 10). Bulky ketones, such as benzo-
phenone, were too sterically congested to give any product
and the reactions with these ketones showed minimal imine
formation by 1H NMR spectroscopy.
1
observed in the H NMR spectrum of the crude residue. To
promote formation of the imine, higher boiling solvents were
screened. 1,2-Dimethoxyethane, 1,2-dichloroethane, and 2-
methyltetrahydrofuran (entries 2-4) gave inferior results,
while toluene (entry 5) proved to be the best solvent. The
reaction of acetophenone and amine (9) gave 71% yield of the
corresponding 1,10-disubstituted tetrahydroisoquinoline after
24 h at 100 °C with 10 mol % Ca(HFIP)2. In the absence of
catalyst, the reaction proceeded sluggishly, giving 29% yield
after 24 h at 100 °C (entry 7). Increasing the catalyst loading
to 20 mol % provided quantitative conversion to product
after 24 h (entry 8-9). After screening lower loadings and
reaction times (entry 10-11), 20 mol % of Ca(HFIP)2 (1) in
The formation of 1,2,3,4-tetrahydroisoquinolines with
ketones employing amine (2) would provide products that
mimic more naturally occurring tetrahydroisoquinolines
because of the guaiacol motif. Good yields were obtained
when employing acetone or related ketones (Table 4, entry
1-4). In these entries, the reaction could be conducted at
23 °C. However, the reaction of these ketones with amine 9
required higher temperatures, which may be caused by poorer
solubility of the intermediates in these reactions. Unfortu-
nately, acetophenones were not converted to the corresponding
tetrahydroisoquinolines in similarly high yields (entry 5-6).
The proposed catalytic cycle for the calcium-catalyzed
Pictet-Spengler reaction is shown in Scheme 3. The initial
step of the reaction involves the formation of the imine. The
calcium complex coordinates to the imine nitrogen, activat-
ing the substrate toward attack to create the resonance
stabilized carbocation and a covalently bound calcium ami-
do complex. Deprotonation of the acidic hydrogen by the
alkoxy ligand followed by hydrolysis of the amido ligand
generates the uncomplexed tetrahydroisoquinoline. Currently,
(14) Meyers, A. I.; Du, B.; Gonzalez, M. A. J. Org. Chem. 1990, 55, 4218.
(15) After working extensively with these THIQ compounds, a comment
on their physical properties requires further discussion. Most of these
compounds are poorly soluble in organic solvents aside from alcohols and
other polar solvents such as DMSO, which may be attributed to the
zwitterionic nature of the compounds. IR spectroscopy of the starting
phenoxyamines (2) and (9) as well as the tetrahydrosioquinoline products
do not show absorbtions indicative of phenols (3600 cm-1) or amines
(3400 cm-1) in the downfield portion of the infrared spectrum. Instead, a
very large and very broad peak around 2600 cm-1 is observed, which is the
characteristic absorbance for ammonium ions and tetrasubstituted amines.
By observing this peak, we are presuming that under our reaction conditions
the molecules may exist in their zwitterionic form. This form makes for very
difficult separation and purification due to the high polarity of the electro-
static interactions within the molecules. In fact, chromatographic separation
cannot be achieved without strong eluting conditions as the compounds
reside on the baseline. Recrystallization is also an acceptable pathway to
obtain the product, but low yields and the compound’s ability to retain
solvent led us away from this purification method. Therefore, a simple
trituration with a low boiling and relatively low polarity solvent such as
diethyl ether achieved good yields in most cases, even though this isolation
technique is not completely quantitative. Therefore, we observe very high
and sometimes even quantitative conversion of starting materials to pro-
ducts, but the chemical properties of these compounds lower the amount of
isolated material.
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TABLE 3. Pictet-Spengler Reactions of Phenethylamine (9)
TABLE 4. Pictet-Spengler Reactions of Phenethylamine (2)
and Ketonesa
and Ketonesa
aYields are an average of two one mmol scale reactions. bYield
determined by 1H NMR spectroscopy.
SCHEME 3
aYields are an average of two one mmol scale reactions. bYield deter-
mined by 1H NMR spectroscopy. cYield is a 5:2 mixture of 6-ol and 8-ol
regioisomers.
the heterogeneity of this calcium system has prevented exp-
loration of solution phase mechanistic studies.
Literature methods for preparing similar THIQ compounds
rely on the use of strong Brønsted acids or Lewis acids to
perform this transformation.10,16 To compare the effective-
ness of our calcium-catalyzed Pictet-Spengler reaction with
those found in the literature, phenethylamine (9) was treated
with benzyl acetone to synthesize THIQ (12) (Table 5). Using
various concentrations of trifluoroacetic acid (entries 1-3)
at ambient temperature and at 80 °C gave very poor yields.
Heating the reaction mixture in concentrated hydrochloric
acid for 24 h surprisingly gave very poor yields as well (entry 4).
Heating the starting materials in strong aqueous NaOH
(16) Bois-Choussy, M.; Cadet, S.; De Paolis, M.; Zhu, J. P. Tetrahedron
Lett. 2001, 42, 4503.
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SCHEME 4. Substrate Directing of Regioisomers
TABLE 5. Acid- or Base-Promoted Pictet-Spengler Reactionsa
SCHEME 5
entry
conditions
T (°C)
yield (%)
SCHEME 6
1
2
3
4
2% TFA in DCM
1 equiv TFA in DCM
2% TFA in CH3CN
Conc. HCl
12 M NaOH
cat. Yb(OTf)3/toluene
cat. Ca(HFIP)2/toluene
23
23
80
100
100
100
100
<5
<5
<5
<5
58
5
6b
7c
51
78
aYield determined by 1H NMR spectroscopy. bRefer to ref 10a. cTable 3,
Entry 3.
(entry 5) gave the highest result of 58% yield. Employing
conditions previously reported by Kobayashi10 for Pictet-
Spengler reactions of aldehydes and phenethylamine 9 gave
51% yield of the desired THIQ. Moreover, this catalyst
gave <30% yield for reactions of phenethylamine 2 with
benzyl acetone (see Table 4, entry 4). From these observa-
tions, it is unlikely that calcium complex 1 is simply acting as
a simple Brønsted acid or base.
During the course of these studies, we observed that Pictet-
Spengler reactions promoted by calcium complex (1) pro-
duced regioselective products in most cases, giving rise to
only the 6-ol isomer. However, when a nitrogen functionality
is present, the isomeric ratio of products is altered to give
mixtures of the favored 6-ol isomer and the disfavored 8-ol
regioisomer (Scheme 4). For example, pyridine carboxalde-
hyde gave an 8:1 mixture of the 6-ol to 8-ol regioisomers
(entry 1), while a 4:3 mixture of regioisomers was observed
when 2-acetylpyridine was employed (entry 2). The same
effect was not observed when fufural, 2-furyl methyl ketone,
or N-methylpyrrole-2-carboxaldehyde was employed. This
observation shows that a nitrogen-bearing substituent can
greatly affect the regioselective control of the reaction.
The observation that the substrate can direct the regio-
chemistry of the reaction may arise from simultaneous
coordination of the calcium to the phenoxide and an addi-
tional coordinating group, such as the nitrogen in pyridine
(Scheme 5). At this point, attack on the imine will result from
most accessible position, ortho to the phenoxide, resulting in
the 8-ol tetrahydroisoquinoline isomer. This directing effect
could be used to control the regiochemistry of the reaction if
one desired the less favored isomer.
In an effort to exploit this new Pictet-Spengler methodol-
ogy we decided to target spirobenzylisoquinoline alkaloids.
Spirobenzylisoquinoline alkaloids (SBA) are components of
plants that are employed in Eastern medicine17 and have
been shown to exhibit antiviral activity.18 Tetrahydroisoqui-
noline (27) is a common intermediate to several of these
compounds. To examine (1) as a catalyst to prepare inter-
mediate (27), amine (2) and dione (26) were exposed to the
optimized reaction conditions (Scheme 6). The spiroisoquinoline
(17) Kim, D. K.; Shin, T. Y. Arch. Pharm. 2000, 23, 459.
(18) Orhan, I.; Ozcelik, B.; Karaoglu, T.; Sener, B. Z. Naturforsch. C:
Biosci. 2007, 62, 19.
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product was isolated in 55% yield (average of two runs). This
result proves more effective than similar reactions that
required 96 h to obtain 44% yield of 27 using HCl as a
promoter.19
In conclusion, we have demonstrated an efficient calcium-
catalyzed synthesis of various 1,2,3,4-tetrahydrosioquio-
lines. Remarkably, the Ca(HFIP)2 complex also promotes
the Pictet-Spengler reaction of ketones with amines to pro-
duce 1,10-disubstituted 1,2,3,4-tetrahydrosioquinolines in a
single step. Further studies are ongoing in our laboratory to
develop an asymmetric calcium-catalyzed Pictet-Spengler
reaction.
procedure B. Calcium 1,1,1,3,3,3-hexafluoroisopropoxide (75.0 mg,
0.200 mmol, 20.0 mol %) was reacted with 3-hydroxy-4-methox-
yphenethylamine (168 mg, 1.00 mmol) and p-(dimethylamino)-
benzaldehyde (153 mg, 1.02 mmol) in DCM for 22 h at ambient
temperature to give the product 5 (272 mg, 0.912 mmol, 91%) as an
off-white solid. 1H NMR (400 MHz, DMSO): δ 2.50-2.58
(m, 1H), 2.65-2.72 (m, 1H), 2.75-2.82 (m, 1H), 2.86 (s, 6H), 2.95-
3.01 (m, 1H), 3.50 (s, 3H), 4.76 (s, 1H), 6.17 (s, 1H), 6.50 (s, 1H),
6.65 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 8.68 (bs, 1H);
13C NMR (100 MHz, DMSO): 28.6, 40.2, 41.3, 55.7, 60.1, 111.8,
112.0, 115.4, 127.8, 129.2, 129.7, 133.3, 144.8, 145.4, 149.4; IR
(KBr): 3270, 3010, 2972, 2950, 2892, 2559, 1616, 1523, 1444, 1352,
1328, 1271, 1255, 1215, 1164, 797. HRMS (ESI): calcd for C18H21-
N2O2 [M þ H]þ 299.1754, found 299.1744.
1-(p-Cyanophenyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroi-
soquinoline (6). The compound is prepared using general proce-
dure B. Calcium 1,1,1,3,3,3-hexafluoroisopropoxide (74.3 mg,
0.201 mmol, 20.0 mol %) was reacted with 3-hydroxy-4-methoxy-
phenethylamine (167 mg, 1.00 mmol) and p-cyanobenzaldehyde
(132 mg, 1.01 mmol) in DCM (10 mL) for 48 h at ambient
temperature to give the product 6 (231 mg, 0.824 mmol, 82%) as
a white solid. 1H NMR (400 MHz, DMSO): δ 2.53-2.59
(m, 1H), 2.66-2.73 (m, 1H), 2.78-2.84 (m, 1Hþ1H), 2.88-
2.94 (m, 1H), 3.51 (s, 3H), 4.98 (s, 1H), 6.15 (s, 1H), 6.54 (s, 1H),
7.42 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 8.81 (bs, 1H);
13C NMR (100 MHz, DMSO): 28.3, 40.8, 55.7, 59.8, 109.5, 111.6,
115.6, 119.0, 127.5, 128.0, 129.7, 131.9, 145.2, 145.7, 151.5; IR
(KBr):3270, 3044, 2999, 2916, 2840, 2559, 2226, 1607, 1508, 1449,
1281, 1203, 1096, 1018, 830, 813, 763, 564. HRMS (ESI): calcd
for C17H16N2O2 [M þ H]þ 281.1285, found 281.1290.
Experimental Section
General Procedure for Calcium-Catalyzed Pictet-Spengler
Reactions: Procedure A. 1-Phenyl-6-hydroxy-7-methoxy-1,2,3,4-
tetrahydroisoquinoline (3). In a drybox, an oven-dried 50 mL
RBF with stir bar is charged with calcium 1,1,1,3,3,3-hexafluoro-
isopropoxide (75.2 mg, 0.201 mmol, 19.9 mol %), 3-hydroxy-
˚
4-methoxyphenethylamine (168 mg, 1.01 mmol) and 3 A MS
(400 mg). The flask is sealed and removed from the drybox
where dry DCM (10 mL) and benzaldehyde (112 mg, 1.06 mmol)
are added via syringe, respectively. The reaction is allowed to stir
for 22 h at ambient temperature. The reaction suspension was
added to a separatory funnel containing H2O (5 mL) and brine
(10 mL). The organic layer is removed and the aqueous layer is
extracted (EtOAc, 2 ꢀ 10 mL) and the organic layers combined,
dried (Na2SO4), filtered through Celite and concentrated. The
crude residue is triturated with small amounts of Et2O to give
the product 3 (222 mg, 0.868 mmol, 86%) as an off-white solid.
1H NMR (400 MHz, DMSO): δ 2.52-2.59 (m, 1H), 2.68-2.75
(m, 1H), 2.79-2.85 (m, 1H), 2.96-3.01 (m, 1H), 3.49 (s, 3H),
4.89 (s, 1H), 6.14 (s, 1H), 6.53 (s, 1H), 7.22-7.32 (m, 5H), 8.74
(bs, 1H); 13C NMR (100 MHz, DMSO): δ 28.5, 41.2, 55.6, 60.5,
111.7, 115.4, 126.7, 127.9, 128.7, 128.7, 144.9, 145.5, 145.6; IR
(KBr): 3283, 3034, 2934, 2911, 2836, 2706, 2536, 1601, 1522, 1458,
1433, 1412, 1361, 1254, 1207, 1112, 1098, 1020, 804, 700. HRMS
(ESI): calcd for C16H17NO2 [M þ H]þ 256.1332, found 256.1326.
General Procedure for Calcium-Catalyzed Pictet-Spengler
Reactions: Procedure B. 1-(p-Nitrophenyl)-6-hydroxy-7-methoxy-
1,2,3,4-tetrahydroisoquinoline (4). In a drybox, an oven-dried 50 mL
RBF with stir bar is charged with calcium 1,1,1,3,3,3-hexafluor-
oisopropoxide (76.7 mg, 0.205 mmol, 20.5 mol %), 3-hydroxy-4-
methoxyphenethylamine (168 mg, 1.00 mmol), p-nitrobenzalde-
(E)-1-Styryl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline
(7). The compound is prepared using general procedure A. Calcium
1,1,1,3,3,3-hexafluoroisopropoxide (75.2 mg, 0.201 mmol,
20.0 mol %) was reacted with 3-hydroxy-4-methoxyphenethy-
lamine (167 mg, 1.00 mmol) and trans-cinnamaldehyde (136 mg,
1.06 mmol) in DCM (10 mL) for 20 h at ambient temperature.
Purification was achieved by adsorbing the crude reaction
mixture onto silica gel, loading the silica onto a short column
and flushing the column (25% EtOAc in hexanes) to remove
impurities. The remaining silica was washed with MeOH and
filtered. The filtrate was concentrated to dryness to give the
product 7 (227 mg, 0.81 mmol, 81%) as a red crystalline solid.
1H NMR (400 MHz, DMSO): δ 2.53-2.64 (m, 2H), 2.81-2.87
(m, 1H), 3.04-3.09 (m, 1H), 3.65 (s, 3H), 4.45 (d, J = 7.2 Hz,
1H), 6.33-6.39 (m, 1H), 6.51-6.58 (m, 3H), 7.20-7.25 (m, 1H),
7.27-7.33 (m, 2H), 7.38-7.45 (m, 2H), 8.77 (bs, 1H); 13C NMR
(100 MHz, DMSO): δ 28.5, 40.8, 55.8, 58.1, 111.2, 115.7, 126.2,
127.2, 127.5, 127.8, 128.6, 129.9, 133.4, 137.0, 145.0, 145.7; IR
(KBr): 3282, 3059, 3021, 2932, 2835, 2582, 1598, 1509, 1448,
1328, 1274, 1209, 1128, 1022, 967, 692. HRMS (ESI): calcd for
C18H19NO2 [M þ H]þ 282.1489, found 282.1489.
˚
hyde (155 mg, 1.03 mmol) and 3 A MS (400 mg). The flask is sealed
and removed from the drybox where dry DCM (10 mL) is added
via syringe. The reaction is allowed to stir for 22 h at ambient
temperature. The reaction suspension was added to a separatory
funnel containing H2O (5 mL) and brine (10 mL). The organic
layer is removed and the aqueous layer is extracted (EtOAc, 2 ꢀ
10 mL) and the organic layers combined, dried (Na2SO4), filtered
through Celite and concentrated. The crude residue is triturated
with small amounts of Et2O to give the product 4 (249 mg, 0.829
1-Hexyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline
(8). The compound is prepared using general procedure A.
Calcium 1,1,1,3,3,3-hexafluoroisopropoxide (75.3 mg, 0.201 mmol,
20.1 mol %) was reacted with 3-hydroxy-4-methoxyphenethy-
lamine (168 mg, 1.00 mmol) and heptanal (122 mg, 1.07 mmol)
in DCM (10 mL) for 24 h at ambient temperature. Purification
was achieved by adsorbing the crude reaction mixture onto silica
gel, loading the silica onto a short column and flushing the
column (25% EtOAc in hexanes) to remove impurities. The
remaining silica was washed with MeOH and filtered. The
filtrate was concentrated to dryness to give the product 8 (210
mg, 0.797 mmol, 79%) as a yellow solid. 1H NMR (400 MHz,
CDCl3): δ 0.85-0.91 (m, 3H), 1.29-1.48 (m, 8H), 1.65-1.83 (m,
2H), 2.58-2.74 (m, 2H), 2.91-2.98 (m, 1H), 3.18-3.24 (m, 1H),
3.84 (s, 3H), 3.88-3.91 (m, 1H), 4.17 (bs, 1H), 6.58 (s, 1H), 6.59
(s, 1H); 13C NMR (100 MHz, CDCl3): δ 14.3, 22.8, 26.3, 29.4,
29.7, 32.1, 36.8, 41.2, 55.7, 56.2, 10.8, 115.0, 128.0, 131.1, 144.2,
1
mmol, 83%) as a yellow solid. H NMR (400 MHz, DMSO): δ
2.54-2.60 (m, 1H), 2.67-2.74 (m, 1H), 2.80-2.95 (m, 2Hþ1H),
3.51 (s, 3H), 5.04 (s, 1H), 6.16 (s, 1H), 6.56 (s, 1H), 7.51 (d, J =
8.4 Hz, 2H), 8.17 (d, J = 8.8 Hz, 2H), 8.82 (bs, 1H); 13C NMR
(100 MHz, DMSO): 28.3, 40.8, 55.7, 59.5, 111.6, 115.6, 123.1,
127.4, 127.9, 129.9, 145.2, 145.7, 146.3, 153.7; IR (KBr): 3262,
3074, 3020, 2944, 2874, 1593, 1516, 1436, 1350, 1278, 1239, 1213,
1118, 1090, 1024, 855, 814, 747, 701. HRMS (ESI): calcd for C16H16-
N2O4 [M þ H]þ 301.1183, found 301.1170.
1-(p-Dimethylaminophenyl)-6-hydroxy-7-methoxy-1,2,3,4-tetra-
hydroisoquinoline (5). The compound is prepared using general
(19) McLean, S.; Lin, M.-S.; Whelan, J. Can. J. Chem. 1970, 48, 948.
J. Org. Chem. Vol. 75, No. 24, 2010 8547

Vanden Eynden et al.
JOCArticle
145.3; IR (KBr): 3292, 3267, 3066, 3006, 2925, 2851, 2716, 1606,
1514, 1466, 1273, 1214, 1110, 1028, 846, 806. HRMS (ESI): calcd
for C16H25NO2 [M þ H]þ 264.1958, found 264.1959.
Calcium 1,1,1,3,3,3-hexafluoroisopropoxide (75.0 mg, 0.200 mmol,
20.0 mol %) was reacted with 3-hydroxyphenethylamine
(138 mg, 1.01 mmol) and cyclohexanone (99.4 mg, 1.01 mmol)
in toluene (10 mL) for 24 h at 100 °C to give the product 14
(170 mg, 0.781 mmol, 78%) as an off-white crystalline solid.
1H NMR (400 MHz, DMSO): δ 1.17-1.25 (m, 1H), 1.40 (d, J =
12.4 Hz, 2H), 1.52-1.70 (m, 7H), 1.80 (bs, 1H), 2.53 (t, J = 5.6
Hz, 2H), 2.83 (t, J = 6.0 Hz, 2H), 6.39 (d, J = 2.0 Hz, 1H), 6.54
(dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 9.10 (bs,
1H); 13C NMR (100 MHz, DMSO): δ 21.3, 25.5, 30.5, 37.6, 37.8,
53.3, 113.1, 114.7, 126.5, 135.7, 136.1, 154.6; IR (KBr): 3305,
3049, 3028, 2925, 2861, 2532, 1606, 1502, 1456, 1257, 1242, 1232,
1145, 1123, 1066, 1034, 972, 944, 863, 850, 826, 808. HRMS
(ESI): calcd for C14H19NO [M þ H]þ 218.1539, found 218.1533.
2,3,30,40-Tetrahydro-20H-spiro[indene-1,10-isoquinolin]-60-ol (15).
The compound is prepared according to general procedure B.
Calcium 1,1,1,3,3,3-hexafluoroisopropoxide (76.1 mg, 0.203 mmol,
20.2 mol %) was reacted with 3-hydroxyphenethylamine (138
mg, 1.01 mmol) and 1-indanone (151 mg, 1.14 mmol) in toluene
(10 mL) for 24 h at 100 °C to give the product 15 (175 mg, 0.696
1-Methyl-1-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline
(10). The compound is prepared using general procedure A.
Calcium 1,1,1,3,3,3-hexafluoroisopropoxide (75.0 mg, 0.200
mmol) was reacted with 3-hydroxyphenethylamine (137 mg,
1.00 mmol) and acetophenone (129 mg, 1.07 mmol) in toluene
(10 mL) for 24 h at 100 °C to give the product 10 (156 mg, 0.650
mmol, 65%) as a white solid. 1H NMR (400 MHz, DMSO): δ
1.65 (s, 3H), 2.54-2.60 (m, 2H), 2.68-2.76 (m, 1H), 2.80-2.85
(m, 1H), 6.50 (s, 1H), 6.56 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.87
(d, J = 8.4 Hz, 1H), 7.11-7.14 (m, 1H), 7.19-7.22 (m, 4H), 9.13
(bs, 1H); 13C NMR (100 MHz, DMSO): δ 29.7, 30.4, 38.4, 58.1,
112.8, 114.9, 125.8, 127.0, 127.5, 128.4, 132.7, 136.3, 149.7,
155.1; IR (KBr): 3294, 3231, 3055, 3023, 2990, 2964, 2931,
2583, 1605, 1579, 1500, 1444, 1373, 1351, 1295, 1245, 1186,
1162, 1138, 1084, 1028, 977, 868, 843, 822, 769, 706. HRMS
(ESI): calcd for C16H17NO [M þ H]þ 240.1383, found 240.1372.
1,1-Dimethyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline (11).
The compound is prepared according to general procedure A.
Calcium 1,1,1,3,3,3-hexafluoroisopropoxide (74.7 mg, 0.200
mmol, 20.0 mol %) was reacted with 3-hydroxyphenethylamine
(137 mg, 0.997 mmol) and acetone (61.8 mg, 1.06 mmol) in
toluene (10 mL) for 24 h at 100 °C to give the product 11 (152 mg,
1
mmol, 69%) as a gray solid. H NMR (400 MHz, DMSO): δ
2.21-2.33 (m, 3H), 2.61-2.66 (m, 1H), 2.77-3.08 (m, 5H), 6.42-
6.48 (m, 3H), 6.79 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H),
7.17 (td, J = 7.2 Hz, 1.2 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 9.08
(bs, 1H); 13C NMR (125 MHz, DMSO, relaxation time = 5 s): δ
29.5, 29.8, 39.5, 42.4, 67.6, 113.3, 114.4, 124.3, 124.3, 126.1,
127.0, 128.1, 132.7, 136.6, 143.5, 150.8, 155.0; IR (KBr): 3386,
3265, 3066, 3018, 2939, 2855, 2588, 1607, 1456, 1360, 1304, 1252,
1156, 765. HRMS (ESI): calcd for C17H17NO [M þ H]þ
252.1383, found 252.1394.
1-Methyl-1-(3-methoxyphenyl)-6-hydroxy-1,2,3,4-tetrahydro-
isoquinoline (16). The compound is prepared according to general
procedure A. Calcium 1,1,1,3,3,3-hexafluoroisopropoxide (76.0
mg, 0.203 mmol, 20.0 mol %) was reacted with 3-hydroxyphe-
nethylamine (141 mg, 1.03 mmol) and 30-methoxyacetophenone
(156 mg, 1.04 mmol) in toluene (10 mL) for 24 h at 100 °C to give
the product 16 (189 mg, 0.701 mmol, 68%) as an off-white solid.
1H NMR (400 MHz, DMSO): δ 1.62 (s, 3H), 2.53-2.59 (m, 2H),
2.68-2.73 (m, 1H), 2.80-2.82 (m, 1H), 3.68 (s, 3H), 6.49 (s, 1H),
6.55 (dd, J = 2.8 Hz, 8.4 Hz, 1H), 6.71-6.73 (m, 1H), 6.77 (s,
2H), 6.90 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 9.15 (bs,
1H); 13C NMR (100 MHz, DMSO): δ 29.6, 30.4, 38.4, 54.8, 58.1,
110.5, 112.7, 113.5, 114.8, 119.4, 128.3, 128.4, 132.6, 136.2,
151.5, 155.1, 158.7; IR (KBr): 3276, 3245, 3000, 2961, 2931,
2588, 1606, 1582, 1486, 1451, 1430, 1293, 1254, 1163, 1040, 858,
826, 786, 705. HRMS (ESI): calcd for C17H19NO2 [M þ H]þ
270.1489, found 270.1485.
1
0.857 mmol, 86%) as an off-white solid. H NMR (400 MHz,
DMSO): δ 1.28 (s, 6H), 2.56 (t, J = 5.6 Hz, 2H), 2.90 (t, J =
5.6 Hz, 2H), 6.398 (s, 1H), 6.52 (d, J = 1.6 Hz, 1H), 6.99 (d, J =
8.4 Hz, 1H); 13CNMR(100MHz, DMSO):δ30.4, 31.1, 38.4, 51.9,
113.2, 114.7, 126.6, 134.9, 135.4, 154.73; IR (KBr): 3415, 3261,
3038, 3016, 2972, 2951, 3797, 2694, 2610, 1618, 1582, 1498, 1367,
1264, 1256, 1242, 1158, 1127, 1088, 1061, 991, 868, 812. HRMS
(ESI): calcd for C11H15NO [M þ H]þ 178.1226, found 178.1221.
1-Methyl-1-phenethyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline
(12). The compound is prepared according to general procedure
A. Calcium 1,1,1,3,3,3-hexafluoroisopropoxide (75.8 mg, 0.203
mmol, 20.3 mol %) was reacted with 3-hydroxyphenethylamine
(137 mg, 1.00 mmol) and benzylacetone (148 mg, 1.00 mmol) in
toluene (10 mL) for 24 h at 100 °C to give the product 12 (210 mg,
1
0.784 mmol, 78%) as an off-white crystalline solid. H NMR
(400 MHz, DMSO): δ 1.31 (s, 3H), 1.76 (td, J = 12.8 Hz, 4.8 Hz,
1H), 2.00 (td, J = 13.6 Hz, 4.4 Hz, 1H), 2.30 (td, J = 12.6 Hz,
4.0 Hz, 1H), 2.50-2.52 (m, 1H), 2.53-2.68 (m, 2H), 2.94 (t, J =
5.2 Hz, 2H), 6.44 (d, J = 2.8 Hz, 1H), 6.58 (dd, J = 8.4 Hz,
2.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 7.11 (dd, J = 9.2 Hz,
6.8 Hz, 3H), 7.20-7.24 (m, 2H); 13C NMR (100 MHz, DMSO):
δ 29.2, 30.0, 30.5, 38.4, 45.0, 54.5, 113.3, 114.7, 125.3, 126.6,
128.1, 133.9, 136.2, 143.1, 154.6; IR (KBr) 3274, 3232, 3022,
2946, 2681, 2580, 1602, 1577, 1496, 1453, 1379, 1350, 1296, 1250,
1159, 1114, 881, 855, 817, 754, 702. HRMS (ESI): calcd for
C18H21NO [M þ H]þ 268.1696, found 268.1682.
1-Methyl-1-(4-nitrophenyl)-6-hydroxy-1,2,3,4-tetrahydroiso-
quinoline (17). The compound is prepared according to general
procedure B. Calcium 1,1,1,3,3,3-hexafluoroisopropoxide (75.9
mg, 0.203 mmol, 20.0 mol %) was reacted with 3-hydroxyphe-
nethylamine (141 mg, 1.02 mmol) and 40-nitroacetophenone
(182 mg, 1.10 mmol) in toluene (10 mL) for 24 h at 100 °C to
give the product 17 (246 mg, 0.865 mmol, 84%) as a brown-red
solid. 1H NMR (400 MHz, DMSO): δ 1.67 (s, 3H), 2.48-2.53
(m, 1H), 2.66-2.73 (m, 2H), 2.83-2.86 (m, 1H), 6.50 (s, 1H),
6.55 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 7.49
30,40-Dihydro-20H-spiro[cyclopentane-1,10-isoquinolin]-60-ol (13).
The compound is prepared according to general procedure A.
Calcium 1,1,1,3,3,3-hexafluoroisopropoxide (75.8 mg, 0.207
mmol, 20.5 mol %) was reacted with 3-hydroxyphenethylamine
(139 mg, 1.01 mmol) and cyclopentanone (93.5 mg, 1.11 mmol)
in toluene (10 mL) for 24 h at 100 °C to give the product 13 (150
mg, 0.740 mmol, 73%) as a tan solid. 1H NMR (400 MHz,
DMSO): δ 1.69-1.77 (m, 8H), 2.55 (t, J = 5.6 Hz, 2H), 2.83
(t, J = 5.6 Hz, 2H), 6.37 (s, 1H), 6.53 (dd, J = 2.4 Hz, 8.2 Hz,
1H), 6.95 (d, J = 8.4 Hz, 1H), 9.08 (bs, 1H); 13C NMR (100
MHz, DMSO, relaxation time = 10 s): δ 24.5, 30.3, 39.4, 42.4,
63.6, 113.4, 114.4, 126.6, 134.1, 136.4, 154.5; IR (KBr): 3260,
3021, 2949, 2872, 2790, 2701, 2611, 1618, 1581, 1498, 1117, 853,
807. HRMS (ESI): calcd for C13H17NO [M þ H]þ 204.1383, found
204.1391.
(d, J = 8.8 Hz, 2H), 8.07 (d, J = 8.8 Hz, 2H), 9.19 (bs, 1H); 13
C
NMR (100 MHz, DMSO): δ 29.5, 29.9, 38.5, 58.3, 113.1, 115.1,
122.7, 128.3, 131.6, 136.4, 145.7, 155.5, 157.8; IR (KBr): 3265,
3252, 3109, 3054, 2979, 2939, 2695, 1604, 1579, 1517, 1500, 1464,
1351, 1296, 1250, 1111, 1068, 855, 818, 789, 755, 699. HRMS
(ESI): calcd for C16H15N2O3 [M þ H]þ 285.1234, found 285.1226.
1-Methyl-1-(ethylcarboxylate)-6-hydroxy-1,2,3,4-tetrahydro-
isoquinoline (18). The compound is prepared according to general
procedure A. Calcium 1,1,1,3,3,3-hexafluoroisopropoxide (75.8 mg,
0.203 mmol, 20.1 mol %) was reacted with 3-hydroxyphenethyla-
mine (138 mg, 1.01 mmol) and ethyl pyruvate (140 mg, 1.20 mmol)
30,40-Dihydro-20H-spiro[cyclohexane-1,10-isoquinolin]-60-ol (14).
The compound is prepared according to general procedure A.
8548 J. Org. Chem. Vol. 75, No. 24, 2010

Vanden Eynden et al.
JOCArticle
in toluene (10 mL) for 24 h at 100 °C to give the product 18
(104 mg, 0.442 mmol, 44%) as a yellow solid. 1H NMR (400 MHz,
DMSO): δ 1.14 (t, J = 7.2 Hz, 3H), 1.47 (s, 3H), 2.52-2.54 (m,
1H), 2.64-2.71 (m, 1H), 2.88-3.00 (m, 2H), 4.06 (q, J = 2.8 Hz,
2H), 6.44-6.44 (m, 1H), 6.55-6.58 (m, 1H), 7.09 (d, J = 8.4 Hz,
1H), 9.21 (bs, 1H); 13C NMR (100 MHz, DMSO): δ 14.0, 28.0,
29.6, 60.1, 60.4, 113.2, 114.7, 128.0, 128.2, 128.9, 136.3, 155.6,
175.3; IR (KBr): 3299, 3063, 2977, 2929, 2683, 2602, 1724, 1608,
1508, 1458, 1356, 1313, 1246, 1149, 1111, 1014, 843. HRMS (ESI):
calcd for C13H17NO3 [M þ H]þ 236.1281, found 236.1277.
1,1-Dimethyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydrosioqui-
nol-ine (20). The compound is prepared according to general
procedure A. Calcium 1,1,1,3,3,3-hexafluoroisopropoxide (75.3
mg, 0.201 mmol, 20.1 mol %) was reacted with 3-hydroxy-4-
methoxyphenethylamine (167 mg, 1.00 mmol) and acetone (59.0
mg, 1.02 mmol) in DCM (10 mL) for 24 h at ambient tempera-
ture to give the product 20 (149 mg, 0.721 mmol, 72%) as an off-
white solid. 1H NMR (400 MHz, DMSO): δ 1.31 (s, 6H), 2.49 (t,
J = 5.6 Hz, 2H), 2.89 (t, J = 5.6 Hz, 2H), 3.72 (s, 3H), 6.40 (s,
1H), 6.71 (s, 1H); 13C NMR (100 MHz, DMSO): δ 29.3, 30.9,
38.5, 52.2, 55.9, 110.0, 115.3, 126.5, 134.8, 144.4, 145.8; IR
(KBr): 3267, 3012, 2962, 2829, 2683, 2588, 1570, 1512, 1442,
1266, 1222, 1208, 1150, 1066, 787; HRMS (ESI): calcd for
C12H17NO2 [MþH]þ: 208.1332, found 208.1327.
3-hydroxy-4-methoxyphenethylamine (167.6 mg, 1.01 mmol)
and benzylacetone (153.2 mg, 1.03 mmol) in DCM (10 mL)
for 24 h at ambient temperature to give the product 23 (210 mg,
1
0.704 mmol, 70%) as an off-white solid. H NMR (400 MHz,
DMSO): δ 1.33 (s, 3H), 1.79 (td, J = 12.6, 5.2 Hz, 1H), 2.02 (td,
J = 13.2, 4.4 Hz, 1H), 2.32 (td, J = 12.8 Hz, 4.4 Hz, 1H),
2.43-2.48 (m, 1H), 2.53-2.67 (m, 2H), 2.92 (t, J = 5.2 Hz, 2H),
3.72 (s, 3H), 6.43 (s, 1H), 6.73 (s, 1H), 7.10-7.15 (m, 3H),
7.22-7.25 (m, 2H), 8.63 (bs, 1H); 13C NMR (100 MHz, DMSO):
δ 29.1, 29.6, 30.1, 38.5, 44.9, 54.6, 55.9, 110.0, 115.3, 125.3,
127.4, 128.2, 134.0, 143.2, 144.2, 145.9; IR (KBr): 3265,
3024, 2954, 2836, 2705, 2559, 1508, 1452, 1259, 1208, 789.
HRMS (ESI): calcd for C19H23NO2 [M þ H]þ 298.1802, found
298.1798.
60-Hydroxy-70-methoxy-30,40-dihydro-20H-spiro[indeno[5,4-d]-
[1,3]dioxole-7,10-isoquinolin]-6(8H)-one (27). The compound is
prepared according to general procedure B. Calcium 1,1,1,3,3,3-
hexafluoroisopropoxide (8.0 mg, 0.020 mmol, 20.4 mol %) was
reacted with 3-hydroxy-4-methoxyphenethylamine (17.2 mg,
0.103 mmol) and 4,5-methylenedioxyindane-1,2,-dione19 26
(19.0 mg, 0.100 mmol) in DCM (10 mL) for 18 h at ambient
temperature. The product was isolated by column chromatog-
raphy (2% MeOH in DCM) to give the product 27 (17.8 mg,
0.052 mmol, 52%) as an off-white solid. A second run gave the
product (19.7 mg, 0.058 mmol) in a 58% yield for a two-run
average of 55%. 1H NMR (400 MHz, CDCl3): δ 2.66-2.72
(m, 1H), 2.79-2.86 (m, 1H), 3.01-3.08 (m, 1H), 3.37 (s, 2H),
3.39-3.45 (m, 1H), 3.65 (s, 3H), 6.09-6.14 (m, 3H), 6.67 (s, 1H),
6.95 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 29.0, 40.5, 42.0, 56.2, 67.0, 77.4, 102.5,
107.3, 109.5, 115.2, 121.1, 128.9, 129.3, 131.0, 132.2, 144.2,
145.0, 145.7, 153.6, 204.5; IR (KBr): 3281, 3004, 2934, 1719,
1633, 1510, 1472, 1378, 1259, 1049, 1021, 923, 880, 817, 736.
HRMS (ESI): calcd for C19H17NO5 [M þ H]þ 340.1179, found
340.1162.
70-Methoxy-30,40-dihydro-20H-spiro[cyclohexane-1,10-isoquinoli-
n]-60-ol (21). The compound is prepared according to general
procedure A. Calcium 1,1,1,3,3,3-hexafluoroisopropoxide
(78.2 mg, 0.209 mmol, 20.4 mol %) was reacted with 3-hydro-
xy-4-methoxyphenethylamine (171 mg, 1.02 mmol) and cyclo-
hexanone (103.5 mg, 1.05 mmol) in DCM (10 mL) for 24 h at
ambient temperature to give the product 21 (212 mg, 0.856
mmol, 84%) as an off-white solid. 1H NMR (400 MHz, CDCl3):
δ 1.22-1.36 (m, 1H), 1.60-1.80 (m, 9H), 2.66 (t, J = 6.0 Hz,
2H), 3.02 (t, J = 6.0 Hz, 2H), 3.88 (s, 3H), 6.60 (s, 1H), 6.72 (s,
1H); 13C NMR (100 MHz, CDCl3): δ 22.0, 25.9, 38.3, 38.6, 54.5,
56.3, 108.5, 114.8, 128.2, 136.6, 143.8, 145.1; IR (KBr): 3308,
3010, 2929, 2843, 2591, 1607, 1528, 1450, 1331, 1255, 1216, 1121,
1043, 839, 779. HRMS (ESI): calcd for C15H21NO2 [M þ H]þ
248.1645, found 248.1637.
Acknowledgment. This work was generously supported
by The Ohio State University.
1-Methyl-1-(2-phenylethyl)-6-hydroxy-7-methoxy-1,2,3,4-tet-
rahydroisoquinoline (23). The compound is prepared according
to general procedure A. Calcium 1,1,1,3,3,3-hexafluoroisoprop-
oxide (74.0 mg, 0.198 mmol, 20.0 mol %) was reacted with
Supporting Information Available: Full experimental pro-
cedures and NMR spectra of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 24, 2010 8549