Efficient synthesis of N-alkyl tetrahydroisoquinolines by reductive amination

Article abstract of DOI:10.1055/s-2005-872081

An expedient access to diverse N-alkyl 1,2,3,4-tetrahydroisoquinolines is reported by reductive amination of aldehydes and ketones with tetrahydroisoquinoline (THIQ) in the presence of Ti(Oi-Pr)₄ and NaBH₄. The N-alkyl THIQ products

Full text of DOI:10.1055/s-2005-872081

PAPER
2205
Efficient Synthesis of N-Alkyl Tetrahydroisoquinolines by Reductive
Amination
Efficient
S
ynthesis
e
of
N
-Alky
p
l
Tetrahydro
h
a
Department of Chemistry, University of Wisconsin-Whitewater, WI 53190, USA
E-mail: Sukanta_Bhattacharyya@moldev.com
b
Argonaut Technologies, 220 Saginaw Drive, Redwood City, CA 94063, USA
Received 28 September 2004; revised 17 February 2005
In the context of our continued investigations on amine
synthesis9 by reductive amination, we reported previously
a versatile reagent system for reductive amination using a
combination of Ti(Oi-Pr)4 and NaBH4.10 The reaction
Abstract: An expedient access to diverse N-alkyl 1,2,3,4-tetrahy-
droisoquinolines is reported by reductive amination of aldehydes
and ketones with tetrahydroisoquinoline (THIQ) in the presence of
Ti(Oi-Pr)4 and NaBH4. The N-alkyl THIQ products were rapidly
purified by flow-through catch and release technique using com- may proceed (Scheme 1) through an intermediate titani-
um(IV) complex 1,11 which is either reduced directly or
via equilibration of 1 with a transient iminium species in
the presence of NaBH4.
mercially available polymer-supported sulfonic acid, MP-TsOH
columns.
Key Words: reductive amination, tetrahydroisoquinoline, Ti(Oi-
Pr)4, NaBH4, polymer-supported sulfonic acid column
We describe12 here an efficient method for the synthesis of
N-alkyl THIQ derivatives. Reductive amination of alde-
hydes and ketones with THIQ was performed in the pres-
ence of Ti(Oi-Pr)4 and NaBH4 (Scheme 2). Upon
completion of the reaction, the N-alkyl THIQ compounds
were rapidly isolated in their pure forms by catch and re-
lease purification using commercially available polymer-
supported sulfonic acid, MP-TsOH columns13 in analogy
to silica-based SCX columns reported in the literature.14
Synthesis of amines is a topic of paramount interest as
amines and their derivatives are the most prevalent struc-
tural moieties found in the comprehensive medicinal
chemistry database.1 In particular, synthesis of tetrahy-
droisoquinoline (THIQ) derivatives is an objective of high
priority as numerous natural products and synthetically
derived molecules containing the THIQ ring system ex-
hibit versatile biological and pharmacological properties.2
A few significant examples include antitumor and antimi-
crobial activities,3 5-HT1A receptor antagonism4 and stim-
ulation of b3 adrenergic receptors.5 Another noteworthy
example includes the design and synthesis of sterically
constrained analogs of medicinally important peptides by
incorporating THIQ moieties in their amino acid frame-
work.6 Very recently, the synthesis and screening of a se-
ries of N-alkyl THIQ derivatives as selective dopamine D3
receptor ligands have been reported in the literature.7
1. Ti(OiPr)4, 75 °C, 6 h
O
2. NaBH4, EtOH, 25 °C, 3 h
+
NH
R1
R2
3. aqueous quench, filter
4. catch and release purification
using MP-TsOH column
N
R2
R1
Scheme 2
The scope of the present synthesis was evaluated using a
structurally diverse set of aldehydes and ketones, and
1,2,3,4-tetrahydroisoquinoline (THIQ). The carbonyl
compounds were allowed to react with THIQ and neat
Ti(Oi-Pr)4 at 75 °C followed by the addition of EtOH and
NaBH4 under ambient conditions. A 20% molar excess of
carbonyl compounds and 2-fold molar excess of Ti(Oi-
Pr)4 were employed to drive the reactions for completion.
The results obtained from a group of ketones and alde-
hydes are summarized in Tables 1 and 2, respectively.
Reductive amination8 of carbonyl compounds is a very
powerful tool for chemists to target the synthesis of struc-
turally diverse primary, secondary and tertiary amines.
The sequence proceeds through the formation of an imine
or iminium intermediate upon reaction of a carbonyl com-
pound with ammonia, primary amine or secondary amine
followed by in situ reduction to an amine of higher order.
Scheme 1
SYNTHESIS 2005, No. 13, pp 2205–2209
x
x.
x
x
.
2
0
0
5
Advanced online publication: 20.07.2005
DOI: 10.1055/s-2005-872081; Art ID: M07404SS
© Georg Thieme Verlag Stuttgart · New York

2206
H. J. Kumpaty, S. Bhattacharyya
PAPER
Typically, the intermediate titanium(IV) complex similar
to 1 was allowed to form first by stirring a mixture of the
carbonyl compound, THIQ and Ti(Oi-Pr)4 at 75 °C for six
hours. Absolute EtOH was then added followed by
NaBH4, and the resulting mixture stirred for another three
hours at room temperature. The initial workup process in-
volved aqueous quenching of the reaction mixture fol-
lowed by filtration of the resulting inorganic precipitate
and extraction with CH2Cl2.
Table 1 Reductive N-Alkylation of THIQ with Ketones
Entry Ketone
Product Amine
Yield
(%)
1
2
O
85
N
84
O
N
N
N
N
The product N-alkyl THIQ derivatives were rapidly iso-
lated in their pure forms by catch and release purification
using MP-TsOH columns13 similar to silica-supported
SCX columns.14 The combined organic extracts were add-
ed onto an MP-TsOH column, preconditioned with
CH2Cl2. The solution was allowed to flow through the col-
umn, followed by washing with CH2Cl2 to remove the
non-basic impurities such as the excess carbonyl com-
pound and its reduced byproduct. Finally, the product N-
alkyl THIQ was released from the MP-TsOH column by
the addition of a solution of NH3 in MeOH. The NH3 ex-
changed with the N-alkyl THIQ on the column, releasing
it into the solution. Evaporation of the solvent typically af-
forded analytically pure N-alkyl THIQ samples. In gener-
al, full retention of a range of N-alkyl THIQ was observed
using a 1.5-fold molar excess of MP-TsOH relative to the
amine. The macroporous polystyrene-supported sulfonic
acid, MP-TsOH has a typical loading of 3.0 mmol/g,
which is 3–4 times higher than that of SCX, silica-based
sulfonic acid. Other advantages of MP-TsOH include the
stability of polystyrene support under a broad range of pH
as opposed to silica-based SCX, and the absence of con-
tamination of amine products with particulates that some-
times happen with SCX by media decomposition.15
3
4
80
78
O
O
5
6
85
87
O
OMe
O
N
MeO
O
7
8
9
88
86
78
O
N
N
O
S
S
O
Cl
Cl
S
S
As demonstrated in Table 1, the protocol worked well us-
ing a broad set of ketones with varied reactivity profiles.
This includes both aliphatic and less reactive aromatic ke-
tones, sterically hindered ketones, heterocyclic ketones,
ferrocenyl ketones as well as enolizable ketones. Thus, the
enolizable aliphatic ketones (entries 1–3) underwent re-
ductive amination with THIQ affording the corresponding
N-alkyl THIQ derivatives in high yields. The reaction us-
ing the sterically hindered ketone, 2-adamantanone (entry
4) afforded N-adamantyl THIQ in good yield. Likewise,
N-alkyl THIQ derivatives were obtained in good to high
yields from the reactions using acetophenones (entries 5
and 6), and heterocyclic ketones containing furan (entry
7) and thiophene (entries 8–10) moieties. Ferrocenyl
methyl ketone (entry 11) also provided the corresponding
THIQ derivative in good yield. Table 2 summarizes the
reactions using a set of aldehyde substrates. A number of
aliphatic, heterocyclic and aromatic aldehydes were react-
ed with THIQ to produce the corresponding tertiary
amines in high yields.
O
N
N
10
11
85
77
O
S
S
O
N
Fe
Fe
ing commercially available polymer-supported sulfonic
acid, MP-TsOH columns. We believe this rapid synthesis
and purification protocol will find significant applications
in organic synthesis.
1H NMR spectra were obtained using a 300 MHz Bruker AM spec-
trometer, using CDCl3 as the solvent with TMS as the internal ref-
erence. 13C NMR spectra were obtained at 75.5 MHz in CDCl3.
Elemental analyses were performed at Atlantic Microlab Inc., Geor-
gia, USA. Mass spectra were recorded on an EI-500 spectrometer at
the University of Wisconsin-Milwaukee. Analytical TLC was per-
formed on pre-coated Alumina plates with fluorescent indicator us-
In summary, we have described a highly effective synthe-
sis of N-alkyl THIQ derivatives by reductive amination of
aldehydes and ketones with THIQ in the presence of
Ti(Oi-Pr)4 and NaBH4. The N-alkyl THIQs were rapidly
purified by flow-through catch and release technique us-
Synthesis 2005, No. 13, 2205–2209 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of N-Alkyl Tetrahydroisoquinolines
2207
Table 1, Entry 1
Table 2 Reductive N-Alkylation of THIQ with Aldehydes
1H NMR: d = 1.04 (t, J = 6 Hz, 6 H), 1.51 (quintet, J = 5.8 Hz, 2 H),
1.66 (quintet, J = 5.8 Hz, 2 H), 2.42 (quintet, J = 6 Hz, 1 H), 2.83
(m, 4 H), 3.50 (s, 2 H), 6.99–7.32 (m, 4 H).
Entry Aldehyde
Product Amine
Yield
(%)
EIMS: m/z calcd for C14H21N: 203.3; found: 203.0.
CH3CH2CHO
1
85
86
88
Anal. Calcd for C14H21N: C, 82.70; H, 10.41; N, 6.89. Found: C,
82.96; H, 10.14; N, 6.88.
N
N
2
CH3CH2CH2CHO
Table 1, Entry 2
1H NMR: d = 1.59–1.62 (m, 8 H), 2.81 (quintet, J = 6 Hz, 1 H), 2.82
(t, J = 5.8 Hz, 2 H), 2.92 (t, J = 5.8 Hz, 2 H), 3.70 (s, 2 H), 6.82–
7.28 (m, 4 H).
3
CHO
OMe
N
N
MeO
13C NMR: d = 24.1, 29.0, 30.6, 49.6, 55.3, 66.8, 125.5, 125.9, 126.6,
128.4, 134.2, 134.8.
4
5
85
82
CHO
EIMS: m/z calcd for C14H19N: 201.3; found: 201.0.
CHO
Cl
Anal. Calcd for C14H19N: C, 83.53; H, 9.51; N, 6.96. Found: C,
83.26; H, 9.54; N, 6.98.
N
N
Cl
6
82
CHO
Table 1, Entry 3
1H NMR: d = 1.18 (d, J = 6.6 Hz, 3 H), 1.77 (m, 1 H), 2.05 (m, 1 H),
2.75–3.00 (m, 5 H), 3.86 (q, J = 6.7 Hz, 2 H), 3.94 (d, J = 14.7 Hz,
2 H), 7.00–7.37 (m, 9 H).
Cl
Cl
7
8
78
84
CHO
NO2
EIMS: m/z calcd for C19H23N: 265.18; found: 265.0.
N
O2N
Anal. Calcd for C19H23N: C, 85.99; H, 8.74; N, 5.28. Found: C,
85.63; H, 8.53; N, 5.57.
S
CHO
N
S
Table 1, Entry 4
1H NMR: d = 1.18–1.56 (m, 14 H), 2.72–2.90 (m, 5 H), 3.70 (d, J =
10.8 Hz, 2 H), 7.15 (m, 4 H).
ing anhyd solvents, followed by UV visualization as necessary. The
products were characterized by their 1H and 13C NMR spectral data,
and elemental or mass spectral analyses.
EIMS: m/z calcd for C19H25N: 267.0; found: 267.0.
Anal. Calcd for C19H25N: C, 85.34; H, 9.42; N, 5.24. Found: C,
84.96; H, 9.28; N, 5.20.
Reductive Amination Using 1,2,3,4-Tetrahydroisoquinoline
(THIQ) and Carbonyl Compounds; General Procedure
A mixture of THIQ (1.0 mmol), Ti(Oi-Pr)4 (0.6 mL, 2 mmol) and
the respective carbonyl compound (1.2 mmol) was allowed to stir at
75 °C under an atmosphere of N2 for 6 h. The reaction mixture was
next cooled to r.t. under N2, and absolute EtOH (2.0 mL) and
NaBH4 (0.12 g, 3 mmol) were added in sequence. The reaction mix-
ture was further allowed to stir for 3 h at ambient temperature and
quenched with water (2.0 mL). The resulting white inorganic pre-
cipitate was separated by filtration and washed with CH2Cl2 (10
mL). The organic layer was separated and the product N-alkyl
THIQ was rapidly isolated in its pure form by catch and release pu-
rification using polymer-supported sulfonic acid, MP-TsOH col-
umns.13
Table 1, Entry 5
1H NMR: d = 1.61 (d, J = 6.6 Hz, 3 H), 2.92 (m, 2 H), 3.67 (m, 2 H),
3.69 (q, J = 6.7 Hz, 1 H), 3.94 (d, J = 14.8 Hz, 2 H), 7.23 (m, 4 H),
7.73 (m, 5 H).
13C NMR: d = 20.0, 29.2, 47.9, 53.5, 64.3, 125.4, 125.9, 126.7,
126.8, 127.5, 128.2, 128.5, 130.8, 134.5, 135.1, 144.2.
EIMS: m/z calcd for C17H19N: 237.3; found: 237.0.
Anal. Calcd for C17H19N: C, 86.03; H, 8.07; N, 5.90. Found: C,
85.71; H, 8.03; N, 5.56.
Table 1, Entry 6
1H NMR: d = 1.53 (d, J = 6.7 Hz, 3 H), 2.81–2.90 (m, 3 H), 3.50–
4.00 (m, 7 H), 6.86–7.37 (m, 8 H).
For catch and release purification, the organic solution was added
onto a MP-TsOH column (0.5 g/6 mL, 1.5 mmol) preconditioned
with CH2Cl2 (4 mL). The solution was allowed to flow through the
MP-TsOH column, followed by washing with CH2Cl2 (3 × 2 mL) to
remove the non-basic impurities such as the excess carbonyl com-
pound and its reduced byproduct. Finally, the product N-alkyl THIQ
was released from the column by the addition of a solution of NH3
in MeOH (4 M, 4 mL). Concentration of the resulting solution typ-
ically afforded the N-alkyl THIQ in high yield and purity (Tables 1
and 2). In most of the cases, the catch and release purification pro-
tocol afforded analytically pure samples. In certain cases, however,
preparative TLC or flash chromatography (Et2O–MeOH, 9:1) was
performed to obtain analytical samples.
EIMS: m/z calcd for C18H21NO: 267.3; found: 267.0.
Anal. Calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C,
80.90; H, 7.89; N, 5.44.
Table 1, Entry 7
1H NMR: d = 1.54 (d, J = 7 Hz, 3 H), 2.66–2.93 (m, 4 H), 3.73 (d,
J = 14.4 Hz, 2 H), 3.97 (q, J = 7 Hz, 1 H), 6.24 (d, J = 32 Hz, 1 H),
6.35 (d, J = 33 Hz, 1 H), 6.9–7.15 (m, 4 H), 7.40 (s, 1 H).
13C NMR: d = 15.8, 29.6, 47.0, 51.9, 56.7, 106.9, 106.6, 109.6,
125.4, 125.8, 126.5, 128.5, 134.3, 135.0, 141.4, 155.5.
EIMS: m/z calcd for C15H17NO: 227.3; found: 227.0.
Anal. Calcd for C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C,
79.22; H, 7.51; N, 5.93.
Synthesis 2005, No. 13, 2205–2209 © Thieme Stuttgart · New York

2208
H. J. Kumpaty, S. Bhattacharyya
PAPER
Table 1, Entry 8
Table 2, Entry 4
1H NMR: d = 1.60 (d, J = 6.5 Hz, 3 H), 2.60–2.93 (m, 4 H), 3.82 (q,
J = 14.7 Hz, 2 H), 4.15 (q, J = 6.7 Hz, 1 H), 6.87–6.97 (m, 4 H),
7.09–7.19 (d, J = 3.5 Hz, 2 H), 7.25 (dd, J = 8.7, 3.5 Hz, 1 H).
1H NMR: d = 2.37 (s, 3 H), 2.73 (t, J = 5.9 Hz, 2 H), 2.91 (t, J = 5.9
Hz, 2 H), 3.60 (s, 2 H), 3.64 (s, 2 H), 7.10 (m, 4 H), 7.18–7.31 (dd,
J = 11.7, 2.8 Hz, 4 H).
EIMS: m/z calcd for C15H17NS: 243.3; found: 243.0.
EIMS: m/z calcd for C17H19N: 237.3; found: 237.0.
Anal. Calcd for C15H17NS: C, 74.03; H, 7.04; N, 5.76. Found: C,
74.02; H, 7.07; N, 5.61.
Table 2, Entry 5
1H NMR: d = 2.85 (t, J = 5.8 Hz, 2 H), 2.95 (t, J = 5.5 Hz, 2 H), 3.74
(s, 2 H), 3.87 (s, 2 H), 7.03–7.38 (m, 8 H).
Table 1, Entry 9
1H NMR: d = 1.51 (d, J = 6.4 Hz, 3 H), 2.75–3.1 (m, 4 H), 3.90 (m,
2 H), 6.70–7.31 (m, 7 H).
EIMS: m/z calcd for C16H16ClN: 257.0; found: 257.0.
Anal. Calcd for C16H16ClN: C, 74.55; H, 6.26; N, 5.43. Found: C,
74.52; H, 6.06; N, 5.33.
EIMS: m/z calcd for C15H16ClNS: 277.07; found: 277.0.
Anal. Calcd for C15H16NClS: C, 64.85; H, 5.80; N, 5.04. Found: C,
65.25; H, 5.65; N, 5.02.
Table 2, Entry 6
1H NMR: d = 2.85 (t, J = 5.8 Hz, 2 H), 2.95 (t, J = 5.5 Hz, 2 H), 3.74
(s, 2 H), 3.87 (s, 2 H), 7.03–7.38 (m, 8 H).
Table 1, Entry 10
1H NMR: d = 1.44 (d, J = 6.6 Hz, 3 H), 2.37 (s, 3 H), 2.42 (s, 3 H),
2.64 (m, 1 H), 2.83 (m, 3 H), 3.60 (m, 2 H), 3.83 (d, J = 14.8 Hz, 1
H), 6.60 (s, 1 H), 7.04–7.15 (m, 4 H).
EIMS: m/z [M + H] calcd for C16H16ClN: 257.0; found: 257.0.
Anal. Calcd for C16H16ClN: C, 74.55; H, 6.26; N, 5.43. Found: C,
74.98; H, 6.06; N, 5.33.
13C NMR: d = 13.9, 15.1, 19.0, 29.1, 47.7, 53.6, 57.2, 125.0, 125.4,
125.8, 126.7, 128.6, 130.5, 134.5, 135.0, 139.3.
Table 2, Entry 7
1H NMR: d = 2.75 (t, J = 5.8 Hz, 2 H), 2.93 (t, J = 5.5 Hz, 2 H), 3.75
(s, 2 H), 3.79 (s, 2 H), 6.98–7.68 (m, 8 H).
EIMS: m/z calcd for C17H21NS: 271.04; found: 271.0.
Anal. Calcd for C17H21NS: C, 75.23; H, 7.80; N, 5.16; S, 11.81.
Found: C, 75.05; H, 7.81; N, 4.96; S, 11.92.
EIMS: m/z calcd for C16H16N2O2: 268.3; found: 268.0.
Table 2, Entry 8
1H NMR: d = 2.90 (t, J = 5.7 Hz, 2 H), 3.02 (t, J = 5.7 Hz, 2 H), 3.81
(s, 2 H), 4.01 (s, 2 H), 6.9–7.2 (m, 7 H).
Table 1, Entry 11
1H NMR: d = 2.06 (d, J = 6.9 Hz, 3 H), 2.71–2.50 (m, 1 H), 2.72–
2.86 (m, 3 H), 3.51 (d, J = 14.6 Hz, 1 H), 3.71 (d, J = 14.7 Hz, 1 H),
3.89 (q, J = 6.8 Hz, 1 H), 4.16–4.25 (m, 9 H), 6.99–7.17 (m, 4 H).
EIMS: m/z calcd for C14H15NS: 229.3; found: 229.0.
13C NMR: d = 16.7, 29.7, 46.1, 51.1, 58.5, 66.9, 67.2, 67.6, 68.5,
69.3, 69.8, 72.3, 87.0.
Anal. Calcd for C14H15NS: C, 73.32; H, 6.59; N, 6.11. Found: C,
73.28; H, 6.48; N, 6.00.
EIMS: m/z calcd for C21H23FeN: 345.2; found: 345.0.
Anal. Calcd for C21H23FeN: C, 73.05; H, 6.71; N, 4.06. Found: C,
72.77; H, 6.49; N, 3.82.
Acknowledgment
H.J.K. thanks the Department of Chemistry, University of Wis-
consin at Milwaukee for allowing her to use their NMR facility.
Thanks are also due to Frank E. Laib at UWM for assistance on
mass spectral analysis.
Table 2, Entry 1
1H NMR: d = 1.06 (t, J = 7.2 Hz, 3 H), 1.69 (quintet, J = 7.4 Hz, 2
H), 2.51 (t, J = 5.3 Hz, 1 H), 2.7–3.1 (m, 5 H), 3.63 (s, 1 H), 4.04 (s,
1 H), 7.23 (m, 4 H).
EIMS: m/z calcd for C12H17N: 175.2; found: 175.0.
References
Anal. Calcd for C12H17N: C, 82.23; H, 9.78; N, 7.99. Found: C,
82.66; H, 9.38; N, 8.25.
(1) (a) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J.
Comb. Chem. 1999, 1, 55. (b) Henkel, T.; Brunne, R. M.;
Mueller, H.; Reichel, F. Angew. Chem. Int. Ed. 1999, 38,
643.
Table 2, Entry 2
1H NMR: d = 0.91 (t, J = 6.4 Hz, 3 H), 1.41 (sextet, J = 6.5 Hz, 2
H), 2.51 (t, J = 6 Hz, 2 H), 2.66–2.71 (m, 4 H), 2.96 (t, J = 6 Hz, 2
H), 3.63 (s, 2 H), 7.02–7.36 (m, 4 H).
(2) See for example: (a) Nielsen, T. E.; Diness, F.; Meldal, M.
Curr. Opin. Drug Discov. Dev. 2003, 6, 801. (b) Griffith,
M. C.; Dooley, C. T.; Houghten, R. A.; Kiely, J. S. In
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Libraries and Drug Discovery; Chaiken, I. M.; Janda, K. D.,
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50. (c) Rozwadowska, M. D. Heterocycles 1994, 39, 903;
and references therein. (d) Gray, N. M.; Cheng, B. K.; Mick,
S. J.; Lair, C. M.; Contreras, P. C. J. Med. Chem. 1989, 32,
1242. (e) Herbert, R. B. In Chemistry and Biology of
Isoquinoline Alkaloids; Phillipson, J. D.; Roberts, M. F.;
Zenk, M. H., Eds.; Springer-Verlag: Berlin, 1985, 213.
(3) (a) Scott, J. D.; Williams, R. D. Chem. Rev. 2002, 102,
1669. (b) Aune, G. J.; Furuta, T.; Pommier, Y. Anti-Cancer
Drugs 2002, 13, 545.
EIMS: m/z calcd for C13H19N: 189.3; found: 189.0.
Table 2, Entry 3
1H NMR: d = 2.76 (t, J = 6 Hz, 2 H), 2.94 (t, J = 6 Hz, 2 H), 3.42 (s,
1 H), 3.71–3.77 (m, 2 H), 3.84 (s, 3 H), 4.05 (s, 1 H), 6.91 (d, J =
8.7 Hz, 2 H), 7.02–7.17 (m, 4 H), 7.34 (d, J = 8.6 Hz, 2 H).
13C NMR: d = 29.0, 50.4, 55.1, 55.9, 62.0, 113.5, 114.2, 125.4,
125.9, 126.5, 128.5, 130.1, 130.3, 131.9, 134.3, 134.8, 158.6.
EIMS: m/z calcd for C17H19NO: 253.1; found: 253.0.
Anal. Calcd for C17H19NO: C, 80.60; H, 7.56; N, 5.53. Found: C,
80.66; H, 8.01; N, 5.75.
(4) Mokrosz, M. J.; Bojarsky, A. J.; Duszynska, B.;
Tatarczynska, E.; Klodzinska, A.; Deren-Wesolek, A.;
Synthesis 2005, No. 13, 2205–2209 © Thieme Stuttgart · New York

PAPER
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Efficient Synthesis of N-Alkyl Tetrahydroisoquinolines
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(10) For example, see: (a) Kumpaty, H. J.; Bhattacharyya, S.;
Rehr, E. W.; Gonzalez, A. M. Synthesis 2003, 2206.
(b) Miriyala, B.; Bhattacharyya, S.; Williamson, J. S.
Tetrahedron 2004, 60, 1463; and references cited therein.
(11) (a) Imwinkelried, R.; Seebach, D. Helv. Chim. Acta 1984,
67, 1496. (b) Takahashi, H.; Tsubuki, T.; Higashiyama, K.
Synthesis 1988, 238.
(12) The work was presented in part by: Kumpaty H. J.,
Bhattacharyya S.; 228th ACS National Meeting,
Philadelphia; American Chemical Society: Washington,
DC, August 2004; paper ORGN-701
(13) The macroporous polystyrene-supported sulfonic acid, MP-
TsOH columns (part number: 800477-0050-C) were
obtained from Argonaut Technologies.
(8) Reductive amination reactions are extensively reviewed, see
for example: Baxter, E. W.; Reitz, A. B. Org. React. (N.Y.)
2002, 59, 1; and references 1-17 therein.
(9) For example, see: (a) Bhattacharyya, S.; Rana, S.; Gooding,
O. W.; Labadie, J. Tetrahedron Lett. 2003, 44, 4957.
(b) Bhattacharyya, S.; Gooding, O. W.; Labadie, J.
Tetrahedron Lett. 2003, 44, 6099. (c) Bhattacharyya, S.;
Tamanaha, L.; Vo, L.; Labadie, J. Comb. Chem. High
Throughput Screening 2000, 3, 117.
(14) (a) Siegel, M. G.; Hahn, P. J.; Dressman, B. A.; Fritz, J. E.;
Grunwell, J. R.; Kaldor, S. W. Tetrahedron Lett. 1997, 38,
3357. (b) Shuker, A. J.; Siegel, M. G.; Matthews, D. P.;
Weigel, L. O. Tetrahedron Lett. 1997, 38, 6149.
(c) Lawrence, M. R.; Biller, S. A.; Fryszman, O. M.; Poss,
M. A. Synthesis 1997, 553.
(15) (a) Thurman, E. M.; Mills, M. S. In Solid-Phase Extraction:
Principles and Practice; Wiley: New York, 1998, 55.
(b) Thurman, E. M.; Mills, M. S. In Solid-Phase Extraction:
Principles and Practice; Wiley: New York, 1998, 131.
Synthesis 2005, No. 13, 2205–2209 © Thieme Stuttgart · New York