Regioselective assembly of 3,4-dihydroisoquinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.06.047

A facile two-step sequence (9→10→1) of regioselective assembly of 3,4-dihydroisoquinoline derivatives 1 is reported. The halogen derivatives provide opportunity for Suzuki, Buchwald, and related coupling reactions useful for expanding the scaffold and lea

Full text of DOI:10.1016/j.tetlet.2012.06.047

Tetrahedron Letters 53 (2012) 4429–4432
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Regioselective assembly of 3,4-dihydroisoquinoline derivatives
Zhongli Gao a, , Larry Davis b, Yulin Chiang b, Randall Munson b, James A. Hendrix b
⇑
a Medicinal Chemistry, LGCR, Sanofi US, 1041 Rt. 202-206, Bridgewater, NJ 08807, USA
b Member of CNS, Medicinal Chemistry, Sanofi-Aventis, 1041 Rt. 202-206, Bridgewater, NJ 08807, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile two-step sequence (9?10?1) of regioselective assembly of 3,4-dihydroisoquinoline derivatives
1 is reported. The halogen derivatives provide opportunity for Suzuki, Buchwald, and related coupling
reactions useful for expanding the scaffold and lead optimization in drug discovery.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 30 May 2012
Accepted 8 June 2012
Available online 16 June 2012
Keywords:
3,4-Dihydroisoquinoline
Alkaloids
Bischler–Napieralski reaction
Pictet–Spengler reaction
Alkaloids are an important class of natural products that are
widely distributed in nature and produced by a large variety of
organisms. The tetrahydroisoquinoline core is a structural center-
piece found in a number of biologically active synthetic and natural
products with a wide spectrum of biological activities and for
many years was used in folk medicines (Fig. 1).1–7
The importance of these natural products in inspiring drug dis-
covery programs is proven and, therefore, their continued synthe-
sis is of significant interest. The Bischler–Napieralski reaction is a
commonly used strategy to achieve the synthesis of alkaloids and
has been well documented.8–12 For example in Scheme 1, the key
intermediate 3,4-dihydroisoquinoline 1, generated from 2 by the
Bischler–Napieralski reaction, was reported to undergo dehydra-
tion to isoquinoline derivatives 3,9,13 and reduction to tetrahydro-
isoquinoline analogs 4,10,14 and condensation of 2 with alkyl vinyl
ketone (MVK) to form b-keto-tertiary amine intermediates 515
from which more complex alkaloids could be derived. Thus, the
synthesis of the key intermediate 3,4-dihydroisoquinoline 1 is a
cornerstone for the synthesis of many of these alkaloids.
electron-rich functional groups, such as alkoxy (2, R1, R2 = alkoxy),
at the aromatic ring C6 and C7 positions. We were surprised to find
that Bischler–Napieralski reactions bearing groups such as halo-
gens in the aromatic ring at the C6 and C7 positions were, to the
best of our knowledge, poorly precedented in the literature17,18 de-
spite their importance and potential utilities in construction of
synthetic building blocks. We needed to explore structural–activity
relationships (SAR) and to replace the metabolically labile 6-meth-
oxy group19 with metabolically stable functional groups. More
importantly, we were interested in preparing the 6-bromo deriva-
tives (1, R1 = Br) as scaffolds to synthesize more complex com-
pounds via Suzuki and Buchwald coupling or related reactions.
Herein, we describe a facile two-step sequence of regioselective
assembly of 3,4-dihydroisoquinoline derivatives 1 bearing groups
positioned for further elaboration of this scaffold.
We commenced our initial exploration of Bischler–Napieralski
reaction of the N-formyl compound 2 to the 3,4-dihydroisoquino-
line 1 (R1 = F, R2 = OCH3) (Scheme 1) under the standard literature
reaction conditions (P2O5 or POCl3, toluene).20,21 Only black tar
was obtained in many trials under a range of temperatures (80–
120 °C). There was no desired product 1 (R1 = F, R2 = OCH3) detected
(LC/MS). When CH3CN was used as the solvent and POCl3 as the
catalyst at lower temperature (80 °C, 25 h), a small amount of the
desired product was isolated (1, R1 = F, R2 = OCH3: <5% yield; 1,
R1 = CH3, R2 = OCH3: 20% yield) with the dimers, trimers, and tetra-
mers (by LC/MS) as the major side products. We hypothesized that
the polymerization could be avoided by masking the free-hydrogen
on nitrogen of the b-arylethyl amine intermediate with a proper
protecting group and then condense this material with formalde-
hyde to achieve cyclization. The protecting group could be removed
and the imine functionality could be subsequently introduced to
In our ongoing drug discovery program, we needed to synthe-
size a series of the target molecules based on the isoquinolone scaf-
fold with wide range of functional groups R1 and R2 (Scheme 1).
The most direct route would be via the intermediates 1 and 5 using
the Bischler–Napieralski reaction as a key step.
The Bischler–Napieralski reaction16 is an intramolecular elec-
trophilic aromatic substitution reaction that allows for the
cyclization of b-arylethyl amides or b-arylethyl carbamates. Gener-
ally speaking, the reaction favors the b-arylethyl amides with
⇑
Corresponding author. Tel./fax: +1 908 231 3601.
E-mail address: zhongli.gao@sanofi-aventis.com (Z. Gao).
realize the desired 3,4-dihydroisoquinoline intermediate
1
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.047

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Z. Gao et al. / Tetrahedron Letters 53 (2012) 4429–4432
OH
O
O
O
MeO
HO
H
H
N
O
HO
N
H
N
OMe
OH
HO
O
(-)-Govadine
Corydalmine
(-)-Stepholidine
OH
O
OH
N
HO
HO
O
N+
H
OH
N
H
H
O
O
N
H
H
OH
OH
(+)Butaclamol
(-)-latifolian A
(-) Emetine
Figure 1. Natural products and bioactive drug candidates containing tetrahydroisoquinoline core structures.
(Scheme 2). In order to test this hypothesis, the 6-bromo-7-
methyoxyphenethylamine was protected as N-formyl, was then
condensed with paraformaldehyde under Pictet–Spengler condi-
tions.21 The desired products were observed in good yield (97% col-
lectively). Unfortunately, the formation of regioisomers 6 and 7
(2.5–1 by NMR) arose as a new issue (Scheme 2). To demonstrate
the usefulness of this strategy for ultimate synthesis of intermedi-
ate 1, the desired regioisomer 6 was isolated, and was then
hydrolyzed (NaOH, EtOH, 80 °C, 10 h) to obtain the tetrahydroiso-
quinoline 8 in quantitative yield. Subsequently, 8 was transformed
into imine 1 under known conditions.22
chosen as a N-protecting group and the reaction of 9?10 was con-
ducted under our new conditions (paraformaldehyde, TFA, toluene,
60 °C). The reaction was very clean and provided 10 in 81% yield.
None of the regioisomer was detected by LC/MS (Scheme 3).
The next task was to remove the tosyl protecting group. Under
various conditions (KOH, EtOH, reflux overnight; KOBut, THF, reflux
overnight), mainly starting material 10 was recovered with only a
small amount of desired product 11 isolated along with a small
amount of 1 detected (LC/MS). Clearly, 1 (R1 = Br, R2 = OCH3) was
generated via an elimination mechanism. This observation led us
to explore a stronger base to promote elimination. LDA (À78 °C,
THF, 10 min) was tried initially. The elimination reaction was read-
ily achieved in 80—100% yield for variety of substrates (Table 1).
The cyclization reaction conditions were further refined by
using dimethoxymethane instead of paraformaldehyde and dilute
With these preliminary results in hand, we initiated optimiza-
tion of the reaction conditions to improve the regioselectivity.
We thought a bulkier protecting group might be able to direct
the regiochemistry toward the desired regioisomer 6. Tosyl was
R3
R1
R2
N
3
R3
R1
R2
R3
R1
R2
R3
R1
R2
Bischler-Napieralski
MVK
N
O
TARGETS
NH
N
O
1
H
5
2
R3
R1
NH
R2
4
Scheme 1. The Bischler–Napieralski reaction as a key step for alkaloid syntheses.

Z. Gao et al. / Tetrahedron Letters 53 (2012) 4429–4432
4431
O
H
N
Br
Br
a
+
Br
HN
H
N
H
O
O
O
O
O
6
7
2.5 : 1 (NMR)
b
Br
Br
c
N
NH
O
O
1
8
Scheme 2. Exploration of the Bischler–Napieralski reaction conditions. Reagents and conditions: (a) Paraformaldehyde, TFA, toluene, 60 °C, 97%; (b) NaOH, EtOH, 80 °C, 10 h,
100%; (c) NBS, DCM, rt, 15 min; NaOH, EtOH, rt, 4 h, 94%.
Br
Br
Br
a
c
HN
N
N
O
S
O
O
S
O
O
O
O
9a
10a
1a
b
Br
NH
O
11
Scheme 3. Two-step sequence for construction of Bischler–Napieralski product. Reagents and conditions: (a) Dimethoxymethane, toluene, H3PO4 (85%, w/w), 60 °C, 25 h,
91%. (b) KOH, EtOH, reflux overnight; (c) LDA (1.0 equiv), THF, À78 °C, 10 min 92%.
Table 1
Reaction scopea
R1
R2
R3
S
R1
R2
R3
S
R1
R2
R3
Step 1
Step 2
HN
N
N
O
O
O
O
9
10
1
Product
R1
R2
R3
Step 1 reaction time (h)
Step 1 yieldb (%)
Step 2 yieldb (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
Br
F
Cl
CH3
Et
Br
H
OMe
OMe
MeO
MeO
MeO
MeO
MeO
H
MeO
F
H
H
H
H
H
H
H
H
H
Et
25
25
12
12
12
15
15
12
15
91
88
86
100
100
90
91
87
65
92
80
88
95
95
70
88
85
72
a
General procedure: To a solution of sulfonamide in toluene and dimethoxymethane (1:1, v/v) (1.6 ml/mmol of sulfonamide) was added 60% (w/w) sulfuric acid. The
reaction was stirred at 50–60 °C for the time specified. The product was isolated by separating the two layers and extracting the aqueous layer with ether.
b
Isolated yield.
phosphoric acid or sulfuric acid instead of TFA. The major advan-
tage for using dimethoxymethane was a liquid biphasic reaction
instead of a solid–liquid heterogeneous mixture. In addition, the
product could be obtained simply by separation of the two layers
and extraction. The typical reaction sequence23 is shown in Scheme
3 in which the tosyl protected 6-bromo-7-methyoxyphenethyl-
amine was heated (50–60 °C) with dimethoxymethane in toluene
(1:1, v/v) and catalyzed by dilute sulfuric acid (60%, w/w) or

4432
Z. Gao et al. / Tetrahedron Letters 53 (2012) 4429–4432
15. Maryanoff, B. E.; McComsey, D. F.; Taylor, R. J., Jr.; Gardocki, J. F. J. Med. Chem.
1981, 24, 79.
16. Stockigt, J.; Antonchick, A. P.; Wu, F.-R.; Waldmann, H. Angew. Chem., Int. Ed.
2011, 50, 8538.
phosphoric acid (85%, w/w). The product obtained was treated
with 1.0 equiv of LDA in THF at À78 °C for 10–15 min to yield
the desired Bischler–Napieralski product 1a.
17. Whaley, W. M.; Govindachari, T. R. Org. React. (N.Y.) 1951, VI, 151.
18. Whaley, W. M.; Govindachari, T. R. Org. React. (N.Y.) 1951, VI, 74.
19. Li, C. M.; Lu, Y.; Narayanan, R.; Miller, D. D.; Dalton, J. T. Drug Metab. Dispos.:
Biol. Fate Chem. 2010, 38, 2032.
20. Brossi, A.; Dolan, L. A.; Teitel, S. Org. Synth. 1977, 56, 1–2.
21. Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. (Washington, DC, U.S.) 2004,
104, 3341.
With this preliminary protocol in hand, we explored the scope
of the reaction starting from 9 with a variety of substituents in
the aromatic ring. The reaction is tolerant of a range of substituents
at different positions (Table 1).
In conclusion, we have developed a facile two-step sequence
(9?10?1) to achieve the synthesis of 3,4-dihydroisoquinoline
derivatives 1 in good yield bearing groups positioned for further
elaboration of the scaffold. The functional groups at C6, especially
6-halogen analogs, offer opportunities for Suzuki, Buchwald, and
related coupling reactions to open another dimension of diversity
in medicinal chemistry lead optimization for drug discovery.
22. Mohamed, M. A.; Yamada, K.-i.; Tomioka, K. Tetrahedron Lett. 2009, 50, 3436.
23. Representative procedure for the synthesis of 1b: (step 1) A solution of 4.12 g of
N-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-4-methyl-benzenesulfonamide (9b),
phosphoric acid (85% w/w, 7.3 g) in 20 mL of toluene, and 20 mL of
dimethoxymethane was heated by an oil bath set at 60 °C externally with
stirring under nitrogen for 15 h. The reaction was complete (LC/MS). The
reaction mixture was cooled to rt and diluted with ether (50 mL). The two
layers were separated and the aqueous layer was extracted with ether (25 mL).
The combined ethereal solution was washed sequentially with water (15 mL),
saturated sodium bicarbonate (15 mL), and brine (10 mL). The ethereal
solution was then dried over anhydrous granular potassium carbonate,
filtered, and concentrated in vacuo. The crude product, a solid after standing,
was re-crystallized from ether (30 mL) and pentane (50 mL). The material was
collected by suction filtration and dried under vacuum to give 3.75 g (88%) of
the product 10b as white crystalline solid. 1H NMR (CDCl3, 300 MHz) d: 7.73 (d,
J = 8.7 Hz, 2H,) 7.34 (d, J = 8.7 Hz, 2H), 6.80 (m, 1H), 6.61 (m, 1H), 4.18 (s, 3H),
3.82 (s, 3H), 3.32 (t, J = 6.0 Hz, 2H), 2.82 (t, J = 6.0 Hz, 2H,), 2.42 (s, 3H); LC:
3.22 min; MS m/z = 336. (step 2) Diisopropyl amine (3.42 g, 33.82 mmol) was
weighted in a RBF. Anhydrous THF (44 mL) was introduced. The solution was
cooled to À78 °C and the air was replaced with nitrogen by cooling-vacuum-
nitrogen, three circles. To this cooled (À78 °C) solution was added butyl
lithium (20 mL, 32 mmol). The almost colorless solution was stirred at À78 °C
for 5 min; the ice-bath was removed and the stirring was continued for 5 min,
then the reaction flask was submerged into an ice-water bath for 15 mins. To
another flask was added sulfonamide 10b (4.6 g, 14.22 mmol) and anhydrous
THF (140 mL). The solution was cooled to À78 °C. To this solution was
transferred LDA solution prepared above at À78 °C. The solution turned light
yellow, then bright yellow, then orange, and finally reddish orange. This
solution was stirred for 10 min TLC (DCM) showed that the reaction was
complete. The reaction was quenched by the addition of saturated aqueous
ammonium chloride solution (20 mL). The mixture was diluted with ethyl
acetate (50 mL). The two layers were separated, and the aqueous layer was
extracted with ethyl acetate (40 mL Â 2). The combined ethyl acetate extracts
were washed with sodium bicarbonate (20 mL) and brine (15 mL Â 2), dried
(anhydrous potassium carbonate), filtered, and concentrated in vacuo. The
crude product was purified on a silica gel column, eluted with 3% MeOH in
DCM to give 1b as a colorless liquid (2.01 g, 80%). 1H NMR (CDCl3, 300 MHz) d:
8.27 (br. s, 1H), 6.93 (s, 1H), 6.90 (d, J = 2.3 Hz, 1H), 3.92 (s, 3H), 3.75 (dt,
J = 2.3 Hz, 7.8 Hz, 2H), 2.68 (t, J = 7.8 Hz, 2H); LC: 0.84 min; MS m/z = 180
(M+H+).
Acknowledgments
The authors are grateful to the Analytical Science Department of
Sanofi for their generous support in confirmation of the structures.
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