Convenient Synthesis of 6-Bromo-1,2,3,4-tetrahydroisoquinoline and 3-Methoxy-1,2,3,4-tetrahydro-[2,7]-naphthyridine via Reductive Amination of Schiff's Bases

Article abstract of DOI:10.1080/00397910902730911

Synthesis of 7-bromo-1,2,3,4-tetrahydroisoquinoline and 6-methoxy-1,2,3,4-tetrahydro-[2,7]-naphthyridine via lithiation of 2-methylarylidene-tert-butylamines, followed by formylation, reductive amination in one-pot, and removal of the tert-butyl group fro

Full text of DOI:10.1080/00397910902730911

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Convenient Synthesis
of 6-Bromo-1,2,3,4-
tetrahydroisoquinoline and 3-
Methoxy-1,2,3,4-tetrahydro-
[2,7]-naphthyridine via
Reductive Amination of Schiff's
Bases
Pavol Zlatoidský a & Bálint Gábos a
a AstraZeneca AB, Discovery Lund, Lund, Sweden
Published online: 03 Aug 2009.
To cite this article: Pavol Zlatoidsk & Blint Gbos (2009) Convenient Synthesis of
6-Bromo-1,2,3,4-tetrahydroisoquinoline and 3-Methoxy-1,2,3,4-tetrahydro-[2,7]-
naphthyridine via Reductive Amination of Schiff's Bases, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
39:17, 3060-3068
To link to this article: http://dx.doi.org/10.1080/00397910902730911
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Synthetic Communications1, 39: 3060–3068, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902730911
Convenient Synthesis of
6-Bromo-1,2,3,4-tetrahydroisoquinoline and
3-Methoxy-1,2,3,4-tetrahydro-[2,7]-naphthyridine
via Reductive Amination of Schiff’s Bases
´
ꢀ
ꢀ
Pavol Zlatoidsky and Balint Gabos
AstraZeneca AB, Discovery Lund, Lund, Sweden
Abstract: Synthesis of 7-bromo-1,2,3,4-tetrahydroisoquinoline and 6-methoxy-
1,2,3,4-tetrahydro-[2,7]-naphthyridine via lithiation of 2-methylarylidene-
tert-butylamines, followed by formylation, reductive amination in one-pot, and
removal of the tert-butyl group from the nitrogen, is described.
Keywords: Cyclization, formylation, lithiation, reductive amination
INTRODUCTION
Tetrahydroisoquinolines (THQs) are important structural motifs found
in biologically active substances that have been used extensively in the
synthesis of drug candidates.[1,2] The corresponding isoelectronic tetra-
hydronapthyridines (THNPs) are important bioisosteres of this fragment,
providing a more polar structural alternative (clogP 1.59 was calculated
for 1,2,3,4-tetrahydroisoquinoline and clogP ꢀ0.09 for 1,2,3,4-tetrahydro-
[2,7]-naphthyridine) (Fig. 1).
Unfortunately, synthetic access to this structural class has proven
cumbersome, and not surprisingly, there are consequently only a few
examples in the literature that describes the synthesis of simple analogs.[3–8]
In the course of our studies, we decided to prepare compounds
containing THQs, substituted in 6-position as a starting material for
Received October 1, 2008.
Address correspondence to Pavol Zlatoidsky´, AstroZeneca AB, Discovery
Lund, S-221 87, Lund, Sweden. E-mail: Pavol.Zlatoidsky@astrazeneca.com
3060

Tetrahydroisoquinoline Derivatives
3061
Figure 1. X ¼ aryl, heteroaryl; R ¼ acyl, alkyl, aryl=alkylsulfonyl.
6-aryl (heteroaryl)–substituted THQs and 3-substituted THNPs.[1]
Substitutions should optionally allow for the introduction of aryl or
heteroaryl groups as well as for N-substitution of the heterocyclic nitrogen.
The syntheses of 6-methoxy-1,2,3,4-tetrahydroisoquinoline[3] as well
as 6-nitro-3-alkyl-1,2,3,4-tetrahydroquinolines[4] have been described,
but the reaction conditions are not generally applicable. For instance,
when attempting to use selective hydrogenation of the pyridine ring of
3-methoxy-[2,7]-naphthyridine, this leads to a complicated mixture of
products. Other approaches to this heterocyclic ring system have been
described, for instance using the reduction of 6-bromo-4H-isoquinoline-
1,3-dione[5,6] or approaches involving Diels–Alder reactions,[7] both
including multistep syntheses with poor yield.
The most practical approach to the target heterocycles involves the
benzylic lithiation of a Schiff base as described by Flippin et al.[8] The
modified route described in this communication involves the use of
dimethylformamide (DMF) as the electrophile instead of methyl iodide,
followed by cyclization of the aldehyde via reductive amination.
CHEMISTRY
6-Bromo-THQ (1) and 2-tert-butyl-6-methoxy-1,2,3,4-tetrahydro-[2,7]-
naphthyridine (2) are valuable intermediates for synthesis of libraries of
compounds targeting metalloproteinases. We found that they could be
readily accessible starting from 3-bromo-6-methylbenzaldehyde (3)
for 6-bromo-1,2,3,4-tetrahydroisoquinoline (1) and for 2-tert-butyl-6-
methoxy-1,2,3,4-terahydro-[2,7]-naphthyridine (10), and then 6-methoxy-
4-methylpyridine-3-carbaldehyde (4) is the most available starting
material, prepared via routine lithiation=formylation of the correspond-
ing bromoderivative. As demonstrated in the article by Flippin et al.,[8]
Schiff’s bases 5 and 6, prepared from these aldehydes, undergo smooth
proton abstraction from the methyl group using lithium-2,2,6,6-
tetramethylpiperidide, apparently facilitated by the neighboring imine
function, forming a chelated lithium complex similar to 7, which was
smoothly alkylated with methyl iodide as electrophile.

´
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P. Zlatoidsky and B. Gabos
3062
˚
Scheme 1. (i) tert-Butylamine, mol. sieve 3 A, (ii) LiTMP=THF, (iii) DMF, and
(iv) NaBH3CN=MeOH=AcOH.
We subjected 7 to treatment with dimethylformamide (DMF) as an
electrophile. The resulting aldehydes 8 and 9 were not isolated but imme-
diately cyclized under reductive amination conditions, yielding the
compounds 2 and 10 as required templates in their protected form. The
reductive amination conditions chosen for the cyclization step included
sodium cyanoborohydride in the presence of acetic acid and methanol,
added directly to the reaction mixture. This was an efficient way to allow
selective reduction of the carbon–nitrogen double bond prior to reductive
amination and ring closure (Scheme 1).
Removal of the t-butyl group from (2) with 1-chloroethyl chlorofor-
mate generates the required 1 (Scheme 2). The removal of tert-butyl group,
however, requires greater temperature and excess of chloroformate, com-
pared to the conditions described for corresponding N-demethylations.[9]
One can further elaborate on this strategy in the THNP case. Depro-
tection of the methoxy group provides 11, and transformation to its
trifluoromethanesulfonic acid ester provides a suitable starting material
for further transformation steps, as exemplified here: Coupling with
Scheme 2. (i) 1-Chloroethyl chloroformate, reflux; then MeOH, reflux.

Tetrahydroisoquinoline Derivatives
3063
Scheme 3. (i) HBr=AcOH=100ꢁC, (ii) (a) triflic anhydride=pyridine=rt, (b) 4-
cyanophenyl boronic acid, Pd(dppf)Cl2, AcOK, dioxane, 90ꢁC, (iii) 1-chloroethyl
chlorformate (neat)=120ꢁC.
4-cyanophenyl boronic acid under catalysis of dichloro[1,1-bis(diphenyl-
phosphino)ferrocene] palladium (II) DCM complex [Pd(dppf)Cl2][10]
provides the aryl-coupled derivative 12 in good yield. The 2-tert-butyl
group can again be cleaved by 1-chloroethyl chloroformiate[9] to generate
13 (Scheme 3).
In conclusion, we have developed a convenient method for the
preparation of THQ (1) and THNP (2), both versatile building blocks
in medicinal chemistry. We have used a Schiff base–directed lithiation
sequence followed by formylation of DMF. Reductive amination results
in ring closure and heterocycle formation, yielding the required templates
in a one-pot procedure.
EXPERIMENTAL
Melting points were measured on a Stuart MP3 capillary melting-point
apparatus and are uncorrected. NMR spectra were measured at 300 MHz
or 400 MHz on Varian 300 and Varian 400 instruments. Chemical shifts
are reported in part per million (ppm) downfiled from tetramethylsilane
(TMS) as internal standard. Mass spectra (MS) were measured on an HP
5890 GC-MS spectrometer and on an HP 1100 HPLC-MS spectrometer.
Infrared (IR) spectra were measured on a Perkin-Elmer 10 PC-FTIR
spectrometer as a film and are reported in cmꢀ1. Elemental analyses were
performed by Belab AB, Norrko¨ping. All chemicals and solvents were
obtained from Sigma Aldrich or Fisher Scientific; silica gel 60 (230–400
mesh) used in flash chromatography was obtained from Merck Co.
Preparative high-performance liquid chromatography (HPLC) was carried

´
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P. Zlatoidsky and B. Gabos
3064
out on a Gilson liquid chromatography preparative system using a Chira-
pack C-18 column (25 ꢂ 10cm).
2-Methoxy-4-methylnicotinaldehyde (4)
To a stirred solution of 5-bromo-2-methoxy-4-methylpyridine (5 g,
24.75 mmol) in dry tetrahydrofuran (THF) (55 mL) under argon atꢀ
70ꢁC, 2.5 M n-BuLi in hexanes were added (9.9 mL, 25 mmol) over
10 min. The mixture was stirred atꢀ70ꢁC for 30 min, and then anhydrous
DMF (2.4 ml, 30.1 mmol) was added portionwise, maintaining the tem-
perature at ꢀ70ꢁC. The mixture was stirred atꢀ70ꢁC for 30 min and at
rt overnight. The reaction was quenched with 1 M hydrochloric acid
(60 mL) and then extracted three times with TBME. The combined
organic phases were washed with brine, dried with magnesium sulfate,
filtered, and evaporated to dryness. The compound was pure enough to
be used in the next step. The Analytical sample was recrystallized from
isohexane=tert.butyl methylether (TBME). Mp 90–91ꢁC (lit.[11]. 91–
1
92ꢁC). Yield: 3.2 g, 86%. H NMR (CDCl3): 2.60 (s, 3H), 4.11 (s, 3H),
6.59 (s, 1H), 8.62 (s, 1H), 10.06 (s, 1H). 13C NMR (CDCl3): 21.88,
54.50, 112.15, 125.55, 148.10, 155.22, 170.10, 194.33.
(4-Bromo-2-methylbenzylidene)-tert-butylamine (5)
˚
tert-butylamine (15 mL) and activated 4 A mol.sieve (4 g) were added to
the 3-bromo-6-methylbenzaldehyde (3) (2.55 g, 12.8 mmol). The vessel
was sealed, and the mixture was stirred for 48 h at rt, filtered through a
cellite pad, and eluted with 2 ꢂ 10 mL diethylether. The solution of the
Schiff’s base was evaporated to dryness, and the compound was used
without purification immediately in the next step. Yield: 2.86 g, 88%.
1H NMR (CDCl3): 1.30 (s, 9H), 2.47 (s, 3H), 7.33 (d, 1H, J ¼ 1.8 Hz)
7.35 (dd, J ¼ 8.4 Hz,1.8 Hz, 1H), 7.89 (d, J ¼ 8.4 Hz, 1H), 8.49 (s, 1H).
13C NMR (CDCl3): 20.19, 29.75, 57.55, 125.47, 128.97, 129.56, 130.56,
140.11, 156.22.
tert-Butyl-[(6-methoxy-4-methylpyridin-3-yl)methylene]-amine (6)
The compound was prepared according to the procedure described for 5,
starting from 4 (1.93 g, 12.8 mmol), and was used without purification in
the next step. Yield: 2.26 g, 86%. 1H NMR (CDCl3): 1.32 (s, 9H), 2.49 (s,
3H), 3.94 (s, 3H), 6.53 (s, 1H), 8.52 (s, 1H), 8.53 (brs, 1H). 13C NMR

Tetrahydroisoquinoline Derivatives
3065
(CDCl3): 19.78, 29.62, 53.37, 57.55, 111.51, 125.55, 147.85, 149.01,
151.78, 164.58.
6-Bromo-2-tert-butyl-1,2,3,4-tetrahydroisoquinoline (2)
n-BuLi solution in pentanes (11.3 mL of 1.7 M, 0.022 mol) was added to a
stirred solution of 2,2,6,6-tetramethylpiperidine (3.45 mL, 0.022 mol) in
90 ml of dry THF atꢀ40ꢁC under argon. The mixture was stirred for
25 min at the same temperature, and then the Schiff’s base (5)
(0.011 mol) dissolved in dry THF (30 mL) was added portionwise, keep-
ing the temperature atꢀ40ꢁC. The mixture was then stirred atꢀ15 toꢀ
20ꢁC for 1.5 h and recooled toꢀ40ꢁC, and DMF (2.5 mL, 0.03 mol) was
injected through a septum in three portions. The mixture was stirred at
rt for 2 h, and liquid chromatography–mass spectrometry (LC-MS)
showed the presence of the expected aldehyde (8). A mixture of methanol
(80 mL) and acetic acid (20 mL) was added at once, followed immediately
with sodium cyanoborohydride (1.131 g, 0.018 mol), added in one por-
tion. The mixture was stirred overnight, evaporated to dryness, parti-
tioned between sat. potassium carbonate (300 mL) and ethyl acetate
(100 mL), extracted twice with ethyl acetate, washed with brine, dried
with magnesium sulfate, and evaporated to dryness. The residue was
flashed on 110 g silica (eluted with TBME) to obtainþa pale yellow solid,
mp 72–74ꢁC. Yield: 1.32 g, 43%. MS: m=z ¼ 269 (MH ), other fragments:
1
213 (MHþꢀ56). H NMR (CDCl3): 1.11 (s, 9H), 2.03 (m, 2H), 3.49 (t,
J ¼ 13.9 Hz, 1H), 3.77 (d, J ¼ 10.5 Hz, 1H), 3.97 (d, J ¼ 14.4 Hz, 1H),
4.57 (d, J ¼ 14.4 Hz, 1H), 6.95 (d, J ¼ 8.1 Hz, 1H), 7.27 (d, J ¼ 1.8 Hz,
1H), 7.30 (dd, J ¼ 8.1 Hz, J ¼ 1.8 Hz, 1H). 13C NMR (CDCl3): 26.46,
47.25, 47.23, 63.80, 122.17, 127.52, 128.73, 130.70, 131.40, 134.10. IR
(film): 979, 1486, 1531,1626, 2358, 2782.
2-tert-Butyl-6-methoxy-1,2,3,4-tetrahydro-[2,7]-naphthyridine (10)
This compound was prepared according to the procedure described for 2,
starting from 6 (2.26 g, 0.011 mol). The compound was obtained as a
colorless oil. Vacuum distillation gave 1.8 g (74.3%) (bp 105–106ꢁC=
1
0.5 torr). MS: m=z ¼ 221 (MHþ), other fragments: 165 (MHþ ꢀ56). H
NMR (CD3OD): 1.13 (s, 9H), 2.77 (t, 2H, J ¼ 4.7 Hz), 2.81 (t, 2H,
J ¼ 4.7 Hz) (m, 3.85 (s, 3H), 6.6 (s, 1H), 7.9 (s, 1H). 13C NMR (CD3OD):
31.95, 39.81, 50.22, 53.02, 58.76, 68.95, 113.68, 122.87, 149.06, 149.91,
168.80. IR (cmꢀ1): 1180, 1401, 1665, 2604, 2981.

´
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P. Zlatoidsky and B. Gabos
3066
6-Bromo-1,2,3,4-tetrahydroisoquinoline Hydrochloride (1)
1-Chloroethyl chloroformate (15 mL) was added to 2 (1.32 g, 0.0049 mol)
at once, and the reaction mixture was refluxed overnight under a calcium
chloride tube. The reaction mixture was evaporated to dryness, and the
residue was refluxed for 4 h in methanol (15 mL) and evaporated to
dryness. The crude product (0.9 g, 74%) was pure enough to be used in
the next synthetic steps. Analytical sample was purified via preparative
reverse-phase chromatography and recrystallized from ethanol. Mp
131–132ꢁC. Element. anal. for C9H11BrClN: calcd. C, 43.49%; H,
4.46%; N, 5.64%. Found: C, 43.41%; H, 4.84%; N, 5.72%. MS: m=z ¼ 213
1
(MHþ). H NMR (CD3OD): 3.12 (t, J ¼ 6.9 Hz, 2H), 3.48 (t, J ¼ 6.9 Hz,
2H), 4.44 (s, 2H), 7.1 (d, J ¼ 7.81 Hz, 1H), 7.5 (d, J ¼ 7.81 Hz, 1H), 7.46
(s, 1H). 13C NMR (CD3OD): 24.42, 40.25, 43.36, 120.31, 127.30, 128.91,
129.49, 131.35, 137.36. IR (film): 1071, 1186, 1393, 1592, 1641, 2978, 3395.
2-tert-Butyl-6-hydroxy-1,2,3,4-tetrahydro-[2,7]-naphthyridine (11)
A solution of 2-tert-butyl-6-methoxy-1,2,3,4-tetrahydro-[2,7]-naphthyridine
(10) (0.5 g, 2.27 mmol) and 45% hydrobromic acid in acetic acid
(20 mL) was heated in a sealed tube at 100ꢁC for 1 h, cooled to rt, and
concentrated by rotary evaporation. The residue was dissolved in 20%
potassium carbonate solution (20 mL) and extracted four times with
EtOAc. The combined organic phases were dried, filtered and con-
centrated. Recrystallization from TBME=hexanes gave 0.33 g (71%) of
the title compound as a white solid, mp 126–127ꢁC. MS: m=z ¼ 208
1
(MHþ); other fragments: 152 (MHþꢀ56). H NMR (CDCl3): 1.34 (s,
9H), 2.88 (t, 2H, J ¼ 5.6 Hz), 3.17 (t, 2H, J ¼ 5.6 Hz), 4.72 (s, 2H), 6.39
(s, 1H), 7.17 (s, 1H). 13C NMR (CDCl3): 24.26, 25.85, 45.74, 54.25,
63.76, 116.68, 117.16, 130.93, 151.96, 164.40. IR (film): 1134, 1202,
1604, 1682, 1978, 2962.
2-tert-Butyl-6-(4-cyanophenyl)-1,2,3,4-tetrahydro-[2,7]-naphthyridine (12)
Trifluoromethane sulfonic acid anhydride (0.14 mL, 0.80 mmol) was
slowly added to a stirred and cold (4ꢁC) solution of 2-tert-butyl-6-
hydroxy-1,2,3,4-tetrahydro-[2,7]-naphthyridine (11) (0.15 g, 0.73 mmol)
in pyridine (5.0 mL). When the addition was complete, the mixture was
stirred at 4ꢁC for 30 min, quenched with 20% potassium carbonate solu-
tion (10 mL), and extracted four times with dichloromethane (DCM).
The combined organic phases were dried, filtered, and concentrated to

Tetrahydroisoquinoline Derivatives
3067
give a crude product. Flash chromatography with EtOH-TBME (1:9) as
eluent gave 0.30 g of the trifuoromethanesulfonic acid ester as an oil
(containing solvent residues). MS: m=z ¼ 339 (MHþ). The crude trifluor-
omethanesulfonic acid ester (0.30 g, 0.89 mmol) was dissolved in dioxane
(10 mL), and then anhydrous potassium acetate (0.43 g, 4.5 mmol), 4-
cyanophenylboronic acid (0.14 g, 0.89 mmol), and PdCl2(dppf) (13 mg,
0.0178 mmol) were added. The mixture was degassed with argon, sealed,
and stirred at 90ꢁC overnight. After cooling, the solution was partitioned
between water and ethyl acetate, and the water phase was extracted three
times with ethyl acetate. The combined organic phases were washed with
brine, dried, filtered, and concentrated. The compound was subjected to
silica-gel column chromatography and eluted with EtOH-TBME (1:9)
and TBME-EtOH-TEA (20:2:1) to give 0.12 g (53% from two steps) of
the title compound as a light brown solid. The analytical sample was
precipitated from TBME as hydrochloride after additionþof 4 N HCl in
dioxane. Mp: decomp.220–230ꢁC. MS: m=z ¼ 292 (MH ); other frag-
1
ments: 236 (MHþꢀ56). H NMR (CDCl3): 1.04 (s, 9H), 3.25 (t, 2H,
J ¼ 6.1 Hz) 3.61 (t, 2H, J ¼ 6.1 Hz) 3.86 (s, 2H), 7.44 (s, 1H), 7.84 (d,
1H, J ¼ 8.8 Hz), 7.91 (s, 1H) 8.21 (d, 1H, J ¼ 8.8 Hz). 13C NMR (CDCl3):
25.38, 25.46, 43.39, 45.93, 54.11, 109.11, 112.15, 118.85, 120.41, 127.27,
127.30, 132.48, 143.33, 148.57. IR (film): 884, 1130, 1202, 1603, 1681,
2217, 2596, 3412.
6-(4-Cyanophenyl)-1,2,3,4-tetrahydro-[2,7]-naphthyridine
hydrochloride (13)
A
mixture of 2-tert-butyl-6-(4-cyanophenyl)-1,2,3,4-tetrahydro-[2,7]-
naphthyridine (12) (0.12 g, 0.41 mmol), 1-chloroethyl chloroformate
(1.0 mL, 5.8 mmol), and dry toluene (5 mL) was refluxed for 4 h under a
calcium chloride tube. After being concentrated in vacuo, the dark residue
was dissolved in methanol (10 mL) and refluxed for 3 h more. Charcoal
(1 g) was added and refluxed for additional 20 min. Then the mixture
was filtered through a Cellite pad and washed with methanol, and the clear
filtrate was concentrated to give the title compound as a solid, which was
recrystallized from TBME=MeOH to give a white powder. Mp 232–234ꢁC.
Yield: 0.08 g, 72%. Element. anal. for C15H14ClN3: calcd. C, 66.30%; H,
5.19%; N, 15.46%. Found: C, 66.20%; H, 5.36%; N, 15.56%. MS:
1
m=z ¼ 236 (MHþ). H NMR (CD3OD): 3.54 (d, 2H, J ¼ 5.9 Hz), 3.58 (d,
2H, J ¼ 5.9 Hz), 4.41 (s, 2H), 7.93 (d, 1H, J ¼ 7.9 Hz), 8.26 (d, 1H,
J ¼ 7.9 Hz) 8.64 (s, 1H), 9.19 (bs, 2H). 13C NMR (CD3OD): 24.88, 43.77,
48.58, 114.05, 119.75, 122.36, 126.72, 133.98, 134.01, 143.98, 144.56,
149.39, 155.68. IR (film): 843, 1132, 1201, 1600, 1683, 2217, 2962, 3402.

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P. Zlatoidsky and B. Gabos
3068
ACKNOWLEDGMENT
The help of Dr. Klaus Uhrbans, Dr. Lena Bo¨rjesson, and Dave Chapman
with the text is gratefully appreciated.
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