A convenient synthesis of 1-amino-7-(piperidin-4-yl)isoquinoline

Article abstract of DOI:10.1081/SCC-200050372

An optimized synthesis of 2-amino-7-(piperidin-4-yl)isoquinoline, starting from 4-bromocinnamic acid, was developed.

Full text of DOI:10.1081/SCC-200050372

This article was downloaded by: [Northeastern University]
On: 25 November 2014, At: 21:21
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
A Convenient Synthesis of
1‐Amino‐7‐(Piperidin‐4‐yl)Isoquinoline
Sergey Shkavrov a , Sergey Popov a , Dmitry Kravchenko a & Mikhail Krasavin
a
a Chemical Diversity Research Institute , Khimki, Moscow Reg., Russia
Published online: 20 Aug 2006.
To cite this article: Sergey Shkavrov , Sergey Popov , Dmitry Kravchenko & Mikhail Krasavin (2005) A
Convenient Synthesis of 1‐Amino‐7‐(Piperidin‐4‐yl)Isoquinoline, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 35:5, 725-730, DOI: 10.1081/SCC-200050372
To link to this article: http://dx.doi.org/10.1081/SCC-200050372
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 35: 725–730, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050372
A Convenient Synthesis of 1-Amino-
7-(Piperidin-4-yl)Isoquinoline
Sergey Shkavrov, Sergey Popov,
Dmitry Kravchenko, and Mikhail Krasavin
Chemical Diversity Research Institute, Khimki
Moscow Reg., Russia
Abstract: An optimized synthesis of 2-amino-7-(piperidin-4-yl)isoquinoline, starting
from 4-bromocinnamic acid, was developed.
Keywords: Isoquinoline, lithium-halogen exchange, microwave irradiation
INTRODUCTION
7-Substituted 1-aminoisoquinolines have been reported to possess various
biological activities. For instance, a recent report on factor Xa inhibitors[1]
revealed that incorporation of 1-aminoisoquinol-7-yl moiety resulted in the
best inhibitory potency in the series.
In our continuing search for novel combinatorial library scaffolds with a
high degree of medicinal relevance, we required multigram quantities of
1-amino-7-(piperidin-4-yl)isoquinoline (1).
We chose known 7-bromo-1-chloroisoquinoline (2) as the key intermediate
in the synthesis. Reported methods for preparation of (2) employed Pomerantz-
Fritsch isoquinoline synthesis resulting in mixture of regioisomers.[2] Thus, our
Received in Poland 10 November 2004
Address correspondence to Mikhail Krasavin, Chemical Diversity Research Institute,
2a Rabochaya St., KhimkiMoscow Reg. 114401, Russia. Fax: þ7(095)926-9780; E-mail:
myk@chemdiv.com

726
S. Shkavrov et al.
immediate goal was to elaborate a synthetic protocol that would not include
tedious separation of isomeric products (Scheme 1).
4-Bromocinnamyl azide (5) was prepared from 4-bromocinnamic acid (3)
and subjected to thermal Curtius rearrangement into an intermediate isocya-
nate, which, after replacement of reaction solvent, underwent intramole-
cular electrophilic cyclization into 7-bromoisoquinolone (6), the process
driven by catalytic iodine and microwave irradiation. Notably, conventional
heating of the above isocyanate in the same reaction medium resulted only
in extensive decomposition and no appreciable formation of the desired cycli-
zation product. Subsequent treatment with phosphorus oxychloride gave the
7-bromo-1-chloroisoquinoline (2). No chromatographic purification was
required at any stage of the described four-step synthetic sequence.
The reaction sequence leading to the final product (1) is outlined in
Scheme 2. Lithium-halogen exchange proceeded selectively at C-Br and the
resultant aryl anion was intercepted by 1-benzyl-4-piperidone at carefully
controlled low temperature. Higher reaction temperatures resulted in lower
yields and by-product formation, presumably due to enolization and self-
condensation of the ketone electrophile.
The isolated tertiary alcohol (7) was treated with ammonia at high
temperature and pressure in an autoclave. This 1-chloroisoquinoline
proved to be surprisingly resistant toward ammonolysis conditions and the
full conversion was achieved only upon prolonged treatment for seven
days. Without further purification, compound 8 was dehydrated in hot
70% sulfuric acid and the isolated N-benzyl-1,2,5,6-tetrahydropyridine (9)
was boiled in an ethanolic solution of ammonium formate in presence of
10% palladium on charcoal. This process resulted in fast (over 3 hours)
reduction of the olefinic portion and much slower N-debenzylation due to
poisoning of the Palladium (Pd) catalyst by the secondary amine formed
(the poisoned catalyst was replaced by a fresh batch once during the
reaction). The target isoquinoline (1) was isolated as a dihydrochloride
salt of 95% purity.
Scheme 1.

Synthesis of 1-Amino-7-(Piperidin-4-yl)Isoquinoline
727
Scheme 2.
EXPERIMENTAL
All reactions were run in oven-dried glassware in a nitrogen atmosphere.
Melting points were measured with a Buchi B-520 melting point apparatus
and were not corrected. Analytical thin-layer chromatography (TLC) was
carried out on EM Separations Technology F254 silica gel plates.
Compounds were visualized with short-wavelength ultraviolet (UV) light.
1H NMR and 13C NMR spectra were recorded on Varian Gemini-300 and
Bruker DRX-500 spectrometers in DMSO-d6 using tetramethylsilane (TMS)
as an internal standard. Mass-spectral analyses were obtained on a PE
SCIEX API 150EX mass spectrometer. All solvents and reagents were
obtained from commercial sources and used without purification.
4-Bromocinnamyl Azide (5)
To a suspension of 4-bromocinnamic acid (3, 150 g, 0.66 mol) in benzene
(750 mL), thionyl chloride (96 mL, 1.32 mol) was added and the mixture
was refluxed for 2 hrs (or until full dissolution of solids) and for an additional
1 hr to ensure completeness of the conversion. The excess thionyl chloride was
distilled off and the crystalline residue (160 g, 89%) was taken on to the next
step as sufficient purity (.90%) was established by liquid crystal-mass
spectrometry (LC-MS) analysis.

728
S. Shkavrov et al.
One mole (67 g) of sodium azide was suspended in a mixture of water and
acetone (1:1, 300 mL). The mixture was cooled down to 08C and a solution of
4-bromocinnamyl chloride (4, 125 g, ca. 0.5 mol) in dry acetone (400 mL) was
added at such a rate as to maintain the temperature below 58C. The resulting
mixture was stirred at 0–68C for 4 hrs and then poured into water (1.5 L). The
precipitate was filtered off, washed with copious amounts of water, and air
dried. Additional drying in vacuo over P2O5 afforded 124 g (0.48 mol, 96%)
of the solid (5). 1H NMR (300 MHz, d6-DMSO): d 7.68 (AA’BB’, J ¼ 8.6 Hz,
4H), 6.73 (d, J ¼ 15 Hz, trans-CH55CH, 2H); 13C NMR (75 MHz,
d6-DMSO): d 167.3, 142.5, 131.8, 130.1, 123.5, 117.7, 120.1; MS MHþ ¼ 227.
7-Bromo-1(2H)-isoquinolone (6)
A 500 mL flask was charged with 4-bromocinnamyl azide (5, 54.2g, 0.24mol)
and anhydrous benzene (300mL) and the mixture was brought to moderate
reflux with quiet evolution of N2. The reflux was continued for 7 hrs until gas
evolution ceased. The solvent was removed in vacuo and the residue with
added catalytic amount (1.4g) of finely ground iodine were dissolved in
molten diphenyl ether (125mL). The bulk solution was split into 5 mL
microwave vials with septa and heated at 2208C for 30min using Personal
Chemistry Emrys Optimizerw microwave reactor. After cooling down, the
gummy solid was transferred into a 1 L beaker, triturated with ether, filtered,
thoroughly washed with ether, and air-dried. The brown powdered residue
(ca. 20g) was dissolved at 50–608C in DMF (150mL). The solution was
slowly added to thoroughly stirred 2% aqueous NaOH (900 mL). A black
sticky precipitate was removed by filtration and the light-yellow filtrate was
diluted with water up to a volume of 2.1 L and allowed to stand for 1 hr. The
precipitated material was filtered off, washed with water, and dried at 100–
1108C to provide 10.5g (20%) of solid isoquinolone (6): mp 2308C
1
(decomp). H NMR (300MHz, d6-DMSO): d 11.38 (br s, N-H, 1H), 8.26
(d, J ¼ 2.2 Hz, 1H), 7.84 (dd, J ¼ 8.1, 2.2 Hz, 1H), 7.63 (d, NH-CH,
J ¼ 8.1 Hz, 1H), 7.22 (dd, J ¼ 6.6, 5.1 Hz, 1H), 6.56 (d, NHCH ¼ CH,
J ¼ 8.1 Hz, 1H); 13C NMR (75 MHz, d6-DMSO): d 160.6, 136.8, 135.1,
130.8, 129.7, 128.8, 128.6, 119.0, 118.6; MS MHþ ¼ 225.
7-Bromo-1-chloroisoquinoline (2)
To solid 7-bromo-1(2H)-isoquinolone (6, 10 g, 44.6 mmol) POCl3 (40 mL)
was added and the mixture was heated at reflux for 1 hr, at which point the
reaction was complete by TLC analysis. The cooled solution was poured
over crushed ice. Exothermic hydrolysis of the remaining POCl3 occured
after 5–10 min and the temperature rose up to 70–808C. Most of the
material was in solution except for black tar, which was removed by filtration.

Synthesis of 1-Amino-7-(Piperidin-4-yl)Isoquinoline
729
The filtrate was diluted with water up to a volume of 1 L and the resulting
white precipitate was collected, washed with water, air-dried, and crystallized
from butan-1-ol and then from heptane to afford (2) as white solid (7.5 g,
1
31 mmol, 70%): mp 123–1258C. H NMR (300 MHz, d6-DMSO): d 8.41
(s, 1H), 8.37 (d, J ¼ 5.9 Hz, 1H), 8.02–8.09 (m, 2H), 7.94 (d, J ¼ 5.1 Hz,
1H); 13C NMR (75 MHz, d6-DMSO): d 148.9, 142.1, 136.1, 134.8, 129.7,
127.3, 126.9, 122.2, 121.2; MS MHþ ¼ 244.
1-Benzyl-4-(1-chloro-7-isoquinolyl)-4-piperidinol (7)
A
suspension of 7-bromo-1-chloroisoquinoline (48.5 g, 0.20 mol) in
anhydrous THF (1 L) was treated at 2788C at with 1.6 M solution of
n-BuLi in hexane (145 mL, 0.23 mol). The resulting clear red solution was
stirred for 20 min, then cooled to 21008C (ethanol-dry ice), and solution of
N-benzylpiperidone (41.6 g, 0.22 mol) in THF (50 mL) was added dropwise
to maintain temperature below 2608C. After the addition was completed, the
reaction mixture was stirred for 2–3 hrs while the temperature rose up to
08C. Water (300 mL) was added and the biphasic mixture was transferred
into a separatory funnel. Organic phase was separated and the aqueous
phase was extracted with ethyl acetate (2 ꢀ 150 mL). Combined organic
extracts were dried over anhydrous sodium sulfate, filtered, and concentrated
in vacuo. The oily residue was boiled with heptane for 15 min and the resulting
solution was left to stand overnight. The light crystalline product was
collected by filtration, washed with heptane, and air dried to provide 56.5 g
(80%) of the piperidinol 7: mp 141–1428C. 1H NMR (500 MHz,
d6-DMSO): d 8.39 (s, 1H), 8.26 (d, J ¼ 5.5 Hz, 1H), 8.03 (s, 2H), 7.86
(d, J ¼ 5.5 Hz, 1H), 7.32–7.38 (m, 4H), 7.25 (dd, J ¼ 6.8, 7.3 Hz, 1H), 5.13
(s, OH, 1H), 3.55 (s, PhCH2, 2H), 2.68 (d, CH-N-CH, J ¼ 11.0 Hz, 2H),
2.52 (d, CH-N-CH, J ¼ 11.0 Hz, 2H), 2.08 (td, Jt ¼ 12.8 Hz, Jd ¼ 3.7 Hz,
2H), 1.68 (d, J ¼ 13.5 Hz, 2H); 13C NMR (75 MHz, d6-DMSO): d 151.4,
150.3, 141.1, 138.6, 136.3, 129.8, 128.8, 128.1, 127.1, 126.8, 125.8, 121.0,
120.5, 70.1, 62.4, 49.1, 37.7; MS MHþ ¼ 354.
1-Amino-7-(piperidin-4-yl)isoquinoline Dihydrochloride (1)
An autoclave chamber cooled to 2788C was charged with piperidinol (7) (50 g,
0.14mol) and liquid ammonia (800mL), sealed, and heated at 1358C and
1.8 kpsi for seven days. The chamber was cooled to room temperature, the
gaseous ammonia was let out, the chamber contents were washed out with
ethanol. The solution was concentrated in vacuo and the residue was partitioned
between dichloromethane (500mL) and water. The organic layer was separated,
dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.

730
S. Shkavrov et al.
The resulting brown oil (containing over 90% of 4-(1-amino-7-isoquinolyl)-
1-benzyl-4-piperidinol (8) by LC-MS analysis: MS MHþ ¼ 334, 99% yield)
was dissolved in hot 70% sulfuric acid (400 mL) and heated at 80–1008C
for 48 hours. The completeness of the conversion was determined by liquid
chromatography-mass spectrometry (LC-MS) analysis of reaction mixture
aliquots (after neutralization and extraction with ethyl acetate). The reaction
mixture was cooled down and poured into ice-cold 40% aqueous KOH
(1 L). The mixture was extracted with ethyl acetate (3 ꢀ 250 mL), organic
phase was dried over anhydrous sodium sulfate, filtered, and concentrated
in vacuo to provide brown oil. The latter was analyzed by LC-MS (to
reveal that it contains at least 80% of the desired olefin 9: MS MHþ ¼ 316)
and taken on to the last step without further purification.
The crude olefin (9) was dissolved in ethanol (1 L) along with ammonium
formate (50g). Pd on charcoal (10%, 8 g) was added and the reaction mixture
was heated at reflux for 3 hrs. Then it was cooled down and filtered. The
fresh Pd catalyst (5 g) and ammonium formate (10 g) were added and the
mixture was brought to reflux again. After additional 3 hrs, the reaction was
cooled down, filtered, and concentrated in vacuo. Toluene (150 mL) was
added and the volatiles were removed again. The residue was redissolved in
isopropyl alcohol (200 mL), concentrated hydrochloric acid (50 mL) was
added, and the mixture was left at 2208C for 48hrs to ensure complete precipi-
tation of the dihydrochloride salt. The latter was isolated by filtration, washed
with cold isopropanol, and air dried to provide (1). 2HCl as white crystals
1
(15.6 g, 37% for three steps): mp . 2008C (decomp). H NMR (500MHz,
d6-DMSO): d 13.50 (br s, isoquinoline-bound HCl, 1H), 9.22 (unresolved d,
protonated CH2NH2CH2, 2H), 9.12 (unresolved d, NH2, 2H), 8.48 (s, 1H),
7.93 (d, J ¼ 8.5 Hz, 1H), 7.88 (dd, J ¼ 8.5, 1.3 Hz, 1H), 7.67 (d, J ¼ 7.3 Hz,
1H), 7.20 (d, J ¼ 7.3 Hz, 1H), 3.39 (d, CH-þNH2-CH, J ¼ 12.8Hz, 2H),
3.01–3.08 (overlapped d CH-þNH2-CH and m Ar-CH, 3H), 2.08 (m, 2H),
1.98 (m, 2H); 13C NMR (75 MHz, d6-DMSO): d 154.1, 145.3, 135.6, 134.0,
127.9, 127.1, 122.7, 117.7, 110.8, 43.1, 38.8, 28.8; MS MHþ ¼ 228; HRMS
(EI) m/z calcd. for C14H18N3 (MHþ) 228.3197, found 228.3201
REFERENCES
1. Song, Y.; Clizbe, L.; Bhakta, C.; Teng, W.; Li, W.; Wong, P.; Huang, B.; Sinha, U.;
Park, G.; Reed, A.; Scarborough, R. M.; Zhu, B.-Y. Substituted acrylamides as
factor Xa inhibitors: improving bioavailability by P1 modification. Bioorg. Med.
Chem. Lett. 2002, 12, 2043.
2. Rewinkel, J. B.M.; Lucas, H.; Smit, M. J.; Noach, B. J.; van Dinther, T. G.;
Rood, A. M.M.; Jenneboer, J. S.M.; van Boeckel, C. A.A. Design, synthesis and
testing of amino-bicycloaryl based orally bioavailable thrombin inhibitors.
Bioorg. Med. Chem. Lett. 1999, 9, 2837.