Facile synthesis of isoquinolines, β-carbolines, and 3-deazapurines

Article abstract of DOI:10.1080/00397910701392459

Isoquinoline, β-carbolines, and 3-deazapurines were prepared in 52-81% yields via oxidative decarboxylation of cyclic α-amino acids using ammonium persulfate as an oxidant in the presence of catalytic silver. Copyright Taylor & Francis Group, LLC.

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Facile Synthesis of Isoquinolines,
β‐Carbolines, and 3‐Deazapurines
Wenhua Huang a , Jingyi Li a & Lihua Ou a
a Department of Chemistry , Tianjin University , Tianjin, China
Published online: 03 Jul 2007.
To cite this article: Wenhua Huang , Jingyi Li & Lihua Ou (2007) Facile Synthesis of Isoquinolines,
β‐Carbolines, and 3‐Deazapurines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:13, 2137-2143, DOI: 10.1080/00397910701392459
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Synthetic Communicationsw, 37: 2137–2143, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701392459
Facile Synthesis of Isoquinolines,
b-Carbolines, and 3-Deazapurines
Wenhua Huang, Jingyi Li, and Lihua Ou
Department of Chemistry, Tianjin University, Tianjin, China
Abstract: Isoquinoline, b-carbolines, and 3-deazapurines were prepared in 52–81%
yields via oxidative decarboxylation of cyclic a-amino acids using ammonium persul-
fate as an oxidant in the presence of catalytic silver.
Keywords: b-carboline, 3-deazapurine, isoquinoline, oxidative decarboxylation,
persulfate, silver
Isoquinolines, b-carbolines, and 3-deazapurines are of great interest because
of their occurrence in nature and their biological activities.[1–4] One of
classical methods of synthesizing these heterocyclic compounds utilizes the
Pictet–Spengler reaction[5] to construct
a tetrahydropyridine moiety
followed by dehydrogenation. Natural b-aryl-a-amino acid 1 can also
undergo Pictet–Spengler cyclization to produce tetrahydropyridine derivative
2, whose oxidative decarboxylation can produce pyridine derivative 3
(Scheme 1). Such oxidative decarboxylation has been widely employed in
synthesizing b-carbolines, but uses stoichiometric K2Cr2O7 or toxic SeO2 as
an oxidant.[6,7] In this article, we report our results on oxidative decarboxyla-
tion of tetrahydropyridine derivative 2 using persulfate as an oxidant in the
presence of catalytic silver (Agþ/S2O822).
Induced by Agþ/S2O822, a-amino acids can undergo smoothly oxidative
decarboxylation,[8,9] which has been widely applied in Minisci radical
Received September 2, 2006
Address correspondence to Wenhua Huang, Department of Chemistry, Tianjin
University, 92 Weijin Road, Tianjin 300072, China. E-mail: huangwh@tju.edu.cn
2137

2138
W. Huang, J. Li, and L. Ou
Scheme 1.
alkylation.[10,11] To the best of our knowledge, however, little attention has
been paid to tetrahydropyridine derivative 2 under similar reaction conditions.
As shown in Scheme 1, oxidative decarboxylation of 2 induced by Agþ/
S2O282 would lead to the formation of radical 4. This radical should then be
oxidized[12,13] to imine 5, which would give aromatization product 3 after
further oxidation. Starting from phenylalanine, tyrosine, and histidine, this
synthetic route would provide a facile entry into isoquinolines, b-carbolines,
and 3-deazapurines, respectively.
Cyclic amino acids 2a–f were prepared via the Pictet–Spengler cycliza-
tion according to the literature procedure.[14–17] Their oxidative decarboxyla-
tion was carried out at 808C using CH3CN/water as solvents in the presence of
10% mol of silver nitrate. Ammonium persulfate was washed dropwise from a
small filter-like unit into the reaction mixture by condensing solvents (see the
experimental section). Unlike traditional addition methods such as using a
syringe, this reduced the risk of introducing air into the reaction mixture
and persulfate’s decomposition in aqueous solution.
Initially we used tetrahydroisoquinoline 2a prepared from the conden-
sation of L-phenylalanine and formaldehyde to optimize the usage of persul-
fate. As shown in Table 1, the best yield (70%) of isoquinoline was obtained
by using 2.5 equivalents of persulfate, whereas both 3.0 and 2.0 equivalents of
persulfate resulted in lower yield (54%). In the absence of silver nitrate, the
reaction gave isoquinoline in only 24% yield, and TLC analysis showed
that most of the starting material was not consumed.

Isoquinolines, b-Carbolines, and 3-Deazapurines
2139
Table 1. Synthesis of isoquinoline, b-carbolines, and 3-deazapurines
S2O282 Yielda
(equiv) of 3 (%)
Entry
1
Substrate 2
Product 3
3.0
54
2
3
4
5
2a
2a
2a
3a
3a
3a
2.0
2.5
2.5
2.5
54
70
24b
52
6
7
2.5
2.5
56
59
8
9
2.5
2.5
79
81
aIsolated yields by preparative TLC.
bWithout using AgNO3.
Oxidative decarboxylation of tetrahydrocarboline 2b gave b-carboline in
lower but reasonable yield (52%). Introduction of a methyl or phenyl group at
the 1 position afforded harman 3c or 1-phenyl-b-carboline 3d in slightly
higher yield (56%, 59%). In sharp contrast, oxidative decarboxylation of spi-
nacines 2e and 2f produced 3-deazapurines 3e and 3f in 79% and 81% yields,
respectively. The lower yields of tetrahydrocarbolines 2b–2d were possibly
due to their low solubility in CH3CN/water.
In conclusion, we have demonstrated a general synthetic method for the
synthesis of isoquinolines, b-carbolines, and 3-deazapurines starting from
naturally occurring amino acids under mild conditions and using catalytic
silver with a greener oxidant.

2140
W. Huang, J. Li, and L. Ou
EXPERIMENTAL
Ammonium persulfate, silver nitrate, and acetonitrile were purchased from
a commercial vendor and were used directly. All melting points were
measured on a melting-point apparatus with microscope and hot stage and
1
are uncorrected. H and 13C NMR spectra were recorded on a Varian Inova
500 NMR spectrometer. IR spectra were recorded on a Thermo Nicolet
Avatar 360 IR spectrometer. Elemental analyses were performed on a
Heraeus Vanio-EL CHN analyzer. All reactions were carried out under
nitrogen.
Typical Procedure for the Synthesis of Isoquinoline
To a reaction tube with a condenser, compound 2a (1.0 mmol), silver nitrate
(0.1 mmol), acetonitrile (8 mL), and deionized water (7.5 mL) were added.
Ammonium persulfate (2.5 mmol) was added to a small glass container
with pinholes covered with glass wool at the bottom, which was hung on
the condenser to allow condensing solvents to wash persulfate dropwise
into the reaction mixture. The reaction mixture was degassed by sparging
nitrogen, and then the reaction tube was placed in a water bath preheated to
808C. After persulfate was completely washed out (ca. 30–40 min), the
reaction mixture was stirred further for 1 h and then cooled down to room
temperature. The reaction mixture was filtered to remove some precipitates
after addition of concentrated ammonium hydroxide (2 mL) and then was
extracted twice with chloroform (20, 10 mL). Isoquinoline was isolated as
an orange oil in 70% yield from the combined organic phase by preparative
thin-layer chromatography (TLC) (eluent: EtOAc/petroleum ether 1/3,
v/v) after being dried over anhydrous Na2SO4 and evaporated. The spectral
data of the product were in agreement with those reported.[18,19] 1H NMR
(500 MHz, CDCl3) d 7.25–7.61 (3H, m, 4,6,7-H), 7.81 (1H, d, J ¼ 8.0 Hz,
5-H), 7.94–7.97 (1H, m, 4-H), 8.52 (1H, d, J ¼ 6.0 Hz, 3-H), 9.25 (1H, s,
1-H); IR (KBr) 1627, 1588, 1497 cm21
.
Data
1
b-Carboline (3b). A yellow solid: mp 194–1968C (lit.[20] 1968C); H NMR
(500 MHz, CDCl3) d 7.26–7.34 (1H, m), 7.58–7.60 (2H, m), 8.02–8.04 (1H,
m, 4-H), 8.15–8.17 (1H, m), 8.46 (1H, d, J ¼ 5.5 Hz, 3-H), 9.05 (1H, s, 1-H),
9.51 (1H, br, NH); IR (KBr) 1623, 1557, 1495 cm21; eluent: CHCl3/MeOH
10/1, v/v.
Harman (3c). A yellow solid: mp 214–2168C (lit.[21] 235–2368C); 1H NMR
(500 Hz, CDCl3) d 2.92 (3H, s, CH3), 7.29–7.33 (1H, m, 6-H), 7.55–7.62 (2H,

Isoquinolines, b-Carbolines, and 3-Deazapurines
2141
m, 7,8-H2), 7.87–7.89 (1H, m, 4-H), 8.12–8.14 (1H, m, 5-H), 8.35 (1H, d,
J ¼ 5.5 Hz, 3-H), 9.23 (1H, br, NH); IR (KBr) 1625, 1605, 1564,
1506 cm21; eluent: CHCl3/MeOH 10/1, v/v.
1-Phenyl-b-carboline (3d). A pale yellow solid: mp 234–2368C (lit.[21]
245–2468C); 1H NMR (500 MHz, CDCl3) d 7.31–7.35 (1H, m, 6-H),
7.50–7.62 (5H, m, ArH), 7.95–7.99 (3H, m, 7,8, 4-H), 8.16–8.19 (1H, m,
5-H), 8.58–8.60 (2H, m); IR (KBr) 1624, 1594, 1560, 1496 cm21; eluent:
CHCl3/MeOH 10/1, v/v.
3-Deazapurine (3e). A pale yellow solid: mp 164–1668C (lit.[22]
1
165–1688C); H NMR (500 MHz, D2O) d 7.55 (1H, dd, J ¼ 1.0, 6.0 Hz,
NCH55CH), 8.17 (1H, d, J ¼ 5.5 Hz, NCH55CH), 8.24 (1H, s, N55CHC),
8.77 (1H, d, J ¼ 1.0 Hz, NCHN); IR (KBr) 3382, 1633, 1471, 1462,
1434 cm21. Because of its solubility in water, the workup procedure was
modified: the reaction mixture was evaporated to remove all solvents after
reaction, and the product was isolated by preparative TLC (eluent: CHCl3/
MeOH 5/1, v/v) from the extracts of the resulting residue with MeOH
(2 ꢀ 20 mL).
6-Phenyl-3-deazapurine (3f). A pale yellow solid: mp 166–1698C; 1H NMR
(500 MHz, CDCl3) d 7.26–7.50 (4H, m, ArH þ NCH55CH), 8.03 (1H, s,
NCHN), 8.28–8.30 (2H, m, ArH), 8.43 (1H, d, J ¼ 5.5 Hz, NCH55CH);
13C NMR (125.7 MHz, DMSO-d6) d 107.4, 128.8, 129.5, 129.6, 138.3,
138.7, 140.0, 141.7, 144.1, 147.9; IR (KBr) 1611, 1586, 1493, 1463 cm21
.
Anal. calcd. for C12H9N3: C, 73.83; H, 4.65; N, 21.52. Found: C, 73.85; H,
4.46; N, 21.40.
ACKNOWLEDGMENT
We thank Tianjin University for providing a starting research fund to W. H.
REFERENCES
1. Ding, H.; Lu, W.; Li, H.; Yang, L.; Zhang, Q.; Zhou, C.; Wu, X.; Bandoin, O.;
Cai, J.; Gueritte, F.; Zhao, Y. Synthesis and biological evaluation of novel
compounds related to 1-arylnaphthalene lignans and isoquinolines. Chem. Biodi-
versity 2005, 2, 1217–1231.
2. Parker, C. A.; Anderson, N. J.; Robinson, E. S. J.; Price, R.; Tyacke, R. J.;
Husbands, S. M.; Dillon, M. P.; Eglen, R. M.; Hudson, A. L.; Nutt, D. J.;
Crump, M. P.; Crosby, J. Harmane and harmalan are bioactive components of
classical clonidine-displacing substance. Biochem. 2004, 43, 16385–16392.

2142
W. Huang, J. Li, and L. Ou
3. Cristalli, G.; Costanzi, S.; Lambertucci, C.; Taffi, S.; Vittori, S.; Volpini, R. Purine
and deazapurine nucleosides: Synthetic approaches, molecular modeling and bio-
logical activity. Il Farmaco 2003, 58, 193–204.
4. Pari, K.; Sundari, C. S.; Chandani, S.; Balasubramanian, D. b-Carbolines that
accumulate in human tissues may serve a protective role against oxidative
stress. J. Biol. Chem. 2000, 275, 2455–2462.
5. Whaey, W. H.; Govindachari, T. R. The Pictet–Spengler synthesis of tetrahydroi-
soquinolines and related compounds. Org. React. 1951, 6, 151–206.
6. Song, Y.; Wang, J.; Teng, S. F.; Kesuma, D.; Deng, Y.; Duan, J.; Wang, J. H.;
Qi, R. Z.; Sim, M. M. b-Carbolines as specific inhibitors of cyclin-dependent
kinases. Bioorg. Med. Chem. Lett. 2002, 12, 1129–1132.
7. Hagen, T. J.; Skolnick, P.; Cook, J. M. Synthesis of 6-substituted b-carbolines that
behave as benzodiazepine receptor antagonists or inverse agonists. J. Med. Chem.
1987, 30, 750–753.
8. Zelechonok, Y.; Silverman, R. B. Silver(I)/peroxydisulfate–induced oxidative
decarboxylation of amino acids: A chemical model for a possible intermediate
in the monoamine oxidase–catalyzed oxidation of amines. J. Org. Chem. 1992,
57, 5787–5790.
9. Bacon, R. G. R.; Hanna, W. J. W.; Stewart, D. Oxidation by persulphate, part V:
Silver-catalysed oxidation of secondary aliphatic amines and a-amino-acids.
J. Chem. Soc. C 1966, 1388–1399.
10. Cowden, C. J. Use of N-protected amino acids in the Minisci radical alkylation.
Org. Lett. 2003, 5, 4497–4499.
11. Minisci, F.; Vismara, E.; Fontana, F. Recent developments of free-radical substi-
tuents of heteroaromatic bases. Heterocycles 1989, 28, 489–519.
12. Chao, W.; Weinreb, S. M. Radical-based methodology for efficient generation of
acyclic N-acylimines. Tetrahedron Lett. 2000, 41, 9199–9204.
13. Renaud, P.; Giraud, L. 1-Amino- and 1-amidoalkyl radicals: Generation and
stereoselective reactions. Synthesis 1996, 913–926.
14. Schiller, P. W.; Weltrowska, G.; Nguyen, T. M.-D.; Lemieux, C.; Chung, N. N.;
Marsden, B. J.; Wilkes, B. C. Conformational restriction of the phenylalanine
residue in a cyclic opioid peptide analogue: Effects on receptor selectivity and
stereospecificity. J. Med. Chem. 1991, 34, 3125–3132.
15. Lippke, K. P.; Schunack, W. G.; Wenning, W.; Muller, W. E. b-Carbolines as
benzodiazepine receptor ligands, I: Synthesis and benzodiazepine receptor inter-
action of esters of b-carboline-3-carboxylic acid. J. Med. Chem. 1983, 26,
499–503.
16. Snyder, H. R.; Hansch, C. H.; Katz, L.; Parmerter, S. M.; Spaeth, E. C. The
synthesis of drivatives of b-carboline, II: Syntheses from dl-tryptophan and
aldehydes. J. Am. Chem. Soc. 1948, 70, 219–222.
17. Guzman, F.; Cain, M.; Larscheid, P.; Hagen, T.; Cook, J. M.; Schweri, M.;
Skolnick, P.; Paul, S. M. Biomimetic approach to potential benzodiazepine
receptor agonists and antagonists. J. Med. Chem. 1984, 27, 564–570.
18. Krishnakumar, V.; Ramasamy, R. DFT studies and vibrational spectra of
isoquinoline and 8-hydroxyquinoline. Spectrochim. Acta, Part A 2005, 61,
673–683.
19. Waston, C. Y.; Whish, W. J. D.; Threadgill, M. D. Synthesis of 3-substituted ben-
zamides and 5-substituted isoquinolin-1(2H)-ones and preliminary evaluation as
inhibitors of poly(ADP-ribose)polymerase (PARP). Bioorg. Med. Chem. 1998,
6, 721–734.

Isoquinolines, b-Carbolines, and 3-Deazapurines
2143
20. Parameswaran, P. S.; Naik, C. G.; Hegde, V. R. Secondary metabolites from the
sponge tedania anhelans: Isolation and characterization of two novel pyrazole
acids and other metabolites. J. Nat. Prod. 1997, 60, 802–803.
21. Kusurkar, R. S.; Goswami, S. K. Efficient one-pot synthesis of anti-HIV and anti-
tumour b-carbolines. Tetrahedron 2004, 60, 5315–5318.
22. Katner, A. S.; Brown, R. F. A novel preparation of thiazolo[5,4-c]pyridine and
the synthesis of some imidazo[4,5-c]pyridines and oxazolo[4,5-c]pyridine.
J. Heterocycl. Chem. 1990, 27, 563–566.