Facile synthesis of 5-amino- and 7-amino-6-azaoxindole derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.07.140

An efficient approach for the formation of 5-amino- and 7-amino-6-azaoxindole derivatives was developed. 2-Amino-4-chloro-3- nitropyridine (8), and its 5-nitro-substituted regioisomer (9), respectively, were obtained by reaction with ethyl malonate. The resulting 2-amino-3/5-nitropyridine derivatives substituted in the 4-position with malonic acid diethyl ester (10, 11) were subjected to reductive cyclization yielding 3-ethoxycarbonyl-6-azaoxindole derivatives 4a and 5a. Protection of the amino function was not required. Intermediates 10 and 11 could also be converted to the corresponding 4-acetic acid ethyl esters 12 and 13 by dealkoxycarbonylation with LiCl, and subsequently cyclized under reductive conditions yielding 3-unsubstituted 5-/7-aminooxazindoles.

Full text of DOI:10.1016/j.tetlet.2012.07.140

Tetrahedron Letters 53 (2012) 5597–5601
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of 5-amino- and 7-amino-6-azaoxindole derivatives
⇑
Nikolay T. Tzvetkov, Christa E. Müller
PharmaCenter Bonn, University of Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, An der Immenburg 4, D-53121 Bonn, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient approach for the formation of 5-amino- and 7-amino-6-azaoxindole derivatives was devel-
oped. 2-Amino-4-chloro-3-nitropyridine (8), and its 5-nitro-substituted regioisomer (9), respectively,
were obtained by reaction with ethyl malonate. The resulting 2-amino-3/5-nitropyridine derivatives
substituted in the 4-position with malonic acid diethyl ester (10, 11) were subjected to reductive cycli-
zation yielding 3-ethoxycarbonyl-6-azaoxindole derivatives 4a and 5a. Protection of the amino function
was not required. Intermediates 10 and 11 could also be converted to the corresponding 4-acetic acid
ethyl esters 12 and 13 by dealkoxycarbonylation with LiCl, and subsequently cyclized under reductive
conditions yielding 3-unsubstituted 5-/7-aminooxazindoles.
Received 9 June 2012
Revised 27 July 2012
Accepted 31 July 2012
Available online 15 August 2012
Keywords:
Azaindole
6-Azaoxindole
Facile synthesis
Reductive cyclization
Ó 2012 Elsevier Ltd. All rights reserved.
Indoles are present in numerous natural products as well as in
synthetic compounds with biological activity. In contrast, azain-
doles, which represent bioisosteres of indoles and purines, are
rarely found in nature.1,2 There has been an increasing interest in
azaindoles as versatile scaffolds, so-called ‘privileged structures’,
in drug development.3 For example, 3-oxoacetyl-4-benzoylpipe-
razino-substituted 6- and 7-azaindoles, such as BMS-488043 (1)
and BMS-378806 (2), have been identified as promising antiviral
agents active against HIV-1 (Fig. 1).3a,b The efficacy of 1 as a virus
attachment inhibitor was demonstrated in vivo in HIV-1-infected
patients.4 The azaindole scaffold shows better water-solubility
than the indole structure due to the pyridine fragment by featuring
an additional site for protonation and salt formation.5 Conse-
quently, several synthetic methods for the construction of differ-
ently substituted azaindole derivatives involving a variety of
heterocyclizations6–12 and palladium-catalyzed heteroannula-
tions9e,13 have been developed. The most common methods have
been inspired by various synthetic strategies applied for indole
ring formation.6,7 The majority of synthetic procedures was devel-
oped for the preparation of 7-azaindoles, while relatively a few
have been applied to the synthesis of substituted 6-azaindole
derivatives.8,9a,b,10b,11,13b,c This fact could be explained by the unfa-
vorable electron-deficient character of the pyridine ring condi-
O
O
N
N
CH3
O
N
N
O
O
O
NH
NH
MeO
MeO
N
N
OMe
6-azaindole scaffold
7-azaindole scaffold
1
2
BMS-378806
BMS-488043
Figure 1. Anti-HIV agents with a 6- and 7-azaindole core.
electron-abundant pyrrole ring resulting in pyrrolo[2,3-
c]pyridine.14
In the present study we were interested in the preparation of 6-
azaindole derivative substituted with an amino group in the 5- or
7-position, respectively. The desired structure consisting of a
hydrogen bond acceptor (pyridine N) and an adjacent hydrogen
bond donor (NH2 function) in a bi-heterocyclic ring system would
imitate the nucleobase adenine. Such compounds may interact
with adenine nucleoside- and/or nucleotide-binding proteins, such
as adenosine receptors,15 P2 purinergic (ATP/ADP) receptors,16 pro-
tein kinases,17 nucleoside/nucleotide kinases,18 and ecto-nucleoti-
dases,19 some of which are considered as important new drug
targets. In contrast to unsubstituted 6-azaindole the synthesis of
tioned by an alteration of the
p-electron system during the
heterocyclization step.6b,13d Thus, many classical indole synthesis
methods are not useful for the formation of 6-azaindole scaffold.13d
Formally, 6-azaindoles can be considered as compounds formed by
condensation of the
p-electron-deficient pyridine ring and the p-
⇑
Corresponding author. Tel.: +49 228 73 2301; fax: +49 228 73 2567.
E-mail address: christa.mueller@uni-bonn.de (C.E. Müller).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.140

5598
N. T. Tzvetkov, C. E. Müller / Tetrahedron Letters 53 (2012) 5597–5601
R1
R1
HO
HO
1
R2
N
HN
route A
7
7
H2N
N
H2N
N
Cl
7
5
3
5
H2N
N
R1
R1
OH
OH
NH
3
1
R2
N
route B
H2N 5N
H2N 5N
6
4
Scheme 1. Retrosynthesis of 5- and 7-amino-6-azaoxindoles.
amino-substituted 6-azaindole derivatives is more difficult be-
cause of the existence of tautomeric forms, and due to the basicity
of the amino function.
Herein we describe a synthetic access to 5-amino- and 7-ami-
no-6-azaindole derivatives which allows a broad variation of the
substitution pattern.
Our synthetic concept is illustrated in Scheme 1. Starting from
2-amino-4-chloropyridine (3) both, 5-amino- and 7-amino-2-hy-
droxy-1H-pyrrolo[2,3-c]pyridine (4 and 5) should be accessible.
In either case the nitrogen atom N1 may be substituted with a vari-
ety of residues (R2) in the very last step leading to compounds 6
and 7, respectively.
5- and 7-aminosubstituted 6-azaoxindoles 4a/5a and 4b/5b
were synthesized adapting a reaction procedure described for 6-
azaindoles without the amino group.20 We found that the reaction
sequence did not require protection of the amino function (see
Scheme 2). 2-Amino-4-chloro-3-nitropyridine (8) and 2-amino-4-
chloro-5-nitropyridine (9) were prepared from 3 as previously
described.21
Nitration of 3 yielded a mixture of 3- and 5-nitro-substituted
regioisomers (8:9 = 1.3:1) by 2-nitraminopyridine rearrange-
ment.22 The regioisomers were separated and isolated as described
with some modifications and improvements.23 Condensation of 8
and 9 with diethyl malonate using sodium hydride as a base in
DMF20a afforded 10 (route A) and 11 (route B) in 82 and 73% yield,
respectively. We observed that reaction times for the conversion of
3-substituted pyridines were shorter (40 min for 8 to 10 cf. 4 h for
9 to 11) than for the 5-substituted regioisomer probably due to the
faster mesomeric destabilization of the reactive intermediate 8 un-
der basic conditions. This may be explained by the para-position of
the amino group with respect to the nitro function in compound 9,
which is more favorable for mesomeric stabilization. Reduction of
the nitro group in 10 and 11 followed by in situ heterocyclization
led to the formation of 5-amino- and 7-amino-6-azaoxindoles 4a
and 5a in 96% and 78% yields, respectively. Reductive cyclization
was performed under two different conditions: (i) using a large ex-
cess of zinc dust in an acetic acid–water mixture (3:1) followed by
heterocyclization with 25% aqueous ammonia solution at room
EtO2C
O2N
CO2Et
EtO2C
O2N
(ii)
(iii)
route C
H2N
N
10
H2N
N
12
route B
Cl
Cl
Cl
O2N
H2N
NO2
(i)
3
5
+
H2N
N
N
H2N
N
3
8
9
CO2Et
NO2
CO2Et
NO2
EtO2C
H2N
route A
(ii)
(iii)
route D
N
H2N
N
11
13
Scheme 2. Synthesis of ethyl 2-(2-amino-3/5-nitropyridin-4-yl)acetates 12 and 13. Reagents and conditions: (i) (1) (c) H2SO4/c. HNO3, 0–5 °C, 2–3 days, (2) H2SO4 (92%), 0 °C
to rt, 3 h;21–23 Yield 41% (8) and 30% (9); (ii) NaH (3.6 equiv), malonic acid diethyl ester (3.6 equiv), DMF, 40–50 °C, 50 min (for 10) and 4 h (for 11);20 Yield 82% (10) and 73%
(11); (iii) LiCl (3.0 equiv), DMSO, reflux, 28 h (for 12) and 41 h (for 13);22 Yield 91% (12) and 75% (13).

N. T. Tzvetkov, C. E. Müller / Tetrahedron Letters 53 (2012) 5597–5601
5599
Table 1
Yields and reaction conditions of the reductive cyclization step
Starting compd.
Conditionsa
Method
1
Solvent
Time (min)
Product
Yield (%)
10
(1) Zn (5.0 equiv), NH4Cl
(2) NH4OAc
MeOH–THF (1:1)
H2O
AcOH–H2O (3:1)
H2O
AcOH–H2O (3:1)
H2O
AcOH–H2O (3:1)
H2O
EtOH
EtOH
AcOH–H2O (3:1)
H2O
EtOH
EtOH
AcOH–H2O (3:1)
H2O
120
30
120
15
40
10
15
5
5a
40c
65d
74d
78d
20c
96d
94d
78d
65c
32c
10
10
10
10
11
11
12
13
13
(1) Zn (5.0 equiv)
(2) NH4OH (25%)
(1) Zn (10.0 equiv)
(2) NH4OH (25%)
(1) Zn (20.0 equiv)
(2) NH4OH (25%)
(1) Pd/C (10%), 40 psib
(2) HCl (18%)
(1) Zn (20.0 equiv.)
(2) NH4OH (25%)
(1) Pd/C (10%), 40 psib
(2) HCl (18%)
(1) Zn (20.0 equiv.)
(2) NH4OH (25%)
(1) Zn (20.0 equiv)
(2) NH4OH (25%)
(1) Pd/C (10%), 40 psib
(2) HCl (18%)
1
1
1
2
1
2
1
1
2
5a
5a
5a
5a
4a
4a
5b
4b
4b
120
300
30
10
180
720
5
10
5
10
90
720
AcOH–H2O (3:1)
H2O
EtOH
EtOH
a
b
c
Reactions were carried out at room temperature.
Hydrogenation was carried out in a Parr apparatus.28
Product yields were determined by quantitative LC/ESI-MS of the free amines.
Isolated yields.
d
temperature; (ii) in the presence of palladium as a catalyst in eth-
anol in a Parr hydrogenation apparatus and subsequent ring clo-
sure with 18% aqueous hydrochloric acid at room temperature
(for more details, see Table 1). Pure products 4a and 5a were iso-
lated and characterized by NMR and LC/ESI-MS analyses. Both
products may exist as a mixture of their oxo and hydroxy tautom-
ers. However, based on NMR analysis in DMSO we found that only
the enol form was present, which can be explained by a stabilizing
effect of the ester group at the 3-position of 4a and 5a.
In an attempt to apply this methodology for the preparation of
3-unsubstituted 5-amino- and 7-amino-6-azaoxindoles 4b and 5b,
the malonic acid diethylester derivatives 10 and 11 were converted
into the corresponding dealkoxycarbonylated compounds in anal-
ogy to a method described by Krapcho25 using lithium chloride
(3.0 equiv) in refluxing water:DMSO (1:1). The products 12 (route
C) and 13 (route D) were isolated after purification by column
chromatography in 91% and 75% yield, respectively (Scheme 2).
In a subsequent step the acetic acid ethyl esters 12 and 13 were
reductively cyclized yielding 5-amino- and 7-amino-6-azaoxin-
doles, 4b and 5b (Scheme 3). The same conditions could be suc-
cessfully applied for the cyclization of 12 and 13 as for 10 and
11. Alternatively, 3-unsubstituted amino-substituted 6-azaoxin-
doles may also be obtained by saponification and subsequent
decarboxylation27 of 4a (route E) and 5b (route F) (Scheme 3).26
However, this procedure would require prior protection of the ami-
no function to avoid side-reactions.
Different experiments were performed in order to improve the
product yields of the key step of the synthesis of amino-substituted
HO
CO2Et
EtO2C
O2N
CO2Et
1
HN
(i) or (ii)
7
H2N
N
10
H2N
N
5a
route F
O
CO2Et
NO2
1 NH
(i) or (ii)
7
N
N
H2N
H2N
12, 3-NO2
13
4b, 5-NH2
5b, 7-NH2
, 5-NO2
OH
NH
EtO2C
CO2Et
NO2
EtO2C
H2N
route E
1
(i) or (ii)
5
N
H2N
N
11
4a
Scheme 3. Synthesis of 5- and 7-amino-6-azaoxindole derivatives 4a,b and 5a,b. Reagents and conditions: (i) method 1;23,24 (ii) method 2.25

5600
N. T. Tzvetkov, C. E. Müller / Tetrahedron Letters 53 (2012) 5597–5601
7. For general review for the Fischer indole-type cyclization, see: Humphrey, G.
R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875–2911.
6-azaindole derivatives, the reductive cyclization. Thus, solvent,
reaction time, and the amount of reagents were varied (Table 1).
In general, fast reactions and highest yields of 4a (96%), 5a (78%),
and 4b (65%) were obtained when the reduction was performed
in AcOH:water (3:1) in the presence of a large excess of zinc dust
(20.0 equiv) followed by ring closure in 25% aqueous ammonia at
room temperature (method 1).23,24 A similarly high yield of 4a
(94%) was obtained when the reduction was performed with palla-
dium as a catalyst in ethanol in a Parr hydrogenation apparatus at
40 psi and subsequent treatment of the diamino intermediate with
18% aqueous hydrochloric acid (method 2).25 However, the reduc-
tive cyclization took longer requiring a reaction time of up to 18 h.
No significant improvement was observed for the preparation of 4b
and 5a (32% and 20% determined yields) when using method 2.
In conclusion, the preparation of drug-like 5-amino- and 7-ami-
no-6-azaoxindole derivatives, substituted at the 1- and 3-position,
has been efficiently achieved. For this purpose, we applied a con-
vergent synthetic concept starting from the commercially available
2-amino-4-chloropyridine (3) without the necessity for protection
of the amino group. The reaction sequence involves reductive cycli-
zation as a key step affording the 6-azaoxindoles 4a/5a and 4b/5b
in a regioselective manner. The synthetic procedure was optimized
for several steps. Our results demonstrate that the described proce-
dures are suitable for the preparation of compound libraries that
can be used for drug screening and drug development.
8. For the Madelung-type cyclization, see: Hands, D.; Bishop, B.; Cameron, M.;
Edwards, J. S.; Conttrell, I. F.; Wright, S. H. B. A. Synthesis 1996, 877–882.
9. For the Reissert-type procedure, see: (a) Yakhontov, L. N.; Azimov, V. A.; Lapan,
E. I. Tetrahedron Lett. 1969, 24, 1909–1912; (b) Fischer, M. H.; Matzuk, A. R. J.
Heterocycl. Chem. 1969, 6, 775–776; (c) Dodd, R. H.; Ouannes, C.; Robert-Gero,
M.; Potier, P. J. Med. Chem. 1989, 32, 1272–1276; (d) Dodd, R. H.; Doisy, X.;
Potier, P.; Potier, M.-C.; Rossier, J. Heterocycles 1989, 28, 1101–1113; (e) Curtis,
N. R.; Kulagowski, J. J.; Leeson, P. D.; Ridgill, M. P.; Emms, F.; Freedman, S. B.;
Patel, S.; Patel, Sm. Bioorg. Med. Chem. Lett. 1999, 9, 585–588.
10. For the Batcho-Leimgruber synthesis, see: (a) Battersby, A. R.; McDonald, E.;
Wurziger, H. K. W.; James, K. J. J. Chem. Soc., Chem. Commun. 1975, 493–494; (b)
Mahadevan, I.; Rasmussen, M. J. Heterocycl. Chem. 1992, 29, 359–367.
11. For the Lorenz-type cyclization, see: Lorenz, R. R.; Tullar, B. F.; Koelsch, C. F.;
Archer, S. J. Org. Chem. 1965, 30, 2531–2533.
12. For the Bartoli sequence, see: Zhang, Z.; Yang, Z.; Meanwell, N. A.; Kadow, J. F.;
Wang, T. J. Org. Chem. 2002, 67, 2345–2347.
13. (a) Park, S. S.; Choi, J.-K.; Yum, E. K. Tetrahedron Lett. 1998, 39, 627–630; (b) Xu,
L.; Lewis, I. R.; Davidsen, S. K.; Summers, J. B. Tetrahedron Lett. 1998, 39, 5159–
5162; (c) Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39, 5355–5358; (d)
McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8, 3307–3310; (e)
Fang, Y.-Q.; Yuen, J.; Lantens, M. J. Org. Chem. 2007, 72, 5152–5160.
14. Prokopov, A. A.; Yakhontov, L. N. Pharm. Chem. J. 1994, 28, 471–506.
15. Müller, C. E.; Jacobson, K. A. Biochim. Biophys. Acta 1808, 2011, 1290–1308.
16. Müller, C. E.; Scior, T. Pharm. Acta Helv. 1993, 68, 77–111.
17. Noble, M. E. M.; Endicott, J. A.; Johnson, L. N. Science 2004, 303, 1800–1805.
18. Deville-Bonne, D.; El Amri, C.; Meyer, P.; Chen, Y.; Agrofoglio, L. A.; Janin, J.
Antiviral Res. 2010, 86, 101–120.
19. Zimmermann, H. Prog. Neurobiol. 1996, 49, 589–618.
20. (a) Prokopov, A. A.; Yakhontov, L. N. Khim. Geterotsikl. Soedin. 1978, 12, 1224–
1227; (b) Daisley, R. W.; Hanbali, J. R. Synth. Commun. 1981, 11, 743–749; (c)
Andreassen, E. J.; Bakke, J. M. J. Heterocycl. Chem. 2006, 43, 49–54; (d) Jiang, J.
Z.; Koehl, J. R.; Mehdi, S.; Moorcraft, N. D.; Musick, K. Y.; Weintraub, P. M.;
Eastwood, P. R. Pat. Appl. US2005/0054631 A1.; (e) Pitts, W. J.; Kempson, J.;
Guo, J.; Das, J.; Langevire, C. M.; Spergel, S. H.; Watterson, S. P. PCT Int. Appl.
WO2006/122137 A1.
Acknowledgments
Annette Reiner, Marion Schneider, and Sabine Terhart-Krabbe
are gratefully acknowledged for skillful technical assistance. We
are grateful to the German Federal Ministry of Education and Re-
search (BMBF) and UCB Pharma for financial support (BIOPHARMA
Neuroallianz project).
21. (a) De Roos, K. B.; Salemink, C. A. Rec. Trav. Chim. Des Pays. Bas 1969, 88, 1263–
1274; (b) Deady, L. W.; Korytsky, O. L.; Rowe, J. E. Aust. J. Chem. 1982, 35, 2025–
2034.
22. Optimization of the 2-nitraminopyridine rearrangement was achieved by
stirring of the nitramine intermediate over night at À5 °C followed by
neutralization of the reaction mixture with 25% aqueous ammonia solution.
23. The product ratio of the regioisomeric mixture 8:9 was determined by LC/ESI-
MS analysis. The 3- and 5-nitro isomers 8 and 9 were separated by column
chromatogryphy on silica gel following by recrystallization from
dichloromethane:petroleum ether (1:1, 100 mL per 1.0 g of product), giving
41% and 30% yield, respectively.
Supplementary data
Supplementary data (all synthetic procedures and analytical
data of compounds 4a, 5a, and 10–13) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.07.140.
24. Representative procedure for reductive cyclization of 8 and 9 (Table 1, method
1):
(a) Ethyl 5-amino-2-hydroxy-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (4a): To a
stirred solution of diethyl 2-(2-amino-5-nitropyridin-4-yl)malonate (11,
180 mg, 0.61 mmol) in AcOH:water (36 mL, 3:1) was added to zinc dust in
small portions (800 mg, 12.2 mmol). The mixture was stirred at rt for 30 min
and filtered under reduced pressure to remove the zinc dust. The residue was
diluted with water (2 mL) and treated with 25% aqueous ammonia (10 mL).
The resulting mixture was stirred at rt for 10 min and extracted with n-butanol
(3 Â 10 mL). The combined organic layer was dried over Na2SO4, filtered, and
evaporated to dryness under reduced pressure. The residue was re-crystallized
from ethyl acetate:petroleum ether and/or methanol (3:1, 15 mL) to yield
129 mg (96%) of the product as a white solid. Mp 328–330 °C (dec.); 1H NMR
(500 MHz, DMSO-d6) d [ppm]: 1.27 (t, J = 7.25 Hz, 3H, OCH2CH3), 4.10 (q,
J = 7.25 Hz, 2H, OCH2CH3), 4.65 (s-broad, 2H, NH2), 6.43 (s, 1H), 7.23 (s, 1H),
7.30 (d, J = 6.30 Hz, 1H), 9.13 (s, 1H, OH), 11.1 (s, 1H, NH); 13C NMR (125 MHz,
DMSO-d6) d [ppm]: 15.2 (OCH2CH3), 56.9 (OCH2CH3), 95.9, 112.9, 114.1, 123.9,
137.1, 152.8, 159.7, 166.9 (O@COEt); LC/ESI-MS m/z: negative mode 220
([MÀH]À), positive mode 222 ([M+H]+). Purity (HPLC-UV 328 nm): 97.6%.
(b) Ethyl 7-amino-2-hydroxy-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (5a): To a
stirred solution of diethyl 2-(2-amino-3-nitropyridin-4-yl)malonate (10,
300 mg, 1.01 mmol) in AcOH: water (60 mL, 3:1) was added to zinc dust in
small portions (1.32 g, 20.2 mmol). The mixture was stirred at rt for 15 min
and filtered under reduced pressure to remove the zinc dust. The residue was
diluted with water (3 mL) and treated with 25% aqueous ammonia (14 mL).
The resulting mixture was stirred at rt for 5 min and extracted with n-butanol
(3 Â 10 mL). The combined organic layer was dried over Na2SO4, filtered, and
evaporated to dryness under reduced pressure. The residue was re-crystallized
from petroleum ether:dichloromethane:methanol (10:5:1, 16 mL) to yield
174 mg (78%) of the product as a white solid. Mp 302–303 °C (dec.); 1H NMR
(500 MHz, DMSO-d6) d [ppm]: 1.25 (t, J = 6.94 Hz, 3H, OCH2CH3), 4.13 (q,
J = 6.63 Hz, 2H, OCH2CH3), 6.84 (s-broad, 2H, NH2), 7.01 (d, J = 8.10 Hz, 1H),
7.05 (d, J = 5.99 Hz, 1H), 7.30 (d, J = 6.30 Hz, 1H), 10.2 (s, 1H, OH), 11.6 (s, 1H,
NH); 13C NMR (125 MHz, DMSO-d6) d [ppm]: 14.9 (OCH2CH3), 57.5 (OCH2CH3),
87.7, 104.5, 110.0, 126.0, 135.7, 137.9, 164.9, 166.5 (O@COEt); LC/ESI-MS m/z:
negative mode 220 ([MÀH]À), positive mode 222 ([M+H]+). Purity (HPLC-UV
342 nm): 98.6%.
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25. Krapcho, A. P. Synthesis 1982, 805–822.

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26. Ester cleavage of 5a was achieved with lithium hydroxide in a methanol–THF
solution (1:1) at room temperature. The yield was determined by quantitative
LC/ESI-MS analysis. Initial experiments for decarboxylation under different
conditions (e.g., 18% aqueous HCl solution, or LiCl in water–DMSO) showed a
formation of by-products when the amino group remained unprotected.
27. Protection of the amino group in
8
and
9
was performed with N,N-
dimethylformamide dimethyl acetal (DMA) in methanol at 75 °C for 16 h to
yield the amino-protected pyridines in good yields (85% on average).
28. Hydrogenation was performed in a Hogen GC hydrogen generator (Proton
Energy Systems, Inc.).