Efficient and selective synthesis of alkoxy substituted di(pyridin-2-yl)amines and N-arylpyridin-2-ylamines

Article abstract of DOI:10.1016/j.tetlet.2012.01.084

The formation of alkoxy substituted di(pyridin-2-yl)amines and N-arylpyridin-2-ylamines by nitro group reduction is described. Unexpected substitution of ortho with the amino at C-6 was observed during the reduction using SnCl₂·2H₂O

Full text of DOI:10.1016/j.tetlet.2012.01.084

Tetrahedron Letters 53 (2012) 1885–1888
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient and selective synthesis of alkoxy substituted
di(pyridin-2-yl)amines and N-arylpyridin-2-ylamines
Irina-Claudia Grig-Alexa a,b, Iuliana Simionescu a,b, Oana-Irina Patriciu a,b, Stéphane Massip c,
c
c
a,
Adriana-Luminita Fînaru b, , Christian Jarry , Jean-Michel Léger , Gérald Guillaumet
⇑
⇑
a Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 7311, BP 6759, 45067 Orléans Cedex 2, France
b Laboratorul de Sinteza˘ Organica˘ ßsi Analiza˘ Structurala˘, Universitatea ‘‘Vasile Alecsandri’’ din Baca˘u, 157, Calea Ma˘ra˘ßseßsti, 6000115 Baca˘u, Romania
c Pharmacochimie, EA 4138, Université Victor Segalen Bordeaux II, 146, rue Léo Saignat, 33076 Bordeaux Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The formation of alkoxy substituted di(pyridin-2-yl)amines and N-arylpyridin-2-ylamines by nitro group
reduction is described. Unexpected substitution of ortho with the amino at C-6 was observed during the
reduction using SnCl2ꢀ2H2O in different alcohols. The influence of the nature of the atom at the 3- and
5-positions of nitro-substituted di(pyridin-2-yl)amines and N-arylpyridin-2-ylamines was investigated.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 21 October 2011
Revised 12 December 2011
Accepted 20 January 2012
Available online 28 January 2012
Keywords:
Pyridines
Amines
Reduction
Stannous chloride dihydrate
Ortho position
Among the wide variety of chemical structures in development
as new potential drugs, small molecules based on an aminopyri-
dine scaffold have attracted significant interest.1 For example, a
potent and novel class of mGlu5 receptor antagonists was recently
indentified, based on dipyridylamines substituted at optimal posi-
tions.1a Also, several aminopyridine derivatives have exhibited
pharmaceutical activity as antitumor1b or anti-infective1c agents.
As part of our research program, nitro dipyridinylamines were
obtained through Pd-catalyzed reactions2 or via oxidative nucleo-
philic substitution of hydrogen.3 Some of these compounds were
used as starting materials for the synthesis of dihydrodipyridopyr-
azines, a family of planar nitrogen heterocycles with potential anti-
tumor activity.4
Based on our experience on the conversion of the nitro group of
nitroindazole derivatives into the corresponding amino group with
SnCl2, in alcoholic solution, we decided to extend this reduction
method, originally described by Bellamy,5 to our nitro dipyridinyl-
amines series, in order to prepare new bi and tri substituted com-
pounds by a simple route.
to the 1H NMR spectrum of the crude product, to a mixture of two
different compounds, the desired amine 2, and the amine 3 substi-
tuted with an ethoxy group at the ortho position (60-position)
(Scheme 1).
The ability of SnCl2, in alcoholic solution, to form the corre-
sponding ethoxy-substituted derivatives, was observed for the first
time during the synthetic procedure developed in our laboratory to
obtain the corresponding indazole derivatives starting from
7-nitroindazole, and a plausible mechanism was proposed.6a The
reduction of aromatic nitro compounds with metals in protic sol-
vents such as alcohols, acetic acid, water or in aqueous mineral
acid, is usually presumed to proceed by way of hydroxylamine-like
intermediates. Hence, we assume that the nucleophilic attack of
ethanol present in the reaction mixture occurs via the lone oxygen
Preliminary reduction of the nitro group of dipyridinylamine 1a
with SnCl2ꢀ2H2O in the presence of ethanol gave access, according
⇑
Corresponding authors. Tel.: +40 234 542411 (A.-L.F.); tel.: +33 238 417354;
fax: +33 238 417281 (G.G.).
E-mail addresses:
adrianaf@ub.ro (A.-L. Fînaru),
gerald.guillaumet@
univ-orleans.fr (G. Guillaumet).
Scheme 1. Reduction of 1a with stannous chloride dihydrate in ethanol.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.084

1886
I.-C. Grig-Alexa et al. / Tetrahedron Letters 53 (2012) 1885–1888
H+
NO2
NO
NH-OH
NH2
.
SnCl2 2H2O
Ar
Ar
Ar
Ar
N
R
N
Y
N
R
N
N
R
N
N
R
N
EtOH
HOC2H5
X
NH2
OC2H5
NH
OC2H5
H
Ar =
Ar
Ar
N
R
N
N
R
N
R = H, Me
Scheme 2. Proposed mechanism for the reduction of aromatic nitrocompounds with stannous chloride dihydrate in ethanol.
As shown in Table 1, the nature of groups X, Y and R led to
different ratios of 6 and 7.
First, we studied the influence of the nature of the atom at the
3-position of nitro-substituted dipyridinylamines 1a–f (Table 1,
entries 1–6). When the 3-position was occupied with a halogen
or a methyl group, the major product was the amine substituted
with an ortho ethoxy group 7a–e (Table 1, entries 1–5). Moreover,
we observed that when the reduction-protection reaction was con-
ducted with 1a–c, the presence of bromo 1a, chloro 1b or iodo 1c
substituents at the 3-position led to similar ratios of products 6
and 7. As expected, a quite different order of reactivity was found
for fluorine-substituted 1d which afforded a ratio comparable with
that obtained using the methyl-substituted compound (1e).
In the case of 1f where the 3-position was vacant, we observed a
decrease in the amount of 7f compared with 7a–e (Table 1, entry
6). On the other hand, if the halogen was at the 5-position and
the 3-position was unoccupied, we registered similar behavior,
the ratio of the two amines being 50/50 (Table 1, entry 8). Hence,
we note the importance of the presence of a substituent at the 3-
position (halogen or alkyl group) in order to obtain the product
substituted with an ethoxy group as the major product.
Scheme 3. Reduction of 4 with stannous chloride dihydrate in ethanol.
pair (Scheme 2). This substitution proceeds during this intermedi-
ate stage of the reduction process through protonated hydroxyl-
amine compounds.7
It is noteworthy that only the corresponding amine 5 was ob-
tained when the reduction of the nitro group of dipyridinylamine
4 was carried out using the same method (Scheme 3).2a
These results could be related to the important role played by
the position of the nitro group in this reduction reaction as was
reported for nitroarenes and nitroindazoles.6
In order to show the generality and flexibility of this reaction
we used different nitro-substituted dipyridinylamines 1a–h and
N-arylpyridin-2-ylamines 1i and 1j as starting materials.8 As signif-
icant degradation of the amines was observed during separation by
flash chromatography, we immediately protected this using
pivaloyl chloride in dichloromethane (Scheme 4, Table 1).9
As shown in Table 1 (entry 7) and according to 1H NMR data11
the introduction of a methyl group on the dipyridylamino N-atom
Scheme 4. Reduction of the nitro group of compounds 1a–j and protection with pivaloyl chloride.
Table 1
Reduction of the nitro group of compounds 1a–j
Entry
Substrate
X
Y
R
Ratio 6/7a
Product 6
Product 7
Total
yieldb (%)
yieldb (%)
yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
3-Br
3-Cl
3-I
N
N
N
N
N
N
N
N
H
H
H
H
H
H
Me
H
H
H
20/80
20/80
17/83
30/70
32/68
45/55
75/25
50/50
80/20
60/40
1510a
14
—
5210b
50
78
57
30
24
17
32
10
67
64
78
86
30
40
77
69
60
67
c
3-F
29
c
3-Me
3-H
3-Br
5-Br
3-H
3-Br
—
16
60
37
50
43
CH
CH
10
1j
24
a
b
c
Ratio determined by 1H NMR spectroscopy of the crude mixture of amines.
Isolated yield after separation by flash chromatography.
Only trace amounts (<5%) of the purified product were isolated.

I.-C. Grig-Alexa et al. / Tetrahedron Letters 53 (2012) 1885–1888
1887
Figure 1. X-ray crystal structure of compound 7h.
Scheme 7. Reduction of 1a in ethyl acetate and protection with pivaloyl chloride.
Scheme 5. Synthesis of pivalamide 6k from N-(3-bromopyridin-2-yl)-N-(6-chloro-
5-nitropyridin-2-yl)-N-methylamine 1k.
Scheme 8. Reduction of 1a and protection with 4-methoxybenzenesulfonyl
chloride and benzyl chloroformate in pyridine.
series with N-arylpyridin-2-ylamines, we used compounds 1i and
1j as substrates for reduction of the nitro group with SnCl2 in the
presence of ethanol (Table 1, entries 9 and 10). In these cases,
the major compounds in the mixture were the amines 6i,j as
opposed to the substituted ethoxy amines 7i,j.
Scheme 6. Reduction of 1a in different alcohols and protection with pivaloyl
chloride.
Table 2
Reduction of 1a in different alcohols
We observed that, as with the dipyridinyl amine series, the
presence of a bromide at the 3-position was important, increasing
the amount of ethoxy substituted compound 7j.
Entry
R
Product Ratio
Product 6a Product 8 Total
6a/8
yield (%)
yield (%)
yield (%)
For product 7h,13 it was possible to isolate single crystals per-
mitting its study by X-ray crystallography.14 The ORTEP represen-
tation of this product clearly indicates the presence of an ethoxy
group at the pyridine C-6 position (Fig. 1).
1
2
3
4
CH3
8a
16/84 15
30/70 22
70/30 45
50/50 33
75
56
21
31
90
78
66
64
CH3(CH2)2 8b
(CH3)2CH 8c
CH3(CH2)3 8d
Under the same conditions, N-(3-bromopyridin-2-yl)-N-(6-
chloro-5-nitropyridin-2-yl)methylamine (1k), gave access, only to
the corresponding amine, isolated as its pivalamide 6k, because
of the presence of a substituent at the 60-position (Scheme 5).
(1g) led to an inversion of the proportion of the two compounds 6g
and 7g12 (75/25). Also, in order to compare the dipyridinylamine

1888
I.-C. Grig-Alexa et al. / Tetrahedron Letters 53 (2012) 1885–1888
Table 3
Reduction of 1a and protection with 4-methoxybenzenesulfonyl chloride or benzyl chloroformate in pyridine
Entry
R0Cl
Ratio 9/10
Product 9 yield (%)
Product 10 yield (%)
Total yield (%)
1
2
MeO-C6H4-SO2Cl
C6H5-CH2OCOCl
24/76
20/80
18
14
55
64
73
78
7. (a) Okamoto, T.; Shudo, K.; Ohta, T. J. Am. Chem. Soc. 1975, 97, 7184–7185; (b)
Makosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104, 2631–2666; (c) Ung, S.;
Falguieres, A.; Guy, A.; Ferroud, C. Tetrahedron Lett. 2005, 46, 5913–5917; (d)
Zhou, Y.; Li, J.; Liu, H.; Zhao, L.; Jiang, H. Tetrahedron Lett. 2006, 47, 8511–8514;
(e) Gamble, A. B.; Garner, J.; Gordon, C. P.; O’Conner, S. M. J.; Keller, P. A. Synth.
Commun. 2007, 37, 2777–2786.
8. (a) Compounds 1a–e and 1g–h were prepared using the method described in
Ref. 3. (b) Compounds 1f, 1i and 1j were prepared using the method described
by El-Bardan, A. A.; El-Subruiti; G. M.; El-Hegazy, F. E.-Z. M.; Hamed, E. A. Int. J.
Chem. Kinet. 2002, 34, 645–650.
9. General procedure for the preparation of compounds 6 and 7. A mixture of
dipyridinylamine or N-arylpyridin-2-ylamine 1a–j and SnCl2ꢀ2H2O (5 equiv) in
10 mL of EtOH was heated at 60 °C. After reduction, the solution was allowed to
cool. The pH was made slightly basic (pH 7–8) by the addition of 5% aqueous
KHCO3 before extraction with EtOAc. The organic phase was dried over MgSO4.
The solvent was removed to afford the amine, which was immediately
dissolved in CH2Cl2 (10 mL) and then Et3N (1.5 equiv) and trimethylacetyl
chloride (1.1 equiv) were added. The reaction mixture was stirred at room
temperature overnight, concentrated in vacuo and the resulting residue was
purified by flash chromatography (eluted with EtOAc/PE).
Taking into account the widespread use and the high efficiency
of bromo compounds for further cyclizations via palladium-
catalyzed intramolecular C–C and C–N bond formation,2,15 we
chose to continue our study using N-(3-bromopyridin-2-yl)-N-(5-
nitropyridin-2-yl)methyalamine (1a) as the substrate for further
investigations.
Thus, the reduction was achieved with SnCl2ꢀ2H2O in different
alcohols, in order to introduce various alkoxy groups at the 60-
position (Scheme 6, Table 2).
In all cases, compounds 8a–d were easily obtained, illustrating
the ability to introduce various alkoxy groups.
The addition of different Lewis acids, such as BF3ꢀEt2O or
Sc(OTf)3, to the reaction mixtures did not have any significant
influence on the yields of the ortho-alkoxysubstituted derivatives.
The reduction of 1a using ethyl acetate as the solvent led to the
exclusive generation of the corresponding amine and no trace of
substitution at the ortho position was observed. After protection,
we obtained compound 6a (Scheme 7).
We also used other amine protecting groups such as 4-
methoxybenzenesulfonyl chloride and benzyl chloroformate in
pyridine (Scheme 8). Hence, compounds 9a, 10a and 9b, 10b were
obtained in good yields (Table 3).
10. (a) Compound 6a: IR (ATR): 1506, 2960, 3440 cmꢁ1; MS: m/z = 349.0 ([M+H]+,
79Br), 351.0 ([M+H]+, 81Br); HRMS calculated for C15H18N4OBr [M+H]+
349.0668, found 349.0664; 1H NMR (CDCl3, 400 MHz) d = 1.33 (s, 9H, 3CH3),
6.70 (dd, 1H, J = 4.8, 7.7 Hz), 7.32 (br s, 1H, NH), 7.77 (dd, 1H, J = 1.5, 7.7 Hz),
7.81 (br s, 1H, NH), 7.99 (dd, 1H, J = 2.4, 9.0 Hz), 8.20 (dd, 1H, J = 1.4, 4.7 Hz),
8.34 (d, 1H, J = 2.4 Hz), 8.42 (d, 1H, J = 9.0 Hz); 13C NMR (CDCl3, 100.6 MHz)
d = 27.8 (3CH3), 39.7 (Cq), 106.9 (Cq), 112.4 (CH), 116.7 (CH), 129.6 (Cq), 130.7
(CH), 139.9 (CH), 140.6 (CH), 146.3 (CH), 149.6 (Cq), 150.8 (Cq), 176.9 (Cq). (b)
Compound 7a: IR (ATR): 1426, 2962, 3441 cmꢁ1; MS: m/z = 393.0 ([M+H]+,
79Br), 395.0 ([M+H]+, 81Br), 415.0 ([M+Na]+, 79Br), 417.0 ([M+Na]+, 81Br); HRMS
In summary, we have studied the reduction of the nitro group of
dipyridinylamines and N-arylpyridin-2-ylamines. All the synthetic
achievements described herein are operationally simple and the
corresponding bi- and trisubstituted amines were easily obtained
by reduction using SnCl2ꢀ2H2O in an alcohol.
calculated for
C
17H22N4O2Br [M+H]+ 393.0926, found 393.0920; 1H NMR
(CDCl3, 400 MHz) d = 1.32 (s, 9H, 3CH3), 1.43 (t, 3H, J = 7.0 Hz, CH3), 4.43 (q, 2H,
J = 7.0 Hz, CH2), 6.68 (dd, 1H, J = 4.8, 7.7 Hz), 7.51 (br s, 1H, NH), 7.75 (dd, 1H,
J = 1.5, 7.7 Hz), 7.85 (br s, 1H, NH), 7.95 (d, 1H, J = 8.6 Hz), 8.22 (dd, 1H, J = 1.5,
4.8 Hz), 8.59 (d, 1H, J = 8.6 Hz); 13C NMR (CDCl3, 100.6 MHz) d = 14.8 (CH3),
27.7 (3CH3), 39.9 (Cq), 62.3 (CH2), 103.9 (CH), 106.7 (Cq), 116.3 (CH), 117.3
(Cq), 129.3 (CH), 140.3 (CH), 145.2 (Cq), 146.6 (CH), 150.8 (Cq), 151.6 (Cq),
176.5 (Cq).
Moreover, it is noteworthy that the 3-bromo dipyridinylamines
substituted at the 50- and 60-positions, represent good starting
materials for other types of functionalization (e.g., cyclizations
via palladium-catalyzed intramolecular C–C bond formation), in
order to obtain new compounds which may be of interest for het-
erocyclic chemistry and medical purposes.
11. Compound 7g: IR (ATR): 796, 1665, 2965 cmꢁ1; MS: m/z = 407.0 ([M+H]+, 79Br),
409.0 ([M+1]+, 81Br), 429.0 ([M+Na]+, 79Br), 431.0 ([M+Na]+, 81Br); HRMS
calculated for
C
18H24N4O2Br [M+H]+ 407.1083, found 407.1098; 1H NMR
(CDCl3, 400 MHz) d = 1.29 (s, 9H, 3CH3), 1.30 (t, 3H, J = 7.0 Hz, CH3), 3.46 (s, 3H),
4.24 (q, 2H, J = 7.0 Hz, CH2), 6.08 (d, 1H, J = 5.3 Hz), 6.98 (dd, 1H, J = 4.7, 7.8 Hz),
7.75 (br s, 1H, NH), 7.88 (dd, 1H, J = 1.6, 7.8 Hz), 8.42–8.45 (m, 2H); 13C NMR
(CDCl3, 100.6 MHz) d = 14.8 (CH3), 27.7 (3CH3), 37.3 (CH3), 39.8 (Cq), 62.0
(CH2), 101.7 (CH), 115.0 (Cq), 118.5 (Cq), 121.3 (CH), 129.3 (CH), 142.3 (CH),
147.7 (CH), 151.2 (Cq), 151.6 (Cq), 156.8 (Cq), 176.4 (Cq).
References and notes
12. The structure of product 7g was also proved by independent synthesis.
1. (a) Kamenecka, T. M.; Bonnefous, C.; Govek, S.; Vernier, J.-M.; Hutchinson, J.;
Chung, J.; Reyes-Manalo, G.; Anderson, J. J. Bioorg. Med. Chem. Lett. 2005, 15,
4350–4353; (b) Cocco, M. T.; Congiu, C.; Lilliu, V.; Onnis, V. Bioorg. Med. Chem.
Lett. 2004, 14, 5787–5791; (c) Mazu, T. K.; Etukala, J. R.; Zhu, X. Y.; Jacob, M. R.;
Khan, S. I.; Walker, L. A.; Ablordeppey, S. Y. Bioorg. Med. Chem. 2011, 19, 524–
533; (d) Antonini, I.; Polucci, P.; Cola, D.; Bontemps-Gracz, M.; Pescalli, N.;
Menta, E.; Martelli, S. Anti-Cancer Drug Des. 1996, 11, 339–349.
2. (a) Patriciu, O.-I.; Fînaru, A.-L.; Massip, S.; Léger, J.-M.; Jarry, C.; Guillaumet, G.
Org. Lett. 2009, 11, 5502–5505; (b) Patriciu, O.-I.; Fînaru, A.-L.; Massip, S.; Léger,
J.-M.; Jarry, C.; Guillaumet, G. Eur. J. Org. Chem. 2009, 3753–3764.
Treatment
of
N-(3-bromopyridin-2-yl)-N-(6-chloro-5-nitropyridin-2-
yl)methylamine (1k) with 10 equiv of NaOEt in absolute EtOH on heating
gave access to the corresponding 6-ethoxy substituted derivative in a 65%
yield. After reduction of the nitro group using SnCl2ꢀ2H2O in EtOH and
protection using the same conditions we obtained the analogous compound 7g
in an 81% yield.
13. Compound 7h: IR (ATR): 1475, 2957, 3438 cmꢁ1; MS: m/z = 393.5 ([M+H]+,
79Br), 395.5 ([M+H]+, 81Br), 415.5 ([M+Na]+, 79Br), 417.5 ([M+Na]+, 81Br); HRMS
calculated for
C
17H22N4O2Br [M+H]+ 393.0911, found 393.0926; 1H NMR
(CDCl3, 400 MHz) d = 1.31 (s, 9H, 3CH3), 1.44 (t, 3H, J = 7.0 Hz, CH3), 4.38 (q, 2H,
J = 7.0 Hz, CH2), 6.74 (d, 1H, J = 5.3 Hz), 7.41 (br s, 1H, NH), 7.61–7.66 (m, 2H),
7.79 (br s, 1H, NH), 8.26 (d, 1H, J = 1.5 Hz), 8.52 (d, 1H, J = 5.3 Hz); 13C NMR
(CDCl3, 100.6 MHz) d = 14.8 (CH3), 27.7 (3CH3), 39.9 (Cq), 62.5 (CH2), 103.0
(CH), 110.4 (Cq), 112.1 (CH), 116.2 (Cq), 129.8 (CH), 140.0 (CH), 146.2 (Cq),
148.7 (CH), 151.8 (Cq), 152.8 (Cq), 176.6 (Cq).
3. Patriciu, O.-I.; Pillard, C.; Fînaru, A.-L.; Sa˘ndulescu, I.; Guillaumet, G. Synthesis
2007, 3868–3876.
4. (a) Caubère, P.; Guillaumet, G.; Rodriguez, I.; Vinter-Pasquier, K.; Kuehm-
Caubère, C.; Blanchard, S.; Atassi, G.; Pierre, A.; Pfeiffer, B.; Renard, P. P. Eur. Pat.
Appl. EP 96986, 1999; Chem. Abstr. 2000, 132, 22978.; (b) Blanchard, S.;
Rodriguez, I.; Tardy, C.; Baldeyrou, B.; Bailly, C.; Colson, P.; Houssier, C.; Léonce,
S.; Kraus-Berthier, L.; Pfeiffer, B.; Renard, P.; Pierre, A.; Caubère, P.; Guillaumet,
G. J. Med. Chem. 2004, 47, 978–987; (c) Grig-Alexa, I. C.; Fînaru, A. L.; Routier, S.;
Bailly, P.; Caubère, P.; Guillaumet, G. Rev. Chim.-Bucharest 2008, 59, 266–268.
5. Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839–842.
14. Crystal structure data for compound 7h: CCDC 821396. These data can be
obtained free of charge at www.ccdc.cam.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.; e-mail: deposit@ccdc.cam.ac.uk.).
15. (a) Loones, K. T. J.; Maes, B. U. W.; Meyers, C.; Deruytter, J. J. Org. Chem. 2006,
71, 260–264; (b) Kumar, S.; Ila, H.; Junjappa, H. J. Org. Chem. 2009, 74, 7046–
7051; (c) Patriciu, O.-I.; Grig-Alexa, I.-C.; Fînaru, A.-L.; Guillaumet, G.,
unpublished results.
6. (a) Bouissane, L.; El Kazzouli, S.; Rakib, M. E.; Khouili, M.; Léger, J.-M.; Jarry, C.;
Guillaumet, G. Tetrahedron 2005, 61, 8218–8225; (b) Makosza, M.;
Wojciechowski, K. Heterocycles 2001, 54, 445–474; (c) Makosza, M.;
Winiarski, J. Acc. Chem. Res. 1987, 20, 282–289; (d) Makosza, M.; Stalewski, J.
Tetrahedron 1995, 51, 7277–7286; (e) Makosza, M.; Sienkiewiez, K. J. Org. Chem.
1998, 63, 4199–4208.