A modular 'click' approach to substituted 2,2′-bipyridines

Article abstract of DOI:10.1055/s-0030-1259304

The CuAAC reaction was used for the development of a click approach to a series of triazole-substituted bipyridinyl derivatives. 4,4′-Diethinyl 2,2′-bipyridine and 4,4′-diazido 2,2′-bipyridine were synthesized and tested in the cycloaddition reactions. While 4,4′-diazido 2,2′-bipyridine revealed unreactive in CuAAC reactions, its corresponding N,N′-dioxide afforded the expected cycloaddition product. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259304

LETTER
223
A Modular ‘Click’ Approach to Substituted 2,2¢-Bipyridines
‘Click’
A
ppro
i
ach to
S
e
ubstituted
r
2,2
¢
-Bipy
a
r
idines ngelo Fabbrizzi, Bianca Cecconi, Stefano Cicchi*
Dipartimento di Chimica ‘Ugo Schiff’, Università degli Studi di Firenze, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Firenze, Italy
Fax +39(055)4573531; E-mail: stefano.cicchi@unifi.it
Received 11 October 2010
Dedicated to Prof. Alberto Brandi on the occasion of his 60th birthday
different strategies that should afford compounds of gen-
Abstract: The CuAAC reaction was used for the development of a
eral structure 3 and 4. The different orientation of triazole
rings should provide for different chemical-physical prop-
erties (Scheme 1).
click approach to a series of triazole-substituted bipyridinyl deriva-
tives. 4,4¢-Diethinyl 2,2¢-bipyridine and 4,4¢-diazido 2,2¢-bipyridine
were synthesized and tested in the cycloaddition reactions. While
4,4¢-diazido 2,2¢-bipyridine revealed unreactive in CuAAC reac-
tions, its corresponding N,N¢-dioxide afforded the expected cy-
cloaddition product.
N3
N3
Key words: cycloaddition, azides, alkynes, copper, ligands
N
N
N
N
1
2
Since its first synthesis, more than 120 years ago,1 2,2¢-bi-
pyridine (from now on referred as bpy) has found a wide-
spread use in many sectors of research ranging from
analytical2 to organometallic chemistry.3 Despite the
many years of application, it is still used in frontier re-
search topics.4 Its special versatility was made possible by
the large variety of derivatives synthesized during this
time which helped the fine tuning of the chemical-physi-
cal properties of bpy as well as the properties of its metal
complexes. In turn the quest for new derivatives boosted
up the study of the reactivity of bpy with the aim to pro-
duce new synthetic strategies for the decoration of its
skeleton.5 The use of substituted bpy as ligand in su-
pramolecular chemistry6 and for the production of Ru
complexes as dye sensitizer in solar cells (DSSC)7 re-
vealed extremely demanding for the variety of structure
requested. On the other hand since the introduction of the
concept of ‘click chemistry’8 the CuAAC reaction re-
vealed the method of choice for the conjugation of differ-
ent molecular fragments through simple and efficient
reactions.9 For this reason we envisioned that it would be
fruitful to explore the application of the copper-catalyzed
azide-alkyne cycloaddition (CuAAC) reaction to produce
new bpy derivatives. Furthermore, the introduction of the
triazole ring, with its mimicking ability of an amide
group,10 onto the bpy skeleton could pave the way to the
synthesis of new biologically active compounds resem-
bling the activity of natural compound that contains the
bpy moiety. In the literature there is only one recent pre-
cedent focused on the preparation of new ruthenium com-
plexes for application in DSSC.11
R
N3 Cu(I)
Cu(I)
R
R
N
R
R
R
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
3
4
Scheme 1
Compound 1 was obtained following a known synthetic
procedure starting from bpy (Scheme 2).12
O2N
NO2
1) H2O2, AcOH
2) HNO3, H2SO4
41%
N
N
+N
–O O–
N+
5
6
R
R
Br
Br
AcBr
AcOH
Me3Si
CuI/Pd(PPh3)2Cl2
68%
31%
N
N
N
N
8 R = SiMe3
K2CO3
78%
7
1 R = H
Scheme 2 Synthesis of compound 1 starting from 5
Compound 1 was used in CuAAC reactions with four dif-
ferent azides, chosen to verify the generality of the ap-
proach. The reaction were initially performed using
CuSO4/sodium ascorbate to produce the catalytically ac-
tive Cu(I) species. However, this procedure did not af-
forded good reaction yields (both at room temperature and
under microwave irradiation (MW) presumably due to
partial complexation of the metal ions by the bipyridine
In this work we disclose our preliminary results in the ap-
plication of the CuAAC reaction to the two bpy deriva-
tives 1 and 2. The use of 1 and 2 allowed us to explore two
SYNLETT 2011, No. 2, pp 0223–0226
x
x.
x
x.
2
0
1
1
Advanced online publication: 05.01.2011
DOI: 10.1055/s-0030-1259304; Art ID: G30910ST
© Georg Thieme Verlag Stuttgart · New York

224
P. Fabbrizzi et al.
LETTER
moiety itself. Better results were obtained using the com- tified by 1H NMR and mass spectrometry (see Supporting
plex CuI–P(OEt)3 as catalyst and MW irradiation at 150 Information). Any attempt to minimize the amount of 13,
W for a period of 20 minutes (Table 1).13
increasing the reaction time or temperature, was frustrated
by the thermal lability of 2, which decomposes upon pro-
longed heating. An alternative synthetic approach was ex-
plored transforming the diamino derivative 14 into the
corresponding bisdiazonium salt which should react with
NaN3 to afford compound 2 (Scheme 4).15–17
Table 1 Synthesis of Compounds 3
catalyst
3
+
1
R
N3
MW (300 W)
THF, 20 min
RN3
Product
Yield of CuSO4 Yield of CuI–
ascorbate (%) P(OEt)3 (%)
Pd/C
N2H4
EtOH
H2N
NH2
NaNO2, HCl
NaN3
6
2
20%
N3
N
N
3a
3b
3c
29
67
51
57
91
55
14
9
Scheme 4
N3
6
Again the reaction yield was modest but before trying to
optimize the reaction conditions we preferred to explore
the reactivity of 2 towards the CuAAC procedure. Despite
the use of different catalysts [CuSO4/Na ascorbate, CuI–
P(OEt)3, CuI(PPh3)3] no reaction between 2 and terminal
alkynes (ethinylbenzene, 1-octyne) was detected. While
the reaction at room temperature yielded only starting ma-
terial, the use of MW caused the decomposition of 2. This
result was surprising if we consider that CuAAC reactions
of 4-azidopyridine18 and 4¢-azido-2,2¢:6¢,2¢¢-terpyridine19
with terminal alkynes are known and proceed in good
yields. The lack of the reactivity of some azido derivatives
is attributed to their electron-deficient nature.20 For this
reason we decided to test also the reactivity of the corre-
sponding bis-N-oxide derivative 15. Compound 15 was
easily obtained from the dinitro derivative 6 by simple re-
fluxing in EtOH in the presence of NaN3 (Scheme 5).21
10
N3
11
OAc
O
N3
OAc
AcO
3d
–
97
AcO
12
The yields are good except for the adamantly derivative
3c; in this case the steric hindrance hampered a complete
conversion of the substrates. Compound 3a, obtained
from benzylazide 9, revealed fairly unsoluble, and this
was the reason for a lower yield. All compounds were ful-
ly characterized and easily identified by 1H NMR spectra
showing the diagnostic singlet ranging between d = 9.0
and 8.5 ppm, assigned to the hydrogen atom placed on the
triazole ring. Compound 3d demonstrates the easy access
to sugar-substituted bipyridines which can find applica-
tion in supramolecular as well as biological studies. We
then turned our attention to the second synthetic approach
to produce compounds of general structure 4. For this pur-
pose we explored a few procedures for the synthesis of
compound 2. A straightforward synthesis was offered by
the nucleophilic substitution of the bromine atoms by
treatment of dibromide 7 with NaN3.14 Optimization of the
reaction required the use of DMF as solvent and heating
at 100 °C for 18 hours (Scheme 3).
N3
N3
NaN3
EtOH
6
+N
–O O–
15
N+
Scheme 5
The diazido derivative 15 was poorly soluble in many
common solvent, and it resulted more convenient to use it
crude for the subsequent reaction. A small sample was pu-
rified for characterization.22
N3
N3
Br
N3
DMF
100 °C, 18 h
7
+
N
N
N
N
2
9
27%
29%
Scheme 3
The crude reaction mixture always contained compound 2
together with compound 13, a product derived from the
substitution of a single bromine atom that was easily iden-
Figure 1
Synlett 2011, No. 2, 223–226 © Thieme Stuttgart · New York

LETTER
‘Click’ Approach to Substituted 2,2¢-Bipyridines
225
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The different nature of the two heterocyclic derivatives 2
and 15 are well described by their 1H NMR spectra report-
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compound 15 are remarkably shifted upfield with respect
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benzene using CuI–P(OEt)3 as catalyst. This time
compound 15 was reactive towards the terminal alkynes
and afforded compound 16 with an acceptable overall
yield, two steps starting from 6 (51%; Scheme 6).23 At
present, further experiments to expand the scope of this
synthetic approach are ongoing in our laboratories.
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Ph
N
N
CuI P(OEt)3
THF–MeOH
N
N
N
N
15
+
r.t., 18 h
51%
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–O –O
16
N+
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(13) 4,4¢-Bis{1-benzyl-1H-[1,2,3]triazol-4-yl}-
[2,2¢]bipyridinyl (3a)
Scheme 6
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
experimental procedures, spectroscopic ad analytical characteriza-
tion of new compounds.
1H NMR (400 MHz, DMSO-d6): d = 9.00 (s, 2 H), 8.87 (dd,
J = 0.8, 1.6 Hz, 2 H), 8.76 (dd, J = 0.8, 5.2 Hz, 2 H), 7.89
(dd, J = 1.6, 5.2, Hz, 2 H), 7.44–7.33 (m, 10 H), 5.70 (s, 4 H).
13C NMR (50 MHz, CDCl3): d = 155.9, 149.5, 138.7, 133.8,
129, 128.7, 127.9, 121.1, 119.8, 117, 54.2. IR (KBr): 3112,
3000, 1607, 1400, 1207 cm–1. MS (EI, 70 eV): m/z (%) =
470.2 (33.3) [M+], 236.7 (6.9), 60 (12.2), 43.8 (100), 32
(71.6). Anal. Calcd for C28H22N8: C, 71.47; H, 4.71; N,
23.81. Found C, 71.23; H, 4.85; N, 23.96.
Acknowledgment
Ente Cassa di Risparmio di Firenze and MIUR (Ministero Istruzio-
ne, Università e Ricerca) are acknowledged for financial support.
Mr. Maurizio Passaponti and Mrs. Brunella Innocenti are acknowl-
edged for technical assistance.
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product: Barral, K.; Moorhouse, A. D.; Moses, J. E. Org.
Lett. 2007, 9, 1809.
(17) Caution: Azido derivatives are known as potentially
explosive compounds. Although we encountered no
problems in manipulating these products, it is important to
protect the operator from any possible explosion hazard.
4,4¢-Diazido[2,2¢]bipyridinyl (2)
References and Notes
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1H NMR (300 MHz, CDCl3): d = 8.58 (d, J = 5.3 Hz, 2 H),
8.15 (d, J = 2.3 Hz, 2 H), 6.96 (dd, J = 2.3, 5.3 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 157.3, 150.1, 134.1, 114.2,
111.1. IR (KBr): 2117, 1580, 1456, 1207 cm–1. MS (EI, 70
eV): m/z (%) = 238 (49) [M+], 182 (66), 155 (22), 128 (53),
104 (34), 77 (49), 64 (46), 52 (100). Anal. Calcd for
C10H6N8O2: C, 50.42; H, 2.54; N, 47.04. Found C, 50.76; H,
2.26, N, 46.68.
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Synlett 2011, No. 2, 223–226 © Thieme Stuttgart · New York

226
P. Fabbrizzi et al.
131, 3122.
LETTER
(32), 229.1 (11). Anal. Calcd for C10H6N8O2: C, 44.45; H,
2.24; N, 41.47. Found: C, 44.12; H, 1.92; N, 41.54.
(23) 4,4¢-Bis{4-phenyl[1,2,3]triazol-1-yl}-[2,2¢]bipyridinyl
1,1¢-Dioxide (16)
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9817.
(22) 4,4¢-Diazido[2,2¢]bipyridinyl 1,1¢-Dioxide (15)
1H NMR (200 MHz, CDCl3): d = 8.28 (d, J = 7.2 Hz, 2 H),
7.43 (d, J = 3.2 Hz, 2 H), 7.01 (dd, J = 7.2, 3.2 Hz, 2 H).
13C NMR (50 MHz, DMSO-d6): d = 143.1, 140.5, 136.5,
119.6, 118.4. IR (KBr): 3025, 2122, 1461, 1430 cm–1. ESI-MS:
m/z (%) = 293.1 (31) [M + Na+], 271.1 (99) [M + H+], 245.1
1H NMR (400 MHz, DMSO-d6): d = 9.44 (s, 2 H), 8.65 (d,
J = 6.4 Hz, 2 H), 8.47 (s, 2 H), 8.19 (d, J = 6.4 Hz, 2 H), 7.91
(m, 4 H), 7.51 (m, 4 H), 7.40 (m, 2 H). 13C NMR (100 MHz,
DMSO-d6): d = 148.2, 143.2, 141.1, 131.9, 130.2, 129.6,
129, 125.8, 120.1, 119.6, 118.28 IR (KBr): 3055, 1653, 1506
cm–1. ESI-MS: m/z (%) = 475 (100) [M – H+], 419.3 (36),
376.1 (27), 347.2 (66), 319.3 (32), 284.4 (22), 233.2 (16).
Anal. Calcd for C26H18N8O2: C, 65.82; H, 3.82; N, 23.62.
Found C, 65.52; H, 3.93; N, 23.27.
Synlett 2011, No. 2, 223–226 © Thieme Stuttgart · New York