Synthesis of diisothiocyanato-functionalized 2,2-bipyridines

Article abstract of DOI:10.1055/s-0030-1258342

Three new diisothiocyanato-functionalized 2,2-bipyridines have been synthesized in four consecutive steps. Starting from 4-amino-2-chloro- and 2-amino-6-bromopyridine, respectively, we first prepared the corresponding diamino-2,2-bipyridines via homo- or Negishi cross-coupling reactions which were subsequently reacted with thiophosgene.

Full text of DOI:10.1055/s-0030-1258342

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210
SHORT PAPER
Synthesis of Diisothiocyanato-Functionalized 2,2¢-Bipyridines
Christopher Kremer, Arne Lützen*
University of Bonn, Kekulé-Institute of Organic Chemistry and Biochemistry, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
Fax +49(228)739608; E-mail: arne.luetzen@uni-bonn.de
Received 15 October 2010
O
Abstract: Three new diisothiocyanato-functionalized 2,2¢-bipy-
Cl
N
Cl
N
ridines have been synthesized in four consecutive steps. Starting
from 4-amino-2-chloro- and 2-amino-6-bromopyridine, respective-
ly, we first prepared the corresponding diamino-2,2¢-bipyridines via
homo- or Negishi cross-coupling reactions which were subsequent-
ly reacted with thiophosgene.
O
N
N
H2N
p-TsOH, toluene
93%
1
3
O
Key words: bipyridine, isothiocyanates, amines, thiophosgene,
cross-coupling reactions
O
H2N
p-TsOH, toluene
94%
N
N
Functionalized 2,2¢-bipyridines represent a very impor-
tant class of chelating ligands1 that have found numerous
applications in supra-, nano-, and macromolecular chem-
istry,2–4 but also in analytical and photochemistry5 as well
as in catalysis.6 They are even found as structural motifs
in natural products.7 Therefore, many efforts have been
made to develop reliable protocols for the synthesis of
2,2¢-bipyridines carrying a broad variety of functional
groups that ensure the desired properties or establish inter-
esting building blocks for the synthesis of more sophisti-
cated ligand architectures.8
Br
Br
2
4
Scheme 1 Synthesis of pyrrole-protected aminopyridines 3 and 4
NiBr2(PPh3)2
Zn powder, LiCl
N
N
Et4NI, THF, Δ
N
N
99%
N
N
3
Cl
5
6
NiBr2(PPh3)2
Zn powder, LiCl
Et4NI, THF, Δ
We became interested in this class of compounds and their
synthesis during the course of our studies on self-assem-
bled supramolecular aggregates9 and allosteric recep-
tors.10 During the latter ones we employed ester and
ethynyl groups to link recognition units such as resor-
cinarene cavitands to a central 2,2¢-bipyridine core. In or-
der to enlarge the number of suitable linker groups we
were wondering if we could install other functional
groups on the bipyridine skeleton. One very attractive
group would be the thiourea group that can, itself, be used
for very different purposes ranging from anion
recognition11 to organocatalysis12 and it even has applica-
tion as an antifungal agent.13
N
N
N
N
N
98%
N
Br
4
1. t-BuLi, THF,
–78 °C
2. ZnCl2, r.t.
3. Pd(PPh3)4, 3,
THF, Δ
N
N
N
70%
N
N
Br
N
4
7
The synthesis of thioureas, however, can best be achieved
through nucleophilic addition of an amine to an isothiocy-
anate. Isothiocyanates are very important compounds that
are widely applied as chemoselective electrophiles that
even tolerate aqueous reaction conditions.14 So far only
5,5¢-diisothiocyanato-2,2¢-bipyridine15 has been synthe-
sized which, however, is the only substitution pattern of a
2,2¢-bipyridine that is not suitable to let the bipyridine unit
act as an allosteric center for our purposes. Thus, we
would like to report the synthesis of 4,4¢-, 6,6¢- and 4,6¢-
diisothiocyanate-functionalized 2,2¢-bipyridines.
Scheme 2 Synthesis of pyrrole-protected diamino-2,2¢-bipyridines
5–7
The syntheses started from commercially available 4-ami-
no-2-chloro- (1) and 2-amino-6-bromopyridine (2), re-
spectively, which were transformed into the
corresponding 4,4¢-, 6,6¢- and 4,6¢-diamino-2,2¢-bipyri-
dine dihydrochlorides (8–10) as reported earlier.16 This
was achieved in three consecutive steps involving the in-
troduction of pyrrole protecting groups via reaction of the
amines with hexane-2,5-dione, nickel-catalyzed homo- or
palladium-catalyzed Negishi cross-coupling, and subse-
quent deprotection of the amines as depicted in
Schemes 1–3.
SYNTHESIS 2011, No. 2, pp 0210–0212
x
x
.
x
x
.2
0
1
0
Advanced online publication: 26.11.2010
DOI: 10.1055/s-0030-1258342; Art ID: Z25410SS
© Georg Thieme Verlag Stuttgart · New York

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SHORT PAPER
Synthesis of Diisothiocyanato-2,2¢-bipyridines
211
TLC was performed on aluminum plates (silica gel 60 F254) from
Merck and the products were visualized under UV light (254 or 366
nm). Products were purified by column chromatography on silica
gel 60 (0.04–0.063 mm).
NH2
N
N
NH2OH•HCl
Et3N, EtOH–H2O
Δ
N
N
N
1H and 13C NMR spectra were recorded at 298 K at 300.1 and 75.5
MHz, respectively; 1H NMR relative to residual non-deuterated sol-
vent as the internal standard and 13C NMR relative to the deuterated
solvent as the internal standard. Signals were assigned on the basis
• 2HCl
N
1
of H, 13C, HMQC, and HMBC-NMR experiments. ESI-MS were
H2N
recorded on an ESI-QToF mass spectrometer. Elemental analyses
were carried out with a Heraeus Vario EL.
5 (4,4'-subst.)
6 (6,6'-subst.)
7 (4,6'-subst.)
8 (4,4'-diamino, 98%)
9 (6,6'-diamino, 60%)
10 (4,6'-diamino, 84%)
Chemicals and reagents (except for the solvents) obtained from
commercial sources were used as received. 2-Chloro-4-(2,5-di-
methyl-1H-pyrrol-1-yl)pyridine (3),18 2-bromo-6-(2,5-dimethyl-
1H-pyrrol-1-yl)pyridine (4),19 4,4¢-bis(2,5-dimethyl-1H-pyrrol-1-
yl)-2,2¢-bipyridine (5),16 6,6¢-bis(2,5-dimethyl-1H-pyrrol-1-yl)-
2,2¢-bipyridine (6),16 4,6¢-bis(2,5-dimethyl-1H-pyrrol-1-yl)-2,2¢-bi-
pyridine (7),16 4,4¢-diamino-2,2¢-bipyridine dihydrochloride (8),16
and 6,6¢-diamino-2,2¢-bipyridine dihydrochloride (9)16 were pre-
pared according to published procedures.
Scheme 3 Synthesis of diamino-2,2¢-bipyridine dihydrochlorides
With the diamine hydrochlorides 8–10 in hand, we then
explored the transformation into the corresponding di-
isothiocyanates. The first protocol we tested has recently
been developed by Boas and co-workers using a mixture
of carbon disulfide, di-tert-butyl dicarbonate (Boc2O), tri-
ethylamine, and 4-(dimethylamino)pyridine (DMAP)
which was reported to convert alkyl- and arylamines
4,6¢-Diamino-2,2¢-bipyridine Dihydrochloride (10)
4,6¢-Bis(2,5-dimethyl-1H-pyrrol-1-yl)-2,2¢-bipyridine (7, 0.83 g,
2.4 mmol) was mixed with NH2OH·HCl (3.36 g, 48 mmol, 20
smoothly into the corresponding isothiocyanates.17 Unfor- equiv), Et3N (1.2 mL), EtOH (23 mL), and H2O (6 mL). The result-
ing mixture was refluxed for 4 d. After cooling to r.t. the mixture was
tunately, this reaction did not work at all in our case, pre-
quenched by pouring into ice-cold 1 M HCl (20 mL). The resulting
sumably because the electron-poor aminopyridines are
simply not nucleophilic enough to attack the carbon disul-
fide.
soln was washed with i-Pr2O (20 mL) and the pH was adjusted to 9–
10 by careful addition of 6 M NaOH. The resulting mixture was ex-
tracted with CH2Cl2 (3 × 20 mL) and the combined extracts were
dried (Na2SO4). After removal of the solvent the brownish residue
was dissolved in EtOH. Et2O (30 mL) was added and the mixture
was filtered. 2 M HCl in Et2O (2.2 mL, 4.4 mmol) was added to the
filtrate and pure 10 precipitated, which was collected and dried in
vacuo to give a slightly off-white solid; yield: 520 mg (84%).
Therefore, we changed to a protocol developed by Janiak
and co-workers using thiophosgene and calcium carbon-
ate in a two-phase system of dichloromethane and water.15
Employing this procedure we were able to prepare 4,4¢-,
6,6¢-, and 4,6¢-diisothiocyanato-2,2¢-biypridines (11–13)
in acceptable to good yields as shown in Scheme 4.
3
1H NMR (300.1 MHz, D2O, 298 K): d = 6.94 (dd, J = 7.1 Hz,
4J = 2.4 Hz, 1 H, H5), 7.15 (dd, 3J = 9.0 Hz, 4J = 0.8 Hz, 1 H, H5¢),
7.19 (d, 4J = 2.4 Hz, 1 H, H3), 7.26 (dd, 3J = 7.4 Hz, 4J = 0.8 Hz, 1
3
3
S
H, H3¢), 7.97 (dd, J = 9.0 Hz, J = 7.4 Hz, 1 H, H4¢), 8.09 (d,
NH2
NCS
3J = 7.1 Hz, 1 H, H6).
Cl
Cl
13C NMR (75.8 MHz, D2O, 298 K): d = 110.3 (C3), 111.2 (C5),
115.1 (C3¢), 117.7 (C5¢), 140.5 (C2¢), 142.2 (C6), 144.7 (C2), 145.1
(C4¢), 157.5(C6¢), 162.1 (C4).
CaCO3, CH2Cl2/H2O
r.t.
N
N
• 2HCl
N
N
This compound has been described as the non-protonated diamine
before.16
H2N
SCN
8 (4,4'-diamino)
9 (6,6'-diamino)
10 (4,6'-diamino)
11 (4,4'-subst., 41%)
12 (6,6'-subst., 78%)
13 (4,6'-subst., 40%)
4,4¢-Diisothiocyanato-2,2¢-bipyridine (11); Typical Procedure
Compound 8 (0.2 g, 0.77 mmol) and CaCO3 (0.39 g, 3.9 mmol, 5
equiv) were suspended in a mixture of CH2Cl2 (7 mL) and H2O (4
mL). After the addition of thiophosgene (0.2 mL, 2.5 mmol), the
mixture was stirred at r.t. for 24 h. Excess CaCO3 was filtered off
and washed with CH2Cl2 (3 × 10 mL); the filtrates were collected.
The combined organic phases were dried (MgSO4). After evapora-
tion of the solvent the crude product was washed with H2O (15 mL)
and subjected to column chromatography (silica gel, cyclohexane–
EtOAc, 9:1) to give the desired product as a light-yellow solid;
yield: 85 mg (41%); mp 143 °C; Rf = 0.39 (cyclohexane–EtOAc,
9:1).
Scheme 4 Synthesis of diisothiocyanato-2,2¢-bipyridines
These diisothiocyanates are versatile building blocks for
the synthesis of more sophisticated ligand structures and
we are currently exploring their potential in the synthesis
of new allosteric receptors. Furthermore, however, these
compounds can also be envisioned to act as starting points
for the synthesis of thioureas or heterocyclic systems for
other purposes.
3
1H NMR (300.1 MHz, CDCl3, 298 K): d = 7.13 (dd, J = 5.1 Hz,
4J = 1.9 Hz, 2 H, H5, H5¢), 8.26 (d, 4J = 1.9 Hz, 2 H, H3/H3¢), 8.64
(d, 3J = 5.1 Hz, 2 H, H6/H6¢).
Solvents were dried, distilled and stored under argon according to
standard procedures. Reactions with air- and moisture-sensitive
transition-metal compounds were performed under an argon atmo-
sphere in oven-dried glassware using standard Schlenk techniques.
13C NMR (75.8 MHz, CDCl3, 298 K): d = 118.1 (C3/C3¢), 120.2
(C5/C5¢), 140.6 (NCS), 141.1 (C4/C4¢), 150.6 (C6/C6¢), 156.7 (C2/
C2¢).
Synthesis 2011, No. 2, 210–212 © Thieme Stuttgart · New York

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212
C. Kremer, A. Lützen
SHORT PAPER
MS (ESI+, MeOH): m/z (%) = 271.0 [M + H]+.
280 and 281; Balzani, V.; Campagna, S., Eds.; Springer
Verlag: Berlin, 2007.
(6) Recent reviews with focus on chiral 2,2¢-bipyridines:
(a) Malkov, A. V.; Kočovsý, P. Curr. Org. Chem. 2003, 7,
1737. (b) Kwong, H.-L.; Yeung, H.-L.; Yeung, C.-T.; Lee,
W.-S.; Lee, C.-S.; Wong, W.-L. Coord. Chem. Rev. 2007,
251, 2188.
(7) (a) Trecourt, F.; Gervais, B.; Mongin, O.; Le Gal, C.;
Mongin, F.; Quéguiner, G. J. Org. Chem. 1998, 63, 2892.
(b) Mongin, F.; Trecourt, F.; Gervais, B.; Mongin, O.;
Quéguiner, G. J. Org. Chem. 2002, 67, 3272. (c) Du, W.
Tetrahedron 2003, 59, 8649. (d) Bringmann, G.; Reichert,
Y.; Kane, V. V. Tetrahedron 2004, 60, 3539.
(e) Sammakia, T.; Stangeland, E. L.; Whitcomb, M. C. In
Strategies and Tactics in Organic Synthesis, Vol. 6;
Harmata, M., Ed.; Elsevier: New York, 2005, 415.
(8) (a) Newkome, G. R.; Patri, A. K.; Holder, E.; Schubert, U. S.
Eur. J. Org. Chem. 2004, 235. (b) Hapke, M.; Brand, L.;
Lützen, A. Chem. Soc. Rev. 2008, 37, 2782.
Anal. Calcd for C12H6N4S2·0.5H2O·0.125EtOAc: C, 51.71; H, 2.78;
N, 19.30; S, 22.09. Found: C, 51.62; H, 3.07; N, 19.02; S, 22.39.
6,6¢-Diisothiocyanato-2,2¢-bipyridine (12)
Following the typical procedure using 9 (0.2 g, 0.77 mmol), CaCO3
(0.39 g, 3.9 mmol, 5 equiv), and thiophosgene (0.2 mL, 2.5 mmol)
with column chromatography (silica gel, cyclohexane–EtOAc, 9:1)
as a light-yellow solid; yield: 160 mg (78%); mp 154 °C; Rf = 0.42
(cyclohexane–EtOAc, 9:1).
1H NMR (300.1 MHz, CDCl3, 298 K): d = 7.15 (dd, J = 7.8 Hz,
3
4J = 0.8 Hz, 2 H, H5, H5¢), 7.85 (dd, 3J = 7.8 Hz, 3J = 7.8 Hz, 2 H,
H4/H4¢), 8.32 (dd, 3J = 7.8 Hz, 4J = 0.8 Hz, 2 H, H3/H3¢).
13C NMR (75.8 MHz, CDCl3, 298 K): d = 119.8 (C3/C3¢), 120.3
(C5/C5¢), 139.7 (C4/C4¢), 141.5 (NCS), 145.7 (C6/C6¢), 155.0 (C2/
C2¢).
MS (ESI+, MeOH): m/z (%) = 271.0 [M + H]+, 303.1 [M + MeOH
+ H]+.
(9) (a) Lützen, A.; Hapke, M.; Griep-Raming, J.; Haase, D.;
Saak, W. Angew. Chem. Int. Ed. 2002, 41, 2086; Angew.
Chem. 2002, 114, 2190. (b) Kiehne, U.; Weilandt, T.;
Lützen, A. Org. Lett. 2007, 9, 1283. (c) Kiehne, U.; Lützen,
A. Org. Lett. 2007, 9, 5333. (d) Kiehne, U.; Weilandt, T.;
Lützen, A. Eur. J. Org. Chem. 2008, 2056. (e) Bunzen, J.;
Bruhn, T.; Bringmann, G.; Lützen, A. J. Am. Chem. Soc.
2009, 131, 3621. (f) Bunzen, J.; Hovorka, R.; Lützen, A.
J. Org. Chem. 2009, 74, 5228. (g) Bunzen, J.; Hapke, M.;
Lützen, A. Eur. J. Org. Chem. 2009, 3885. (h) Bunzen, J.;
Kiehne, U.; Benkhäuser-Schunk, C.; Lützen, A. Org. Lett.
2009, 11, 4786. (i) Dalla Favera, N.; Kiehne, U.; Bunzen, J.;
Hytteballe, S.; Lützen, A.; Piguet, C. Angew. Chem. Int. Ed.
2010, 49, 125; Angew. Chem. 2010, 122, 129. (j) Piehler,
T.; Lützen, A. Z. Naturforsch. B: Chem. Sci. 2010, 65, 329.
(10) (a) Lützen, A.; Haß, O.; Bruhn, T. Tetrahedron Lett. 2002,
43, 1807. (b) Zahn, S.; Reckien, W.; Staats, H.; Matthey, J.;
Lützen, A.; Kirchner, B. Chem. Eur. J. 2009, 15, 2572.
(c) Staats, H.; Eggers, F.; Haß, O.; Fahrenkrug, F.; Matthey,
J.; Lüning, U.; Lützen, A. Eur. J. Org. Chem. 2009, 4777.
(d) Staats, H.; Lützen, A. Beilstein J. Org. Chem. 2010, 6,
No. 10; http://www.beilstein-journals.org/bjoc/home/
home.htm.
Anal. Calcd for C12H6N4S2·0.125EtOAc: C, 53.36; H, 2.51; N,
19.91; S, 22.79. Found: C, 53.63; H, 2.66; N, 19.83; S, 23.00.
4,6¢-Diisothiocyanato-2,2¢-bipyridine (13)
Following the typical procedure using 10 (0.2 g, 0.77 mmol),
CaCO3 (0.39 g, 3.9 mmol, 5 equiv), and thiophosgene (0.2 mL, 2.5
mmol) with column chromatography (silica gel, cyclohexane–
EtOAc, 2:1) as a light-yellow solid; yield: 82 mg (40%); mp 98 C;
Rf = 0.37 (cyclohexane–EtOAc, 2:1).
3
1H NMR (300.1 MHz, CDCl3, 298 K): d = 7.12 (dd, J = 5.2 Hz,
4J = 2.0 Hz, 1 H, H5), 7.17 (dd, 3J = 7.8 Hz, 4J = 0.7 Hz, 1 H, H5¢),
7.85 (dd, 3J = 7.8 Hz, 3J = 7.8 Hz, 1 H, H4¢), 8.20 (d, 4J = 2.0 Hz, 1
3
4
H, H3), 8.33 (dd, J = 7.8 Hz, J = 0.7 Hz, 1 H, H3¢), 8.63 (d,
3J = 5.2 Hz, 1 H, H6).
13C NMR (75.8 MHz, CDCl3, 298 K): d = 117.9 (C3), 119.8 (C3¢),
120.2 (C5), 120.6 (C5¢), 139.7 (C4¢), 140.2 (NCS at C6¢), 141.0
(C4), 141.4 (NCS at C4), 145.8 (C6¢), 150.6 (C6), 155.2 (C2¢),
156.7 (C2).
MS (ESI+, MeOH): m/z (%) = 271.0 [M + H]+, 303.1 [M + MeOH
+ H]+.
Anal. Calcd for C12H6N4S2·0.1H2O·0.1EtOAc: C, 53.01; H, 2.51; N,
19.94; S, 22.83. Found: C, 52.98; H, 2.58; N, 20.03; S, 23.07.
(11) Gunnlaugsson, T.; Glynn, M.; Tocci (née Hussey), G. M.;
Kruger, P. E.; Pfeffer, F. M. Coord. Chem. Rev. 2006, 250,
3094.
(12) (a) Connon, S. J. Chem. Eur. J. 2006, 12, 5418. (b)Miyabe,
H.; Takemoto, Y. Bull. Chem. Soc. Jpn. 2008, 81, 785.
(c) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38,
1187. (d) Takemoto, Y. Chem. Pharm. Bull. 2010, 58, 593.
(13) Rodríguez-Fernández, E.; Manzano, J. L.; Benito, J. J.;
Hermosa, R.; Monte, E.; Criado, J. J. J. Inorg. Biochem.
2005, 99, 1558.
(14) Braverman, S.; Cherkinsky, M.; Birsa, M. L. Science of
Synthesis, Vol. 18; Knight, J., Ed.; Georg Thieme Verlag:
Stuttgart, 2005, 65.
Acknowledgment
Financial support from the DFG (SFB 624) is gratefully acknowled-
ged. C.K. thanks the Studienstiftung des Deutschen Volkes for a
student grant.
References
(1) Smith, A. P.; Fraser, C. L. In Comprehensive Coordination
Chemistry II, Vol. 1; McCleverty, J. A.; Meyer, T. J., Eds.;
Elsevier: Oxford, 2004, 1.
(2) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100,
3553.
(3) Schalley, C. A.; Lützen, A.; Albrecht, M. Chem. Eur. J.
2004, 10, 1072.
(4) Hannon, M. J.; Childs, L. J. Supramol. Chem. 2006, 16, 7.
(5) Photochemistry and Photophysics of Coordination
Compounds I + II, In Topics in Current Chemistry, Vols.
(15) Janiak, C.; Deblon, S.; Wu, H.-P. Synth. Commun. 1999, 29,
3341.
(16) Hapke, M.; Staats, H.; Wallmann, I.; Lützen, A. Synthesis
2007, 2711.
(17) Munch, H.; Hansen, J. S.; Pittelkow, M.; Christensen, J. B.;
Boas, U. Tetrahedron Lett. 2008, 49, 3117.
(18) Lützen, A.; Hapke, M.; Staats, H.; Bunzen, J. Eur. J. Org.
Chem. 2003, 3948.
(19) Kiehne, U.; Bunzen, J.; Staats, H.; Lützen, A. Synthesis
2007, 1061.
Synthesis 2011, No. 2, 210–212 © Thieme Stuttgart · New York