2
Tetrahedron
to see that this change led to a 50% boost in yield, but
recognized that if 1 equiv of Ni(II) would be necessary a more
economical replacement for Ni(PPh Cl would also be required.
2. (a) Chan, K. S.; Tse, A. K. S. Synth. Commun. 1993, 23, 1929–
1
934. (b) Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.; Oda, M.
Bull. Chem. Soc. Jpn. 1990, 63, 80–87. (c) Furue, M.; Maruyama,
K.; Oguni, T.; Naiki, M.; Kamachi, M. Inorg. Chem. 1992, 31,
3
)
2
2
3
792–3795. (d) McFarland, S. A.; Lee, F. S.; Cheng, K. A. W. Y.;
Cozens, F. L.; Schepp, N. P. J. Am. Chem. Soc. 2005, 127, 7065–
070. (e) Crouch, R. D.; Nelson, T. D. Cu, In Ni, and Pd Mediated
An obvious alternative would be to form Ni(PPh
3 2 2
) Cl from
NiCl and PPh in situ as NiCl •6H O and PPh are both readily
3
2
3
2
2
7
available in kilogram quantities at a fraction the cost of the
Homocoupling Reactions in Biaryl Syntheses: The Ullmann
Reaction, John Wiley & Sons: New York, 2004.
3. (a) Coe, B. J.; Peers, M. K.; Scrutton, N. S. Polyhedron 2015, 96,
6
preassembled catalyst. We chose DMF as the solvent to enable
higher reaction temperatures and possibly eliminate the need for
5
7–65. (b) Schultz, D. M.; Sawicki, J. W.; Yoon, T. P. Beilstein J.
4
Et NI by virtue of better solubility. As Scheme 2 shows, these
Org. Chem. 2015, 11, 61–65. (c) Benson, E. E.; Grice, K. A.;
Smieja, J. M.; Kubiak, C. P. Polyhedron 2013, 58, 229–234. (d)
Hsu, C. M.; Li, C. B.; Sun, C. H. J. Chin. Chem. Soc.-Taip. 2009,
56, 873–880.
modifications not only made the reaction more economical, but
also improved the reaction outcome as 2 was isolated in 89%
7
yield.
4
.
(a) Jayasundara, C. R. K.; Unold, J. M.; Oppenheimer, J.; Smith,
M. R., III; Maleczka, R. E.; Jr. Org. Lett. 2014, 16, 6072–6075.
2
3 4
.2. Improving the synthesis of bpy(CF ) (4)
(
b) Ghaffari, B.; Preshlock, S. M.; Plattner, D. L.; Staples, R. J.;
Deeming the synthesis of 2 efficient enough for our needs, we
then turned to the more challenging 4,4’,5,5’-
Maligres, P. E.; Krska, S. W.; Maleczka, R. E.; Jr.; Smith, M. R.,
III J. Am. Chem. Soc. 2014, 136, 14345–14348. (c) Mkhalid, I. A.
I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F.
Chem. Rev. 2010, 110, 890–931. (d) Ros, A.; Fernández, R.;
Lassaletta, J. M. Chem. Soc. Rev. 2014, 43, 3229–3243.
tetrakis(trifluoromethyl)-2,2'-bipyridine (ttfbpy) (4). Directly
applying the modified conditions improved the isolated yield of 4
2c
from 3 to 31%. We attempted to further optimize the reaction
by doubling the zinc load. After 48 hours of heating, GC-MS
indicated the full consumption of 3, but the desired product was
not found. Instead, two byproducts were isolated in a combined
5
.
(a) Bisht, R.; Chattopadhyay, B. J. Am. Chem. Soc. 2016, 138, 84–
8
7. (b) Smith, M. R., III; Maleczka, R. E., Jr.; Li, H.; Jayasundara,
C.; Oppenheimer, J. U.S. Pat. Appl. 2015, US 20150065743 A1
20150305. (c) Oppenheimer, J.; Maleczka, R. E.; Smith, M. R.; Li,
th
H.; Sabasovs, D. 246 American Chemical Society National
Meeting, September 8–12, Indianapolis, IN; The Division of
Organic Chemistry of the American Chemical Society:
Washington, DC, 2013; ORGN 381.
1
structures of bpy(CF
reduction of one of the CF
8% yield, for which all spectroscopic data pointed to isomeric
8
3 3 3
) CH . Presumably the excess Zn lead to
9 10
3
groups, perhaps under Ni catalysis.
Given this outcome, we then reduced the load of Zn to 1
equivalent. This eliminated the byproduct formation and afforded
2 2
6. Neither NiCl •6H O or DMF were dried prior to use.
7. See the Supplementary Material for experimental details.
8. See the Supplementary Material for the putative structure
7
,11
bpy(CF
3 4
) (4) in 71% isolated yield (Scheme 3), representing a
assignment of the isomers of bpy(CF
Greene, J. L., Jr.; Montgomery, J. A. J. Med. Chem. 1963, 6, 294–
97.
10. Zhao, W.; Wu, J.; Cao, S. Adv. Synth. Catal. 2012, 354, 574–578.
3 3 3
) CH .
>20 fold increase over the previously reported yields for this
compound. Usefully this procedure could be run at 10 mmol
scale with little change in the isolated yield (67%).
9
.
2
c
2
1
1. Representative Experimental: In a Schlenk flask, NiCl
mg, 1.0 mmol) and PPh (524 mg, 2.0 mmol) were dissolved in 5
mL of reagent grade DMF. The resulting blue solution was
2 2
•6H O (238
Scheme 3. Improved synthesis of bpy(CF ) (4).
3
4
3
1
2
sparged by argon for 30 min. Activated zinc dust (65 mg, 1.0
mmol) was added and the mixturewas stirred with further argon
sparging for 30 min. To the resulting red-brown slurry was added
2
-chloro-4,5-bis(trifluoromethyl)pyridine (3) (250 mg, 1 mmol).
The Schlenk flask was connected to an argon manifold through a
water cooled condenser and heated in an 80 °C oil bath for 48 h, at
which time GC-MS showed full consumption of 3. The reaction
was then poured into a beaker containing 2 mL ammonia (24%,
3
. Conclusions
Through the use of stoichiometric Ni(II), yields for the
preparation of two CF substituted electron deficient bipyridine
aq) and 20 g ice. The resulting mixture was extracted with CH Cl2
2
(3 x 20 mL). The combined organics were washed with water (2 x
3
5
0 mL), dried over MgSO
evaporator. The residue was purified on a silica gel column (4:1
hexane/ CH Cl ) giving 152 mg (71%) of 4 as a white solid; mp
4
, filtered, and concentrated on a rotary
ligands have been significantly improved over those previously
reported. The downside of needing 1 equiv of catalyst was
minimized by the finding that NiCl
economical alternative to Ni(PPh
stoichiometry of Zn used in these Ullman couplings is impactful
as excess Zn can lead to unwanted reduction of the CF group.
2
2
12 1
2
•6H
2
O and PPh
3
provided an
1
27–120 °C. H NMR (500 MHz, CDCl
3
) δ 9.20 (s, 2 H), 8.96
) δ 157.9, 148.9 (q, J = 6.7
Hz), 137.8 (q, J = 36 Hz), 123.8 (q, J = 32 Hz), 122.1 (q, J = 274
1
3
3
)
2
Cl . We also note that the
2
(
s, 2 H); C NMR (125 MHz, CDCl
3
1
9
Hz), 121.5 (q, J = 275 Hz), 119.2 (q, J = 5.7 Hz); F NMR (470
MHz, CDCl ) δ –59.2 (q, J = 12.2 Hz), –61.6 (q, J = 12.2 Hz).
2. Yamamura, S.; Toda, M.; Hirata, Y. Org. Synth. 1973, 53, 86.
3. A small sample was recrystalized from Et O at rt and an x-ray
3
3
This should be noted when designing syntheses of extremely
electron deficient bipyridines or biaryls under similar conditions.
1
1
2
crystal structure was obtained and deposited in the Cambridge
Crystallographic Data Centre and allocated deposition number
CCDC 1044026.
Acknowledgments
We thank the Dow Chemical Company for funding, Shawn
Feist (Dow) for helpful discussions and Dr. Richard Staples
Supplementary Material
(
MSU) for crystallographic analysis.
Supplementary material (experimental details for the
preparation of 2 and 4, the preparations of putative structure
References and notes
assignment of bpy(CF
crystallographic data for 4) associated with this article can be
found, in the online version, at
http://dx.doi.org/xx.xxxx/j.tetlet.2015.xx.xxx.
3 3 3
) CH , NMR spectra, and X-ray
1
.
For recent examples see: (a) Coe, B. J.; Helliwell, M.; Raftery, J.;
Sanchez, S.; Peers, M. K.; Scrutton, N. S. Dalton Trans. 2015, 44,
2
0392–20405. (b) Takizawa, S.-y.; Shimada, K.; Sato, Y.; Murata,
S. Inorg. Chem. 2014, 53, 2983–2995. (c) Steves, J. E.; Stahl, S. S.
J. Am. Chem. Soc. 2013, 135, 15742–15745. (d) Gueden-Silber,
T.; Klein, K.; Seitz, M. Dalton Trans. 2013, 42, 13882–13888.