From Dimethylamine to Pyrrolidine: The Development of an Improved Nickel Pincer Complex for Cross-Coupling of Nonactivated Secondary Alkyl Halides

Article abstract of DOI:10.1021/acscatal.5b02324

Replacement of a dimethyl amino group of the amidobis(amine) nickel(II) pincer complex (1), [(^MeN₂N)Ni-Cl], by a pyrrolidino group resulted in a new nickel(II) pincer complex (2), [(^PyrN^MeNN)Ni-Cl]. Complex 2 is an efficient catalyst for Kumada and Suzuki-Miyaura cross-coupling of nonactivated secondary alkyl halides, while complex 1 is largely inactive. The significant activity difference is tentatively attributed to a minimal structural difference, which leads to a more hemilabile ligand.

Full text of DOI:10.1021/acscatal.5b02324

Letter
pubs.acs.org/acscatalysis
From Dimethylamine to Pyrrolidine: The Development of an
Improved Nickel Pincer Complex for Cross-Coupling of Nonactivated
Secondary Alkyl Halides
Pablo M. Perez Garcia,‡ Thomas Di Franco,‡ Alexandre Epenoy, Rosario Scopelliti, and Xile Hu*
́
Laboratory of Inorganic Synthesis and Catalysis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fed
Lausanne (EPFL), 1015 Lausanne, Switzerland
́ ́
erale de
S
* Supporting Information
ABSTRACT: Replacement of a dimethyl amino group of the
amidobis(amine) nickel(II) pincer complex (1), [(MeN2N)-
Ni−Cl], by a pyrrolidino group resulted in a new nickel(II)
pincer complex (2), [(PyrNMeNN)Ni−Cl]. Complex 2 is an
efficient catalyst for Kumada and Suzuki−Miyaura cross-
coupling of nonactivated secondary alkyl halides, while
complex 1 is largely inactive. The significant activity difference
is tentatively attributed to a minimal structural difference,
which leads to a more hemilabile ligand.
KEYWORDS: nickel, pincer ligands, Kumada coupling, Suzuki−Miyaura coupling, secondary alkyl halide
ross-coupling reactions have become one of the most
powerful synthetic methodologies.1 However, the cou-
seemingly insignificant change of one pair of dimethyl groups of
C
1 into a 1,4-butanediyl group has led to a dramatic
improvement in catalytic activity. The new pincer complex 2
(Figure 1) is an excellent catalyst for Kumada and Suzuki−
Miyaura coupling of secondary alkyl halides.
The new pincer proligand 3 was prepared in a good yield by
Pd-catalyzed C − N coupling of 2-(pyrrolidin-1-yl)aniline and
2-bromo-N,N-dimethylaminobromobenzene (Scheme 1).
pling of nonactivated alkyl halides, especially secondary alkyl
halides, is challenging due to their reluctance to oxidative
addition and the tendency of metal alkyl intermediates to
undergo unproductive β-hydride elimination.2 By judicious
choices of metal, ligand, and reaction condition, many catalytic
systems have recently been developed for the cross-coupling of
nonactivated alkyl halides.3−7
The majority of these systems are developed by ligand-
screening, and the active catalysts are often unidentified. In an
alternative approach, we have developed a well-defined nickel
pincer complex, Nickamine (1, Figure 1), which is an unusually
Scheme 1. Synthesis of the New Pincer Complex 2
The proligand was then lithiated by n-BuLi, followed by
treatment with NiCl2·dme, to give the Ni(II) pincer complex 2.
The molecular structure of 2 was determined by single-crystal
diffraction study (Figure 2).13
The Ni ion is in the expected square-planar coordination
geometry. The structural parameters of 2 are very similar to
those of 1 (Figure 2 and Table 1). The corresponding Ni−N
Figure 1. Amido bis(amine) pincer complexes 1 and 2.
general catalyst for a large number of cross-coupling8−10 and
related C−H functionalization11 reactions of nonactivated alkyl
halides. The modularity of the pincer ligand system allows for
systematic modifications, an important tool for rational
improvement of catalysts.12 While 1 is very efficient for the
coupling of primary alkyl halides, it has low activity for the
coupling of secondary alkyl halides. Here, we report that the
Received: October 16, 2015
Revised: December 4, 2015
© XXXX American Chemical Society
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Letter
Complex 2 was then applied for the coupling of various
functionalized primary and cyclic secondary alkyl halides (Table
2).14 Good yields were obtained in many cases. Functional
Table 2. Kumada Coupling of Primary Alkyl and Cyclohexyl
a
Halides using 2 as Catalyst
Figure 2. (Left) Crystal structure of complex 2. Hydrogens atoms are
omitted for clarity. (Right) Overlapping of the crystal structure of 1 (in
red) with the crystal structure of 2 (in green).
Table 1. Comparison of Key Structural Parameters between
Complexes 2 and 1
length (Å) or
angle (deg)
corresponding length (Å) or
entry
selected units
angle (deg) in 1
1
Ni1−Cl1
Ni1−N1
Ni1−N2
Ni1−N3
N1−Ni1−N2
N1−Ni1−Cl1
N2−Ni1−N3
N3−Ni1−Cl1
C1−N1−C2
Ni1−N3−C15
Ni1−N3−C18
C15−N3−C18
2.2130 (13)
1.963 (4)
1.854 (4)
1.968 (4)
86.76 (18)
92.9 (1)
2.2029 (7)
1.9598 (19)
1.835 (2)
1.956 (2)
86.64 (8)
93.59 (6)
85.89 (9)
94.49 (6)
108.4 (2)
112.4 (1)
108.9 (2)
108.9 (2)
2
3
4
5
6
7
86.02 (17)
94.3 (1)
8
9
108.1 (4)
118.5 (3)
103.3 (3)
104.7 (4)
10
11
12
and Ni−Cl bond lengths have a difference of no more than
0.019 Å between 1 and 2. Likewise, the corresponding bond
angles around the Ni ions have the difference of no more than
0.49°. Only the pyrrolidino group in 2 and the dimethylamino
group in 1 exhibit appreciable structural difference: the C−N−
C angle in the pyrrolidino group is 4.2° smaller than its
counterpart in the dimethylamino group. This contraction of
the C−N−C angle in 2 is consistent with the steric property of
the pyrrolidino group.
The catalytic activity of complex 2 was first probed in the
Kumada coupling reactions. The coupling of 1-iodooctane with
butylmagnesium chloride, and the coupling of 1-iododecane
with phenylmagnesium chloride, were used as the test reactions
(Scheme 2, eq 1 and 2). The previously optimized conditions
for complex 1 were employed.8a,b High yields of cross-coupling
were obtained using 3.5 mol % of 2 as catalyst. The yields are
comparable to those using 1 as catalyst. The catalyst loading
could be decreased to 1 mol % without influencing the yield for
catalyst 2, but not for catalyst 1 (Table S1 and Figure S1). This
result suggests a higher activity of 2.
a
b
Reactions were performed on a 0.5 mmol scale. Isolated yields
c
relative to alkyl halide. GC-MS yields relative to alkyl halide.
groups such as ester (Table 2, Entry 1), nitrile (Table 2, Entry
2), trifluoromethyl (Table 2, Entry 3), furane and tetrahy-
dropyrane were tolerated (Table 2, Entries 4−5 and 12).
Cyclohexyl halides were also coupled (Table 2, Entries 6−7 and
13). Both alkyl−alkyl and alkyl−aryl coupling were successful.
These results are somewhat expected because previous work
shows that the analogous catalyst 1 was active for the coupling
of these substrates.
As mentioned above, a general limitation of catalyst 1 is the
inactivity in the coupling of nonactivated secondary halides,
especially acyclic substrates. Surprisingly, 2 exhibited good
efficiency for the Kumada coupling of such substrates with alkyl
or aryl Grignard reagents (Table 3).14 Acyclic secondary alkyl
iodides could not be coupled using 1 as catalyst, but were
coupled in good yields using 2 as catalyst (Table 3, Entries 1−
3, 5−7). Cycloheptyl iodide was coupled in low yield using 1 as
catalyst, but the yields were significantly improved using 2 as
catalyst (Table 3, Entries 4 and 6). These results confirm that 2
is a superior catalyst than 1 for the Kumada coupling of alkyl
halides.
Scheme 2. Test Reactions for Kumada Cross-Coupling using
1 or 2 as Catalyst
The improved activity of 2 in the Kumada coupling
encouraged us to further explore its application in other
coupling reactions. It was previously shown that 1 was active
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Table 3. Kumada Coupling of Acyclic Secondary Alkyl
Iodides and Cycloheptyl Iodide using 1 or 2 as Catalyst
Table 4. Scope of Suzuki−Miyaura Coupling of Alkyl
a
a
Halides Using 1 or 2 as Catalyst
a
b
Reactions were performed on a 0.5 mmol scale. GC-MS yields
c
relative to alkyl halide. Isolated yields relative to alkyl halide.
for the Suzuki−Miyaura coupling of primary alkyl halides with
9-organo-9-borabicyclo[3.3.1]nonane at 80 °C.10a At room
temperature, however, the coupling was sluggish.
Complex 2 was tested as catalyst for these Suzuki−Miyaura
coupling reactions. Indeed, this catalyst exhibited enhanced
activity, allowing the coupling to occur at room temperature
(Scheme 3). A secondary alkyl iodide, (3-iodobutyl)benzene
Scheme 3. Suzuki−Miyaura Coupling of a Secondary Alkyl
Iodide with 1 and 2
a
b
Reactions were performed on a 0.5 mmol scale. GC-MS yields
c
relative to alkyl halide. Isolated yields relative to alkyl halide.
Entries 6, 8 and 12). These results further attest the superior
activity and broader scope of catalyst 2 over catalyst 1.
The significantly enhanced catalytic activity of 2 is
remarkable given its electronic and structural similarity to 1.
The pKa and nucleophilicity of pyrrolidino and dimethylamino
groups are very close.15 To compare the redox properties of Ni
ions in 1 and 2, cyclic voltammetry was conducted on
[(PyrNMeNN)Ni-(CH3CN)]PF6. One quasi-reversible reduction
at −1.64 V and one quasi-reversible oxidation at −0.09 V vs
ferrocene/ferrocenium were observed (Figure S2). These
potentials are only 30 and 60 mV lower than the corresponding
potentials for [(MeN2N)Ni-(CH3CN)]PF6.16 Given the peak
separation of more than 200 mV, this small difference suggests
similar electronic properties of 1 and 2. Thus, the activity
difference is tentatively assigned to structural factors. The main
structural difference between 1 and 2 is the 4° decrease of the
C−N−C angle (see above). This small decrease is apparently
sufficient for the access of bulky secondary alkyl halides, which
is impossible by catalyst 1. Alternatively, the pyrrolidino group
might be more “hemilabile” than the dimethylamino group,17
thus opening the Ni center during catalysis. To probe the latter
possibility, exogenous ligands were added to representative
Kumada and Suzuki−Miyaura reactions catalyzed by 2 (Scheme
4).
was coupled to 9-octyl-9-borabicyclo[3.3.1]nonane and 9-
phenyl-9-borabicyclo[3.3.1] nonane in good yields. On the
contrary, the yields were low or negligible using 1 as catalyst
under identical conditions (Scheme 3, eq 3 and 4).
Table 4 shows the scope of the room-temperature Suzuki−
Miyaura couplings catalyzed by 2. Both alkyl- and aryl-(9-BBN)
reagents could be used as the nucleophilic coupling partners,
and both primary and secondary alkyl halides could be coupled.
A variety of functional groups such as pyrrole (Table 4, Entry
1), thiophene (Table 4, Entry 2), ester (Table 4, Entries 3 and
9), ether (Table 4, Entries 4, 10, and 11), carbazole (Table 4,
Entry 5), N-Boc (Table 4, Entry 7) and furan (Table 4, Entry
13) were tolerated. In contrast, when 1 was used as catalyst,
primary alkyl and cyclohexyl halides were coupled in much
lower yields (Table 4, Entry 1), and the coupling of acylic
secondary alkyl halides was generally inefficient (Table 4,
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Letter
(3) For selected recent reviews of transition-metal-catalyzed cross-
coupling reactions, see: (a) Jana, R.; Pathak, T. P.; Sigman, M. S.
Chem. Rev. 2011, 111, 1417−1492. (b) Kambe, N.; Iwasaki, T.; Terao,
J. Chem. Soc. Rev. 2011, 40, 4937−4947. (c) Johansson Seechurn, C. C.
C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed.
2012, 51, 5062−5085. (d) Han, F.-S. Chem. Soc. Rev. 2013, 42, 5270−
5298.
Scheme 4. Effect of the Addition of Exogenous Ligands on
Representative Reactions Catalyzed by Complex 2
(4) For selected examples of Fe-catalyzed cross-coupling of
nonactivated alkyl halides, see: (a) Sherry, B. D.; Furstner, A. Acc.
Chem. Res. 2008, 41, 1500−1511. (b) Hatakeyama, T.; Hashimoto, T.;
Kathriarachchi, K. K. A. D. S.; Zenmyo, T.; Seike, H.; Nakamura, M.
Angew. Chem., Int. Ed. 2012, 51, 8834−8837. (c) Guisan-Ceinos, M.;
Tato, F.; Bunuel, E.; Calle, P.; Cardenas, D. J. Chem. Sci. 2013, 4,
1098−1104. (d) Cheung, C. W.; Ren, P.; Hu, X. L. Org. Lett. 2014, 16,
2566−2569. (e) Bedford, R. B. Acc. Chem. Res. 2015, 48, 1485−1493.
(5) For selected examples of Co-catalyzed cross-coupling of
nonactivated alkyl halides, see: (a) Ohmiya, H.; Yorimitsu, H.;
Oshima, K. J. Am. Chem. Soc. 2006, 128, 1886−1889. (b) Shukla, P.;
Hsu, Y.-C.; Cheng, C.-H. J. Org. Chem. 2006, 71, 655−658. (c) Cahiez,
G.; Chaboche, C.; Duplais, C.; Giulliani, A.; Moyeux, A. Adv. Synth.
Catal. 2008, 350, 1484−1488. (d) Hammann, J. M.; Haas, D.;
Knochel, P. Angew. Chem., Int. Ed. 2015, 54, 4478−4481.
(6) For selected recent examples of Ni-catalyzed cross-coupling of
nonactivated alkyl halides, see: (a) Lu, Z.; Fu, G. C. Angew. Chem., Int.
Ed. 2010, 49, 6676−6678. (b) Zultanski, S. L.; Fu, G. C. J. Am. Chem.
Soc. 2013, 135, 624−627. (c) Liang, Y.; Fu, G. C. J. Am. Chem. Soc.
2015, 137, 9523−9526. (d) Liang, Y.; Fu, G. C. Angew. Chem., Int. Ed.
2015, 54, 9047−9051. (e) Terao, J.; Kambe, N. Acc. Chem. Res. 2008,
41, 1545−1554.
(7) For selected examples of Cu-catalyzed cross-coupling of
nonactivated alkyl halides, see: (a) Yang, C.-T.; Zhang, Z.-Q.; Liu,
Y.-C.; Liu, L. Angew. Chem., Int. Ed. 2011, 50, 3904−3907. (b) Ren, P.;
Stern, L.-A.; Hu, X. L. Angew. Chem., Int. Ed. 2012, 51, 9110−9113.
(c) Yang, C.-T.; Zhang, Z.-Q.; Liang, J.; Liu, J.-H.; Lu, X.-Y.; Chen, H.-
H.; Liu, L. J. Am. Chem. Soc. 2012, 134, 11124−11127.
(8) (a) Vechorkin, O.; Hu, X. L. Angew. Chem., Int. Ed. 2009, 48,
2937−2940. (b) Vechorkin, O.; Proust, V.; Hu, X. L. J. Am. Chem. Soc.
2009, 131, 9756−9766. (c) Perez Garcia, P. M.; Di Franco, T.; Orsino,
A.; Ren, P.; Hu, X. L. Org. Lett. 2012, 14, 4286−4289.
The addition of 5 equiv (relative to 2) of an exogenous
ligand (lutidine, pyridine, or PPh3) to the cross-coupling of the
(3-iodobutyl)benzene decreased significantly the yields. These
results are consistent with the hypothesis that the pyrrolidino
group is “hemilabile” and de-coordinate from the Ni center to
create a more open, and thus, accessible reaction site for
secondary alkyl halides.12,17
In summary, a small modification of the N2N pincer ligand
results in a drastically improved Ni catalyst. The new Ni pincer
complex 2 is efficient for Kumada and Suzuki−Miyaura
coupling of both primary and secondary alkyl halides. Further
structural modifications, for example, replacing the second
dimethyl amino group by a pyrrolidino group and systemati-
cally changing the dimethyl amino groups to 3, 4, 6-membered
cyclic amines, will lead to a structure−activity study that gives
more insights in the key factors controlling the reactivity of
these nickel pincer complexes.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.5b02324.
■
(9) (a) Vechorkin, O.; Barmaz, D.; Proust, V.; Hu, X. L. J. Am. Chem.
Soc. 2009, 131, 12078−12079. (b) Vechorkin, O.; Godinat, A.;
Scopelliti, R.; Hu, X. L. Angew. Chem., Int. Ed. 2011, 50, 11777−11781.
(10) (a) Di Franco, T.; Boutin, N.; Hu, X. L. Synthesis 2013, 45,
2949−2958. (b) Di Franco, T.; Epenoy, A.; Hu, X. L. Org. Lett. 2015,
17, 4910−4913.
S
Experimental details (PDF)
Characterization data (CIF)
(11) Vechorkin, O.; Proust, V.; Hu, X. L. Angew. Chem., Int. Ed. 2010,
49, 3061−3064.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xile.hu@epfl.ch.
■
(12) Ren, P.; Vechorkin, O.; von Allmen, K.; Scopelliti, R.; Hu, X. L.
J. Am. Chem. Soc. 2011, 133, 7084−7095.
(13) For crystallographic details of complex 2, see the Supporting
Information.
Author Contributions
‡These authors contributed equally (P.M.P.G. and T.D.F.).
(14) For practical convenience, catalyst loading was 3.5 mol % for the
Kumada coupling reactions shown in Table 2. However, a catalyst
loading of 1 mol % is sufficient to obtain the cross-coupling products
in the same yields.
Notes
The authors declare no competing financial interest.
(15) Mayr, H.; Ofial, A. R. J. Phys. Org. Chem. 2008, 21, 584−595.
(16) Vechorkin, O.; Csok, Z.; Scopelliti, R.; Hu, X. L. Chem. - Eur. J.
2009, 15, 3889−3899.
(17) Perez García, P. M.; Ren, P.; Scopelliti, R.; Hu, X. L. ACS Catal.
2015, 5, 1164−1171.
ACKNOWLEDGMENTS
This work is supported by the Swiss National Science
Foundation (no. 200020_144393/1).
■
REFERENCES
■
(1) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: New York, 2004.
(2) (a) Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346,
1525−1532. (b) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005,
44, 674−688. (c) Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed.
́
2009, 48, 2656−2670. (d) Phapale, V. B.; Cardenas, D. J. Chem. Soc.
Rev. 2009, 38, 1598−1607. (e) Hu, X. L. Chem. Sci. 2011, 2, 1867−
1886.
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ACS Catal. 2016, 6, 258−261