Ruthenium(0)-catalyzed sp3 C-H bond arylation of benzylic amines using arylboronates

Article abstract of DOI:10.1021/ol300627p

A Ru-catalyzed direct arylation of benzylic sp³ carbons of acyclic amines with arylboronates is reported. This highly regioselective and efficient transformation can be performed with various combinations of N-(2-pyridyl) substituted benzylamines and arylboronates. Substitution of the pyridine directing group in the 3-position proved to be crucial in order to achieve high arylation yields. Furthermore, the pyridine directing group can be removed in high yields via a two-step protocol.

Full text of DOI:10.1021/ol300627p

ORGANIC
LETTERS
Ruthenium(0)-Catalyzed sp3 CÀH Bond
Arylation of Benzylic Amines Using
Arylboronates
2012
Vol. 14, No. 7
1930–1933
€
Navid Dastbaravardeh, Michael Schnurch,* and Marko D. Mihovilovic
Institute of Applied Synthetic Chemistry, Vienna University of Technology,
Getreidemarkt 9/163-OC, 1060 Vienna, Austria
mschnuerch@ioc.tuwien.ac.at
Received March 12, 2012
ABSTRACT
A Ru-catalyzed direct arylation of benzylic sp3 carbons of acyclic amines with arylboronates is reported. This highly regioselective and efficient
transformation can be performed with various combinations of N-(2-pyridyl) substituted benzylamines and arylboronates. Substitution of the
pyridine directing group in the 3-position proved to be crucial in order to achieve high arylation yields. Furthermore, the pyridine directing group
can be removed in high yields via a two-step protocol.
The direct catalytic cleavage of CÀH bonds is highly
attractive and one of the most investigated, but also most
challenging, topics in modern organic synthesis. Within
recent years, the field of transition metal catalyzed CÀH
activation reactions is rapidly expanding.1 Especially, the
field of direct functionalization of sp2 CÀH bonds has
generated many interesting results in previous years.2
On the other hand, the area of catalytic functionalization of
sp3 CÀH bonds has matured to a significantly lesser extent
and many challenges await to be tackled properly.3 In
1998, the group of Jun described the first chelation assisted
alkylation of benzylamine derivatives by a Ru(0) catalyst.
In 2005, Kakiuchi, Chatani, and Murai reported a Ru(0)-
catalyzed regioselective arylation of aromatic ketones with
arylboronates,4 followed by the discovery of the Sames
group to use cyclic imine protecting groups for the aryla-
tion of pyrrolidines and piperidine (Scheme 1).5 Recently,
Maes published a pyridine directed arylation of piperidine
derivatives (Scheme 1).6 However, the last two methods
(1) For recent reviews on CÀH activation, see: (a) Ackermann, L.
Chem. Rev. 2011, 111, 1315–1345. (b) Yeung, C. S.; Dong, V. M. Chem.
Rev. 2011, 111, 1215–1292. (c) Baudoin, O. Chem. Soc. Rev. 2011, 40,
4902–4911. (d) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc.
€
Rev. 2011, 40, 5068–5083. (e) Schnurch, M.; Dastbaravardeh, N.;
Ghobrial, M.; Mrozek, B.; Mihovilovic, M. D. Curr. Org. Chem. 2011,
15, 2694–2730. (f) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem.
Rev. 2010, 110, 624–655. (g) Daugulis, O. Top. Curr. Chem. 2010, 292,
57–84. (h) Fagnou, K. Top. Curr. Chem. 2010, 292, 35–56. (i) Ack-
ermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48,
9792–9826. (j) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009,
38, 2447–2464. (k) Dyker, G., Ed. Handbook of CÀH Transformations:
Applications in Organic Synthesis; Wiley: 2005; Vol. 2.
(3) For selected papers on sp3 CÀH bond functionalzation, see:
(a) Sundararaju, B.; Achard, M.; Sharma, G. V. M.; Bruneau, C.
J. Am. Chem. Soc. 2011, 133, 10340–10343. (b)Pan, S.;Endo, K.;Shibata,
T. Org. Lett. 2011, 13, 4692–4695. (c) Ghobrial, M.; Harhammer, K.;
€
Mihovilovic, M. D.; Schnurch, M. Chem. Commun. 2010, 46, 8836–8838.
(d) Rousseaux, S.; Gorelsky, S. I.; Chung, B. K. W.; Fagnou, K. J. Am.
Chem. Soc. 2010, 132, 10692–10705. (e) Jazzar, R.; Hitce, J.; Renaudat, A.;
Sofack-Kreutzer, J.; Baudoin, O. Chem.;Eur. J. 2010, 16, 2654–2672.
(f) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657–3659.
(4) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N. J. Am. Chem.
Soc. 2005, 127, 5936–5945.
(5) Pastine, S. J.; Gribkov, D. V.; Sames, D. J. Am. Chem. Soc. 2006,
128, 14220–14221.
(6) Prokopcova, H.; Bergman, S. D.; Aelvoet, K.; Smout, V.; Herrebout,
W.; Van der Veken, B.; Meerpoel, L.; Maes, B. U. W. Chem.;Eur. J. 2010,
16, 13063–13067.
(2) For recent papers on sp2 CÀH bond functionalzation, see: (a)
Ackermann, L.; Diers, E.; Manvar, A. Org. Lett. 2012, 14, 1154–1157.
(b) Ackermann, L.; Pospech, J.; Graczyk, K.; Rauch, K. Org. Lett. 2012,
14, 930–933. (c) Wencel-Delord, J.; Nimphius, C.; Patureau, F. W.;
Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 2247–2251. (d) Tauchert,
M. E.; Incarvito, C. D.; Rheingold, A. L.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2012, 134, 1482–1485. (e) Flegeau, E. F.; Bruneau, C.;
Dixneuf, P. H.; Jutand, A. J. Am. Chem. Soc. 2011, 133, 10161–10170.
(f) Shiota, H.; Ano, Y.; Aihara, Y.; Fukumoto, Y.; Chatani, N. J. Am.
Chem. Soc. 2011, 133, 14952–14955.
r
10.1021/ol300627p
Published on Web 03/26/2012
2012 American Chemical Society

were limited to cyclic amines such as pyrrolidine or piper-
idine and the selectivity between mono- and bis-arylation
proved to be difficult to control.
Next, we investigated the role of the aryl donor to
improve conversion. Various aryl-boron species and
arylhalides were submitted to the reaction conditions.
Phenylboronic acid (Table 1, entry 1) displayed low con-
version, and also the addition of base (Table 1, entry 2)
to quench an eventually formed acid equivalent did not
improve the conversion significantly, although the yield
was considerably higher. 1,3-Propanediol derived boronic
ester gave the best result among the various boronic acid
esters investigated (Table 1, entry 8). In addition, this ester
can be hydrolyzed easily to the boronic acid upon workup
which facilitates purification of the product by flash
column chromatography. Aryl halides did not perform
under these conditions at all (Table 1, entry 4 and 5).
Furthermore, the addition of ketones increases the con-
version, which is in accordance with the literature (Table 1,
entry 10 and 11).4À6
Herein, we report a Ru(0)-catalyzed arylation of acyclic
CÀH bonds with arylboronates directed by 3-substituted
pyridin-2-yls (Scheme 1). To the best of our knowledge,
this is the first chelate assisted ruthenium-catalyzed
R-arylation of acyclic amines. Initially the reaction was
optimized using N-substituted benzylamines as substrates,
since it is well-known that an sp3 CÀH bond adjacent to a
heteroatom or in a benzylic position is more easily acti-
vated compared to one surrounded only by carbons.7
Scheme 1. Direct Arylation of sp3 CÀH Bonds Adjacent to
Nitrogen
Table 1. Assigning the Aryl Donor and Solvent as Critical
Parameters for the Direct Arylation of Benylic Amine 4aa
We started our investigations with pyridine as directing
group for a first round of reaction parameter optimization.
Using simple N-benzylpyridine-2-amine 1 as a starting
material, only a very low conversion of 9% was obtained
under the conditions reported by the Sames group using
pyrrolidine substrates. Even by intensively screening dif-
ferent reaction parameters, we were unable to achieve a
higher conversion than 9%. It was speculated that this
could be attributed to a predominant conformation in
which the benzylic CH2 group points away from the
pyridine nitrogen, consequently preventing a site-directing
interaction and disfavoring CÀH activation. By installing
a sterically demanding group in the 3-position the benzylic
CH2-group should be brought into closer proximity of the
pyridine nitrogen and CÀH activation should be facili-
tated. Indeed, a much higher conversion (85%) could be
achieved when a methyl group was installed at the pyridine
ring in the 3-position (Scheme 2). A similar observation
was made by the group of Jun.8
a Reaction conditions: 4a (0.5 mmol), Ph-X (1 mmol), Ru3(CO)12 (5
mol %), and solvent (0.5 mL). b Conversion based on GC analysis with
respect to 4a (dodecane as internal standard). c Yield determined by GC
analysis with respect to 4a (dodecane as internal standard). d Addition of
K2CO3 (1 mmol). e Number in parentheses is isolated yield of 5a.
Hence, it was decided that pinacolone was to be used as
the solvent and 1,3-propandiol derived boronic esters
6aÀp as aryl donors for all further reactions investigating
the scope and limitations of the presented methodology.
We found this catalytic method to be sensitive to the
Scheme 2. Influence of a Substituent in 3-Position of Pyridine
(7) For selected papers on CÀH bond functionalization adjacent to a
heteroatom, see: (a) Kakiuchi, F.; Tsuchiya, K.; Matsumoto, M.;
Mizushima, E.; Chatani, N. J. Am. Chem. Soc. 2004, 126, 12792–
12793. (b) Murai, S.; Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda,
T.; Kakiuchi, F. J. Am. Chem. Soc. 2001, 123, 10935–10941. (c) Murai,
S.; Chatani, N.; Asaumi, T.; Ikeda, T.; Yorimitsu, S.; Ishii, Y.; Kakiuchi,
F. J. Am. Chem. Soc. 2000, 122, 12882–12883.
(8) Jun, C.-H. Chem. Commun. 1998, 1405–1406.
Org. Lett., Vol. 14, No. 7, 2012
1931

electronic and sterical properties of the aryl donor. Steri-
callydemandingarylsgavesignificantlylowerconversions,
and also electron withdrawing or coordinating substitu-
ents (4-Ac, 4-CN, 4-NO2, or 3-pyridyl) were much less
tolerated compared to their neutral and electron donating
counterparts. Phenyl was also tested as an alternative
bulky group in the 3-position of pyridine (Table 2, entries
12À15). It was found that the arylation yield could be
significantly increased compared to the corresponding
methyl examples (Table 2, entries 1, 6, 7, and 9). However,
in light of atom efficency, the methyl group was favored.
reversible CÀH activation step (hence also termed inverse
equilibrium isotope effect) eventually involving a σ-complex
preceding CÀH insertion.9
Scheme 3. Competitive Deuterium Labeling Experiments
Table 2. Scope of Direct Arylations with Arylboronic Esters 6a
entry
R1
Ar
convb
yieldc
1
5a
5b
5c
5d
5e
5f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
86
55
64
n.i.d
n.i.
61
38
62
64
39
66
33
41
90
85
96
72
2
2-Me-Ph
1-Naph
3-Me-Ph
3-Cl-Ph
4-Me-Ph
4-t-Bu-Ph
4-OMe-Ph
4-F-Ph
3
8
4
87
5
59
6
88
7
5g
5h
5i
87
8
50
9
89
10
11
12
13
14
15
5j
4-Cl-Ph
4-CF3-Ph
Ph
49
5k
5l
61
100
100
100
100
5m
5n
5o
4-Me-Ph
4-t-Bu-Ph
4-F-Ph
We propose the following mechanism according to the
plausible hypothesis of Kakiuchi, Chatani, and Murai4
and similarly proposed by Sames and co-workers (Scheme 4).5
The catalytic process is initiated by coordination of
ruthenium(0) to the pyridine nitrogen, followed by oxida-
tive addition to 10. Subsequently, the ketone is reduced to
the corresponding alcohol (which could be detected by
GC-MS analysis), followed by formation of a metal-
alkoxy (Ru-OR) species 12. This intermediate facilitates
the transmetalation with ArÀB(OR)2 to 14. The ketone
simultaneously works as a hydrogen and boron scavenger.
Reductive elimination finally delivers product 5 and re-
generates the catalyst. This mechanistic rationale is sup-
ported by the previous work of Sames and coauthors.5
For the cleavage of the directing group, we used a
strategy recently reported by Studer and co-workers:10
N-carbamoylation of the amino group of 5a and subse-
quent N-methylation of the pyridyl group of 15, followed
by hydrolysis of the pyridinium salt, delivers Boc protected
diphenylmethanamine 16 in high yield (Scheme 5, 84%
a Reaction conditions: 4aÀb (0.5 mmol), 6aÀx (0.75 mmol), Ru3-
(CO)12 (5 mol %), and pinacolone (0.5 mL). b Conversion based on GC
analysis with respect to 4a and 4b (dodecane as internal standard).
c Isolated yield. d Mixture of products which could not be separated.
In order to determine if the CÀH insertion is the rate
limiting step of this arylation protocol, we carried out a
kinetic isotope effect (KIE) study. An intermolecular
competition experiment was set up for compounds 4a
and 7 (Scheme 3). The reaction was carried out with 1
equiv of N-benzyl-3-methylpyridin-2-amine 4a, 1 equiv of
the deuterated analog 7, and 1 equiv of phenylboronic acid
1,3-propanediol ester 6a to achieve a maximum of 50%
conversion. The mixture of both products was isolated and
analyzed by 1HNMR.TheKIEwasfoundtobekH/kD =3.3.
This indicates that the CÀH bond is of course weaker
compared to the CÀD bond, and hence the rate of CÀH
insertion is higher than the rate of CÀD insertion. Inter-
estingly, when the intramolecular KIE was investigated
starting from substrate 9 an inverse KIE of 0.43 was
measured. Inverse KIEs have been previously reported in
CÀH bond activation reactions and were attributed to a
(9) Jones, W. D. Acc. Chem. Res. 2003, 36, 140–146 and references
cited therein.
(10) Jana, K. J.; Grimme, S.; Studer, A. Chem.;Eur. J. 2009, 15,
9078–9084.
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Org. Lett., Vol. 14, No. 7, 2012

instead of 24 h). Notably, the reaction also works with
nonbenzylic sp3 CÀH bonds as shown for compound 19.
However, the reaction required more time (48 h), and the
yield decreased considerably (Scheme 6). This indicates that
the activation of a CH2 group due to its benzylic nature is
more important than activation via an adjacent NH group,
but not mandatory for this kind of transformation.
Scheme 4. Proposed Mechanism
Scheme 6. Direct Arylation of 18 and 20
overall). N-Boc deprotection can then be achieved easily
and often quantitatively following well established
protocols.11 However, also the Boc-protected compounds
can be useful if further manipulations of the products
require the protection of the amino functionality.
In conclusion, acyclic sp3 CÀH bonds adjacent to a free
NH group were readily arylated with various arenes via
pyridine directed cyclometalation with Ru3(CO)12. The
NH group could be replaced by CH2 without a significant
decrease in yield. A bulky group in the 3-position of the
directing group was crucial for high conversions in these
reactions. Finally, removal of the directing group was
successfully demonstrated. Although a two-step protocol
is required, deprotection is achieved in high overall yield,
significantly expanding the general applicability of this
approach. Mechanistic investigations were conducted
and support the mechanism proposed by Kakiuchi and
co-workers.
Scheme 5. Removal of Directing Group
Finally, we conducted a preliminary investigation if the
reaction is limited to benzylamine substrates and to
benzylic positions, in general. We found the NH group
not to be essential; it can be replaced by a CH2 group (17)
without decreasing the yield significantly (Scheme 6),
although a prolonged reaction time was required (36 h
Acknowledgment. We acknowledge the Austrian Science
Foundation (FWF, Project P21202-N17) for financial
support of this work.
Supporting Information Available. Full experimental
details and spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(11) For the N-Boc deprotection, see: (a) Norma, J. T.; Simon,
W. M.; Frost, H. N.; Ewing, M. Tetrahedron Lett. 2004, 45, 905–906. (b)
Srinivasan, N.; Yurek-George, A.; Ganesan, A. Mol. Diversity 2005, 9,
291–293.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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