Synthesis of primary and secondary alkylboronates through site-selective C(sp3)-H activation with silica-supported monophosphine-Ir catalysts

Article abstract of DOI:10.1021/ja3126239

The site-selective activation and borylation of unactivated C(sp³)-H bonds in 2-alkylpyridines to form primary and secondary alkylboronates was achieved using silica-supported monophosphine-Ir catalysts. This borylation occurs selectively at C-H bonds located γ to the pyridine nitrogen atom. The site-selectivity of this reaction suggests that the C-H bond cleavage occurs with the assistance of a proximity effect due to N-to-Ir coordination.

Full text of DOI:10.1021/ja3126239

Communication
pubs.acs.org/JACS
Synthesis of Primary and Secondary Alkylboronates through Site-
Selective C(sp3)−H Activation with Silica-Supported
Monophosphine−Ir Catalysts
Soichiro Kawamorita, Ryo Murakami, Tomohiro Iwai, and Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
S
* Supporting Information
through C−H bond activation assisted by a proximity effect due
ABSTRACT: The site-selective activation and borylation
of unactivated C(sp3)−H bonds in 2-alkylpyridines to
form primary and secondary alkylboronates was achieved
using silica-supported monophosphine−Ir catalysts. This
borylation occurs selectively at C−H bonds located γ to
the pyridine nitrogen atom. The site-selectivity of this
reaction suggests that the C−H bond cleavage occurs with
the assistance of a proximity effect due to N-to-Ir
coordination.
to N-to-Ir coordination.
The ligand effects on the Ir-catalyzed borylation of 2-
ethylpyridine 1a (0.9 mmol) with bis(pinacolato)diboron 2
(0.3 mmol) are summarized in Table 1. With the immobilized-
catalyst system prepared in situ from Silica-SMAP and
[Ir(OMe)(cod)]2, borylation of the terminal C(sp3)−H bond
proceeded over a period of 12 h at 25 °C to give the primary
alkylboronate 3a and the geminal diborylation product 4 in
1
66% and 21% yields, respectively (based on 2 by H NMR)
with complete consumption of the diboron reagent 2 (entry
1).10−12 Borylation did not occur either on the pyridine ring or
at the benzylic position. Entry 2 shows that using 2 equiv of 2
allows the efficient synthesis of the geminal diborylation
product 4a.13
The Silica-TRIP-Ir system, which instead uses a silica-
immobilized triarylphosphine, also showed catalytic activity at
25 °C, affording 3a in 46% yield (Table 1, entry 3), although 2
was not consumed completely. Interestingly, changing from Ir
to Rh in either the Silica-SMAP or Silica-TRIP catalyst systems
resulted in a complete loss of catalytic activity (data not
shown). This is the opposite of the phenomenon observed
during our previous study on N-adjacent C(sp3)−H
borylation.2h
The homogeneous SMAP derivative Ph-SMAP did not
promote borylation at 25 °C, although the reaction proceeded
under mild heating (60 °C) with the partial conversion of 2
(Table 1, entries 4 and 5). These results indicate that the
immobilization of the SMAP structure to a solid surface is
crucial for the catalytic performance. Other homogeneous
monodentate ligands, including PMe3, PCy3, PtBu3, PPh3, and
XPhos were far less efficient, such that either no reaction or
only low conversion reaction occurred even at 60 °C, and
reactions were never observed at 25 °C (entries 6−14). The
use of the bipyridine-based ligand dtbpy (4,4′-di-tert-
butylbipyridine) resulted in efficient borylation of the pyridine
ring at 25 °C (C4 and C5 positions, 64% and 31%
respectively), but did not produce the alkylboronate 3a at all
(entry 15). Surprisingly, 1a underwent efficient borylation in
the absence of any phosphine ligand at 60 °C, with 3a and 4a
obtained in 99% and 15% yields, respectively (entry 17). This
phosphine-free Ir system did not, however, promote borylation
at 25 °C, demonstrating the significant ligand effects of Silica-
he transition metal catalyzed direct borylation of
T
unactivated C(sp3)−H bonds offers a versatile and
efficient strategy for the synthesis of alkylboronates,1−5 which
are useful intermediates in organic synthesis.6 Pioneering work
by the Hartwig group has shown that metal-boryl catalysts
based on Re,2a Rh2b−d,f and Ru2e complexes allow the
preparation of primary alkylboronates from alkanes through
activation of primary C−H bonds at terminal sites on the
alkane. The selectivity of this process is controlled by the steric
properties of the substrate molecule and hence precludes the
efficient borylation of secondary C−H bonds.
Recently, the Hartwig group, as well as our own group,
disclosed different catalyst systems that allow the borylation of
secondary C(sp3)−H bonds within heterocyclic compounds.2g,h
Hartwig et al. used a phenanthroline−Ir system for the
borylation of C−H bonds located β to the oxygen atoms of
cyclic ethers.2g Our group employed a silica-supported
triptycene-type monophosphine−Rh catalyst system (Silica-
TRIP−Rh) for the borylation of C−H bond located α to the
nitrogen atom of amide, urea and aminopyridine derivatives.2h
As a related study, Ohmura, Suginome and co-workers reported
more recently Ir-catalyzed C(sp3)−H borylation at the methyl
groups of methylchlorosilanes.2i Although these methods
demonstrate a significantly expanded substrate scope, no
catalyst has been reported that enables site-selective borylation
of electronically unactivated secondary C(sp3)−H bonds in
acyclic or carbocyclic systems.
Herein, we report that combinations of silica-supported
monophosphines (Silica-SMAP7−9 or Silica-TRIP2h) and
[Ir(OMe)(cod)]2 produce heterogeneous catalyst systems
which are effective for the borylation of unactivated primary
and secondary C(sp3)−H bonds in pyridine-substituted acyclic
or carbocyclic compounds using bis(pinacolato)diboron (2).
This reaction occurs under relatively mild conditions (0.1−2
mol % Ir, 25−80 °C) with excellent site-selectivity, likely
Received: December 27, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja3126239 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
alkylpyridine derivatives under mild conditions (Table 2).
The reaction with 2-isopropylpyridine 1b proceeded efficiently
Table 1. Ligand Effects in Ir-Catalyzed Borylation of 2-
Ethylpyridine (1a) with Bis(pinacolato)diboron (2)
a
Table 2. Silica-SMAP−Ir Catalyzed C(sp3)−H Borylation of
a
Alkylpyridine Derivatives
b
NMR yield , %
entry
1
ligand
temp.°C
3a
4a
Silica-SMAP
Silica-SMAP
Silica-TRIP
Ph-SMAP
Ph-SMAP
PMe3
25
25
25
25
60
25
60
60
25
60
25
60
25
60
25
25
60
66 (64)
21
c
2
trace
46
0
98 (84)
3
0
4
0
5
39
0
12
0
6
7
PMe3
14
0
4
8
PCy3
0
9
PtBu3
0
0
10
11
12
13
14
PtBu3
14
0
0
PPh3
0
PPh3
10
0
0
XPhos
0
XPhos
3
0
d
15
dtbpy
0
0
16
17
none
0
0
a
Conditions: 1 (0.9 mmol), 2 (0.3 mmol), [Ir(OMe)(cod)]2 (Ir:
none
99
15
0.0060 mmol), Silica-SMAP (0.0060 mmol), t-BuOMe (3.0 mL) for
a
b
12−15 h. Conversion of 2 is 100% for all entries. 1H NMR yield
Conditions: 1a (0.9 mmol), 2 (0.3 mmol), [Ir(OMe)(cod)]2 (Ir:
0.0060 mmol), ligand (0.0060 mmol), t-BuOMe (3.0 mL) for 12 h.
based on 2. Isolated yields are in parentheses. Yield in excess of 100%
b
1H NMR yield based on 2. Isolated yields shown in parentheses.
c
indicates a minor contribution of the reaction with pinB−H. Hexane
c
d
Conditions: 1a (0.3 mmol), 2 (0.6 mmol), [Ir(OMe)(cod)]2 (Ir:
was used as a solvent. Geminal diborylation products were observed
e
0.0060 mmol), Silica-SMAP (P: 0.0060 mmol), hexane (3.0 mL) for
22 h. Ring-borylation products (C4; 64% and C5; 31%) were formed.
in entries 1 and 3 (14% and 2%, respectively). Arylboronates were
d
formed in entries 2, 4, and 7 (2%, 11%, and 3%, respectively).
f
Deoxygenated monoborylation products 3a (3%) and diborylation
SMAP and Silica-TRIP in accelerating the C(sp3)−H
borylation (entry 16).
product 4a (5%) were formed. Isolated product is contaminated with a
trace of 1d.
The effect of the Silica-SMAP ligand is also evident in a
gram-scale reaction with Ir loading at a level of 0.1 mol %. In
the presence of Silica-SMAP, the reaction proceeded smoothly
at 80 °C to afford the alkylboronates 3a and 4a in 95% and 11%
NMR yields, respectively, after a reaction time of 12 h (Scheme
1). In contrast, the phosphine-free Ir catalyst produced only 3%
of 3a under otherwise same conditions.
at 60 °C to give the corresponding monoborylation product 3b
with an yield exceeding 100% (109%), along with geminal
diboronate 4b in 14% yield (entry 1).14 This reaction did not
form a 1,3-bisborylation product. The reaction of 2-tert-
butylpyridine 1c at 60 °C gave the C(sp3)−H monoborylation
product 3c in 83% yield along with a trace (2%) of a pyridine
ring borylation product (entry 2). Substitution with a
methoxymethyl ether at the C1 position of 2-ethylpyridine
derivative 1d had virtually no effect on the reactivity of the
primary C(sp3)−H bonds toward the borylation, and the
primary alkylboronate 3d was obtained in 82% yield, but it is
worth mentioning that small amounts of deoxygenated
borylation products 3a (3%) and 4a (5%) were also formed
as side products (entry 3).
The Silica-SMAP-Ir system was further found to allow the
site-selective C(sp3)−H borylation of a variety of 2-
Scheme 1. Ir-Catalyzed Borylation of 1a on a 5 mmol Scale
Importantly, the Silica-SMAP-Ir system is capable of
functionalizing the internal unactivated C(sp3)−H bonds of
2-alkylpyridine derivatives, allowing the preparation of
secondary alkylboronates (Table 2, entries 4−7). The
B
dx.doi.org/10.1021/ja3126239 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
C(sp3)−H borylation occurs with exceptional site-selectivity at
the position γ to the pyridine nitrogen atom with minor
formation (≤11%) of arylboronates due to C(sp2)−H
borylation at the pyridine ring. For example, the reaction of
2-pentylpyridine 1e at 60 °C (15 h reaction with complete
conversion of 2) afforded secondary alkylboronate 3e in a yield
exceeding 100% (79% yield after purification) (entry 4).
Alkylboronate isomers resulting from the activation of other
C(sp3)−H bonds were not detected by 1H NMR in the
unpurified product mixture. No reaction occurred with the
phosphine-free Ir system under otherwise same conditions (see
Supporting Information for ligand effects in the reaction of 1e).
The site-selective secondary C(sp3)−H borylation with the
Silica-SMAP-Ir system also proceeded efficiently with 2-(3-
phenylpropyl)pyridine (1f, 60 °C), giving the corresponding
alkylboronates 3f in 102% yields (Table 2, entry 5).
Comparison of the reactivities of 1e and 1f indicates that the
phenyl substituent in 1f does not affect the reactivity of the
vicinal C−H bonds. It is also noteworthy that the benzylic C−
H bonds of 1f were intact. The reaction of 2-(2-phenylethyl)-
pyridine (1g) proceeded cleanly at 60 °C to afford the benzylic
secondary alkylboronate 3g in 86% yield, no C(sp2)−H
borylation at the pyridine ring being observed (entry 6).
The reaction with 2-cyclohexylpyridine (1h) provides the
first reported instance of the site-selective C(sp3)−H borylation
of a carbocyclic system (Table 2, entry 7). The ring borylation
proceeded with exceptional stereoselectivity to give the 1,2-
disubstituted cyclohexane 3h in the trans configuration.
to the pyridine nitrogen atom, suggesting a proximity effect due
to N-to-Ir coordination. The primary C(sp3)−H borylation is
also useful as a method for the preparation of geminal
diboronates. Even though a phosphine-free catalyst system
using solely [Ir(OMe)(cod)]2 also promoted the primary
C(sp3)−H borylation of 2-ethylpyridine, the activity of the
heterogeneous catalyst system based on Silica-SMAP was much
greater and the use of Silica-SMAP was indispensable for the
borylation of secondary C(sp3)−H bonds. In contrast, the
application of typical soluble phosphine ligands severely
inhibited the Ir catalysis. At present, the exact nature of the
catalytically active species in the homogeneous and heteroge-
neous systems is unclear, but it is likely that the presence of
Silica-SMAP creates a favorable environment for the formation
of a highly active metal−phosphine species with a significant
coordinative vacancy.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and characterization data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
sawamura@sci.hokudai.ac.jp
■
Notes
The authors declare no competing financial interest.
Transformations of the pyridine-containing alkylboronates
were conducted (Scheme 2). The one-carbon homologation of
ACKNOWLEDGMENTS
■
This work was supported by Grants-in-Aid for Scientific
Research on Innovative Areas “Organic Synthesis Based on
Reaction Integration” from MEXT, as well as by CREST and
ACT-C from JST. S.K. thanks JSPS for scholarship support.
Scheme 2. Transformations of Secondary Alkylboronates
REFERENCES
■
(1) A review on transition metal catalyzed C−H borylation: Mkhalid,
I. A.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem.
Rev. 2010, 110, 890.
(2) Transition metal catalyzed C(sp3)−H borylation reactions:
(a) Chen, H.; Hartwig, J. F. Angew. Chem., Int. Ed. 1999, 38, 3391.
(b) Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000,
287, 1995. (c) Lawrence, J. D.; Takahashi, M.; Bae, C.; Hartwig, J. F. J.
Am. Chem. Soc. 2004, 126, 15334. (d) Hartwig, J. F.; Cook, K. S.;
Hapke, M.; Incarvito, C. D.; Fan, Y.; Webster, C. E.; Hall, M. B. J. Am.
Chem. Soc. 2005, 127, 2538. (e) Murphy, J. M.; Lawrence, J. D.;
Kawamura, K.; Incarvito, C.; Hartiwg, J. F. J. Am. Chem. Soc. 2006, 128,
́
13684. (f) Wei, C. S.; Jimenez-Hoyos, C. A.; Videa, M. F.; Hartwig, J.
the secondary alkylboronate 3f with a bromochloromethane/
BuLi reagent furnished the corresponding β-branched primary
alkylborate 5.15 Although isolation of 5 in a pure form was
difficult, this compound, prior to purification, was successfully
oxidized with NaBO3 to give the corresponding primary alcohol
6.16 In addition, cyclohexylboronate 3h was converted into the
secondary alcohol trans-7, which has been reported in the
literature,17 through stereospecific, oxidative transformation.
In summary, a combination of the silica-supported cage-
shaped trialkylphosphine Silica-SMAP and [Ir(OMe)(cod)]2
produces a heterogeneous catalyst that enables the pyridine-
directed borylation of unactivated primary or secondary
C(sp3)−H bonds using bis(pinacolato)diboron. This combina-
tion of a reagent and a catalyst provides a new and efficient
strategy for the preparation of alkylboronates. The C(sp3)−H
borylation occurs with exclusive site-selectivity at the position γ
F.; Hall, M. B. J. Am. Chem. Soc. 2010, 132, 3078. (g) Liskey, C. W.;
Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 12422. (h) Kawamorita, S.;
Miyazaki, T.; Iwai, T.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc.
2012, 134, 12924. (i) Ohmura, T.; Torigoe, T.; Suginome, M. J. Am.
Chem. Soc. 2012, 134, 17416.
(3) Transition metal catalyzed benzylic C(sp3)−H borylation
reactions: (a) Shimada, S.; Batsanov, A. S.; Howard, J. A. K.;
Marder, T. B. Angew. Chem., Int. Ed. 2001, 40, 2168. (b) Ishiyama, T.;
Ishida, K.; Takagi, J.; Miyaura, N. Chem. Lett. 2001, 30, 1082.
(c) Boebel, T. A.; Hartwig, J. F. Organometallics 2008, 27, 6013.
(4) Recent reviews on transition metal catalyzed C(sp3)−H
functionalizations: (a) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc.
Chem. Res. 2009, 42, 1074. (b) Jazzar, R.; Hitce, J.; Renaudat, A.;
Sofack-Kreutzer, J.; Baudoin, O. Chem.Eur. J. 2010, 16, 2654.
(c) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (d) Li,
H.; Li, B.-J.; Shi, Z.-J. Catal. Sci. Technol. 2011, 1, 191. (e) Baudoin, O.
Chem. Soc. Rev. 2011, 40, 4902.
C
dx.doi.org/10.1021/ja3126239 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(5) Selected recent examples of transition metal catalyzed C(sp3)−H
functionalization; (a) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011,
50, 5192. (b) Stowers, K. J.; Fortner, C.; Sanford, M. S. J. Am. Chem.
Soc. 2011, 133, 6541. (c) Hasegawa, N.; Charra, V.; Inoue, S.;
Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 8070. (d) Ano,
Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 12984.
(e) Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 19076.
(f) Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 19598. (g) Ren, Z.; Mo, F.; Dong, G. J. Am.
Chem. Soc. 2012, 134, 16991. (h) Wasa, M.; Chan, S. L. K.; Zhang, X.-
G.; He, J.; Miura, M.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 18570.
(i) Simmons, E. M.; Hartwig, J. F. Nature 2012, 483, 70. (j) Gutekunst,
W. R.; Gianatassio, R.; Baran, P. S. Angew. Chem., Int. Ed. 2012, 51,
7507.
(d) Sandrock, D. L.; Jean-Ger
́
ard, L.; Chen, C.-Y.; Drenher, S. D.;
Molander, G. A. J. Am. Chem. Soc. 2010, 132, 17108. (e) Awano, T.;
Ohmura, T.; Suginome, M. J. Am. Chem. Soc. 2011, 133, 20738. See
also refs 13d, e.
(17) Matsugi, M.; Itoh, K.; Nojima, M.; Hagimoto, Y.; Kita, Y.
Chem.Eur. J. 2002, 8, 5551.
(6) (a) Brown, H. C. In Organic Synthesis via Organoboranes; Wiley
Interscience: New York, 1975. (b) Boronic Acids; Hall, D. G., Ed.;
Wiley-VCH: Weinheim, 2005. (c) Doucet, H. Eur. J. Org. Chem. 2008,
2013. (d) Scott, H. K.; Aggarwal, V. K. Chem.Eur. J. 2011, 17,
13124.
(7) The synthesis, properties, and use of nonimmobilized SMAP
derivatives (silicon-constrained monodentate trialkylphosphine):
(a) Ochida, A.; Hara, K.; Ito, H.; Sawamura, M. Org. Lett. 2003, 5,
2671. (b) Ochida, A.; Hamasaka, G.; Yamauchi, Y.; Kawamorita, S.;
Oshima, N.; Hara, K.; Ohmiya, H.; Sawamura, M. Organometallics
2008, 27, 5494.
(8) The synthesis and applications of Silica-SMAP: (a) Hamasaka,
G.; Ochida, A.; Hara, K.; Sawamura, M. Angew. Chem., Int. Ed. 2007,
46, 5381. (b) Hamasaka, G.; Kawamorita, S.; Ochida, A.; Akiyama, R.;
Hara, K.; Fukuoka, A.; Asakura, K.; Chun, W. J.; Ohmiya, H.;
Sawamura, M. Organometallics 2008, 27, 6495. (c) Kawamorita, S.;
Ohmiya, H.; Iwai, T.; Sawamura, M. Angew. Chem., Int. Ed. 2011, 50,
8363.
(9) Use of Silica-SMAP for directed C(sp2)−H borylation:
(a) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura,
M. J. Am. Chem. Soc. 2009, 131, 5058. (b) Kawamorita, S.; Ohmiya,
H.; Sawamura, M. J. Org. Chem. 2010, 75, 3855. (c) Yamazaki, K.;
Kawamorita, S.; Ohmiya, H.; Sawamura, M. Org. Lett. 2010, 12, 3978.
(d) Kawamorita, S.; Tatsuya, M.; Ohmiya, H.; Iwai, T.; Sawamura, M.
J. Am. Chem. Soc. 2011, 133, 19310.
(10) Silica-SMAP and its parent homogeneous ligand Ph-SMAP are
bench-stable. For convenience, we use a glovebox for setup of the
reaction (see Supporting Information for typical procedures), but the
glovebox operation is not mandatory. See refs 7 and 8a, b for
properties of the phosphine ligands.
(11) Selective functionalization of the terminal C(sp3)−H bond of 2-
ethylpyridine; (a) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657.
(b) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128,
12634. Also see ref 5b.
(12) The Silica-SMAP−Ir and Silica-TRIP−Ir catalysts were readily
removed from the products by Celite filtration, but attempts to reuse
the catalysts were unsuccessful.
(13) For preparation and utility of geminal diborylalkanes, see:
(a) Shimizu, M.; Schelper, M.; Nagao, I.; Shimono, K.; Kurahashi, T.;
Hiyama, T. Chem. Lett. 2006, 35, 1222. (b) Endo, K.; Hirokami, M.;
Shibata, T. Synlett 2009, 1331. (c) Endo, K.; Hirokami, M.; Shibata, T.
J. Org. Chem. 2010, 75, 3469. (d) Endo, K.; Ohkubo, T.; Hirokami, M.;
Shibata, T. J. Am. Chem. Soc. 2010, 132, 11033. (e) Lee, J. C. H.;
McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3, 894.
(14) The yield in excess of 100% indicates that a minor contribution
of the reaction with pinB−H.
(15) (a) Brown, H. C.; Singh, S. M.; Rangaishevi, M. V. J. Org. Chem.
1986, 51, 3150−3155. (b) Matteson, D. S. Chem. Rev. 1989, 89,
1535−1551.
(16) Attempts of Suzuki−Miyaura coupling with the secondary
alkylboronate 3f have so far been unsuccessful. For Suzuki−Miyaura
coupling of secondary alkylboron compounds, see: (a) Doucet, H. Eur.
J. Org. Chem. 2008, 2014. (b) Imao, D.; Glasspoole, B. W.; Laberge, V.
S.; Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024. (c) Ohmura, T.;
Awano, T.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 13191.
D
dx.doi.org/10.1021/ja3126239 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX