Iridium-catalyzed, substrate-directed C-H borylation reactions of benzylic amines

Article abstract of DOI:10.1021/ol301635x

The iridium-catalyzed arene C-H borylation reaction of benzylic amines has been developed, which inverts the typical steric-controlled product distribution to provide ortho-substituted boronate esters. Picolylamine was found to be an ideal ligand to replace 4,4′-di-tert-butylbipyridine to induce the directing effect. Preliminary experiments are consistent with a mechanism involving dissociation of one amine of the hemilabile diamine ligand.

Full text of DOI:10.1021/ol301635x

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3558–3561
Iridium-Catalyzed, Substrate-Directed
CꢀH Borylation Reactions of Benzylic
Amines
Andrew J. Roering, Lillian V. A. Hale, Phillip A. Squier, Marissa A. Ringgold,
Emily R. Wiederspan, and Timothy B. Clark*
ꢀ
Department of Chemistry and Biochemistry, University of San Diego, 5998 Alcala Park,
San Diego, California 92110, United States, and Department of Chemistry,
Western Washington University, 516 High Street, Bellingham, Washington 98225,
United States
clarkt@sandiego.edu
Received June 14, 2012
ABSTRACT
The iridium-catalyzed arene CꢀH borylation reaction of benzylic amines has been developed, which inverts the typical steric-controlled product
distribution to provide ortho-substituted boronate esters. Picolylamine was found to be an ideal ligand to replace 4,40-di-tert-butylbipyridine to induce
the directing effect. Preliminary experiments are consistent with a mechanism involving dissociation of one amine of the hemilabile diamine ligand.
Metal-catalyzed CꢀH borylation reactions have received
significant attention in recent years due to the synthetic utility
of the resulting boronate esters1ꢀ3 and the ability to access
these key intermediates rapidly from simple starting
materials.4ꢀ6 The borylation of arene CꢀH bonds, primarily
discovered and developed by Hartwig, Ishiyama and
Miyaura,7ꢀ9 and Smith and Maleczka,10,11 is most readily
accomplished using an iridium catalyst [Ir(μ-OMe)(COD)]2
(COD = cyclooctadiene) with 4,40-di-tert-butylbipyridine
(dtbpy) as the ligand. The selectivity of arene CꢀH boryla-
tion reactions is governed by steric effects, resulting in
functionalization meta- and para- to arene substituents.5,12ꢀ14
With appropriately chosen substrates (such as 1,2- or 1,3-
disubstituted arenes) high selectivity is observed. The mild
reaction conditions and ability to incorporate a boronate
ester without a preinstalled halogen is the hallmark of this
valuable transformation. Developing an analogous method
that reverses the inherent selectivity to provide ortho boryla-
tion products would complement this method, providing
access to a larger variety of arylboronate esters.
(1) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Middland, M. M. Organic
Syntheses via Boranes; Wiley-Interscience: New York, 1975; Vol. 1.
(2) Brown, H. C.; Zaidlewicz, M. Organic Syntheses via Boranes-Recent
Developments; Aldrich Chemical Company: Milwaukee, 2001; Vol. 2.
(3) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(4) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.;
Hartwig, J. F. Chem. Rev. 2010, 110, 890.
Hartwig and co-workers initially reported a general
method for substrate-directed ortho CꢀH borylation in
2008, which utilized siloxides andsilylamines as the directing
group.15,16 Since that initial discovery several methods have
(5) Hartwig, J. F. Chem. Soc. Rev. 2011, 40, 1992.
(6) Hartwig, J. F. Acc. Chem. Res. 2012, 45, 864.
(7) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390.
(8) Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Chem.
(12) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith,
M. R., III. Science (Washington D. C.) 2002, 295, 305.
(13) Chotana, G. A.; Rak, M. A.; Smith, M. R., III. J. Am. Chem.
Soc. 2005, 127, 10539.
Commun. 2003, 2924.
€
(14) Hurst, T. E.; Macklin, T. K.; Becker, M.; Hartmann, E.; Kugel,
W.; Parisienne-La Salle, J.-C.; Batsanov, A. S.; Marder, T. B.; Sniekus,
V. Chem.;Eur. J. 2010, 16, 8155.
(15) Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534.
(16) Robbins, D. W.; Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc.
2010, 132, 4068.
(9) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura,
N.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 14263.
(10) Iverson, C. N.; Smith, M. R., III. J. Am. Chem. Soc. 1999, 121, 7696.
(11) Cho, J.-Y.; Iverson, C. N.; Smith, M. R., III. J. Am. Chem. Soc.
2000, 122, 12868.
r
10.1021/ol301635x
Published on Web 06/25/2012
2012 American Chemical Society

been reported that provide ortho CꢀH borylation.17ꢀ20 Of
20,21
particular note for this communication, Sawamura19 and
Table 1. Ligand Screen for Directed CꢀH Borylation (eq 1)
ꢀ
Fernandez and Lassaletta
recently reported the first
methods that utilize an amine to direct the CꢀH function-
alization to the ortho position.22,23 Both of these methods
utilize a ligand framework that can form a transient open
coordination site on the metal after the amine binds to the
complex, directing the CꢀH borylation to the ortho position.
Figure 1. Proposed bifunctional directing effect.
Our ongoing interest in metal boryl complexes with
bifunctional ligands24,25 led us to examine ligands that
possess a NꢀH bond that could be used to direct CꢀH
borylation through hydrogen bonding to a Lewis base in
the substrate (Figure 1). To this end, bidentate ligands
possessing a NꢀH bond, in conjunction with [Ir(μ-OMe)-
(COD)]2, were screened with four Lewis base substituted
arenes (anisole, N,N-dimethylaniline, benzyl methyl ether,
and N,N-dimethylbenzylamine). Using a variety of li-
gands, N,N-dimethylbenzylamine was the only substrate
that displayed >10% conversion of arene to the boronate
ester. In contrast, many of these ligands were effective in
promoting CꢀH borylation of N,N-dimethylbenzylamine,
providing selective ortho-functionalization (Table 1).
CꢀH borylation of N,N-dimethylbenzylamine with
dtbpy resulted in an unselective mixture of aryl boronate
ester isomers in 22% conversion (Table 1, entry 1). 2-
(Diphenylphosphino)-ethylamine resulted in low conversion,
but only ortho borylation products were observed (entry 2).
Ethylenediamine, o-phenylenediamine, and 4-trifluoromethyl-
phenylenediamine resulted in increased conversion to ortho
borylation products 1a and 2a (entries 3ꢀ5). Finally, picoly-
lamine (picNH2, entry 6) provided a significant increase in
conversion while maintaining the high selectivity of 1a:2a.
The reaction conditions using picolylamine were optimized
for increased conversion and selectivity (ratio of 1a:2a), as
a % Conversion was determined by 1H NMR spectroscopy using a
5 s relaxation delay to ensure integral integrity. All conversions are based
on the arene substrate. b Ratio of 1a:2a determined by 1H NMR
spectroscopy. c Ratio of 1a:2a not determined. Ratio of meta- þ para-
isomers to 1a þ 2a is ∼3:1.
summarized in Table 2. The temperature was optimized to
70 °C (entries 1ꢀ4), providing the highest combination of
yield and selectivity. The most significant influence on conver-
sion was observed upon adjusting the ratio of B2pin2/arene
(entries 3, 5, and 6); an 88% conversion and a 93:7 ratio of
1a:2a were observed using 1.2 equiv of the arene (entry 6).
Purification by column chromatography (basic alumina)
provided 1a in a 73% isolated yield. Notably, this yield and
the conversions reported in Tables 1 and 2 are calculated with
respect to the arene substrate, demonstrating that B2pin2 can
serve as two equivalents of the boron source. Most yields
reported in the literature in this area are calculated with respect
to B2pin2 (using excess arene) and result in significant amounts
of unreacted arene.4,19
With optimized reaction conditions in hand, the effect
of various arene substituents on yield and selectivity was
explored. Ortho-substituted benzylamines were first examined
to determine the range of simple functional groups that were
tolerated (Figure 2). Methyl- (3b), fluoro- (3c), and chloro-
(3d) substituents were all tolerated, providing a good yield of
the corresponding aryl boronate ester. The bromo-substituted
arene (3e), however, resulted in <5% conversion. The lack of
reactivity was attributed to preferential oxidative addition into
the CꢀBr bond over activation of the CꢀH bond. Accord-
ingly, para-bromo-substituted arene 3f was found to provide
boronate ester 1f, albeit in a modest 37% yield. Other para-
substituted substrates (3g, 3h) provided high yields of the
boronate esters, but bis borylation products were present to a
higher degree with these substrates. Notably, the CꢀH
borylation conditions were tolerated with the ester-substituted
(17) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura,
M. J. Am. Chem. Soc. 2009, 131, 5058.
(18) Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N. Chem. Com-
mun. 2010, 159.
(19) Kawamorita, S.; Miyazaki, T.; Ohmiya, H.; Iwai, T.; Sawamura,
M. J. Am. Chem. Soc. 2011, 133, 19310.
ꢀ
(20) Ros, A.; Estepa, B.; Lopez-Rodrıguez, R.; Alvarez, E.; Fernandez,
ꢀ
ꢀ
R.; Lassaletta, J. M. Angew. Chem., Int. Ed. 2011, 50, 11724.
ꢀ
(21) Ros, A.; Lopez-Rodrıguez, R.; Estepa, B.; Alvarez, E.; Fernandez,
ꢀ
ꢀ
R.; Lassaletta, J. M. J. Am. Chem. Soc. 2012, 134, 4573.
(22) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka,
R. E., Jr.; Smith, M. R., III. J. Am. Chem. Soc. 2006, 128, 15552.
(23) Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 134.
(24) Koren-Selfridge, L.; Londino, H. N.; Vellucci, J. K.; Simmons,
B. J.; Casey, C. P.; Clark, T. B. Organometallics 2009, 28, 2085.
(25) Koren-Selfridge, L.; Query, I. P.; Hanson, J. A.; Isley, N. A.;
Guzei, I. A.; Clark, T. B. Organometallics 2010, 29, 3896.
Org. Lett., Vol. 14, No. 13, 2012
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substituent (4iꢀ4k) was the second major product in
addition to a small amount of the bis borylation products
2iꢀ2k. Borylation between 1,3-disubstituted arenes was
unexpected due to the sensitivity of the catalyst to steric
effects using the nondirected catalyst system.5,12,13 Forma-
tion of this isomer led us to examine 3l, which requires
borylation between the two substituents. Gratifyingly, a
high yield and high selectivity for monoborylation (1l) was
observed. Boronate esters 1aꢀ1l are direct precursors to
Wulff-type boronic acids, saccharide sensors which have
been shown to have appropriate pH tolerance for biologi-
cal applications based on the interaction between the
benzylic amine and boron.26ꢀ29
Table 2. Reaction Optimization (eq 2)
The scope of the amine directing group was examined
next. N,N-Dimethyl-2-phenylethylamine was successfully
utilized in the reaction albeit with reduced conversion,
providing 6a in moderate yield (Figure 3). The sterically
hindered N,N-dimethyl-1-phenylethylamine provided aryl-
boronate ester 6b in high yield and selectivity. Imidazolidine
5c was also successful in directing CꢀH borylation to the
ortho position, but significant quantities of the bis boryla-
tion product was formed under the reaction conditions.
The use of N,N-dimethylbenzamide, however, resulted in
<5% conversion to 6d.
a % Conversion was determined by 1H NMR spectroscopy using a
5 s relaxation delay to ensure integral integrity.
Figure 3. Scope of amine directing group.
The lack of reactivity observed with benzamide 5d sug-
gested that a basic amine is required for the directing effect
and that the directing effect significantly enhanced the reac-
tion rate compared to nonbasic substrates. Accordingly, a
reaction was performed using toluene as the solvent. Toluene
is typically avoided in arene borylation reactions due to the
presence of several reactive CꢀH bonds in the molecule.4
Using the optimized reaction conditions with toluene as
solvent resulted in a 75% yield of 1a (eq 3). This experiment
shows the significant difference of reactivity between the two
Figure 2. Scope of directed CꢀH borylation reaction.
benzylic amine to provide 1h without competitive borylation
directed by the ester.17,18
Finally, meta-substituted arenes 3iꢀ3k were examined
and found to provide good to moderate yields. The major
boronate ester product in each case resulted from CꢀH
borylation away from the meta substituent. Borylation
between the aminomethyl directing group and the meta
(26) Kim, K. T.; Cornelissen, J. J. L. M.; Nolte, R. J. M.; van Hest,
J. C. M. J. Am. Chem. Soc. 2009, 131, 13908.
(27) Li, H.; Liu, Y.; Liu, J.; Liu, Z. Chem. Commun. 2011, 47, 8169.
(28) Wulff, G. Pure Appl. Chem. 1982, 54, 2093.
(29) Burgemeister, T.; Grobe-Einsler, R.; Grotstollen, R.;
Mannschreck, A.; Wulff, G. Chem. Ber. 1981, 114, 3403.
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Org. Lett., Vol. 14, No. 13, 2012

arenes, which is selective for the benzylic amine even in a 19:1
ratio of toluene/N,N-dimethylbenzylamine.
Scheme 2. Proposed Catalytic Cycle
A control experiment was also designed to interrogate
the nature of the directing effect. The proposed hydrogen
bond directing effect (see Figure 1) was probed by replacing
the picolylamine ligand with N,N-dimethylpicolylamine. If
the directing effect is the result of hydrogen bonding, the
lack of NꢀH bonds on dimethylpicolylamine should result
in decreased catalytic activity and primarily meta/para
CꢀH borylation products. Upon performing the experi-
ment (Scheme 1), similar conversion and the selectivity for
ortho borylation products were maintained (with slightly
increased bis borylation). This experiment clearly negates
the possibility of a hydrogen bond directing effect.
Scheme 1. Control Experiment Using Dimethylpicolylamine
the CꢀB bond provides F, which can release boronate ester 1a
and regenerate the active catalyst upon addition ofh B2pin2.
In conclusion, substrate-directed CꢀH borylation of
benzylic amines has been demonstrated using picolylamine
as the ligand. This transformation generally provides good
yields and selectivity for the mono ortho borylation products
when a basic amine is employed. The directing effect is
inconsistent with the originally proposed hydrogen bonding
directing effect and is proposed to result from partial dis-
sociation of one amine nitrogen of the diamine ligand.
The directing effect is proposed to result from dissociation
of one of the two amine nitrogens to open the necessary
coordination site for ortho CꢀH borylation. The catalytic
cycle shown in Scheme 2 begins with the active catalyst
(A),30,31 which is analogous to the accepted complex using
dtbpy.9,32 Association of the substrate nitrogen provides
intermediate B, which can undergo dissociation of one of
the picolylamine nitrogens to provide coordinatively unsa-
turated complex C.33 A mechanism involving a hemilabile
dicoordinate ligand to direct CꢀH borylation is consistent
ortho borylation of hydrazones and pyridine derivatives.20
Complex C is poised for CꢀH activation, which proceeds
through either σ-complex D or standard oxidative addition
to give the 7-coordinate Ir(V) complex (E).9,32 Formation of
Acknowledgment. Acknowledgement is made to the do-
nors of the American Chemical Society Petroleum Research
Fund for partial support of this research (47598-GB3), Cam-
bridge Isotope Laboratories, Inc. Research Grant, which
generously provided methylcyclohexane-d14, Research Cor-
poration for Science Advancement and the M. J. Murdock
Charitable Trust for department development grants, Wes-
tern Washington University, and the University of San Diego.
ꢀ
with the recent report by Fernandez and Lassaletta for the
Supporting Information Available. Detailed experimen-
tal procedures, characterizations of all compounds, and
selected spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(30) NꢀH borylation of picolylamine is likely taking place to a
certain extent (see ref 31) but is not reflected in the catalytic cycle for
the sake of clarity.
(31) Jaska, C. A.; Temple, K.; Lough, A. J.; Manners, I. J. Am. Chem.
Soc. 2003, 125, 9424.
(32) Tamura, H.; Yamazaki, H.; Sato, H.; Sakaki, S. J. Am. Chem.
(33) Crumpton, D. M.; Goldberg, K. I. J. Am. Chem. Soc. 2000, 122, 962.
Soc. 2003, 125, 16114.
The authors declare no competing financial interest.
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