Ester-directed regioselective borylation of heteroarenes catalyzed by a silica-supported iridium complex

Article abstract of DOI:10.1021/jo100352b

Figure presented The ester-directed regioselective borylation of arenes catalyzed by a silica-supported monophosphine-Ir complex displayed a significantly broad substrate scope toward heteroaromatic compounds, including thiophene, pyrrole, furan, benzothiophene, benzofuran, indole, and carbazole derivatives. The regioselectivity is complementary to the selectivities observed in the heteroarene C-H borylation with the dtbpy-Ir catalyst system.

Full text of DOI:10.1021/jo100352b

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and [Ir(OMe)(cod)]2, showed high activity and selectivity for
Ester-Directed Regioselective Borylation of
Heteroarenes Catalyzed by a Silica-Supported
Iridium Complex
the directed ortho borylation of functionalized arenes with
bis(pinacolato)diboron (pinB-Bpin, 2).5-7 Extension of this
method to the regioselective borylation of heteroarenes would
be of particular interest due to the importance of heteroarene
structures in pharmaceuticals, bioactive natural compounds,
and functional organic materials. We were, however, faced with
at least two challenges. First, the heteroatom in the heteroarene
cores might prevent the coordination of the directing group to
the metal center. Second, the electronic effect of the hetero-
atom, which potentially induces the borylation at the 2-position
as observed by Miyaura-Ishiyama’s8 and Smith’s9 groups
with the dtbpy-Ir system (dtbpy: 4,40-di-tert-butylbipyridine),
might compete with the coordination-based directing effect.
Herein we report that the borylation of ester-functiona-
lized heteroarenes with the Silica-SMAP-Ir (1) catalyst
system results in coordination-based regioselectivity that
complements the selectivities observed in sterically and/or
electronically controlled heteroarene borylations with the
dtbpy-Ir catalyst system. The use of the immobilized ligand
(Silica-SMAP) was crucial for the ester-directed regioselec-
tivity in the borylation of various types of heteroarenes
including thiophene, pyrrole, benzothiophene, furan, benzo-
furan, indole, and carbazole derivatives.8-10
Soichiro Kawamorita, Hirohisa Ohmiya, and
Masaya Sawamura*
Department of Chemistry, Faculty of Science,
Hokkaido University, Sapporo 060-0810, Japan
sawamura@sci.hokudai.ac.jp
Received February 25, 2010
The reaction of 5-methyl-2-methoxycarbonylthiophene
(3a, 1 mmol) with an equimolar amount of 2 (1 mmol) in
hexane in the presence of 0.25 mol % of Silica-SMAP-Ir-
(OMe)(cod) (1) proceeded at 70 °C and was complete within
10 h to give borylation product 4a in 99% isolated yield
(based on 3, 100% NMR yield) (Scheme 1).11 The reaction
The ester-directed regioselective borylation of arenes
catalyzed by a silica-supported monophosphine-Ir com-
plex displayed a significantly broad substrate scope to-
ward heteroaromatic compounds, including thiophene,
pyrrole, furan, benzothiophene, benzofuran, indole, and
carbazole derivatives. The regioselectivity is complemen-
tary to the selectivities observed in the heteroarene C-H
borylation with the dtbpy-Ir catalyst system.
(6) SMAP: silicon-constrained monodentate trialkylphosphine. See:
(a) Ochida, A.; Hara, K.; Ito, H.; Sawamura, M. Org. Lett. 2003, 5, 2671–
2674. (b) Ochida, A.; Ito, S.; Miyahara, T.; Ito, H.; Sawamura, M. Chem.
Lett. 2006, 35, 294–295. (c) Ochida, A.; Hamasaka, G.; Yamauchi, Y.;
Kawamorita, S.; Oshima, N.; Hara, K.; Ohmiya, H.; Sawamura, M. Orga-
nometallics 2008, 27, 5494–5503.
Transition metal-catalyzed direct functionalization of
aromatic C-H bonds has recently emerged as an area of act-
ive research in organic synthesis. Catalytic C-H borylation
of arenes has allowed efficient synthesis of various borylated
arenes, which are versatile synthetic intermediates.1-5 We
reported recently that an immobilized monophosphine-Ir
system [Silica-SMAP-Ir (1)], which was prepared in situ from
a silica-supported, compact monophosphine (Silica-SMAP)
(7) For the synthesis and applications of Silica-SMAP, see: (a) Hamasa-
ka, G.; Ochida, A.; Hara, K.; Sawamura, M. Angew. Chem., Int. Ed. 2007, 46,
5381–5383. (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, 6495–6506. (c) Kawamorita, S.; Hamasaka, G.;
Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. Org. Lett. 2008, 10,
4697–4700.
(8) (a) Takagi, J.; Sao, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N.
Tetrahedron Lett. 2002, 43, 5649–5651. (b) Ishiyama, T.; Takagi, J.; Yone-
kawa, Y.; Hartwig, J. F.; Miyaura, N. Adv. Synth. Catal. 2003, 345, 1103–
1106.
(9) (a) Tse, M. K.; Cho, J.-Y.; Smith, M. R., III Org. Lett. 2001, 3, 2831–
2833. (b) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R.
E., Jr.; Smith, M. R., III J. Am. Chem. Soc. 2006, 128, 15552–15553.
(c) Chotana, G. A.; Kallepalli, V. A.; Maleczka, R. E., Jr.; Smith, M. R., III
Tetrahedron 2008, 64, 6103–6114. (d) Kallepalli, V. A.; Shi, F.; Paul, S.;
Onyeozili, E. N.; Maleczka, R. E., Jr.; Smith, M. R., III J. Org. Chem. 2009,
74, 9199–9201. See also: (e) Harrisson, P.; Morris, J.; Marder, T. B.; Steel, P.
G. Org. Lett. 2009, 11, 3586–3589. (f) Chotana, G. A.; Rak, M. A.; Smith, M.
R., III J. Am. Chem. Soc. 2005, 127, 10539–10544.
(10) (a) Chen, J.; Aratani, N.; Shinokubo, H.; Osuka, A. Chem. Asian J.
2009, 4, 1126–1133. (b) Chen, J.; Mizumura, M.; Shinokubo, H.; Osuka, A.
Chem.;Eur. J. 2009, 15, 5942–5949. (c) Klecka, M.; Pohl, R.; Klepetarova,
B.; Hocek, M. Org. Biomol. Chem. 2009, 7, 866–868. (d) Mertins, K.; Zapf,
A.; Beller, M. J. Mol. Catal. A: Chem. 2004, 21–25. (e) Robbins, D. W.;
Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 4068–4069.
(11) The isolated products were contaminated with traces of unidentified
compounds that stem from pinacolborane (H-Bpin) alone (ca. 0.1-3%)
based on the ratio of the integral of the methyl protons of the pinacol moiety
(12H).
(1) For a review, see: Mkhalid, I. A.; Barnard, J. H.; Marder, T. B.;
Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890–931.
(2) (a) Iverson, C. N.; Smith, M. R., III J. Am. Chem. Soc. 1999, 121,
7696–7697. (b) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.;
Smith, M. R., III Science 2002, 295, 305–308. (c) Ishiyama, T.; Takagi, J.;
Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc.
2002, 124, 390–391. (d) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N.
Angew. Chem., Int. Ed. 2002, 41, 3056–3058. (e) Boller, T. M.; Murphy, J. M.;
Hapke, M.; Ishiyama, T.; Miyaura, N.; Hartwig, J. F. J. Am. Chem. Soc.
2005, 127, 14263–14278. (f) Chotana, G. A.; Rak, M. A.; Smith, M. R., III
J. Am. Chem. Soc. 2005, 127, 10539–10544.
(3) For the directed ortho borylation of benzoate derivatives catalyzed by
the Ir-P[3,5-(CF3)2C6H3]3 system, see: Ishiyama, T.; Isou, H.; Kikuchi, T.;
Miyaura, N. Chem. Commun. 2010, 46, 159–161.
(4) For ortho borylation of arenes directed by a Me2HSi group, see:
Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534–7535.
(5) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M.
J. Am. Chem. Soc. 2009, 131, 5058–5059.
DOI: 10.1021/jo100352b
r
Published on Web 04/29/2010
J. Org. Chem. 2010, 75, 3855–3858 3855
2010 American Chemical Society

Kawamorita et al.
JOCNote
SCHEME 1
TABLE 1. Ir-Catalyzed Borylation of 2-Thiophenecarboxylic Acid
Estersa,b
was completely regioselective, delivering the boryl group to
the 3-position. Notably, the reaction was also selective for
monoborylation; no diborylation was observed, even with
use of stoichiometric quantities of the reactants. The corre-
sponding homogeneous catalysts that were prepared in situ
from [Ir(OMe)(cod)]2 and Ph-SMAP6 (0.25 mol % Ir, Ir/P
1:1 or 1:2) afforded no borylation products under otherwise
similar reaction conditions, indicating that phosphine im-
mobilization is crucial, as was the case in the directed ortho
borylation of carbocyclic arenes.3
The regioselectivity observed with the Silica-SMAP-Ir
system is in sharp contrast to that seen with the dtbpy-Ir-
(OMe)(cod) system.8,9 In our hands, the application of the
dtbpy-Ir system to the reaction between 3a and 2 resulted in
the exclusive formation of isomer 4a0 (Scheme 1). The
regioselectivity of the reaction catalyzed by the dtbpy-Ir
system seems to be controlled by steric factors.
The ester-directed borylation was applicable to various
thiophene derivatives (3b-g).11 The results are summarized
in Table 1 along with those obtained with the dtbpy-Ir
system.2,8,9 The borylation of 2-methoxycarbonylthiophene
3b occurred at the 3-position to form 4b selectively but also
formed the minor isomer 4b0 with the boryl group at the
5-position, which is R to the sulfur atom (C3/C5 91:9; 4b/
diborylation product 87:13) (entry 1).12 In contrast, the
dtbpy-Ir-catalyzed borylation took place exclusively at
the 5-position (entry 2).
aConditions: 3 (1.0 mmol), 2 (1.0 mmol), Silica-SMAP-Ir(OMe)-
(cod) (1, 0.25 mol %), hexane or octane (2.0 mL). bConditions: 3
(1.0 mmol), 2 (1.0 mmol), [Ir(OMe)(cod)]2 (0.125 mol %), dtbpy
(0.25 mol %), hexane or octane (2.0 mL). cIsolated yield of 4 based on
3. 1H NMR yield is in parentheses. d3,5-Bis-borylation product was
detected in the crude mixture (12%). The product was obtained as a
mixture of 4b and 4b0 (4b/4b0 91:9). fp-Xylene was used as a solvent. gThe
product was obtained as a mixture of 4f and 4f0 (4f/4f0 97:3).
e
recovery of complete ester-directed regioselectivity (entries 3
and 5). When dtbpy was used as a ligand, the reaction of 3c
was sluggish even at 100 °C, and showed C-4 regioselectivity
(entry 4). Notably, the reaction of the phenyl-substituted
thiophene 3d with the dtbpy ligand resulted in a complex
mixture, which included isomers derived from borylation not
only at the thiophene ring but also the phenyl group (entry 6).
The comparison between entries 5 and 6 demonstrates the
utility of the ester-directed methodology in the preparation
of multiaromatic organoboron compounds. Unfortunately,
the 5-methoxy-2-carbomethoxythiophene (3e) did not react
at all. This result seems to be due to an electronic rather than
a steric effect (entry 7).
The substitution at the 5-position of 2-methoxycarbo-
nylthiophene with Cl (3c) or Ph (3d) groups resulted in the
(12) The lithiation of 3b with LDA and subsequent trapping with
B(OiPr)3 followed by treatment with pinacol provided compound 4b0 with
the boryl group at the 5-position, which is R to the sulfur atom (74%). On the
other hand, the lithiation-borylation of 3a resulted in a complex mixture.
See: (a) Snieckus, V. Chem. Rev. 1990, 90, 879–933. (b) Mackin, T. K.;
Snieckus, V. Org. Lett. 2005, 7, 2519–2522.
The borylation of 4-methyl-2-methoxycarbonylthiophene
(3f) proceeded with excellent selectivity at 70 °C regardless of
the considerable steric congestion at the 3-position (C3/C5
97:3) (entry 8). With dtbpy-Ir, however, the borylation
occurred exclusively at the 5 position (entry 9). In addi-
tion to the methyl ester substituent, the tert-butyl ester
.
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Kawamorita et al.
JOCNote
TABLE 2. Borylation of Hetereoarenes Catalyzed by the Silica-SMAP-Ir
SCHEME 2. Transformations with Borylated Thiophenes
Systema
aromatic C-H bonds (Table 2, entries 3-9).13 The reactions
of benzothiophene (3j) and benzofuran (3k) derivatives with
a 2-methoxycarbonyl substituent occurred exclusively at the
position adjacent to the ester group (entries 3 and 4). The
reaction was also effective for the functionalization of in-
doles (entries 5-8). The ester groups at the 2-position or the
3-position in 1-methylindole directed the borylation to the
adjacent positions with complete selectivity (entries 5 and 7).
Even the NH-free indole 3m underwent the regioselec-
tive borylation, although the occurrence of N-borylation
required the use of an excess amount of 2 (entry 6). In
addition, the methoxycarbonyl group on the nitrogen atom
of the N-protected indole 3o delivered the boryl group to the
2-position of the nitrogen-containing five-membered-ring
moiety (entry 8). Likewise, N-isopropoxycarbonylcarbazole
3p underwent selective monoborylation at the 1-position
(entry 9).
Transformations of selected borylated thiophenes were
conducted to demonstrate their reactivity (Scheme 2). Suzuki-
Miyaura coupling between 4a and 1,4-dibromobenzene
afforded bisthiophenylbenzene 5. The Rh-catalyzed conju-
gate addition of 4c to butyl acrylate furnished the thiophene
derivative with a functionalized alkyl group at the 3-position
in good yield.
In summary, the ester or carbamate-directed borylation of
arenes catalyzed by a silica-supported monophosphine-Ir
complex displayed a broad substrate scope toward hetero-
aromatic compounds, including thiophene, pyrrole, furan,
benzothiophene, benzofuran, indole, and carbazole de-
rivatives. The regioselectivities observed with the Silica-
SMAP-Ir system are complementary to those obtained in
the sterically and/or electronically controlled heteroarene
C-H borylation reactions carried out with the dtbpy-Ir
catalyst system.
aConditions: 3 (1.0 mmol), 2 (1.0 mmol), Silica-SMAP-Ir(OMe)-
(cod) (1, 0.25 mol %), solvent (2.0 mL, entries 1 and 8, hexane; entries 2,
3, 5-7, and 9, mesitylene; entry 4, p-xylene). bIsolated yield of 4 based on
3. cBis-borylation products were detected in the crude mixture (entry 1,
3,5-isomer, 3%; entry 2, 3,5-isomer, 21%; entry 8, 2,7-isomer, 5%). d2.0
e
mmol of 2 was used. 0.5 mol % of Silica-SMAP-Ir(OMe)(cod) was
used. fThe product was obtained as a mixture of 4i and 4i0 (4i/4i0 79:21).
moiety also served as a directing group to deliver the boryl
functionality to the adjacent position with complete selecti-
vity (entry 10).
Experimental Section
Heteroarenes other than thiophenes also participated in
the ester-directed regioselective borylation (Table 2).11 For
instance, 3-borylation of N-TIPS-protected 2-pyrrole car-
boxylic acid ester (3h) was successfully carried out under
essentially the same conditions (entry 1). The borylation of
2-methoxycarbonylfuran (3i) also occurred but with lower
selectivity than that observed for 3b (entry 2).
The highly regioselective nature of the ester-directed bor-
ylation enabled the use of benzofused heteroaromatic com-
pounds as substrates, regardless of the presence of multiple
Typical Procedure for the Borylation of Heteroarenes Cata-
lyzed by the Ir-Silica-SMAP System (Scheme 1, the upper side).
In a glovebox, Silica-SMAP (0.064 mmol P g-1, 39 mg,
0.0025 mmol), bis(pinacolato)diboron (2, 253.9 mg, 1.0 mmol),
and anhydrous, degassed hexane (1.6 mL) were placed in a 10 mL
glass tube containing a magnetic stirring bar, then the mixture
was stirred for 1 min at 25 °C. A solution of [Ir(OMe)(cod)]2
(0.8 mg, 0.00125 mmol) in hexane (0.4 mL) and thiophene-2-
carboxylic acid methyl ester (3a, 156.2 mg, 1.0 mmol) were
added to the tube, which was then sealed with a screw cap. The
tube was removed from the glovebox and the solution was
stirred at 70 °C for 10 h. The mixture was then filtered through
a glass pipet equipped with a cotton filter. Solvent was removed
(13) For the regioselective borylation of benzothiophene, benzofuran,
and indole at the 2-position, see refs 2d and 8a.
J. Org. Chem. Vol. 75, No. 11, 2010 3857

Kawamorita et al.
JOCNote
under reduced pressure. An internal standard (1,1,2,2-tetrachlo-
roethane) was added to the reaction mixture and the product
yield was determined by 1H NMR. The crude material was then
purified by Kugelrohr distillation to give the borylation product
4a (283.1 mg, 0.99 mmol) in 99% isolated yield (contaminated
with 3% impurity). 4a: white solid. 1H NMR (CDCl3) δ 1.39 (s,
12H), 2.49 (d, J = 1.2 Hz, 3H), 3.85 (s, 3H), 6.85 (d, J = 1.2 Hz,
1H, H-4). 13C NMR (CDCl3) δ 15.12, 24.66, 51.89, 84.24,
130.77, 135.42, 147.42, 163.14. A signal for the carbon directly
attached to the boron atom was not observed. HRMS-EI (m/z)
[M]þ calcd for C12H19BO4S 282.10998, found 282.10971. Mp
94.2 °C.
Acknowledgment. This work was supported by Grants-in-
Aid for Scientific Research on Priority Areas (Chemistry of
Concerto Catalysis) (MEXT).
Supporting Information Available: Experimental proce-
dures and NMR spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
3858 J. Org. Chem. Vol. 75, No. 11, 2010