Iridium(I)-catalyzed vinylic C-H borylation of 1-cycloalkenecarboxylates with bis(pinacolato)diboron

Article abstract of DOI:10.1039/c3cc44149k

Ir(i)-catalyzed C-H borylation of 1-cycloalkenecarboxylic derivatives with bis(pinacolato)diboron affords various alkenylboronates with functional groups in excellent yields. This reaction was also used in a one-pot borylation/Suzuki-Miyaura cross-coupling procedure.

Full text of DOI:10.1039/c3cc44149k

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Iridium(I)-catalyzed vinylic C–H borylation of
1-cycloalkenecarboxylates with bis(pinacolato)diboron†
Cite this: Chem. Commun., 2013,
49, 7546
Ikuo Sasaki, Hana Doi, Toshiya Hashimoto, Takao Kikuchi, Hajime Ito* and
Tatsuo Ishiyama*
Received 3rd June 2013,
Accepted 26th June 2013
DOI: 10.1039/c3cc44149k
www.rsc.org/chemcomm
Ir(I)-catalyzed C–H borylation of 1-cycloalkenecarboxylic derivatives
with bis(pinacolato)diboron affords various alkenylboronates with
functional groups in excellent yields. This reaction was also used in a
one-pot borylation/Suzuki–Miyaura cross-coupling procedure.
Scheme 1 Vinylic C–H borylation of 1-cycloalkenecarboxylates.
1-Alkenylboronates are an important class of compounds and
are versatile intermediates in synthetic organic chemistry.1
Their utility has been amply demonstrated in the synthesis of 1 with 2, catalyzed using an in situ-generated Ir complex con-
natural products and biologically active compounds via C–C sisting of readily available [Ir(OMe)(cod)]2 and AsPh3 in octane
bond formation with C–B bonds.2 Conventional methods for solvent. The reaction proceeded chemoselectively at 80 1C or
the preparation of alkenylboronates include the reaction of 120 1C to give the corresponding alkenylboronic compounds 3 in
B(OR)3 with alkenyl-lithium or -magnesium reagents, and the high yields (Scheme 1). This reaction was used in a one-pot
Pd-catalyzed cross-coupling reaction of alkenyl halides or tri- borylation/Suzuki–Miyaura cross-coupling procedure to afford
flates with bis(pinacolato)diboron (B2pin2) (2) or pinacolborane the 2-aryl-substituted 1-cycloalkenecarboxylate in good yield; this
(HBpin).3 An alternative process involving the transition-metal- carboxylate showed biological activity.
catalyzed C–H borylation of alkenyl compounds was recently
We initially examined the borylation of methyl 1-cyclo-
reported.4–6 Although this method is more economical and hexenecarboxylate 1a under the optimum conditions for the
environmentally benign than the above conventional methods, borylation of 1,4-dioxene; we previously reported that a complex
the use of such reactions is still limited for cyclic vinyl ethers5 of [Ir(OMe)(cod)]2 and 4,40-di-tert-butyl-2,20-bipyridine (dtbpy)
and suffers from the formation of a number of different side catalyzed vinylic C–H borylation in good yields and with good
products such as allylboronates and alkylboronates.6c,d,f,g,i
selectivities.5 The reaction of 1a with 2 (1.1 equiv.) in the presence of
Very recently, we reported the regioselective direct ortho boryl- an IrI precursor, [Ir(OMe)(cod)]2 (1.5 mol%), and dtbpy (3 mol%) as
ation of various benzoates or aryl ketones using the complex the ligand, in octane solvent at 120 1C afforded the desired product
[Ir(OMe)(cod)]2/P[3,5-(CF3)2C6H3]3 or AsPh3.7 At the same time, 3a in only 11% yield after 16 h (Table 1, entry 1). We then screened
several groups, including Sawamura’s,8 Lassaletta’s,9 and Hartwig’s possible ligands (entries 2–8). Notable improvements in yields
groups,10 also reported similar borylation of functionalized arenes. were not observed in the reactions with various phosphine ligands
The regioselectivity of these reactions is probably driven by the (3a: 4–20% after 16 h, entries 2–7). The use of AsPh3, which can
interaction between the coordinating O and N atoms in the direct- weakly coordinate with an Ir metal center, significantly improved
ing group and the Ir metal center.7–9 So far, these methods have the yield of 3a, with a shorter reaction time (85%, 1 h, 90%, 16 h,
only been used in the C–H borylation of arenes; to the best of our entry 8).11 The use of less-polar and poorer electron-donating
knowledge, C–H borylation at the vinyl position of a,b-unsaturated solvents gave much better results than the more-polar and better
esters has not been reported previously. In this communication, electron-donating solvents (octane: 90%, mesitylene: 51%, diglyme:
we describe a vinylic C–H borylation of 1-cycloalkenecarboxylate 0%, DMF: 0%, entries 8–11). An appropriate choice of Ir catalyst
precursor was crucial for this borylation. Although the combination
of [IrCl(cod)]2 and AsPh3 gave 3a in good yield (84%, entry 12),
no desired product was obtained when [Ir(cod)2]BF4 was used
(entry 13). The borylation proceeded smoothly, even at 80 1C
Division of Chemical Process Engineering, Graduate School of Engineering,
Hokkaido University, Sapporo 060-8628, Japan.
E-mail: ishiyama@eng.hokudai.ac.jp; Fax: +81 11 706 6562; Tel: +81 11 706 6562
(99%, entry 14). Under these conditions, a reaction with a lower
loading of [Ir(OMe)(cod)]2 (0.5 mol%) also gave 3a in reasonable
† Electronic supplementary information (ESI) available: Experimental procedures
and spectral analyses. See DOI: 10.1039/c3cc44149k
c
7546 Chem. Commun., 2013, 49, 7546--7548
This journal is The Royal Society of Chemistry 2013

View Article Online
Communication
ChemComm
Table 1 Reaction conditions for methyl 1-cyclohexenecarboxylate 1aa
Table 2 C–H borylation of various estersa,b
Entry IrI precursor
Ligand
Solvent
Yieldh (%)
1
2
3
4
[Ir(OMe)(cod)]2 dtbpyg
Octane
Octane
Octane
Octane
Octane
11
20
4
0
[Ir(OMe)(cod)]2 P(C6H5)3
[Ir(OMe)(cod)]2 P(OC6H5)3
[Ir(OMe)(cod)]2 P(4-MeOC6H4)3
[Ir(OMe)(cod)]2 P(4-CF3C6H4)3
5
19
6
7
8
9
10
11
12
13b
14c
15c,d
16e
17f
[Ir(OMe)(cod)]2 P[3,5-(CF3)2C6H3]3 Octane
14
[Ir(OMe)(cod)]2 P(C6F5)3
[Ir(OMe)(cod)]2 AsPh3
[Ir(OMe)(cod)]2 AsPh3
[Ir(OMe)(cod)]2 AsPh3
[Ir(OMe)(cod)]2 AsPh3
Octane
Octane
Mesitylene 51
Diglyme
DMF
Octane
Octane
Octane
Octane
Octane
Octane
10
90 (85)i
0
0
84
[Ir(Cl)(cod)]2
[Ir(cod)2]BF4
AsPh3
AsPh3
0
[Ir(OMe)(cod)]2 AsPh3
[Ir(OMe)(cod)]2 AsPh3
[Ir(OMe)(cod)]2 AsPh3
[Ir(OMe)(cod)]2 AsPh3
99 (87) j
81
99
6
a
Reaction conditions: 1a (0.5 mmol), 2 (0.55 mmol), IrI precursor
(0.0025–0.0075 mmol), ligand (0.01–0.03 mmol), solvent (3 mL).
b
c
3 mol% [Ir(cod)2]BF4 was used. Reaction was carried out at 80 1C.
d
e
0.5 mol% [Ir(OMe)(cod)]2 and 2.0 mol% AsPh3 were used. 5.0 equiv.
f
a
of 1a with respect to 2 were used. HBpin (0.55 mmol) was used.
Reaction conditions: ester (0.5 mmol), 2 (0.55 mmol), [Ir(OMe)(cod)]2
(0.0075 mmol), AsPh3 (0.03 mmol), octane (3 mL). b Yields were determined
by GC analysis. c [Ir(OMe)(cod)]2 (0.0125 mmol), AsPh3 (0.05 mmol).
g
i
h
3 mol% dtbpy was used. Yield was determined by GC analysis.
Reaction time 1 h. Isolated yield.
j
yield (81%, entry 15). No increase in the yield of 3a was achieved
using 5.0 equiv. of 1a with respect to 2 (99%, entry 16). The
product 3a was obtained in only 6% yield when HBpin was used
instead of 2 (entry 17).
without substrate decomposition, and the borylation product 3l
was obtained in 79% yield after 0.5 h. Unlike the cyclohexene-type
substrate discussed above, the reactions of cycloalkenyl substrates
with five-, seven-, and eight-membered rings resulted in low pro-
duct yields, even under harsher reaction conditions (120 1C with
2.5 mol% [Ir(OMe)(cod)]2 and 10 mol% AsPh3) than those used for
the cyclohexene-type substrate. Although the five-membered ring
1m and 2 were completely consumed in the reaction, the product
3m was obtained in low yield (20%). The reactions of the seven-
membered ring 1n and eight-membered ring 1o also gave the
alkenylboronates 3n and 3o in low yields, though the substrates
were completely consumed. We speculate that 1m–1o decom-
posed under the reaction conditions.
We performed a one-pot synthesis of a bioactive compound via
a vinylic C–H borylation/cross-coupling sequence (Scheme 2).12
Compound 4 has been reported to be an inhibitor of monoamine
transporters.13 The alkenylboronate 3a was prepared from 1a
under the optimized conditions shown in Table 1, and then
distilled water was added to the mixture to hydrolyse HBpin
that was generated by the Ir-catalyzed borylation. Finally, the
subsequent cross-coupling reaction was conducted by adding
2-bromonaphthalene (2.5 mmol), K3PO4 (3.0 equiv.), and PdCl2(dppf)
(5 mol%), without solvent evaporation and product purification.
With the optimized conditions in hand, we next investigated
the availability of the ester side-chain and the reactivity depen-
dence on the ring size of the substrate; the borylation of various
1-cycloalkenecarboxylic substrates was examined (Table 2). Ethyl
ester 1b exhibited similar reactivity to that of methyl ester 1a,
producing the corresponding alkenylboronate 3b in 87% yield.
Even the more sterically congested substrates isopropyl ester 1c
and tert-butyl ester 1d showed good reactivity at 120 1C, affording
the corresponding 3c and 3d in 77% and 85% yields, respectively.
Reaction of phenyl ester 1e gave only the vinylic borylation
product 3e in 96% yield at 80 1C. It is noteworthy that the phenyl
group, which has five C(sp2)–H bonds and would be reactive in
Ir-catalyzed borylation, remained intact in the reaction with 1e.7,8
Although some transition-metal complexes exhibit high reactivity
toward C–Cl bonds, 3-chloropropyl ester 1f underwent borylation
at the vinylic C–H bond, in high yield, without any side reactions
involving the C–Cl bond (86%). We then examined the borylation
of CF3-containing ester 1g; the CF3 group is very important in drug
design because it enhances the biological activity. The reaction of
1g afforded 3g in 93% yield. The 3-methoxy ester 1h reacted
completely with 2 within 1 h to produce 3h in high yield (83%).
The reactions of ketone 1i, ester 1j, and carbamate 1k proceeded
at 120 1C to afford 3i (65%), 3j (74%), and 3k (72%), respectively.
Although competitive coordination of the carbonyl group in the
side-chain would inhibit direct borylation, these results showed
that the side-chain carbonyl group did not have a serious detri-
mental effect on the reactivity of the borylation. Epoxide 1l reacted Scheme 2 One-pot synthesis of 4. a GC yield based on 2-bromonaphthalene.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 7546--7548 7547

View Article Online
ChemComm
Communication
Culture, Sports, Science and Technology, Japan, and the Funding
Program for Next Generation World-Leading Researchers (NEXT
Program, no. GR002).
Notes and references
1 N. Miyaura and Y. Yamamoto, in Comprehensive Organometallic
Chemistry III, ed. R. H. Crabtree, D. M. P. Mingos and P. Knochel,
Elsevier, Oxford, 2007, vol. 9, p. 145.
2 (a) M. M. Heravi and E. Hashemi, Tetrahedron, 2012, 68, 9145;
(b) S. Papst, A. F. M. Noisier, M. A. Brimble, Y. Yang and G. W.
Krissansen, Bioorg. Med. Chem., 2012, 20, 5139; (c) V. P. Ghidu, J. Q.
Wang, B. Wu, Q. S. Liu, A. Jacobs, L. J. Marnett and G. A. Sulikowski,
J. Org. Chem., 2008, 73, 4949; (d) E. P. Gillis and M. D. Burke, J. Am.
Chem. Soc., 2007, 129, 6716; (e) S. Harper, S. Avolio, B. Pacini,
M. Di Filippo, S. Altamura, L. Tomei, G. Paonessa, S. Di Marco,
A. Carfi, C. Giuliano, J. Padron, F. Bonelli, G. Migliaccio, R. De Francesco,
R. Laufer, M. Rowley and F. Narjes, J. Med. Chem., 2005, 48, 4547.
3 (a) N. Miyaura and K. Maruoka, in Synthesis of Organometallic Com-
pounds, ed. S. Komiya, Wiley, Chichester, 1997, p. 345; (b) K. L. Billingsley
and S. L. Buchwald, J. Org. Chem., 2008, 73, 5589; (c) K. L. Billingsley,
T. E. Barder and S. L. Buchwald, Angew. Chem., Int. Ed., 2007, 46, 5359;
(d) T. Ishiyama, J. Takagi, A. Kamon and N. Miyaura, J. Organomet. Chem.,
2003, 687, 284; (e) J. Takagi, K. Takahashi, T. Ishiyama and N. Miyaura,
J. Am. Chem. Soc., 2002, 124, 8001; ( f ) T. Ishiyama and N. Miyaura,
J. Organomet. Chem., 2000, 611, 392; (g) K. Takahashi, J. Takagi,
T. Ishiyama and N. Miyaura, Chem. Lett., 2000, 126; (h) P. R. Eastwood,
Tetrahedron Lett., 2000, 41, 3705.
Scheme 3 Proposed catalytic cycle.
4 For aromatic C–H borylation, see: (a) T. Ishiyama and N. Miyaura, Pure
Appl. Chem., 2006, 78, 1369; (b) T. Ishiyama, J. Takagi, Y. Yonekawa,
J. F. Hartwig and N. Miyaura, Adv. Synth. Catal., 2003, 345, 1103;
(c) T. Ishiyama, Y. Nobuta, J. F. Hartwig and N. Miyaura, Chem.
Commun., 2003, 2924; (d) T. Ishiyama and N. Miyaura, J. Organomet.
Chem., 2003, 680, 3; (e) J. Takagi, K. Sato, J. F. Hartwig, T. Ishiyama and
N. Miyaura, Tetrahedron Lett., 2002, 43, 5649; ( f ) T. Ishiyama, J. Takagi,
K. Ishida, N. Miyaura, N. R. Anastasi and J. F. Hartwig, J. Am. Chem. Soc.,
2002, 124, 390; (g) T. Ishiyama, J. Takagi, J. F. Hartwig and N. Miyaura,
Angew. Chem., Int. Ed., 2002, 41, 3056; (h) J. Y. Cho, M. K. Tse,
D. Holmes, R. E. Maleczka and M. R. Smith III, Science, 2002, 295, 305.
5 For our reports on alkenyl C–H borylation, see: (a) T. Kikuchi, J. Takagi,
H. Isou, T. Ishiyama and N. Miyaura, Chem.–Asian J., 2008, 3, 2082;
(b) T. Kikuchi, J. Takagi, T. Ishiyama and N. Miyaura, Chem. Lett., 2008, 664.
6 (a) I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy and J. F.
Hartwig, Chem. Rev., 2010, 110, 890; (b) J. Takaya, N. Kirai and N. Iwasawa,
The cross-coupling product 4 was obtained in 47% yield (78%,
GC yield) from the two-step reaction.
Two proposed catalytic cycles are shown in Scheme 3. In both
the catalytic cycles, the mono- (n = 1) or tris- (n = 3) boryliridium
complex A is first produced by reactions of Ir(I) complexes with
B2pin2.14 In pathway 1, involving oxidative addition and reductive
elimination, the electron-donating oxygen atom in the ester group
coordinates with the Ir metal center (complex B, Scheme 3), and
then oxidative addition of the vinylic C–H bond to A produces the
pseudo-metallacycle C. After reductive elimination, the Ir–hydride
complex D and the product 3a are produced. Finally, oxidative
addition of B2pin2 to D, followed by reductive elimination of
HBpin, regenerates A. In pathway 2, involving a 1,4-insertion
and b-hydride elimination, the 1,4-insertion of the carbonyl-
coordinated complex E produces the iridium enolate F.15 The
subsequent isomerization of F affords the Ir complex G, which
has an Ir–C bond with a syn configuration between the Ir center
and the b-H. The product 3a and D are then formed through
b-hydride elimination from the C-enolate Ir complex G.
´
J. Am. Chem. Soc., 2011, 133, 12980; (c) N. Selander, B. Willy and K. J. Szabo,
Angew. Chem., Int. Ed., 2010, 49, 4051; (d) A. Kondoh and T. F. Jamison,
Chem. Commun., 2010, 46, 907; (e) T. Ohmura, Y. Takasaki, H. Furukawa
and M. Suginome, Angew. Chem., Int. Ed., 2009, 48, 2372; ( f ) V. J. Olsson
´
and K. J. Szabo, J. Org. Chem., 2009, 74, 7715; (g) C. N. Garon, D. I. McIsaac,
C. M. Vogels, A. Decken, I. D. Williams, C. Kleeberg, T. B. Marder and
´
S. A. Westcott, Dalton Trans., 2009, 1624; (h) V. J. Olsson and K. J. Szabo,
Org. Lett., 2008, 10, 3129; (i) I. A. I. Mkhalid, R. B. Coapes, S. N. Edes,
D. N. Coventry, F. E. S. Souza, R. L. Thomas, J. J. Hall, S. W. Bi, Z. Y. Lin
and T. B. Marder, Dalton Trans., 2008, 1055; ( j) A. Caballero and S. Sabo-
´
In summary, an iridium complex consisting of [Ir(OMe)(cod)]2
and AsPh3 was found to be an efficient catalyst for the vinylic
C–H borylation of 1-cycloalkenecarboxylic derivatives with 2. This
borylation proceeded at the vinylic position with good selectivity,
even though substrates have a phenyl group which would be
reactive in Ir-catalyzed borylation. Additionally, the borylation of
substrates containing various functional groups such as halogen,
acyl, alkoxycarbonyl, carbamoyl, and epoxy groups afforded the
corresponding products. Bipyridine, phosphine, and NHC ligands
Etienne, Organometallics, 2007, 26, 1191; (k) V. J. Olsson and K. J. Szabo,
Angew. Chem., Int. Ed., 2007, 46, 6891; (l) R. B. Coapes, F. E. S. Souza,
R. L. Thomas, J. J. Hall and T. B. Marder, Chem. Commun., 2003, 614.
7 (a) T. Ishiyama, H. Isou, T. Kikuchi and N. Miyaura, Chem. Commun.,
2010, 46, 159; (b) H. Itoh, T. Kikuchi, T. Ishiyama and N. Miyaura,
Chem. Lett., 2011, 1007.
8 K. Yamazaki, S. Kawamorita, H. Ohmiya and M. Sawamura, Org.
Lett., 2010, 12, 3978.
9 A. Ros, R. Lopez-Rodrıguez, B. Estepa, E. Alvarez, R. Fernandez and
J. M. Lassaletta, J. Am. Chem. Soc., 2012, 134, 4573.
10 T. A. Boebel and J. F. Hartwig, J. Am. Chem. Soc., 2008, 130, 7534.
11 V. Farina and B. Krishnan, J. Am. Chem. Soc., 1991, 113, 9585.
´
´
´
´
have been used for aromatic and alkenyl C–H borylation, but the 12 We previously reported a one-pot borylation/Suzuki–Miyaura cross-
coupling sequence, see: T. Kikuchi, Y. Nobuta, J. Umeda, Y. Yamamoto,
present results show the first vinylic C–H borylation using AsPh3.
T. Ishiyama and N. Miyaura, Tetrahedron, 2008, 64, 4967.
Additionally, a one-pot borylation/cross-coupling procedure for
13 M. D. Petersen, S. V. Boye, E. H. Nielsen, J. Willumsen, S. Sinning,
the rapid synthesis of a drug candidate was also conducted, and
shows the synthetic usefulness of this reaction.
O. Wiborg and M. Bols, Bioorg. Med. Chem., 2007, 15, 4159.
14 (a) J. F. Hartwig, Acc. Chem. Res., 2012, 45, 864; (b) T. M. Boller,
J. M. Murphy, M. Hapke, T. Ishiyama, N. Miyaura and J. F. Hartwig,
J. Am. Chem. Soc., 2005, 127, 14263.
This work was supported by a Grant-in-Aid for Scientific
´ `
´
Research (B) (No. 21350049) from the Ministry of Education, 15 F. Denes, A. Perez-Luna and F. Chemla, Chem. Rev., 2010, 110, 2366.
c
7548 Chem. Commun., 2013, 49, 7546--7548
This journal is The Royal Society of Chemistry 2013