Iridium-catalyzed triple C(sp3)-H borylations: Construction of triborylated sp3-carbon centers

Article abstract of DOI:10.1039/c3cc42675k

An unprecedented catalytic C(sp³)-H triborylation at a single carbon was developed with the assistance of a nitrogen directing group.

Full text of DOI:10.1039/c3cc42675k

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Iridium-catalyzed triple C(sp3)–H borylations:
construction of triborylated sp3-carbon centers†
Tsuyoshi Mita,*a Yuto Ikeda,a Kenichi Michigamia and Yoshihiro Sato*ab
Cite this: Chem. Commun., 2013,
49, 5601
Received 12th April 2013,
Accepted 29th April 2013
DOI: 10.1039/c3cc42675k
www.rsc.org/chemcomm
An unprecedented catalytic C(sp3)–H triborylation at a single carbon
was developed with the assistance of a nitrogen directing group.
Triborylated compounds possessing three boron atoms on the same
carbon are extremely unique, exhibiting interesting reactivities
toward many electrophiles.1b For the preparation of these fascinat-
ing molecules, traditional methods employed either triborylations
of the corresponding trihalides1a,b or hydroborations of alkenes,
borylalkynes, and borylalkenes with/without a transition metal
Scheme 1 Our synthetic strategy for triple C(sp3)–H borylation.
catalyst.1c–f However, the product yields of triborylated compounds not been reported thus far, even though it would have been an
were not satisfactory, and regioselective introduction of boron undesired pathway. We herein disclose the first and robust syn-
atoms into unsymmetrical double bonds was often problematic.1c,f thesis of triborylated products by triple borylation of terminal
Therefore, we devised a new synthetic method based on a stable primary C(sp3)–H bonds with the aid of a nitrogen directing group
five-membered metallacycle intermediate (Scheme 1). If a nitrogen such as a pyridine as well as an isoquinoline.
atom is located at an appropriate position, C(sp3)–H bond cleavage
According to our previous report on iridium-catalyzed C(sp3)–H
would proceed concomitantly with the five-membered chelation silylation reaction,7 we employed [Ir(cod)Cl]2 as a catalyst without
with a transition metal.2 Therefore, with a highly reactive borylating any additional ligands. Aiming at the selective generation of tri-
reagent, B2pin2, site-selective C(sp3)–H borylation of 2-ethylpyridine borylated compounds, an excess amount of B2pin2 was employed
would be possible at the terminal position, eventually leading to for the borylation of 2-ethylpyridine (1a) using n-octane as a solvent
triborylated products. This strategy would avoid multiple borylations under reflux conditions (bath temp: 150 1C) (Table 1). When
at two vicinal sp3-carbons.
1.5 equiv. of B2pin2 was used, 1a was consumed within 1.5 h and
A transition metal-catalyzed C(sp3)–H borylation is an advanced mono-, di-, and triborylated products 2a, 3a, and 4a were obtained
technology for preparing borylated compounds from simple in 10%, 22%, and 19% yields, respectively (entry 1). Although
alkanes. Since Hartwig developed C(sp3)–H borylation promoted C(sp2)–H bonds of the pyridine ring were over-borylated (5a and
by transition metal complexes in 1997,3a photo and thermal 6a), the total yield of the triborylated compounds was 34% (4a:
catalytic methods using B2pin2 or HBpin have been established.3 19%; 5a: 10%; 6a: 5%). Increased use of B2pin2 led to improvement
Although most of the methods have been limited to borylations of in the total yield (entries 2 and 3). Eventually, both 5a and 6a were
terminal C(sp3)–H bonds,3,4 several new methods that promote produced in total 91% yield by using 3.5 equiv. of B2pin2 (entry 4).
borylation of secondary C(sp3)–H bonds with high efficiency have In this nitrogen-directed borylation, a bidentate amine ligand for an
recently been developed.5,6 Among these methods, double C(sp3)–H iridium center such as 3,4,7,8-tetramethyl-1,10-phenanthroline3f,4c,5
borylation at a single carbon sometimes proceeded to produce was not effective, yielding a complex mixture (entry 5).
geminal diborylated compounds,4a,6 but C(sp3)–H triborylation has
The triborylated compound 4a was isolated in 17% yield (Table 1,
entry 2) by silica gel column chromatography (using pre-dried SiO2:
63–210 mm; eluent: hexane–AcOEt containing 3% of Et3N), and the
solids thus obtained were crystallized from hexane at rt to afford an
appropriate grade of a single crystal. X-ray crystal analysis of 4a
confirmed its exact structure, in which three pinacolborons were
attached to a single carbon (Fig. 1).8 The nitrogen atom of the
pyridine ring coordinated to one of the three boron atoms and the
a Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812,
Japan. E-mail: biyo@pharm.hokudai.ac.jp; Fax: +81-11-706-4982;
Tel: +81-11-706-3722
b Japan Science and Technology Agency, ACT-C, Sapporo 060-0812, Japan
† Electronic supplementary information (ESI) available: Experimental details and
X-ray diffraction data. CCDC 923599. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3cc42675k
c
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Table 1 Screening of the amount of B2pin2
Table 2 Scope and limitations
Yielda (%)
Time (h) tri-B (4) di-B (3) mono-B (2)
Entry Substrate
1
2
3
13
13
0.5
0.5
0.2
0.2
1
1
12
8
5
25
20
16
18
o1
o1
o1
Yielda (%)
Entry
B2pin2 (equiv.)
2a
3ab
4a
5a
6a
4
96 (75) o1
95 (81) o1
99 (64) o1
5b
6
1
2
3
1.5
2
3
3.5
3.5
10
22
13
19
10
24
66
71
5
10
19
20
4
o1
o1
20 (17)
o1
o1
7c
0.5
1.5
89 (77)
3
o1
o1
4
o1
o1
5c
Complex mixture
Yields were determined by 1H NMR analysis using 1,1,2,2-tetrachloro-
a
8d
o1
o1
ethane as an internal standard. The value in parentheses represents
isolated yield. In entries 1–4, C(sp2)–H borylation products of 3a
b
c
(4- and 5-positions) were observed in total ca. 10% yield. 10 mol%
of 3,4,7,8-tetramethyl-1,10-phenanthroline was added.
9e
0.5
77 (52)
7
o1
10f
1.0
1.5
57 (44) 22
o1
11
2
8
21
a
Yields were determined by 1H NMR analysis. The values in parentheses
represent isolated yields. C(sp2)–H borylation product of 4f (5-position)
b
was obtained in 2% yield. C(sp2)–H borylation product of 4h (4-position)
c
was obtained in 7% yield. C(sp2)–H borylation products of 1i (4- and
d
Fig. 1 ORTEP structure of 4a. Thermal ellipsoids are given at the 50% prob-
5-positions) were observed in 31% total yield. C(sp2)–H borylation
e
ability level. Hydrogen atoms are omitted for clarity.
products of 4j (positions not determined) were obtained in 14% total
f
yield. C(sp2)–H borylation products of 4k and 3k (positions not
determined) were obtained in 9% and 10% yields, respectively.
length of N–B was 1.660 Å, suggesting that coordination of the
nitrogen atom stabilized triborylated compounds.
Based on these observations, we next investigated the effects coordination of the nitrogen atom to metals (Ir and B). Further-
of substituents at the 4-position of the pyridine, which might more, reactions of 3- and 1-ethylisoquinolines (1j, and 1k) gave
affect the nucleophilic property of the pyridine nitrogen. Addi- moderate yields with diborylated compounds remaining. Sterically
tionally, one substitution on the pyridine ring might suppress crowded 2-ethylquinoline (1l) was less reactive than other substrates
over-borylation of aromatic C(sp2)–H bonds due to the steric and only 2% of the triborylated product was observed. Based on
repulsion against an introduced substitution.
these experimental results, we concluded that the lone pair of
Several 2-ethylpyridine derivatives bearing electron-withdrawing nitrogen had an important effect on triborylation: electron-rich
and donating substituents at the 4-position of the pyridine ring nitrogen atoms with less steric bulkiness caused high conversion
were prepared and subjected to borylation (Table 2). Triborylated probably due to the facilitation of iridacycle formation in addition to
products obtained by this procedure were not so stable in silica gel stabilization of the corresponding triborylated compounds.
column chromatography, and some decomposition occurred dur-
We next investigated borylation of secondary C(sp3)–H bonds
ing the purification process. Electron-withdrawing substituents since this triborylation is thought to proceed in a stepwise
such as nitro, cyano, and chloro (1b, 1c, and 1d) did not effectively fashion from a monoborylated compound via secondary followed
promote triborylation even with extended reaction time, while the by tertiary C(sp3)–H bond activations. To prove this hypothesis,
use of electron-donating substituents such as Me, OMe, and OBn monoborylated compound 2a was employed for further boryl-
(1e, 1f, and 1g) resulted in completion of triborylation within ation with B2pin2. As a result, 2a, 3a, and 4a were obtained in 32%,
10–30 min with sufficient suppression of over-borylation of aromatic 52%, and 17% yields, respectively, suggesting that triborylation
C(sp2)–H bonds (less than 2%): triborylated compound 1g was actually proceeded in this stepwise manner (Scheme 2).9
obtained in 99% yield after only 10 min (isolated yield of 64%). In
Alkylsilane 1m was also monoborylated to afford 7m in 86% yield
addition, triborylation of 5-OMe-2-ethylpyridne (1h) also proceeded (isolated yield of 71%) along with a small amount of over-borylated
with high conversion, but that of the 6-OMe-derivative (1i) did not, products 8m and 9m. Since the borylation of 2-propylpyridine gave
probably because ortho-substitutions of the pyridine ring prevented a complex mixture under the same conditions (no scheme),
c
5602 Chem. Commun., 2013, 49, 5601--5603
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was financially supported by Grants-in-Aid for Young Scientists (B)
(No. 24750081) and for Scientific Research (B) (No. 23390001)
from JSPS, by a Grant-in-Aid for Scientific Research on Inno-
vative Areas ‘‘Molecular Activation Directed toward Straight-
forward Synthesis (No. 23105501)’’ from MEXT, by the ACT-C
program of JST, by Nissan Chemical Industries Ltd, and by the
Uehara Memorial Foundation.
Scheme 2 Borylation of secondary C(sp3)–H bonds.
Notes and references
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´
´
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´
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Scheme 3 Carboxylation and oxidation of triborylated compounds.
these studies indicate that C(sp3)–H bonds next to a metalloid
atom (Si, B) are easily borylated probably due to their relatively
acidic nature.10
We were then interested in the reactivities of triborylated
compounds and potential transformations were tested. We have
already reported a fluoride-mediated carboxylation of benzylic
4 For benzylic C(sp3)–H borylation, see: (a) S. Shimada, A. S. Batsanov,
J. A. K. Howard and T. B. Marder, Angew. Chem., Int. Ed., 2001,
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C(sp3)–Sn and –Si bonds with CO2 using CsF as a mild activa-
11
tor.7,12 This novel strategy could be applied to carboxylation of
triborylated compounds because fluoride has been reported to
efficiently activate pinacolborates.13 Indeed, isolated products 4a
and 4e were subjected to carboxylation under 1 atm of CO2 in the
presence of CsF, giving the carboxylated products 10a and 10e in
54% and 58% yields, respectively, after esterification with n-C6H13I
(Scheme 3).14 Neither dicarboxylic nor tricarboxylic acids were
observed. Trioxidation of 4e was also examined using H2O2 in the
presence of an acidic additive such as TsOHÁH2O in order to avoid
base-promoted protodeborylation. As a result, one carbon-shortened
carboxylic acid derivative 11e was obtained in 56% yield. These two
5 (a) C. W. Liskey and J. F. Hartwig, J. Am. Chem. Soc., 2012, 134,
12422; (b) C. W. Liskey and J. F. Hartwig, J. Am. Chem. Soc., 2013,
135, 3375.
6 (a) S. Kawamorita, T. Miyazaki, T. Iwai, H. Ohmiya and
M. Sawamura, J. Am. Chem. Soc., 2012, 134, 12924. During the
preparation of this manuscript, a similar approach to mono- and
diborylated compounds from 2-alkyl pyridines was reported. See:
(b) S. Kawamorita, R. Murakami, T. Iwai and M. Sawamura, J. Am.
Chem. Soc., 2013, 135, 2947.
7 T. Mita, K. Michigami and Y. Sato, Org. Lett., 2012, 14, 3462.
8 CCDC 923599 (4a)†.
9 HBpin produced in situ also works as a borylating reagent but is
much less reactive. See ESI† for details.
10 Transition metal-catalyzed C–H borylations usually proceed at more
electron-deficient positions (more acidic C–H bonds). See ref. 3g.
methods are complementary because different chain lengths of 11 For recent reviews on CO2 incorporation reactions, see:
(a) T. Sakakura, J.-C. Choi and H. Yasuda, Chem. Rev., 2007,
107, 2365; (b) M. Mori, Eur. J. Org. Chem., 2007, 4981; (c) A. Correa
carboxylic acids can be prepared only by changing the reagents
employed. When di- and monoborylated compounds 3a and 2a
´
and R. Martın, Angew. Chem., Int. Ed., 2009, 48, 6201;
were used as substrates for fluoride-mediated carboxylation with
CO2, 10a was obtained in 4% and 0% yields,15 strongly indicating
that the generation of a carbanion was facilitated by its delocaliza-
tion with vacant p-orbitals of the remaining two boron atoms.
In summary, we have developed iridium-catalyzed triborylation
reactions of terminal C(sp3)–H bonds. Electron-donating substi-
tuents on the pyridine ring with less steric bulkiness enhanced
the production of triborylated compounds (up to 99% yield). The
products thus obtained were successfully transformed into
carboxylic acid derivatives under 1 atm of CO2 in the presence
of CsF as well as under oxidative conditions.
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2011, 50, 1393; (b) T. Mita, M. Sugawara, H. Hasegawa and Y. Sato,
J. Org. Chem., 2012, 77, 2159; (c) T. Mita, Y. Higuchi and Y. Sato,
Chem.–Eur. J., 2013, 19, 1123; (d) T. Mita, J. Chen, M. Sugawara and
Y. Sato, Org. Lett., 2012, 14, 6202.
13 S. Nave, R. P. Sonawane, T. G. Elford and V. K. Aggarwal, J. Am.
Chem. Soc., 2010, 132, 17096.
14 The sequential process from 1e is also possible without isolation of
4e. See ESI† for details.
15 Fluoride-mediated carboxylation of 7m with CO2 proceeded to
afford 10a in 64% yield. See ESI† for details.
Dr Takashi Matsumoto in Rigaku Corporation is greatly
acknowledged for X-ray crystallographic analysis of 4a. This work
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 5601--5603 5603