Iridium-catalyzed C-H borylation of cyclopropanes

Article abstract of DOI:10.1021/ja400103p

The borylation of cyclopropanes catalyzed by the combination of (η⁶-mes)IrBpin₃ or [Ir(COD)OMe]₂ and a phenanthroline derivative is reported. The borylation occurs selectively at the methylene C-H bonds of the cyclopropane ring over methine or methyl C-H bonds. High diasteroselectivities were observed from reactions catalyzed by the combination of iridium and 2,9-Me₂phenanthroline. The cyclopropylboronate esters that are generated are versatile synthetic intermediates that can be converted to trifluoroborate salts, boronic acids, cyclopropylarenes, cyclopropylamines, and cyclopropanols.

Full text of DOI:10.1021/ja400103p

Communication
pubs.acs.org/JACS
Iridium-Catalyzed C−H Borylation of Cyclopropanes
Carl W. Liskey and John F. Hartwig*
Departments of Chemistry, University of Illinois, Urbana, Illinois 61801, and University of California, Berkeley, California 94720,
United States
S
* Supporting Information
electron-rich iridium-trisboryl complexes react faster with
ABSTRACT: The borylation of cyclopropanes catalyzed
aromatic C−H bonds than do less electron-rich complexes,
by the combination of (η6-mes)IrBpin3 or [Ir(COD)-
OMe]2 and a phenanthroline derivative is reported. The
and iridium-trisboryl complexes containing bulky phosphine
ligands react more slowly with aromatic C−H bonds than do
complexes containing bipyridine ligands.21−25 Based on these
observations, we developed the borylation of primary and
secondary C−H bonds of cyclic ethers with an iridium-catalyst
ligated by 3,4,7,8-tetramethylphenanthroline (Me4phen).26
To expand the synthetic utility of the borylation of aliphatic
C−H bonds, we sought to identify an iridium catalyst for the
C−H borylation of cyclopropanes. The effect of various
reaction parameters on the yields of the borylation of a
representative cyclopropane is shown in Table 1. The reaction
borylation occurs selectively at the methylene C−H bonds
of the cyclopropane ring over methine or methyl C−H
bonds. High diasteroselectivities were observed from
reactions catalyzed by the combination of iridium and
2,9-Me2phenanthroline. The cyclopropylboronate esters
that are generated are versatile synthetic intermediates that
can be converted to trifluoroborate salts, boronic acids,
cyclopropylarenes, cyclopropylamines, and cyclopropanols.
yclopropanes are common structural motifs that are parts
Table 1. Borylation of Bromocyclopropane
C
of natural products and many biologically active
molecules.1−5 Cyclopropanes have unique steric and electronic
properties and reactivities that originate from the rigid and
highly strained structure. A classic method to synthesize
cyclopropanes is the Simmons−Smith cyclopropanation of an
olefin and a carbene.6−8 Many stereoselective variants of this
reaction have been reported.9,10 Recently, other methods to
introduce the cyclopropyl group have emerged that rely on
metal-catalyzed cross-coupling of an organometallic cyclopropyl
precursor and an aryl halide.10−13 In addition, oxidative
coupling reactions of cyclopropylboronic acids and amines to
form cyclopropylamines have been reported.14,15
a
entry
ligand
solvent
yield (%)
d.r.
1
2
3
4
5
6
7
4,4′-dtbpy
Cy-H
Cy-H
Cy-H
THF
Bu2O
THF
THF
42
68
65
59:41
60:40
97:3
97:3
97:3
97:3
97:3
3,4,7,8-Me4phen
2,9-Me2phen
2,9-Me2phen
2,9-Me2phen
2,9-Me2phen
2,9-Me2phen
b
73
53
c
38
d
81
An attractive alternative to the synthesis of cyclopropanes
from olefins is the C−H functionalization of substituted and
readily available cyclopropanes. Yu and co-workers reported the
stereoselective C−H functionalization of cyclopropylamides.16
In this case, the reaction occurred with substrates that contain a
basic group that coordinates to the catalyst to facilitate C−H
functionalization. Based on this directing effect, the products of
these reactions are cis-substituted cyclopropanes. In addition,
Cramer and co-workers reported an asymmetric, intramolecular
C−H functionalization of cyclopropanes, but intermolecular
reactions were not reported.17 Here, we describe the borylation
of cyclopropane C−H bonds in the presence of an iridium-
phenanthroline catalyst to yield predominantly the trans-
substituted cyclopropylboronate esters without a directing
group.
Previously, our laboratory reported the borylation of primary
aliphatic C−H bonds with a diboron reagent in the presence of
rhodium or ruthenium catalysts.18−20 However, these catalysts
were unreactive toward the functionalization of secondary C−
H bonds. Studies on the stoichiometric reactivity of aromatic
C−H bonds with iridium-trisboryl complexes, which are
intermediates in the borylation of arenes, showed that more
a
Yield of boronate ester based on bromocyclopropane (0.25 mmol)
determined by gas chromatographic analysis with isododecane as an
internal standard. 10% diborylation product. Pinacolborane as the
b
c
d
boron reagent. 1.3 equiv of bromocyclopropane and 1.0 equiv of
B2pin2.
catalyzed by (η6-mes)IrBpin3 (mes = mesitylene) and 4,4′-di-
tert-butylbipyridine (dtbpy) proceeded in a modest 42% yield
(Table 1, entry 1). Dtbpy is the ligand that generated the most
reactive iridium catalyst for the borylation of arene C−H
bonds.20,27 The reaction of bromocyclopropane with bis-
(pinacolato)diboron (B2pin2) at 100 °C in the presence of 4
mol % of (η6-mes)IrBpin3 and Me4phen, which is the same
combination of iridium and ligand that catalyzed the borylation
of cyclic ethers, generated 68% yield of the cyclopropylboro-
nate ester product (entry 2). However, this reaction occurred
with low diastereoselectivity (60:40).
Received: January 5, 2013
Published: February 19, 2013
© 2013 American Chemical Society
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High yield and diastereoselectivity were achieved by
conducting the reaction with a more sterically hindered,
chelating nitrogen ligand. The reaction catalyzed by (η6-
mes)IrBpin3 and 2,9-dimethylphenanthroline (Me2phen) oc-
curred with 97:3 diastereoselectivity (entry 3). Presumably, this
increase in diastereoselectivity is due to the greater steric
demand of the 2,9-dimethyl ligand near the metal center.
The borylation of bromocyclopropane occurred faster and in
higher yield when conducted in THF solvent than when
conducted in cyclohexane or Bu2O (entries 3−5); however, a
small amount of product from diborylation of the cyclopropane
(ca. 10%) was observed. Reactions conducted with pinacolbor-
ane as the boron reagent occurred in lower yield than those
with B2pin2. By employing a slight excess of the cyclopropane,
relative to B2pin2, the diborylation of bromocyclopropane was
reduced, and the reaction occurred in 81% yield with 97:3
diastereoselectivity.
Table 2. Scope of the Borylation of Cyclopropanes
The scope of the borylation of cyclopropanes with B2pin2 as
reagent in the presence of (η6-mes)IrBpin3 and Me2phen as
catalyst is shown in Table 2. Cyclopropanes containing halide,
ester, carbonyl, protected carbonyl, and nitrile functionalities
were converted to the corresponding boronate esters in good
yields (entries 1−5).
The diastereoselectivity correlates with the size of the
substituent on the cyclopropane, and the yield depended on
the electronic properties of the cyclopropane. For example, a
much lower diastereoselectivity was observed for cyanocyclo-
propane (64:36) than for bromocyclopropane (97:3) (entries 1
and 5). Cyclopropanes containing alkyl substituents were less
reactive toward C−H borylation than cyclopropanes containing
electron-withdrawing groups. Reactions of these cyclopropanes
in THF solvent gave products from borylation of the
cyclopropane and the THF solvent (ca. 3:1). However, these
less reactive cyclopropanes were converted to the correspond-
ing cyclopropyl boronate esters in acceptable yield in
cyclohexane as solvent and with an excess (3 equiv) of the
cyclopropane to the diboron reagent (entries 6−8). The excess
of the cyclopropane increased the rate of the reaction and
eliminated the formation of diborylation products.
a
Yield of boronate ester based on B2pin2 (0.50 mmol) determined by
gas chromatographic analysis with isododecane as an internal standard.
Reaction conducted with 3 equiv of cyclopropane. Reaction
b
c
Under these conditions, alkylcyclopropanes containing
various substituents formed the borylation product. The
reaction of cyclopropanes containing protected alcohols and
amines were converted to the corresponding boronate esters
(entries 7 and 8). 1,1-Disubstituted cyclopropanes were much
less reactive under these borylation conditions than were
monosubstituted cyclopropanes, but a moderate yield of the
borylcyclopropane was achieved from reactions of 1,1-
disubstituted cyclopropanes in which one of the two
substituents is relatively small (entry 9). Finally, cis-1,2-
disubstituted cyclopropanes underwent the borylation to give
the product containing the boryl group trans to the other two
substituents. A minor diastereomer resulted from epimerization
of the product containing the two ester groups trans to each
other. The origin of this epimerization is not known at this
time.
conducted with 3 equiv of cyclopropane in Cy-H at 100 °C with 6
d
mol % Ir catalyst. Reaction conducted with Me4phen as ligand.
e
Reaction was conducted with 1.0 equiv of cyclopropane and 1.5 equiv
of B2pin2.
yields of the products when the reactions were conducted with
catalyst loadings of 10 mol % and a temperature of 100 °C.28
These loadings and temperatures are higher than those of
reactions initiated with (η6-mes)IrBpin3 (4 mol %, 90 °C; Table
3, entries 1−4), but the reactions do occur in acceptable yield.
The cyclopropylboronate esters that are formed in these
reactions are versatile synthetic intermediates that can be
converted to a number of other products (Scheme 1). The
cyclopropylboronate ester was converted to the trifluoroborate
salt under standard conditions in the presence of KHF2(aq) in
MeOH in good yield. In addition, the same boronate ester was
converted into the boronic acid in the presence of NaIO4 and
HCl(aq). Cyclopropylboronic acids and trifluoroborate salts are
known to undergo Suzuki−Miyaura cross-coupling reactions in
good yields.10,11,13 Cyclopropylboronic acids also react in Cu-
mediated oxidative coupling reactions with amines.14,15
Reactions conducted with (η6-mes)IrBpin3 as a catalyst
precursor are faster and occur with higher turnover numbers
than those conducted with common iridium(I) catalyst
precursors. However, to allow a more widespread use of this
chemistry, we also evaluated the borylation of cyclopropanes
with a commercially available iridium catalyst precursor. The
borylation of cyclopropanes occurred with commercial [Ir-
(COD)OMe]2 (COD = cyclooctadiene) to give moderate
Like their pinacol-substituted arylboronate ester counter-
parts, these pinacol-substituted cyclopropylboronic esters are
less reactive than the corresponding boronic acids and boronic
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Communication
propane formed in 83% yield under these carefully controlled
conditions.
Table 3. Borylation of Cyclopropanes with [Ir(COD)OMe]2
Finally, the borylcyclopropane was converted to the
corresponding cyclopropylamine. So far, Cu-mediated oxidative
coupling reactions of cyclopropylboronate pinacolate esters
with amines (Chan−Lam coupling reactions) have not
generated cyclopropylamine products. However, the trans-1,2-
decylcyclopropylboronate ester formed by C−H borylation was
converted to the corresponding protected amine by a
procedure recently reported by Morken and co-workers.29
The boronate ester was treated with deprotonated MeONH2,
followed by treatment with excess Boc2O to generate the
protected aminocyclopropane in modest yield.
In conclusion, we have identified a catalyst and conditions for
the intermolecular borylation of cyclopropane C−H bonds.
These reactions occur in good yields with good diastereose-
lectivity favoring the trans isomer with the new iridium catalyst
ligated by 2,9-Me2phen. The products of these reactions are
versatile synthetic intermediates that undergo a series of
transformations to substituted cyclopropanes.
a
Yield of boronate ester based on B2pin2 (1.0 mmol) determined by
gas chromatographic analysis with isododecane as an internal standard.
b
Isolated yield following purification by silica gel chromatography.
ASSOCIATED CONTENT
* Supporting Information
a
■
Scheme 1. Functionalization of Cyclopropylboronate Esters
S
Experimental procedures and spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
jhartwig@berkeley.edu
■
Notes
The authors declare no competing financial interest.
a
Conditions: (a) KHF2(aq) (4.5 M, 5 equiv), MeOH, 22 °C, 3 h, 82%
ACKNOWLEDGMENTS
yield; (b) NaIO4 (1.5 equiv), HCl(aq) (1 M, 1 equiv), 22 °C, 12 h,
74% yield; (c) 4-bromoanisole (1.5 equiv), Pd(dba)2 (5 mol %), PCy3
(10 mol %), KOt-Bu (3 equiv), THF, 100 °C, 12 h, 50% yield; (d)
NaOH(aq) (1 M), H2O2 (30%, 2 equiv), THF, 0 °C, 30 min, 83%; (e)
nBu-Li (5 equiv), MeONH2 (5 equiv), THF, −78 °C to 60 °C, 12 h;
Boc2O (5 equiv), 22 °C, 1 h, 40% yield.
■
We thank the NSF (CHE-1213409) for support of this work,
Johnson Mathey for [Ir(COD)OMe]2 and [Ir(COD)Cl]2, and
AllyChem for B2pin2. C.W.L. thanks Abbott Laboratories and
the NSF graduate research fellowship program for predoctoral
fellowships.
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■
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