A traceless directing group for C - H borylation

Article abstract of DOI:10.1002/anie.201306511

Not a trace: Borylation of the nitrogen in nitrogen heterocycles or anilines provides a traceless directing group for subsequent catalytic C - H borylation. Selectivities that previously required Boc protection can be achieved; furthermore, the NBpin directing group can be installed and removed in situ, and product yields are substantially higher. Boc=tert-butoxycarbonyl, pin=pinacolato. Copyright

Full text of DOI:10.1002/anie.201306511

Angewandte
Chemie
DOI: 10.1002/anie.201306511
À
C H Functionalization
Hot Paper
À
A Traceless Directing Group for C H Borylation**
Sean M. Preshlock, Donald L. Plattner, Peter E. Maligres, Shane W. Krska,* Robert E. Maleczka
Jr.,* and Milton R. Smith III*
À
In C H functionalization, directing groups have played
a pivotal role, even in some of the earliest examples that
feature transition-metal catalysis.[1,2] Similarly, directing
À
groups can alter regioselectivities in Ir-catalyzed C H bor-
ylation.[3] Examples fall into two classes: 1) those where the
directing group is already present in the substrate,[4] and
2) those where it must be installed.[5] An example of the latter
class is the use of silylhydrides to facilitate the borylation of
Scheme 1. Boc-directed borylation reactions of pyrroles and indoles.
positions ortho to OH and NH substituents and to effect the
functionalization at sp2-hybridized positions in arylsilanes,
which was described by Hartwig and co-workers.[5a,c] Like-
wise, Lassaletta et al. have shown that the conversion of aryl
aldehydes into hydrazones facilitates borylation of the ortho
position.[5e] Nevertheless, these methods require installation
and removal of a directing group.
In contrast, traceless directing groups, the installation and
removal of which do not require additional steps, would be
attractive alternatives to more traditional approaches.[6]
Herein, we demonstrate that the (pinacolato)boron (Bpin)
be readily installed and removed without requiring isolation
of intermediates.
In this vein, Bpin is potentially an attractive surrogate for
[8]
À
Boc because B N bonds readily hydrolyze. Whereas
À
À
sufficiently acidic N H and O H bonds will react with
boron hydrides to evolve dihydrogen and to form B N or
B O bonds, the N H bonds of pyrrole and indole do not
spontaneously react with HBpin to generate N B bonds. This
À
À
À
À
À
group can function as a traceless directing group for C H
is clearly a kinetic issue as calculations (B3LYP//6-311 ++
À
borylation reactions of nitrogen heterocycles and anilines.
We have previously demonstrated that the tert-butoxy-
carbonyl (Boc) group can be used as a directing group in Ir-
catalyzed borylations of nitrogen-containing heterocycles,
such as pyrroles, indoles, azaindoles, and pyrazoles.[5b] In the
case of pyrrole and indole, the N-Boc-protected compounds
are selectively borylated at the 3 position, whereas the parent
heterocycles react selectively at the 2 position (Scheme 1).[7]
Although the Boc moiety is a widely used protecting
group, its installation and removal are nevertheless required
to produce the 3-borylated isomer of a parent heterocycle.
Boc removal is particularly onerous for N-Boc-protected
heterocycles because the Bpin group is not compatible with
most deprotection methods, and the thermal conditions that
generally proved to be the best failed for some substrates.[5b]
Thus, it would be desirable to use a directing group that could
G(2d,2p)) indicate that N H borylation is thermodynamically
À1
À
preferred over C H borylation by 10–12 kcalmol . We
À
reasoned that B N bond formation could be facilitated by
making the B H bond in HBpin more hydridic. Inspired by
À
the enhancement of hydride transfer with a Lewis base that
was reported by Crudden and co-workers,[9] we examined the
effect of adding tertiary amines to solutions of HBpin and
indole or pyrrole. Gratifyingly, smooth conversion into the
N-borylated heterocycles was observed under these condi-
tions. The reaction with NEt3 as the additive is significantly
faster than that with NEtiPr2, which is consistent with the idea
that heterolysis is promoted by coordination of the nitrogen
lone pair of the tertiary amine to the boron center.
With the problem of N-borylation solved, we turned our
À
attention to the Ir-catalyzed C H borylation of N-borylated
À
indole (3; Scheme 2), expecting that C H borylation would
occur selectively at the 3 position. The reaction was per-
formed in solutions containing tertiary amines, which are
[*] S. M. Preshlock, D. L. Plattner, Prof. Dr. R. E. Maleczka Jr.,
Prof. Dr. M. R. Smith III
[10]
À
compatible with C H borylation. Upon completion, the
Department of Chemistry, Michigan State University
578 S Shaw Lane, East Lansing, MI 48824-1322 (USA)
E-mail: maleczka@chemistry.msu.edu
smithmil@msu.edu
reaction was quenched with MeOH, and routine workup gave
3-borylated indole 5 in 57% yield. This demonstrates that
Bpin can function as a traceless directing group, enabling
a simple one-pot route to 5 from simple indole. This
transformation is preferable to the stepwise Boc-directed
route, as Boc installation and removal introduces two addi-
tional purification steps, reducing the overall yield to 42%,
starting from indole.
Dr. P. E. Maligres, Dr. S. W. Krska
Department of Process Chemistry, Merck Research Laboratories
Rahway, NJ 07065 (USA)
E-mail: shane_krska@merck.com
[**] We thank the NSF (GOALI-1012883), the NIH (GM63188), and the
ACS Green Chemistry Institute Pharmaceutical Roundtable for
generous financial support.
The selectivity that is observed under these conditions
complements the selectivity that is typically found for Ir-
catalyzed borylation. This expands the scope of the reaction
as functionalization at either the 2 or 3 position can be
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306511.
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Scheme 2. Comparison of the Boc-directed and the Bpin-directed syn-
thesis of 3-Bpin-indole.
accomplished by carrying out the reaction in the absence or
presence of a tertiary amine (Scheme 3). Borenium cations
and electrophilic ruthenium catalysts will borylate the 3 posi-
tion of N-methylindole; however, the route that employs the
traceless directing group offers the advantage that unpro-
tected indole can serve as a substrate.[11]
To examine the generality of this strategy, we subjected
a number of other heterocycles that entail an NH moiety to
À
Scheme 4. N Bpin-directed borylation of selected N-heterocycles.
Scheme 3. Selective borylation of the 2 and 3 positions of indole.
Yields of isolated products are given. Yields in parentheses correspond
to the Boc-directed route starting from the parent heterocycle, using
yields reported for Boc protection.[15] The borylation of N-Boc-4-
azaindole has not been reported.
the conditions developed for Bpin-directed functionalization
(Scheme 4). For products
5
and 6, amine-catalyzed
N-borylation must be carried out prior to addition of the Ir
catalyst for selective functionalization at the 3 position. For
thermal deprotection. Compound 10 was synthesized using
B2pin2 (2 equiv). In the presence of Bpin (4 equiv), a second
borylation occurs at the six-membered ring in analogous
fashion to the borylation of N-Boc-7-azaindole with excess
HBpin.[5b,13] Compound 10 can also be obtained with HBpin.
The regioselectivity for pyrroles and related heterocycles,
À
azaindoles and pyrazoles, which feature more acidic N H
À
bonds, N-borylation precedes C H borylation, making the
amine additive unnecessary. The parent heterocycles that are
shown in Scheme 4 undergo borylation at the carbon atom
À
that is in the b position of the NBpin group, and the N Bpin
À
bond hydrolyzes on workup with protic solvents. For pyrazole,
dimeric pyrazabole intermediates may be present prior to
workup.[12]
which are typically borylated at the C H bond next to
nitrogen, has electronic origins.[14] Given the sensitivity of
À
C H borylation to steric bulk, the Bpin group of the
The yields for the syntheses of the borylated heterocycles
using either Bpin or Boc as the directing group are compared
in Scheme 4. It is clear that the approach that employs Bpin as
a traceless directing group not only reduces the number of
purification/isolation steps, but also leads to higher yields. For
example, the yield of 7 is improved by more than 30% with
our novel method. The case for azaindoles is even more
striking, as the traceless-directing-group approach provides
products 8–10 in good yield. Compounds 9 and 10 were
inaccessible through the Boc-directed route because decom-
position to unidentified products occurred during attempts at
N-borylated intermediates may function as a steric director,
although electronic effects have yet to be discounted. The
approach shown in Scheme 4 displays some generality for
N-heterocycles. Nevertheless, imidazole did not give isolable
products with either directing method. Traceless-directing-
group borylation of tryptophan also failed.
We recently showed that N-Boc-protected anilines
undergo ortho borylation.[5d] Theory and experiment support
a mechanism where the selectivity is due to hydrogen bonding
between the NH moiety of the aniline and an oxygen atom of
the Bpin reagent in the transition state (transition state A;
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Figure 1. Calculated transition state for the ortho borylation of N-Boc-
protected aniline (A) and putative transition state analogues for the
ortho borylation of aniline (B) and N-Bpin-modified aniline (C).
Figure 1). In principle, unsubstituted anilines could engage in
this reaction (B; Figure 1); however, conversions are poor
when they are subjected to the reaction conditions that were
effective for N-Boc-protected anilines. Nevertheless, the
major products of the reactions of unprotected anilines are
ortho-borylated, which suggests that practical ortho-selective
borylation of anilines could be realized with a more reactive
catalyst system.
Ultimately, conversions into ortho-borylated anilines
were improved by changing the ligand from dtbpy to
3,4,7,8-tetramethyl-1,10-phenanthroline (tmphen) and using
HBpin (2–3 equiv). Under these conditions, catalyst turnover
numbers improved, making the synthesis of ortho-borylated
anilines practical. The substrate scope of this reaction is
shown in Scheme 5.
With the exception of compounds 11d, 11h, 11l, and 11o,
all compounds shown in Scheme 5 have not been synthesized
previously.[16] The yields of isolated products ranged from
good to excellent, and in most cases, the yields obtained for
the parent anilines exceeded those of their N-Boc-substituted
counterparts. This is particularly noteworthy as the iridium
catalyst loadings were generally eight times lower for the
traceless reactions than for the N-Boc-directed analogues. As
was the case for N-Boc-protected anilines, para-substituted
anilines and meta, para-disubstituted anilines essentially gave
only the ortho-borylated products, whereas meta-substituted
anilines gave mixtures of isomers. In these cases, the ortho-
borylated isomers could be isolated after purification by
column chromatography. For meta-trifluoromethyl- and meta-
chloro substituted anilines, 11o and 11p were formed as the
major isomers. For 3-methoxyaniline, the ortho-borylated
product 11n was obtained as the minor regioisomer, along
with the 5-borylated isomer as the major product. For aniline
itself, 2 borylation is favored, but significant amount of 3 and
4 borylation are observed (ortho/meta/para = 2.3:1.5:1). This
contrasts with what we previously found for PhNHCO2Me,
where the ortho selectivity was considerably higher (ortho/
meta/para = 18:1:1).[5d] The preference for ortho borylation
renders the iridium-catalyzed version complementary to the
borenium-mediated electrophilic substitution developed by
Ingleson and co-workers, who observed para substitution for
N,N-dimethyl aniline.[11a] In contrast to the borenium chemis-
try, our borylation reaction tolerates trifluoromethyl groups
(Scheme 5).
Scheme 5. Traceless Bpin-directed borylation of anilines. Yields are for
isolated materials. Unless otherwise noted, the borylation catalyst was
generated from [{Ir(OMe)(COD)}2] (0.25 mol%) and tmphen
(1 mol%). See the Supporting Information for details. [a] HBpin
(4 equiv). [b] HBpin (2 equiv). [c] 4,4’-bis(dimethylamino)-2,2’-dipyridyl
(3 mol%) instead of tmphen; the reaction was run in hexanes with
[{Ir(OMe)(COD)}2] (1.5 mol%). [d] The substrate is 4-aminobenzoni-
trile. [e] tmphen (5 mol%) and [{Ir(OMe)(COD)}2] (2.5 mol%).
[f] Together with the 5-borylated product (47%). [g] Together with the
5-borylated product (21%). [h] Together with the 5-borylated product
(17%).
evaluated (see the Supporting Information for details).
Solvent affects regioselectivity; less polar solvents enhance
borylation at the 6 position (ortho to the nitrogen), whereas
more polar solvents favor borylation at the 5 position (meta to
the nitrogen). Ligand effects were also significant, with more
electron-rich ligands favoring borylation at the 6 position.
The choice of boron reagent also had an impact on the
selectivities; relative to B2pin2, HBpin favored borylation at
the 6 position.
To provide mechanistic insight, the borylation of
3-trifluormethylaniline with HBpin was monitored by 1H
and 11B NMR spectroscopy. The spectra indicate that the
mono-N-borylated intermediate, ArNHBpin, forms rapidly,
but does not react further with HBpin to form ArNBpin2. The
À
À
The effects of solvent, ligand, and boron reagent on the
regioselectivity for borylations of 3-substituted anilines were
N B bond is maintained during the Ir-catalyzed C H
borylation. Once the reaction has reached completion, the
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addition of MeOH leads to hydrolysis of the N B bond to
give the primary aniline product. These features are summar-
ized in Scheme 6.
Scheme 6. Intermediates in the Bpin-directed aniline borylation.
Scheme 7. Bpin-directed borylation of aminopyridines. Yields of iso-
lated materials are given. See the Supporting Information for details.
In contrast to HBpin, B2pin2 does not borylate the
nitrogen atom of anilines, even after heating at 808C for
one hour. This observation, in combination with the reduced
ortho selectivity with B2pin2, suggests that the aniline NH2
does not direct ortho borylation as effectively as the NHBpin
moiety.
substituent in the ortho position of the pyridine nitrogen was
critical to the success of these reactions, as 2- and 3-amino-
pyridine failed to give the borylated products. Substrates with
an NH2 moiety meta or para to the pyridine nitrogen gave
reasonable to excellent yields of the corresponding products
14a–d. For meta-aminopyridines, the borylation was selective
for the para position (14a,b). For para-aminopyridines,
borylation was observed at the less hindered meta position,
yielding 14c and 14d. In the case of 2-aminopyridines,
N-borylation was observed by 1H and 11B NMR spectroscopy.
However, the reaction was not selective for the ortho position,
and borylation occurred at the least hindered para position,
affording compounds 14e and 14 f.
Ortho-directed borylation is not observed for secondary
aniline substrates. Although ortho selectivity is lost for
À
N-methyl-3-chloroaniline, C H borylation is nevertheless
regioselective, affording compound 12 in high yield following
workup [Eq. (1)].
In summary, we have shown that Bpin can function as
À
a traceless directing group for C H borylations of nitrogen
heterocycles and anilines instead of the Boc moiety. For
nitrogen heterocycles with less acidic NH groups, the addition
of a tertiary amine is critical for successful borylation of the
nitrogen atom. Traceless Bpin protection enables regioselec-
We noted that 2-substituted anilines do not give signifi-
cant amounts of the ortho-borylated products with the Boc-
directed approach or the Bpin-directed approach. This is
likely due to unfavorable steric interactions between the Boc
or Bpin group and the substituent at the 2 position in the
transition states A or C (Figure 1). Whereas 2-methoxyaniline
does not give the ortho-borylated product, it does undergo
regioselective borylation at the 4 position [13; Eq. (2)], with
À
tive functionalization of C H bonds of the parent compound
without the need for separate installation and removal of the
directing group. The resulting reactions are operationally
simpler and generally higher yielding than their Boc-directed
counterparts. For azaindoles, the use of Bpin as a traceless
directing group gave products that are inaccessible with Boc-
directed methods.
Received: July 26, 2013
Revised: September 26, 2013
Published online: November 12, 2013
À
Keywords: anilines · borylation · catalysis · C H activation ·
nitrogen heterocycles
.
the 5-borylated isomer comprising less than 5% of the
borylation products. This finding is surprising in light of the
preference of N,N-dimethyl aniline for meta borylation (meta/
para = 79:21, meta/para selectivity ca. 2:1).[17] The selectivity
almost certainly has electronic origins, albeit non-obvious
ones.
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