Aminoboration: Addition of B-N ? Bonds across C-C ?€ Bonds

Article abstract of DOI:10.1021/jacs.5b06678

This communication demonstrates the first catalytic aminoboration of C-C π bonds by B-N δ bonds and its application to the synthesis of 3-borylated indoles. The regiochemistry and broad functional group compatibility of this addition reaction enable substitution patterns that are incompatible with major competing technologies. This aminoboration reaction effects the formation of C-B and C-N bonds in a single step from aminoboronic esters, which are simple starting materials available on the gram scale. This reaction generates synthetically valuable N-heterocyclic organoboron compounds as potential building blocks for drug discovery. The working mechanistic hypothesis involves a bifunctional Lewis acid/base catalysis strategy involving the combination of a carbophilic gold cation and a trifluoroacetate anion that activate the C-C π bond and the B-N δ bond simultaneously.

Full text of DOI:10.1021/jacs.5b06678

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Aminoboration: Addition of B–N σ Bonds Across C–C π
Bonds
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Eugene Chong and Suzanne A. Blum*
Department of Chemistry, University of California, Irvine, California 92697ꢀ2025, United States
Supporting Information Placeholder
kenes due to the πꢀinteraction between nitrogen’s lone pair and
boron’s empty p orbital.16 Resultantly, prior work on aminoboraꢀ
tion was mostly limited to the addition of B–N bonds to polarized
ABSTRACT: This communication demonstrates the first cataꢀ
lytic aminoboration of C–C π bonds by B–N σ bonds and its apꢀ
plication to the synthesis of 3ꢀborylated indoles. The regiochemisꢀ
try and broad functional group compatibility of this addition reacꢀ
tion enable substitution patterns that are incompatible with major
competing technologies. This aminoboration reaction effects the
formation of C–B and C–N bonds in a single step from aminoboꢀ
ronic esters, which are simple starting materials available on the
gram scale. This reaction generates synthetically valuable Nꢀ
heterocyclic organoboron compounds as potential building blocks
for drug discovery. The working mechanistic hypothesis involves
a bifunctional Lewis acid/base catalysis strategy involving the
combination of a carbophilic gold cation and a trifluoroacetate
anion that activate the C–C π bond and the B–N σ bond simultaꢀ
neously.
C–heteroatom
π
bonds
that
included
isocyanate,17
isothiocyanate,17a and carbodiimide.18 Such an approach is less
synthetically useful, however, as the resulting B–heteroatom bond
formed in those transformations are usually hydrolyzed and the
boryl component lost at the end of the reaction.17,18 To our
knowledge, the only reported wellꢀcharacterized example of amiꢀ
noboration of a C–C multiple bond with a B–N σ bond is the
[4+2] cycloaddition of a strained diazadiboretidine with dimeꢀ
thylacetylenedicarboxylate, which leads to a heterocycle of limꢀ
ited synthetic utility for downstream functionalization (Figꢀ
ure 1b).19 More recently, a formal aminoboration of alkenes was
reported
using
a
Cuꢀcatalyzed
borylation
with
bis(pinacolato)diboron (pinB–Bpin) followed by an electrophilic
amination using OꢀbenzoylꢀN,Nꢀdialkylhydroxylamine (R2N–
OBz).20 Furthermore, despite a recent development on the addiꢀ
tion chemistry involving the analogous B–P bond,21 the catalytic
aminoboration of alkynes with B–N σ bond addition was unꢀ
known prior to this work (Figure 1c).
Boron–element additions to unsaturated compounds have
played a pivotal role in organic synthesis since the discovery of
hydroboration by Hurd1 and Brown.2 These transformations proꢀ
vide a route to synthetically valuable organoboron compounds
that are widely used as versatile reagents in carbon–carbon and
carbon–heteroatom bond forming reactions, such as the Suzukiꢀ
Miyaura reaction3 and ChanꢀLam crossꢀcoupling4. Thus, transiꢀ
tion metalꢀcatalyzed 1,2ꢀaddition of boron–element bonds (B–E,
where E = H,5,6 B,6,7 C,8 Si,6,9,10 Sn,6,11 S,12 Cl,13 Br,14 I14) to C–C
multiple bonds have received significant attention (Figure 1a). In
most of these methods, the B–E single bonds are activated via
oxidative addition to a lowꢀvalent late transition metal center
(e.g., Rh, Ni, Pd, Pt) or via σꢀbond metathesis with a lateꢀmetal
catalyst (e.g., Cu15) prior to insertion across alkynes. Given that
amines are present in 85% of all pharmaceutical compounds, it is
striking that the corresponding addition chemistry with B–N
bonds has not been developed for synthetic applications; possibly
because the relatively high strength of the B–N σ bond prevented
application of existing mechanistic strategies. We herein realize
this aminoboration reaction by employing a different mechanistic
strategy: activation of the C–C π bond—the other partner in the
reaction—with a carbophilic Lewis acid (Figure 1c). This reaction
employs starting materials containing B–N σ bonds that are readiꢀ
ly available on the gram scale from their corresponding amines
and commercially available Bꢀchlorocatecholborane. It generates
3ꢀborylated indoles via unique bond disconnections as potential
building blocks for drug discovery, and it is orthogonal to major
competing technologies as it tolerates aryl halides, nitriles, and
esters.
Figure 1. Addition of B–E σ bonds across C–C π bonds.
Indoles are privileged scaffolds found in numerous biologically
active molecules and employed in medicinal chemistry,22 includꢀ
ing recent therapeutic leads.23 Thus, the construction of indole
The resistance of B–N σ bonds to react with unactivated C–C π
bonds is not surprising given that aminoboranes (R2B–NR2) are
known to have isostructural and isoelectronic relationship to alꢀ
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ring system was targeted (initial development, Table 1), which
This reaction displays a notable dependence on the presence of
1
2
3
4
5
6
7
8
would give access to 3ꢀborylated indoles as potential building
blocks for drug discovery. During initial reaction identification,
the requisite B–N bond of aminoboronic ester 2 was formed from
the reaction of 2ꢀalkynylaniline 1 and commercially available
catecholborane in d8ꢀtoluene with heating and the release of H2.
The formation of this B–N bond was monitored and confirmed by
11B NMR spectroscopy, at δ ~26 ppm24 with concurrent disapꢀ
pearance of the signal from catecholborane at δ 28.7 ppm.
the sodium trifluoroacetate additive. Optimal conditions occurred
with 5 mol % IPrAuTFA catalyst and 20 mol % sodium trifluoroꢀ
acetate additive (using eq 1, in Chart 1) and not simply with the
IPrAuTFA catalyst alone (in Table 1). No reaction occurred when
aminoboronic ester 2, generated from the route (eq 1) using
ClBcat and NEt3, was heated to 110 °C in d8ꢀtoluene for 20 h
using 2.5 mol % IPrAuTFA catalyst in the absence of added sodiꢀ
um trifluoroacetate. A control reaction showed that 20 mol %
sodium trifluoroacetate alone did not catalyze the cyclization of 2
under the conditions reported in Chart 1 (80 °C, 20 h), thereby
supporting cationic gold as the Lewis acid catalyst for the reacꢀ
tion. The added sodium trifluoroacetate may overcome catalyst
inhibition from trace HNEt3Cl leftover during the preparation of 2
via the optimized chlorocatecholborate route.29
Table 1. Initial Development of Aminoboration
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Our aminoboration strategy allows access to 3ꢀborylated inꢀ
doles with complementary regiochemistry and with functional
groups that are incompatible with conventional routes or recent
synthetic efforts (Chart 1). Alternative iridiumꢀcatalyzed C–H
activation routes are predominantly regioselective for borylation
at the 2ꢀ30 or 7ꢀpositions31 of indoles. The 3ꢀposition32 of indoles
can be borylated using iridium catalysts with certain nitrogen
protecting groups under limited conditions. Traditional metalꢀ
halogen exchange/borylation strategy33 of aryl halides with magꢀ
nesium or oꢀlithiation/borylation34 of arenes with organolithium
reagents are unable to tolerate aryl bromides, nitriles, esters, and
other metalationꢀsensitive heterocycles. Palladiumꢀcatalyzed
Miyaura borylation35 of aryl halides or borylative cyclization36 of
2ꢀalkynylanilines are also incompatible for the synthesis of broꢀ
minated indole 3ꢀboronic esters due to the potential oxidative
addition of Pd into Ar–Br bond.
entry
substrate
R
conditions
yield (%)a
3
1
2
3
4
5
6
H
CH2Ph
CH2Ph
Ts
0b
n.r.c
55
n.r.c
64d
66
1a
1b
1b
1c
1c
1d
50 °C, 15.5 h
80 °C, 5 h
110 °C, 17 h
50 °C, 4 h
Ts
80 °C, 20 h
80 °C, 20 h
Mbs
aIsolated yield of the Bpin product. bOnly 2ꢀphenylꢀ1Hꢀindole was
obtained in 69% yield. cNo reaction observed as monitored by 1H
NMR spectroscopy. dAverage of two runs.
Chart 1. Aminoboration Scope of 3-Borylated Indolesa
with Functional Groups Incompatible with Competing
Metalation or Pd(0)-Catalyzed Technologies Shown in
Blue
When the aminoboronic ester 2a (Table 1, entry 1), derived
from primary aniline 1a, was treated with IPrAuTFA catalyst25
and heated at 50 °C, the desired 3ꢀborylated indole 3 was not
obtained. Instead, only 2ꢀphenylꢀ1Hꢀindole was isolated in 69%
yield, suggesting that protodemetalation occurs in the presence of
an N–H bond. To circumvent this problem, secondary anilines
1b–1d (entries 2–6) were examined for aminoboration. Gratifyꢀ
ingly, the use of Nꢀbenzyl substituent provided the first aminoboꢀ
ration reactivity in 55% yield (entry 3), but high temperatures of
110 °C were required. Examination of Nꢀsulfonyl substituents,
tosyl (entries 4 and 5) and 4ꢀmethoxybenzenesulfonyl (Mbs, enꢀ
try 6), showed that the reaction can be accomplished at the lower
temperature of 80 °C. The moderate yields obtained under the
conditions of initial reaction development are attributed to the
degradation of catecholborane (HBcat) into B2cat3 via catechol
ligand redistribution,26 observed by a signal at δ 23.1 ppm in the
11B spectrum, as well as unreacted 1 remaining from the first amiꢀ
nolysis step with HBcat.
Switching to aminolysis of commercially available Bꢀ
chlorocatecholborane (ClBcat) by 2ꢀalkynlaniline 1 provided a
solution for easily assembling the requisite B–N bond at room
temperature within an hour using triethylamine as a base to trap
the released HCl byproduct (eq 1).27,28 In situ formed 2 does not
undergo cyclization in the absence of the IPrAuTFA catalyst; for
example, substrate 2d remains unreacted with the B–N bond
intact when heated to 110 °C in d8ꢀtoluene for 20 h in the absence
of a catalyst.
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aIsolated yield of the Bpin product. b110 °C.
The aminoboration reaction is compatible with a variety of theꢀ
reported biological activities,39 and this aminoboration facilitates
access to such structures.
1
2
3
4
5
6
7
8
9
Scheme 2. Synthetic Versatility of Aminoboration Prod-
ucts
se potentially sensitive functional groups. Compounds with these
functional groups are shown in blue in Chart 1. Pharmaceutically
relevant thiophenes (3e), aryl bromides (3g and 3l), nitriles (3h),
esters (3i) are tolerated by this method, as are alkenes (3j) and
silylꢀprotected alcohols (3m). For bulkier substituents at R2, oꢀ
substituted aryl (3l) and OTBDPS (3m), increased temperatures of
110 °C were required to induce the cyclization. Pharmaceutically
relevant37 1,3ꢀbenzodioxoles (3f) also can be tolerated in this
transformation.
Mbs
N
I
Ph
O
O
Mbs
Mbs
3d
Bpin
N
N
Pd(PPh3)4
(10 mol %)
Pd(PPh3)4
(10 mol %)
nBu
nBu
Br
3g
MbsN
Na2CO3, H2O
MeOH, toluene
rt, 19 h
K3PO4, dioxane
100 °C, 38 h
Ph
O
O
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O
O
Due to the challenge of achieving the required functional group
tolerance with alternative metalation and palladium(0)ꢀcatalyzed
methods, borylated bromoindoles previously were made via
routes with highly toxic mercury acetate.23,38 For example, in the
total synthesis of dragmacidin D by Stoltz and coworkers, a tosylꢀ
ated bromoindole was borylated at the 3ꢀposition using mercuraꢀ
tion with Hg(OAc)2 followed by Hg/B exchange with BH3.38 Reꢀ
cent industrial pharmaceutical leads have also been synthesized
by mercuration routes in order generate these borylated bromoinꢀ
doles.23 In contrast, the functional group tolerance of the amiꢀ
noboration method provides a mercuryꢀfree route to the synthesis
of borylated bromoindoles (e.g., 3g).
4, 87%
5, 47%
The synthetic utility of aminoboration is not limited to indole
scaffolds and has potential for applications in the synthesis of
other Nꢀheterocyclic organoboron compounds (Scheme 3). When
a
simple amine 6, prepared from commercially available
homopropargyl amine, is subjected to standard aminoboration
conditions, 3ꢀborylated dihydropyrrole 8a can be synthesized. The
protodeborylated product 8b is the major byproduct, possibly due
to a source of an acidic proton from the terminal alkyne of 7. This
preliminary result demonstrates that a rigid backbone to aid cyꢀ
clization and a gain of product aromaticity are not absolute reꢀ
quirements for the aminoboration reactivity.
Scheme 1. Mercury-Free Synthesis of 3-Borylated Bro-
moindole 3g on 1 Gram Scale and Characterization by X-
Ray Crystallography
Scheme 3. Synthesis of 3-Borylated Dihydropyrrole
Numerous examples of Lewis acidic goldꢀmediated cyclization
of 2ꢀalkynylanilines exist for the synthesis of indole derivatives,40
but not for the installation of boron on the indole backbone for
downstream reactivity. Based on the known carbophilicity of
gold40,41 and our previous report on bifunctional catalysis on
alkoxyboration of alkynes involving B–O bond activation,42 we
propose the catalytic cycle shown in Scheme 4. The potentially
bifunctional Lewis acidic/basic catalyst IPrAuTFA and substrate
2d associate to generate intermediate 9 containing a tetracoordiꢀ
nate borate. Simultaneous B–N bond activation and cyclization of
9
releases
organogold
intermediate
10
and
Bꢀ
(trifluoroacetyl)catecholborane. The presence of proposed interꢀ
mediates is supported by the detection of neutral organogold 10 in
the reaction mixture by HRMS prior to completion of the reaction.
The aminoboration reaction of 2ꢀalkynylanilines can be easily
run on the gram scale (Scheme 1). The scalability of this halideꢀ
tolerant aminoboration transformation demonstrates its synthetic
utility and allows for generation of quantities suitable for multiꢀ
step synthesis for downstream manipulation of the C–Br and C–B
bonds in crossꢀcoupling reactions.3,4 The solidꢀstate molecular
structure of 3g, obtained from singleꢀcrystal Xꢀray diffraction
analysis, verifies the structure of the aminoborylated product arisꢀ
ing from anti 1,2ꢀaddition of B–N bond across alkynes.
Next,
organogold
species
10
and
Bꢀ
(trifluoroacetyl)catecholborane undergo AuꢀtoꢀB transmetalation43
to furnish the 3ꢀborylated indole product 3d-Bcat and regenerate
the IPrAuTFA catalyst. This reaction manifold is mechanistically
distinct from the previous metalꢀcatalyzed boron–element bond
addition routes that proceed through metalꢀmediated breaking of
the B–element bond through oxidative addition or σ bond metathꢀ
esis.
The employment of bromineꢀcontaining 3ꢀborylated indole 3g
in sequential Suzuki crossꢀcoupling reactions highlights this
downstream synthetic utility (Scheme 2). The C–B bond of 3g
accesses a selective crossꢀcoupling with an aryl iodide at room
temperature to generate a new C–C bond,38 while maintaining the
C–Br bond intact, to afford functionalized indole 4. The Ar–Br
bond of 4 is available for a second crossꢀcoupling with organoboꢀ
ronic acid derivatives, and here we further demonstrate the synꢀ
thetic utility of 3ꢀborylated indole 3d as a building block for C–C
bond formation to construct biindole 5. Biindole scaffolds have
Scheme 4. Postulated Mechanism of Aminoboration
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have shown that the easily generated but rather unreactive B–N σ
bond can be used for this addition reaction, thereby providing a
new bond disconnection strategy for the efficient construction of
indole building blocks for potential applications in drug discovꢀ
ery. The use of carbophilic gold catalyst and mildly basic triꢀ
fluoroacetate provides tolerance of functional groups that are
either incompatible with or difficult to access using existing
methods. Ongoing work focuses on the development aminoboraꢀ
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, spectral data, and crystallographic data
of compound 3g. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*blums@uci.edu
Notes
The authors declare the follow competing financial interest(s): US
Pat. App. No. 14/303,684 and US Provisional Pat. App. No.
62/198,410 have been filed by the University of California.
ACKNOWLEDGMENT
This work was supported by
a grant from the NIH
(1R01GM098512ꢀ01). We thank Dr. Joseph W. Ziller and Dr.
Jordan F. Corbey for assistance with Xꢀray crystallography.
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