Practical and Scalable Synthesis of Borylated Heterocycles Using Bench-Stable Precursors of Metal-Free Lewis Pair Catalysts

Article abstract of DOI:10.1021/acs.oprd.8b00248

A practical and scalable metal-free catalytic method for the borylation and borylative dearomatization of heteroarenes has been developed. This synthetic method uses inexpensive and conveniently synthesizable bench-stable precatalysts of the form 1-NHR₂-2-BF₃-C₆H₄, commercially and synthetically accessible heteroarenes as substrates, and pinacolborane as the borylation reagent. The preparation of several borylated heterocycles on 2 and 50 g scales was achieved under solvent-free conditions without the use of Schlenk techniques or a glovebox. A kilogram-scale borylation of one of the heteroarene substrates was also achieved using this cost-effective green methodology to exemplify the fact that our methodology can be conveniently implemented in fine chemical industries.

Full text of DOI:10.1021/acs.oprd.8b00248

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Full Paper
Practical and Scalable Synthesis of Borylated Heterocycles using
Bench-Stable Precursors of Metal-Free Lewis Pair Catalysts
Arumugam Jayaraman, Luis Carlos Misal Castro, and Frédéric-Georges Fontaine
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00248 • Publication Date (Web): 04 Oct 2018
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Practical and Scalable Synthesis of Borylated Heterocycles using
Bench-Stable Precursors of Metal-Free Lewis Pair Catalysts
Arumugam Jayaraman,‡ Luis C. Misal Castro‡ and FrédéricꢀGeorges Fontaine†*
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Département de Chimie, Centre de Catalyse et de Chimie Verte (C3V), Université Laval, Quebec City, Québec, Canada G1V
0A6
† Canada Research Chair in Green Catalysis and MetalꢀFree Processes.
KEYWORDS. Borylation, Heteroarylboronates, Metalꢀfree synthesis, Frustrated Lewis pair catalysis, CꢀH activation, Organocatalysis.
Supporting
Information
Placeholder
Ni, and Cu, instead of noble metals is an emerging area that proꢀ
vides entries to circumvent the cost problems;8 however, several
of these elements remain toxic.5 Among a variety of products that
can be prepared via C–H bond functionalization and/or reduction
of unsaturated CꢀC bonds, hydrocarbons with a CꢀB functionality
serve as versatile reagents. These reactive C(sp2)–B or C(sp3)–B
bondꢀcontaining reagents provide several synthetic possibilities to
access numerous functional groups.9 Of the widely accepted synꢀ
thetic utilities of organoboronate reagents are the Pdꢀcatalyzed
SuzukiꢀMiyaura and the Cuꢀcatalyzed ChanꢀLam crossꢀcoupling
reactions for the construction of C–C and CꢀN bonds, respectiveꢀ
ly.10 Preparation of a wide variety of organoborane reagents
through CꢀH borylation was achieved efficiently by utilizing
transition metal catalysts, particularly the noble metals,11 and
extending such reactions by using earthꢀabundant transition metal
catalysts has also emerged.12
ABSTRACT: A practical and scalable metalꢀfree catalytic
method for the borylation and borylative dearomatization of hetꢀ
eroarenes has been developed. This synthetic method uses inexꢀ
pensive and conveniently synthesizable benchꢀstable precatalysts
of the form 1ꢀNHR2ꢀ2ꢀBF3ꢀC6H4, commercially and synthetically
accessible heteroarenes as substrates, and pinacolborane as
borylation reagent. Preparation of several borylated heterocycles
in 2 and 50 grams was achieved under solventꢀfree conditions
without the use of Schlenk techniques or a glove box. A kilogramꢀ
scale borylation of one of the heteroarene substrates was also
achieved using this costꢀeffective green methodology to exempliꢀ
fy the fact that our methodology can be conveniently implemented
in fine chemical industries.
INTRODUCTION
In recent years, mainꢀgroup compounds have been shown to
promote catalysis processes classically performed by transition
metal catalysts.13 Among those, the 2006 finding by Stephan and
coworkers of the heterolytic splitting of molecular H2 under the
cooperative effect of a Lewis acid and a Lewis base center has
disregarded the belief that the HꢀH bond activation of molecular
H2 was only possible using transition metals.14 This discovery has
initiated the field of frustrated Lewis pair (FLP) chemistry and
exploration of such chemistry has rapidly expanded from curious
stoichiometric synthetic transformations to useful catalysis,13h, 15
mainly in the hydrogenation of unsaturated compounds.16
For the fineꢀchemical industries, including pharmaceutical and
organic electronic (OE) industries, the development of straightꢀ
forward methods to prepare highly valuable synthetic intermediꢀ
ates from commercial and easily synthesizable chemicals without
using any expensive laboratory equipment is of enormous interꢀ
est.1 Improvements in the selective and direct functionalization of
organic compounds, while avoiding toxic intermediates, hazardꢀ
ous reagents and solvents, and equimolar byꢀproduct wastes, are
an incessant focus for the synthetic chemistry community.2 To
date, highly expensive precious transition metals, including Ru,
Rh, Pd, Ir and Pt, and special ligands as well as several additives,
have often been used as catalysts by synthetic chemists.3 These
systems can notably be used for the highly efficient and atomꢀ
economic regioselective functionalization of unactivated C(sp2)–H
and C(sp3)–H bonds in a myriad of organic compounds.3a, 3b, 3f, 4
Nevertheless, the presence of trace amount of transition metals in
the endꢀproduct raises serious concerns such as toxicity issues in
the case of pharmaceuticals5 and reduced performances in the case
of OEs.6 Thus, complete removal of metals from endꢀproducts
becomes compulsory, adding additional steps in processes, such
as treatments with metal scavengers. As a result, the production of
metalꢀfree synthetic intermediates using transition metal catalysts
in industrial applications becomes overꢀcostly.7 Lessꢀexpensive
and more abundant firstꢀrow transition metals such as Mn, Fe, Co,
In 2015, we have established that an intramolecular B/N FLP, 1ꢀ
TMPꢀ2ꢀBH2ꢀC6H4 (1, Scheme 1a), can be used as a catalyst for
the direct CꢀH borylation of heteroarenes with pinacolborane
(HBpin), via a CꢀH activation/σꢀbond metathesis mechanism
(Figure 1a).17 Due to the high atomꢀefficiency of this metalꢀfree
method, this method was highlighted as potentially interesting to
processing research and development chemists.18 Following our
work on the CꢀH activation using a B/N FLP, such reactivity
pattern was found to be common for other more reactive B/N
FLPs.19 Despite some metalꢀfree electrophilic borylation methods
for borylation of heteroarenes and arenes disclosed before our
discovery,20 there have been many reports appearing on this topic
21
after
our
work
was
published.19,
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Scheme 1. Metalꢀfree catalytic method developed by us towards the CꢀH borylation (a) and borylative dearomatization (b) of heteroarenes.
Figure 1. Mechanisms proposed for CꢀH borylation (a) and borylative dearomatization (b) reactions.
While our methodology affords heteroaryl boronates with high
atomꢀefficiency under mild conditions in good to excellent yields,
catalyst 1 was found to be highly sensitive to the ambient condiꢀ
tions; hence, its synthesis, storage, manipulation, and experiꢀ
mental setup for catalysis should be performed under strict inert
conditions, which may restrict industries in adopting this synthetic
methodology. Previously, Buchwald and coworkers have brought
up an elegant encapsulation method to introduce air and moistureꢀ
sensitive transition metal catalysts to the reaction flask without
using airꢀsensitive operation conditions, leading to easier applicaꢀ
tion in an industrial setꢀup.22 In order to simplify the use of our
B/N FLP catalyzed borylation reactions, we reported in 2016 the
synthesis of the air and waterꢀstable zwitterionic compound 1ꢀ
TMP(H)ꢀ2ꢀBF3ꢀC6H4 (1F, Scheme 1), which acts as a precatalyst
for borylation reactions.23 From this precatalyst, the active cataꢀ
lyst 1 is generated inꢀsitu by a reduction reaction with HBpin and
provided a similar catalytic activity as 1 after an induction period.
BF3ꢀC6H4 (3F, Scheme 1), and their use as precatalysts for CꢀH
borylation reactions. In a subsequent report, we have demonstratꢀ
ed that all these catalysts and BH3.SMe2 can promote the borylaꢀ
tive dearomatization reaction when using electronꢀpoor arylꢀ
sulfonyl indoles as substrates and HBpin as reagent, leading to the
formation of 3ꢀboronyl indoline products (Scheme 1b), through a
1,2ꢀhydroboration/backbone redistribution mechanism (Figure
1b).25 Such products can be viewed as potential synthetic interꢀ
mediates for several pharmaceuticals, natural products, and mateꢀ
rials.26 Herein we report the progress we made in optimizing our
metalꢀfree methodology for borylation and borylative dearomatiꢀ
zation of heteroarenes suitable for an industrial environment.
RESULTS AND DISCUSSION
Synthesis and scale-up of fluoroborate precatalysts. In our
previous preliminary study, we have described the synthetic proꢀ
tocols for four different fluoroborate salts (1F-4F) that have difꢀ
ferent alkyl substituents on the ammonium nitrogen center.24, 27
Yet, these precatalysts were synthesized only on a smaller scale
(2ꢀ5 grams) to explore their catalytic activity towards borylation.
As the preliminary study showed that the piperidyl precatalyst 2F
is more efficient for the borylation and borylative dearomatization
of heteroarenes (vide infra), its synthesis on a 100ꢀgram scale was
Later, in 2017, our group also demonstrated that the less stericalꢀ
lyꢀhindered ambiphilic aminoboranes 1ꢀpiperidylꢀ2ꢀBH2ꢀC6H4 (2,
Scheme 1) and 1ꢀEt2Nꢀ2ꢀBH2ꢀC6H4 (3, Scheme 1) can be used as
borylation catalysts with faster reaction rates than 1, even if these
species generate stable Lewis adducts.24 In addition, a preliminary
study was made on the synthesis of fluoride derivatives of 2 and
3, 1ꢀpiperidyl(H)ꢀ2ꢀBF3ꢀC6H4 (2F, Scheme 1) and 1ꢀEt2NHꢀ2ꢀ
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attempted. The synthetic protocol for 2F involves three steps
(Scheme 2): (i) the formation of the 1ꢀBrꢀ2ꢀpiperidylꢀC6H4 interꢀ
chloroform, first the borylation of 1ꢀmethyl pyrrole in three difꢀ
ferent dried
1
mediate (A) through an amineꢀpromoted cyclocondensation beꢀ
tween 2ꢀbromoaniline and 1,5ꢀdibromopentane, (ii) formation of
the boronic acid 1ꢀB(OH)2ꢀ2ꢀpiperidylꢀC6H4 (B) via lithiation of
A followed by nucleophilic substitution with B(OMe)3 and hyꢀ
drolysis with water, and (iii) formation of fluoroborate salt 2F
from the treatment of boronic acid with KHF2 under acidic condiꢀ
tions. In the first step, after the reaction comes to completion, the
excess dibromopentane can be recovered by simple distillation.
Among the three synthetic steps to 2F, only for step 2, i.e., for
lithiation of A and the later addition of B(OMe)3, is the inert
atmosphere needed. The precatalyst 2F was purified conveniently
by recrystallization in CH2Cl2/hexanes. In total, three 100 g
batches
2
3
4
5
6
7
8
9
Table 1. Conversions (%) of catalytic borylation of 1ꢀMeꢀpyrrole
(5a) under different conditions using precatalysts 1F-4F.
Enꢀ
try
Time
(h)
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Solvent
CDCl3
1F
2F
3F
4F
1
7
64
(98:2)
63
(98:2)
3
4
16
16
16
16
1
(86:14)
(100:0)
97
(88:12)
94
(98:2)
91
(98:2)
31
(100:0)
2
3
4
5
91
(89:11)
93
(98:2)
90
(98:2)
34
(100:0)
Toluene
2ꢀMeꢀ
THF
95
(90:10)
95
(98:2)
90
(98:2)
33
(100:0)
93
(88:12)
93
(98:2)
92
(99:1)
39
(100:0)
THF
41
(95:5)
80
(99:1)
75
(99:1)
9
(100:0)
Neat
57
(95:5)
97
(98:2)
96
(98:2)
23
(100:0)
2
In parenthesis: 6a to 6a’ ratio.
solvents, toluene, THF and 2ꢀMeꢀTHF, were explored using all
four precatalysts. The results obtained and displayed in Table 1
show that the catalytic conversions with all three solvents are
excellent and similar to what was observed in chloroform. Howꢀ
ever, to our delight, this reaction works better and with improved
selectivity under solventꢀfree (neat) conditions (entry 5). Moreoꢀ
ver, the reactions were faster under neat conditions. For example,
the borylation of 1ꢀmethyl pyrrole (5a) using precatalyst 1F under
neat conditions gave a conversion of 41% after 4 h, while the
same reaction in chloroform gave only a 7% conversion in that
time. This outcome is very important for the industrial scale proꢀ
duction since it removes reaction solvent from the production
costs.
Scheme 2. Synthetic steps to precatalyst 2F in 100 grams.
of 2F were synthesized with consistent overall reaction yields (55
– 59%). While the piperidyl precatalyst 2F is more active for the
borylation of most heteroarenes, precatalyst 3F is the second best
in catalyzing borylation reactions. However, the TMPꢀcontaining
precatalyst 1F appears to be better for a minority of heteroarenes
(vide infra). Therefore, to compare their catalytic activity with
that of 2F and to study their stability under ambient conditions,
the syntheses of precatalysts 1F and 3F in a 10 gramꢀscale were
achieved by following our previously established procedure (see
Supporting Information).24
Borylation and borylative dearomatization of heteroarenes on
a 2-gram scale. To show the versatility of our catalytic system
towards producing metalꢀfree borylated heterocycles, borylated
heterocycles that are of interest for pharmaceutical or OE indusꢀ
tries were produced on a 2 gramꢀscale through either CꢀH borylaꢀ
tion or borylative dearomatization reactions. For CꢀH borylation
reactions, N, O and Sꢀcontaining heteroarene substrates were
explored (Scheme 3). More emphasis was placed on Nꢀbased
heteroarenes. From Table 1, it became apparent that the precataꢀ
lyst 4F and its active catalyst 4 show lower catalytic efficiency.
Therefore, only precatalysts 1F-3F were screened further to find a
better catalyst for borylation of some intended substrates (see
Supporting Information for the catalysis screening results). From
screening, it was found that the precatalysts 2F and 3F are more
efficient for the N and Oꢀbased heteroarenes. In addition, these
precatalysts also exhibited an
Choice of solvent. In our earlier CꢀB bond forming reactions, we
used dry dichloromethane and chloroform. However, for practical
considerations these solvents should be avoided.28 Thus, we conꢀ
fined our investigations to certain criteria in choosing the solvent,
including: (i) should be nonꢀchlorinated, (ii) should have a boiling
point higher than 70 °C, and (iii) must be compatible with our
catalysts, substrates and endꢀproducts. To find out the suitable
solvent that provides a catalytic conversion as high as observed in
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Scheme 3. Catalytic borylation of heteroarenes on 2 gramꢀscale using HBpin reagent and the appropriate benchꢀstable fluoroborate precatꢀ
alyst under solventꢀfree conditions. “n” signifies the equivalents of HBpin with respect to the substrate. 1 Celite column using ethyl ether as
eluent. 2 Silica gel column purification using petroleum ether/ethyl ether as eluent.3 Partially decomposed upon silica gel column purificaꢀ
tion.4
Recrystallization
in
CH2Cl2/hexanes.
improved regioselectivity with heteroarenes having multiple
nucleophilic sites. For example, with 1ꢀmethyl pyrrole under neat
conditions, a 98:2 ratio of C2ꢀsubstituted to C3ꢀsubstituted isoꢀ
mers was respectively observed with precatalysts 2F and 3F,
while a 95:5 ratio was formed when using precatalyst 1F. Altꢀ
hough both precatalysts 2F and 3F were found to be quite active,
the easier synthetic protocol for 2F explains our choice of catalyst
for the 2 gramꢀscale borylation reactions. For thiophene derivaꢀ
tives, precatalyst 1F and its active form, 1, were found to be better
than our other catalysts. In these systems it was shown that 2
undergoes two consecutive CꢀH activation steps which prevents
the metathesis reaction to occur, and thus catalytic activity.24
Despite some heteroarenes and all precatalysts being in the solid
state, the liquid HBpin reagent together with the reaction temperaꢀ
tures of 80 ꢀ100
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Scheme 4. Catalytic borylative dearomatization of arylsulfonyl indoles on 2 gramꢀscale using HBpin reagent and precatalyst 2F under
solventꢀfree conditions. “n” signifies the equivalents of HBpin with respect to the substrate. CH2Cl2/H2O extraction. Celite column
using ethyl ether as eluent. 3 Derivatized as alcohol using NaOCl.
1
2
°C bring the reaction mixture to a liquid phase and facilitates the
desired reaction. Only for the 1,2ꢀdimethyl indole substrate such
process proved to be a concern, since the solution solidifies after
FBpin and other volatiles in vacuo, followed by passing the etheꢀ
real solution of the crude product through a short column of Celite
using ethyl ether as eluent, which scrubs the residual catalyst. The
borylated furan derivatives 6f-6i, however, were found be less
stable under the chromatographic conditions, partially decomposꢀ
ing during purification, which was identified through phosphomoꢀ
lybdic acid staining of the eluted silica gel TLC plate. Conseꢀ
quently, to obtain two grams of these products higher substrate
loadings were used. Up to this point, several electronꢀrich hetꢀ
eroarenes can be conveniently borylated using this methodology.
Many Nꢀheteroarenes including indoles and pyrroles protected at
N with BOC, Cbz or phosphinyl group, derivatives of pyridine,
pyrimidine, oxazole, thiazole, imidazole, triazole, isoxazole and
selenophene, and electroꢀrich arenes were not successful toward
borylation.
15 minutes at 80 °C, stopping the reactivity. Therefore, a minimal
amount of 2ꢀmethylꢀTHF was added to push the reaction forward.
The reaction time for the borylation reactions generally varies
with respect to the nucleophilicity of the heteroarenes. More
nucleophilic ones such as 1ꢀmethyl pyrrole (5a), 1ꢀbenzyl pyrrole
(5b), 3,4ꢀethylenedioxythiophene (EDOT, 5d), 1ꢀmethyl indole
(5j), 1,2ꢀdimethyl indole (5k) and 5ꢀmethoxyꢀ1ꢀmethyl indole (5s)
require less than 10 h at 80 °C, while others require 16 h at this
temperature. Using stoichiometric or excess HBpin with respect to
the amount of substrate leads to the formation of a significant
amount of diborylated products in the cases of 5d and 5f-5i.
Therefore, 0.8 equiv HBpin with respect to the substrate was
added. The substrate 1ꢀTBDMSꢀ7ꢀazaindole (5t), which bears a
highly exposed basic pyridine nitrogen, required a longer reaction
time (48 h) and extra precatalyst and HBpin loadings to achieve >
80% conversion. Purification of most borylated heteroarenes was
straightforward as it involves mainly removal of excess HBpin,
For the borylative dearomatization reactions, 1ꢀarylsulfonyl
indoles were used as substrates. The catalytic reactions were
tested using all four precatalysts, 1ꢀtosyl indole as substrate, in the
presence of 1.5 equiv of HBpin at 100 °C. All reactions gave a
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quantitative conversion to 3ꢀBpinꢀ1ꢀtosyl indoline (8a), suggestꢀ
ing
that
1
2
Table 2. Comparison of the catalytic activity between iridium catalyst and metalꢀfree fluoroborate precatalysts
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conv. (%) using
Ir/dtbipy catalyst
conv. (%) using
precatalyst 2F
conv. (%) using
Ir/dtbipy catalyst
conv. (%) using
precatalyst 2F
entry
1
substrate
entry
5
substrate
94.4 (92:8, C2/C3
regioisomers)
51
96
97 (98:2,
C2/C3
regioisomers)
63 (C2
regioisomer)
91 (C2
regioisomer)
94 (C2
regioisomer)
99 (C3
regioisomer)
2
3
4
6
7
8
48 (67:33, mono and
diꢀ
96
89 (C2
regioisomer)
72 (C3
(disubstituted)a
regioisomer) c
substituted)
88 (C2
regioisomer)
> 99 (C3
regioisomer)
69 (C2
regioisomer)
89 (C3
regioisomer)
a Precatalyst 1F was used.
any of the precatalysts among 1F-4F can be used for the borylaꢀ
tive dearomatization transformation. A total of 15 arylsulfonyl
indoles were transformed quantitatively in a 2 gramꢀscale using
precatalyst 2F (10 – 20 mol%) and HBpin reagent (1.5 – 2.6
equiv) at 100 °C under solventꢀfree condition over 16 h of reacꢀ
tion time (Scheme 4). Substrates containing either an electronꢀ
donating substituent or an electronꢀwithdrawing substituent at
different positions on the benzene ring of 1ꢀarylsulfonyl indoles
undergo solely the desired borylative dearomatization reaction. In
this transformation, the Bpin group added exclusively to the C3ꢀ
position of indoles while the H substituent simultaneously added
to the C2ꢀposition. Thus, the borylative dearomatized products
obtained were highly regioselective. Moreover, this 1,2ꢀaddition
occurs on the same face of the aromatic CꢀC double bond, which
leads to highly diastereoselective products. The syn addition and
related high diastereoselectivity was previously evidenced from
the Xꢀray crystallographic characterization of the products derived
from the borylative dearomatization of 2ꢀmethyl substituted 1ꢀ
phenylsulfonyl indoles such as 7n and 7o.25 Despite all substrates
and the precatalyst 2F being solids, none of the catalytic reactions
needed a solvent medium. The 100 °C was found to be an optimal
temperature for this transformation since the reactions conducted
at 80 °C required a longer reaction time (~ 36 h). The purification
procedure to isolate the products was similar to that of the
borylated heteroarenes. However, some products were found to be
quite sensitive to air and moisture; therefore, they were sequenꢀ
tially derivatized to alcohol and silyl ethers respectively through
stereoretentive oxidation, using the household bleach composed
of 6% sodium hypochlorite, and silylation using TBDMSꢀ
chloride. Unlike CꢀH borylation reactions, borylative dearomatiꢀ
zation reactions do not produce any H2 byꢀproduct except for the
generation of active catalyst from the fluoride precatalyst. Thereꢀ
fore, this atomꢀefficient reaction can also be carried out in a
sealed reaction flask at the 2ꢀgram scale.
Comparison of catalytic activity with metal catalysts. Most
procedures to synthesize borylated heteroarenes from the respecꢀ
tive heteroarenes through CꢀH activation use expensive iridium
catalysts, which were notably developed by MiyauraꢀHartwig.11a,
11c, 29 The capability of our metalꢀfree ambiphilic aminoboranes to
catalyze the borylation of heteroarenes has drawn us to compare
their catalytic activity with that of the iridium catalyst. The comꢀ
parison was made with a set of substrates under similar reaction
conditions on a millimole scale (Table 2) using catalyst loadings
typically used in the respective transformations. The exception is
the presence of solvent with the iridium catalysts. Comparing the
catalytic results, it was found that: (i) the catalytic efficiency of
both catalysts is more or less similar only when 10 – 20 mol% of
the FLP catalyst is used in relationship to the 3 mol% iridium
catalyst, and (ii) the regioselectivity pattern for the pyrrole and
thiophene derivatives remains the same whereas it differs with the
indole derivatives, i.e., the iridium catalyst promotes C2ꢀ
borylation while our metalꢀfree catalysts facilitate the C3ꢀ
borylation. Nevertheless, it should be pointed out that the low cost
of precatalyst 2F makes the metalꢀfree approach economically
viable.
Stability of the precatalysts. As the stability of the precatalysts
was marked as an indispensable criterion for the application of
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this synthetic method in fine chemical industries, the stability of
precatalysts 1F-3F towards air and moisture at room temperature,
Table 3. Stabilities of the benchꢀtop kept precatalysts 1F-3F
by
1
2
3
lysts was carried out in a sealed 5 mL vial at 80 °C for 4 h. The
outcome of these studies, as shown in Table 3, indicates that over
a oneꢀyear aging, all these precatalysts still keep excellent catalytꢀ
ic efficacy and similar regioselectivity. Additionally, using comꢀ
mercially available HBpin having 1% of triethylamine stabilizer
did not halt the borylation reaction when tested with the sixꢀ
month old precatalysts. All these results clearly show that the
stability of the precatalysts 1F-3F is excellent towards air and
moisture at room temperature for up to a year. Furthermore, as
noted previously, the thermal stability of the in situ generated
catalysts is adequate since they can withstand temperatures of 100
°C and 120 °C for the catalytic borylation and borylative
dearomatization reactions.
examined periodically through their catalytic activity
4
5
6
7
8
9
conv.
(%) conv.
(%) conv.
(%)
Period
using precat using precat using precat
1F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2F
3F
1st week
73 (88:12)
74 (89:11)
69 (87:13)
71 (89:11)
84 (98:2)
80 (98:2)
86 (97:3)
83 (98:2)
88 (98:2)
82 (98:2)
95 (98:2)
86 (98:2)
3rd month
6th month
12th month
50 gram-scale trials. Given the excellent stability towards the
ambient condition by these precatalysts and the adequate thermal
stability by the active aminoborane catalysts, we next aimed at
preparing some of the borylated heteroarenes and borylative
dearomatized heterocycles in an intermediate scale (about 50
grams). The representative N, O and Sꢀbased heterocycles such as
1ꢀmethyl pyrrole, 2ꢀmethyl furan and EDOT were borylated and
more emphasis was placed on the Nꢀheteroarenes. Purification of
products at this scale involves either recovery or removal of exꢀ
cess HBpin respectively through distillation or evaporation in
vacuo, followed by dissolution of the crude product in a minimum
amount of ethyl ether and filtration through a short Celite column
using another equivalent of ethyl ether eluent. Evaporation of the
solvent from resulting solution yields pure borylated heterocycles.
Numbers in parenthesis denote the ratio of products A and B.
keeping them under ambient conditions of the lab, was checked
four times over a 12ꢀmonth period, starting from their syntheses
(1st week, 3rd, 6th and 12th month). Two ways have been followed
to examine their stability: (i) through inspecting the purity of
these precatalysts by NMR spectroscopy (1H, 13C, 11B, and 19F
nuclei), and (ii) by studying their catalytic activity with one of the
heteroarene substrates, 1ꢀmethyl pyrrole. Over the one yearꢀ
period, all three precatalysts kept their original white color, and
the purity of all these precatalysts, as inspected through NMR
spectroscopy, stayed the same with a purity of >99%. To check
the stability of the precatalysts 1F-3F through catalytic activity
studies, the borylation of 1ꢀmethyl pyrrole (5a) on a 1 mmolꢀscale
using 1.3 equiv of HBpin and a 5 mol% loading of the precataꢀ
1-kilogram trial. We attempted to synthesize one of the borylated
heteroarenes on a kilogramꢀscale. For this, we chose to prepare 3ꢀ
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Chart 1. Borylated and borylative dearomatized products obtained in 50 grams using benchꢀstable fluoroborate precatalysts. “n” signifies
1
2
3
1
2
the equivalents of HBpin with respect to the substrate. Celite column using ethyl ether as eluent. Washed with hexanes. Silica gel
column purification using petroleum ether/ethyl ether as eluent. 4 Partially decomposed. 5 CH2Cl2/H2O extraction. 6 Derivatized to alcohol.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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27
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36
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38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Few experimental stages for the metalꢀfree kilogramꢀscale borylation of 1ꢀmethyl indole; left: initial experimental setup with 1ꢀ
methyl indole substrate and HBpin reagent charged in the reaction flask and the precatalyst loaded in the powder addition funnel attached
to the rightꢀside condenser, center: reaction mix at the start of the reaction at 80 °C, right: reaction mix at the end of the reaction at 80 °C.
Bpinꢀ1ꢀMe indole (6j) from 1ꢀmethyl indole (5j), HBpin (1.6
equiv) and precatalyst 2F (10 mol%) (Scheme 5). The experiꢀ
mental setup is shown in Figure 2. The hot reactor setup was
initially flushed with nitrogen, followed by charging the substrate
1ꢀmethyl indole and the reagent HBpin, heating the solution at 60
°C, and adding the precatalyst 2F in portions using a powder
addition funnel. The reaction temperature was kept at 60 °C until
all precatalyst was introduced and the dramatic brisk effervesꢀ
cence developed within minutes due to evolution of H2, to generꢀ
ate active catalyst, is reduced to a normal rate. During this 1 kiloꢀ
gramꢀscale trial, the addition of the precatalyst in small portions
allows controlling the liberation of H2, which is mostly generated
from the catalyst generation from precatalyst, to reduce the risk of
explosion hazard. Afterwards, the reaction temperature was raised
and maintained at 80 °C for 8 h, which led the conversion to 96%.
After purification by first recovering the excess HBpin through
distillation followed by passing the crude product
A straightforward and practical metalꢀfree synthetic methodology
was developed for the borylation and borylative dearomatization
of heteroarenes. This method uses benchꢀstable precatalysts of the
form 1ꢀNHR2ꢀ2ꢀBF3ꢀC6H4, commercial and easilyꢀsynthesizable
heteroarene substrates and the pinacolborane (HBpin) reagent.
The strategy of this methodology first involves the generation of
ambiphilic organocatalysts of structure 1ꢀNR2ꢀ2ꢀBH2ꢀC6H4 from
the precatalysts and HBpin. Then the organocatalysts can undergo
CꢀH activation of an heteroarene, H2 elimination and transmetallaꢀ
tion with HBpin through σꢀbond metathesis to afford highly regiꢀ
oselective borylated heteroarene products, or 1,2ꢀdearomative
hydroboration and transmetallation of electronꢀpoor indoles to
afford C3ꢀborylated indolines with a high regioꢀ and diasteroseꢀ
lectivity. Several borylated N, O and Sꢀcontaining heterocyles
were produced under solventꢀ and additiveꢀfree conditions in
good to excellent yields in 2 and 50 gramꢀscales. Additionally, the
synthesis of one of the heteroarylboronates, 3ꢀborylꢀ1ꢀMe indole,
was successfully scaled up to 1 kilogram under the solventꢀfree
reaction condition. Although our metalꢀfree methodology demonꢀ
strated here does present some substrate scope limitations comꢀ
pared to transition metal catalysts (Ir, Rh, Pd and others), the
introduction of boronyl group on heteroarenes using this process
has several advantages. These include the use of inexpensive
metalꢀfree catalysts, the absence of trace metals in the endꢀ
products, the absence of solvent, an easy purification process
using ethereal solvents for column chromatography, complemenꢀ
tary reactivity to the most efficient catalysts (iridium complexes),
and a moderate reaction temperature range (80–120 °C). Adopting
this green methodology by pharmaceutical and other fine chemiꢀ
cal industries may well benefit them in many ways.
precatalyst 2F
Bpin
(10 mol%)
HBpin (1.5 equiv)
conv: 96%
yield: 1006g,
95%
N
N
80 °C,
neat, 8 h
purity: > 98%
5j
6j
, 4.1 mmol
Scheme 5. Catalytic borylation of 1ꢀmethyl indole in 1 kilogram
using HBpin reagent and precatalyst 2F under the solventꢀfree
condition.
through a short Celite column using ethyl ether gave ~1 kilogram
(1006 grams) of the product (isolated yield = 95%) in >98%
purity. As this metalꢀfree methodology involves the liberation of a
stoichiometric amount of H2, a good outlet for H2 liberation is
required. Furthermore, the solution becomes more viscous as the
catalytic reaction proceeds. Therefore, we customized our reaction
setup to have a constant stirring rate with the help of a mechanical
stirrer in a 2L threeꢀneck round bottom flask (Figure 2(left)). The
preservation of constant stirring of the reaction solution provided
an excellent conversion within a reasonable reaction time (8 h).
ASSOCIATED CONTENT
Supporting Information
The following files are available free of charge on the ACS Publiꢀ
cations website at DOI: Experimental details and NMR spectra
(PDF).
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail for F.ꢀG.F.: frederic.fontaine@chm.ulaval.ca
CONCLUSIONS
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Author Contributions
Groves, J. T., Manganese Catalyzed C–H Halogenation. Acc. Chem. Res.
2015, 48, 1727ꢀ1735; (c) Misal Castro, L. C.; Chatani, N., Nickel
Catalysts/N,N'ꢀBidentate Directing Groups: An Excellent Partnership in
Directed CꢀH Activation Reactions. Chem. Lett. 2015, 44, 410ꢀ421; (d)
Pototschnig, G.; Maulide, N.; Schnürch, M., Direct Functionalization of
C−H Bonds by Iron, Nickel, and Cobalt Catalysis. Chem. Eur. J. 2017, 23,
9206ꢀ9232; (e) Sun, C.ꢀL.; Li, B.ꢀJ.; Shi, Z.ꢀJ., Direct C−H
Transformation via Iron Catalysis. Chem. Rev. 2011, 111, 1293ꢀ1314; (f)
Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J.
F., C−H Activation for the Construction of C−B Bonds. Chem. Rev. 2010,
110, 890ꢀ931; (g) Obligacion, J. V.; Chirik, P. J., EarthꢀAbundant
Transition Metal Catalysts for Alkene Hydrosilylation and Hydroboration.
Nat. Rev. Chem. 2018, 2, 15ꢀ34.
1
2
3
4
5
6
7
8
‡These authors contributed equally.
Notes
The technology presented within this article is patent pending.
ACKNOWLEDGMENT
We gratefully acknowledge National Sciences and Engineering Research
Council of Canada (NSERC) and Centre de Catalyse et Chimie Verte
(Quebec) for funding, BASF for the generous supply of pinacolborane. F.ꢀ
G.F. also thanks NSERC for a Canada Research Chair.
9
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