Metal-Free Borylation of Heteroarenes Using Ambiphilic Aminoboranes: On the Importance of Sterics in Frustrated Lewis Pair C-H Bond Activation

Article abstract of DOI:10.1021/jacs.7b08143

Two novel frustrated Lewis pair (FLP) aminoboranes, (1-Pip-2-BH₂-C₆H₄)₂ (2; Pip = piperidyl) and (1-NEt₂-2-BH₂-C₆H₄)₂ (3; NEt₂ = diethylamino), were synthesized, and their structural features were elucidated both in solution and in the solid state. The reactivity of these species for the borylation of heteroarenes was investigated and compared to previously reported (1-TMP-2-BH₂-C₆H₄)₂ (1; TMP = tetramethylpiperidyl) and (1-NMe₂-2-BH₂-C₆H₄)₂ (4; NMe₂ = dimethylamino). It was shown that 2 and 3 are more active catalysts for the borylation of heteroarenes than the bulkier analogue 1. Kinetic studies and density functional theory calculations were performed with 1 and 2 to ascertain the influence of the amino group of this FLP-catalyzed transformation. The C-H activation step was found to be more facile with smaller amines at the expense of a more difficult dissociation of the dimeric species. The bench-stable fluoroborate salts of all catalysts (1F-4F) have been synthesized and tested for the borylation reaction. The new precatalysts 2F and 3F are showing higher reaction rates and yields for multigram-scale syntheses.

Full text of DOI:10.1021/jacs.7b08143

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Article
Metal-Free Borylation of Heteroarenes using Ambiphilic Aminoboranes:
On the Importance of Sterics in Frustrated Lewis Pair C-H Bond Activation
Julien Légaré Lavergne, Arumugam Jayaraman, Luis C. Misal-
Castro, Etienne Rochette, and Frédéric-Georges Fontaine
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 13 Sep 2017
Downloaded from http://pubs.acs.org on September 13, 2017
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MetalꢀFree Borylation of Heteroarenes using
Ambiphilic Aminoboranes: On the Importance of
Sterics in Frustrated Lewis Pair CꢀH Bond
Activation
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a
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Julien Légaré Lavergne, Arumugam Jayaraman, Luis C. Misal Castro, Étienne Rochette,
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and Frédéric-Georges Fontaine*
a) Département de Chimie, Université Laval, 1045 Avenue de la Médecine, Québec (Québec),
Canada, G1V 0A6
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
Submitted to Journal of the American Chemical Society
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Abstract
Two novel frustrated Lewis pair (FLP) aminoboranes, (1ꢀPipꢀ2ꢀBH ꢀC H ) (2; Pip = piperidyl)
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and (1ꢀNEt ꢀ2ꢀBH ꢀC H ) (3; NEt = diethylamino), were synthesized and their structural
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features were elucidated both in solution and in the solid state. The reactivity of these species for
the borylation of heteroarenes was investigated and compared to previously reported (1ꢀTMPꢀ2ꢀ
BH ꢀC H ) (1; TMP = tetramethylpiperidyl) and (1ꢀNMe ꢀ2ꢀBH ꢀC H ) (4; NMe =
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dimethylamino). It was shown that 2 and 3 are more active catalysts for the borylation of
heteroarenes than the bulkier analogue 1. Kinetic studies and DFT calculations were performed
with 1 and 2 to ascertain the influence of the amino group of this FLPꢀcatalyzed transformation.
The CꢀH activation step was found to be more facile with smaller amines at the expense of a
more difficult dissociation of the dimeric species. The benchꢀstable fluoroborate salts of all
catalysts (1F-4F) have been synthesized and tested for the borylation reaction. The new
precatalysts 2F and 3F are showing higher reaction rates and yields for multiꢀgram scale
syntheses.
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Introduction
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Arylboronates are ubiquitous reagents in modern synthetic methodologies, notably for the
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SuzukiꢀMiyaura coupling reaction. As such, many researchers have been targeting green and
cheap strategies to generate these ubiquitous reagents. Of particular interest is the catalytic CꢀH
borylation reaction allowing the preparation arylboronates from readily available arenes and
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heteroarenes. To this day, the most efficient CꢀH borylation catalysts use noble metals, but
recent advancements have shown that earthꢀabundant species can also catalyze this challenging
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transformation. Other synthetic strategies to generate arylꢀboron bonds include the electrophilic
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borylation using stoichiometric or catalytic borenium derivatives and the metalꢀcatalyzed CꢀX
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X = Cl, Br, I) borylation. We also recently introduced a promising approach for the borylation
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reaction using metalꢀfree frustrated Lewis pairs (FLPs). Repo and coworkers demonstrated that
the CꢀH activation of arenes, the first step in a FLP catalyzed borylation reaction, is a common
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transformation for ambiphilic aminoborane molecules, suggesting that catalyst design and
optimization of this transformation might make this metalꢀfree borylation process more efficient
and viable for the preparation of a large range of products.
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Since its introduction in 2006 by Douglas Stephan, FLPs have been shown to activate a large
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range of unreactive substrates and to act as catalysts in several transformations. According to
popular perception, a FLP consists of a Lewis acid and base that do not form a Lewis adduct
because of steric or geometric congestion. However, several evidences exist that FLPꢀtype
transformations can be achieved using Lewis adducts exhibiting no “frustration” at the resting
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state; such phenomenon has been referred as thermally induced FLPs. For example, Stephan
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and Ashley demonstrated that B(C F ) can catalyze the hydrogenation of ketones in etheric
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solvents, even if it is well known that B(C F ) forms stable etherate adducts. Several other
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Lewis adducts have also been involved in what are considered FLP transformations,
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suggesting that such reactivity is not dictated by the absence of Lewis pair formation at the
resting state, but rather by the presence of a reactive intermediate or a transition state (TS) where
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a Lewis pair cooperate for bond activation.
To support this hypothesis, we are interested in investigating the importance of steric hindrance
in the borylation of heteroarenes using aminoborane catalysts. Our first report of a catalytic FLP
borylation reaction used as catalyst 1ꢀTMPꢀ2ꢀBH ꢀC H , bearing the sterically hindered 2,2,6,6ꢀ
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tetramethylpiperidine (TMP), and worked according to the mechanism proposed in Figure 1.
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This bulky amine has been a versatile Lewis base in FLPꢀbased transformations, but the
synthesis of TMPꢀderivatives is low yielding and relatively expensive. Using smaller and more
readily available amines, such as piperidine or diethylamine, could lead to more economical and
practical metalꢀfree CꢀH activation processes. We wish to report here that contrarily to
expectations, FLPs with smaller amines generate extremely active catalysts for the metalꢀfree
borylation of heteroarenes, surpassing in activity 1 with the bulkier TMP derivative, even if these
species exist as stable Lewis adducts. Kinetic and computational studies were carried out to
better understand the reasons for such difference in activity.
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Figure 1. Proposed mechanism for the borylation of heteroarenes using aminoborane catalysts.
Pin = pinacol, E = S, O, NR.
Synthesis and characterization of ambiphilic aminoboranes
19d
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While the synthesis of (1ꢀTMPꢀ2ꢀBH ꢀC H ) (1) and (1ꢀNMe ꢀ2ꢀBH ꢀC H ) (4)
was
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previously reported, (1ꢀPipꢀ2ꢀBH ꢀC H ) (2) and (1ꢀNEt ꢀ2ꢀBH ꢀC H ) (3) were prepared
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following a protocol illustrated in Scheme 1. In a typical synthesis, 1.3 equiv of LiAlH were
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added to the corresponding boronic acid or boronate ester to generate the lithium borohydride
salt. The electrophilic abstraction of the hydride was possible by adding 1.1 equiv of TMSBr in
toluene, affording the desired products 2 and 3 in 79 and 50 % yield, respectively. It was possible
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to isolate quality crystals of 2 and 3, allowing their Xꢀray structural characterization. The
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ORTEP representations are illustrated in Figure 2. As previously observed and reported for 4,
these species adopt a dimer where one BꢀH bond is activated by the BꢀN FLP of another
molecule, forming a sixꢀmembered ring. No significant deviation in the bond lengths was
observed between species 2ꢀ4, although the B2ꢀH1ꢀB1 angle and the B1ꢀB2 distance for 2
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(136(1)° and 2.358(2) Å) are slightly different than for 3 (123.8(9)° and 2.275(3) Å) and 4
(123(1)° and 2.255(3) Å).
Scheme 1. Synthesis of aminoborane species 2 (NR = piperidyl; R’ = Me) and 3 (NR = NEt ;
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R’ = H).
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Supporting the solid state structures, the B{ H} NMR spectra of species 2ꢀ4 at ambient
temperature show the presence of two distinct boron resonances in solution (0.5 and ꢀ7.7 ppm for
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; 1.0 and ꢀ10.7 ppm for 3; 3.3 and ꢀ10.4 ppm for 4). In the H NMR spectra, broad signals for
the hydrides are observed at 4.0 and ꢀ0.95 ppm for 2 and at ꢀ0.69 for 3.
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Figure 2. ORTEP representation of compounds 2 and 3. Ellipsoids are drawn at 50% probability.
Hydrogen atoms linked to the carbon atoms are omitted for clarity. Hydrogen (white), carbon
(black), nitrogen (blue) and boron (pink). Selected bond lengths [Å] and angles [°] for 2 : N1ꢀB2
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.633(1), B2ꢀH1 1.26(1), B1ꢀH1 1.29(2), B1ꢀC1 1.585(2), C1ꢀC2 1.391(1), C2ꢀN1 1.496(1), N1ꢀ
B2ꢀH1 109.0(7), B2ꢀH1ꢀB1 136(1), H1ꢀB1ꢀC1 109.3(7), B1ꢀC1ꢀC2 121.0(1), C1ꢀC2ꢀN1
115.1(1), C2ꢀN1ꢀB2 110.31(8); for 3: N1ꢀB2 1.628(1), B2ꢀH1 1.29(1), B1ꢀH1 1.29(1), B1ꢀC1
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.586(2), C1ꢀC2 1.388(2), C2ꢀN1 1.490(2), N1ꢀB2ꢀH1 105.0(5), B2ꢀH1ꢀB1 123.8(9), H1ꢀB1ꢀC1
07.5(5), B1ꢀC1ꢀC2 122.7(1), C1ꢀC2ꢀN1 116.8(1), C2ꢀN1ꢀB2 109.82(9).
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The synthesis of the fluoroborate salts of catalysts 1-4 (1F-4F), which are benchꢀstable
borylation precatalysts, was achieved by following the synthetic protocol reported for 1ꢀ
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TMP(H)ꢀ2ꢀBF ꢀC H (1F).
The addition of KHF to the aminoboronic acid derivatives
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yielded species 2F and 3F in 81% and 85% yield, respectively (Scheme 2). All the BF salts were
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fully characterized by NMR spectroscopy ( H, C{ H}, B and F), elemental analysis, and Xꢀ
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Scheme 2. Synthesis of trifluoroborate precatalysts 2F (NR = piperidyl), 3F (NR = NEt ), and
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2 2
Borylation catalysis
The catalytic activity for the borylation of 1ꢀmethylpyrrole using species 2-4 was monitored and
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compared to that of already reported catalyst 1. The experiments were carried out at 60 °C in a
JꢀYoung NMR tube using chloroformꢀd as solvent, hexamethylbenzene as internal standard and a
catalyst loading of 2.5 mol% (Scheme 3). As seen in Figure 3, a significant difference in the
consumption rate of 1ꢀmethylpyrrole and production of 1ꢀMeꢀ2ꢀBpinꢀpyrrole was observed
between all catalysts. Whereas 1 did show about 25% conversion after one hour, as previously
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reported, over 50% conversion in 25 minutes was observed with 3. The piperidine analogue
was the most active of all catalysts examined, with over 75% conversion in just 20 minutes,
which is about 15 times more active than bulkier FLP 1. The dimethyl analogue 4 presented the
lowest catalytic activity of the four species investigated.
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Scheme 3. Borylation of 1ꢀmethylpyrrole with FLP catalysts 1-4
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Figure 3. Consumption of 1ꢀmethylpyrrole ([C H N]/[C H N] ) upon the borylation reaction
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catalyzed by 1 (blue), 2 (green), 3 (black), and 4 (red).
The catalytic borylation of thiophene was also tested and no significant formation of the
expected 2ꢀBpinꢀthiophene (5) was observed for all catalysts, as previously observed for 1,
although approximately 10% conversion was noticed by using catalyst 2. The analysis of the
reaction mixture allowed us to observe the formation of the bisꢀarylation product 1ꢀPipꢀ2ꢀ
B(thiophenyl) ꢀC H (6) (Scheme 4) as previously reported by Repo when studying the reaction
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independently and HBpin was added (TS2, Figure 1), suggesting that the absence of metathesis
once analogues of 6 are generated is causing the inhibition of catalytic activity in the borylation
of pristine thiophene by aminoborane catalysts.
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Scheme 4. Borylation of thiophene using catalyst 2.
We recently reported that the fluorideꢀprotected FLP 1ꢀTMP(H)ꢀ2ꢀBF ꢀC H (1F) was an active
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precatalyst under typical catalytic conditions, i.e. in presence of excess HBpin, since little change
in yield and activity, other than an induction period for the deprotection step, was observed
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between 1 and 1F. Based on the concomitant generation of FBpin, it was proposed that 1F
generates borohydride 1 under catalytic conditions. Since these benchꢀstable precatalysts allow
for a simplified and practical protocol, a catalytic screening was done using all fluorinated
analogues (1F-4F). First, 1ꢀmethylpyrrole was borylated using 1.3 equiv of HBpin in the
presence of 5 mol% of precatalysts 1F-4F in chloroformꢀd at 80 °C, yielding after 16 hours 2ꢀ
Bpinꢀ1ꢀmethylpyrrole (7a) as main species with conversions of 97, 94, 91 and 31%, respectively
(Table 1). Although 1F-3F all gave similar conversion after 16 hours, the activity of 1F after 4
hours (7%) is significantly lower when compared with 2F and 3F (64 and 63%, respectively),
suggesting that the induction period is shorter with the smaller FLPs. In an effort to circumvent
the use of chlorinated solvents, toluene, THF, and 2ꢀMeꢀTHF were also tested, all giving similar
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activities. However, a significant increase in activity and conversion was observed under solventꢀ
free conditions. For example, 57% conversion of the 1ꢀmethylpyrrole to generate 7a was
observed with the TMP precatalyst 1F in two hours while no conversion was monitored in
chloroform in the same period. Another significant feature is the increase in selectivity under
these new catalytic conditions. Whereas the borylation of 1ꢀmethylpyrrole in chloroform gave a
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88:12 selectivity for the 2ꢀ to 3ꢀposition, respectively, under neat conditions the selectivity was
found to be 95:5. The increase in selectivity is even more pronounced using the piperidine
anologue 2F where a 98:2 ratio of 7a to 7a’ was found under neat conditions.
Table 1. Catalytic borylation of 1ꢀmethylpyrrole in different conditions using precatalysts 1F-
4F.
Solvent
Time (h)
1F
2F
3F
4F
4
7 (86:14)
64 (98:2)
63 (98:2)
3 (100:0)
CDCl3
1
6
97 (88:12)
91 (89:11)
95 (90:10)
93 (88:12)
41 (95:5)
57 (95:5)
94 (98:2)
93 (98:2)
95 (98:2)
93 (98:2)
80 (99:1)
97 (98:2)
91 (98:2)
90 (98:2)
90 (98:2)
92 (99:1)
75 (99:1)
96 (98:2)
31 (100:0)
34 (100:0)
33 (100:0)
39 (100:0)
9 (100:0)
Toluene
2ꢀMeꢀTHF
THF
16
16
16
1
Neat
2
23 (100:0)
In parenthesis C2:C3 regioselectivity
Precatalysts 1F-4F were also tested with additional substrates under neat conditions, as
shown in Table 2. Similarly to the results observed with 1ꢀmethylpyrrole, the borylation of 1ꢀBnꢀ
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
4
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5
5
5
5
5
5
5
6
pyrrole was facilitated using piperidine analogue 2F, obtaining over 90% conversion to 1ꢀBnꢀ2ꢀ
Bpinꢀpyrrole in 6 hours. 65% conversion was observed for 3F and only traces of the desired
product (2 %) was observed with 1F. A similar trend was also observed with 1ꢀMeꢀ and 1ꢀBnꢀ
indole, where 2F gave the highest efficiency of all precatalysts tested, reaching up to 96 and 89
% conversions, respectively. Unfortunately, our attempts to borylate 1ꢀMeꢀ7ꢀazaꢀindole were not
successful, likely due to the coordinative NꢀB interaction between the active catalyst 1 and the
pyridine functionality of 1ꢀMeꢀ7ꢀazaꢀindole. As expected, bulkier protecting groups on the
indole, such as in 1ꢀTBDMSꢀ7ꢀazaꢀindole, allows the borylation at the 3ꢀposition with 82 %
conversion (62 % isolated yield) with precatalyst 2F (100 ºC for 48 hours). The synthesis of 2ꢀ
Meꢀ5ꢀBpinꢀfuran was also possible using catalysts 1Fꢀ3F with conversions over 90 %.
Precatalyst 4F once again proved to be the worst catalyst, with only 34 % conversion.
Interestingly, only for the borylation of EDOT did 1F prove to be a better catalyst than 2F and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3F (96, 31, and 18 % conversion, respectively). It is logical to assume that the second CꢀH
activation of EDOT, which is expected to shut down catalytic activity with all catalysts (vide
supra), might be more difficult with the bulkier TMP analogue 1F. To demonstrate the synthetic
viability and reproducibility of these protocols, all the borylated products were synthesized on a
2
g scale in good to excellent yields using the best catalyst for each system, although some of the
borylation products are sensitive to silica gel complicating the purification procedure.
1
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Table 2. Results of screening the precatalysts with some representative heteroarenes
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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29
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50
51
52
53
54
55
56
57
58
59
60
a
Precatalyst
Temp. Time
Conversion (%)
Entry
1
Product
n
(mol%)
(°C)
(h)
1F
2F
3F
4F
b
b
91(0)
b
(15)
2
80
6
2 (0)
c
65 (0)
0
{
76}
7b 7b’
9
80}
6
2
3
(10)
(20)
2
80
6
8
63
82
c
c
87
82
10
29
{
7c
89
67}
2.6
100
{
{
7d
8
62}
2
4
5
(20)
3
100
48
46
96
c
76
24
7e
d
(10)
0.87
0.8
80
80
6
c
31
18
90
3
{
85}
7f
d
96
77}
6
(10)
16
92
c
34
{
7g
a
1
b
d
Determined by H NMR spectroscopy using hexamethylbenzene as an internal standard.
c
Percentage of the minor C3ꢀregioisomer. Isolated yield based on the 2 gramꢀscale reactions
1
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5
6
Catalyst loading corresponds to the amount of HBpin left after subtracting the required amount
to generate the BH catalyst.
2
Mechanistic investigation of the C-H activation
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
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8
9
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1
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8
9
0
1
2
3
4
5
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7
8
9
0
As observed in the crystallographic studies and in solution, catalysts 1ꢀ4 are stable dimeric
species. Dissociation has to take place in order to generate the FLP intermediate performing the
CꢀH activation step. In addition to the FLP “opened” geometry (Table 3, A), 1ꢀNR ꢀ2BR’ ꢀC H
4
2
2
6
species can adopt a favourable “closed” geometry (Table 3, B) where an intramolecular BꢀN
interaction is present. The latter isomer was structurally characterized with some examples of
1
7a,23
aminoboranes bearing a highly Lewis acidic moiety.
Three different structures have also
been reported for aminoborane dimeric species: a “3ꢀcentreꢀ2ꢀelectron” interaction such as in 1
1
9d
18
(
Table 3, C), a BꢀH bridged dimer as in 2-4 (Table 3, D), and an eightꢀmembered ring where
9
b,18
two BꢀN interactions are present, which was reported as a minor isomer of 4 (Table 3, E).
DFT calculations on all isomers of reported catalysts (Table 3) confirm that the solidꢀstate
structures observed are the lowest in energy for species 1ꢀ4.
Table 3. Stability of the various conformations of aminoborane species 1-4
Open,
Active FLP
A
BꢀH bridged
Eightꢀmembered
Closed
B
Trans dimer
dimer
D
ring dimer
C
ꢁ
E
o
G (kcal/mol)
1
2
7.1
9.6
5.4
1.4
0.0
15.9
0.0
47.1
3.9
4.0
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10.7
10.6
6.2
4.1
5.7
6.1
0.0
0.0
6.6
1.2
Level of theory : ωB97XD/6ꢀ31+G** (SMD, chloroform)
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60
Although the exact value for the dissociation of dimeric 1 has never been measured, it was
ꢀ1
19d
presumed to be in the higher range of the 11ꢀ14 kcal mol value. Dimeric species with smaller
amines are expected to generate more stable adducts since both BꢀH and BꢀN interactions need
to be broken before generating the monomeric species. Using DFT, free energies of 20.7 and
ꢀ1
2
3.3 kcal mol were found for breaking the BꢀH bond of the dimers 2 and 4, respectively, which
is thought to be the limiting step in the dissociation process. Because of the asymmetry in their
dimeric structure, NMR spin saturation transfer experiments can be conducted to determine the
energy required for scrambling both moieties. The cleavage of both the BꢀH and the BꢀN bonds
is required for this process to take place and this value should be close to the energy required to
generate the FLP intermediate.
When irradiating selectively the doublet of 2 at δ = 7.565, we observed saturation of the signal
1
at δ = 6.866, the corresponding proton on the other aromatic ring of the dimer, suggesting that
2
scrambling is taking place between the two aminoboranes moieties. Using a method developed
2
4
by Muñoz and coꢀworkers, the difference in the integration of δ with and without saturation
2
∗
ꢃ ꢄ
ꢆꢃ ꢄ
ꢅ
ꢅ
divided by the integration of δ without saturation (ƞꢀꢀꢁꢂ
=
) was obtained for each
1
ꢃ ꢄ
ꢇ
saturation time and plotted in an exponential curve to determine the rate constants (k) of the
scrambling according to the following equation:
ꢊ
ƞꢀꢀꢁꢂꢈtꢉ =
ꢈ1 − expꢎꢈ−ꢈ1⁄ꢋꢌꢍ + ꢊꢉ ∙ ꢏꢉꢉ
ꢈ1⁄ꢋꢌꢍ + ꢊꢉ
1
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
4
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4
4
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5
5
5
5
5
5
5
6
The NMR experiments were performed at 60, 57, 54 and 51 °C and the rate constants were
‡
plotted according to the Eyring equation (see ESI). Using these results, we obtained a ꢁG of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
2
0.5 ± 3.1 kcal.mol , which correlates with the energy barrier found computationally.
Unfortunately, it was not possible to determine the energy required for breaking the dimeric
species 4 because of the equilibrium between the BꢀH bridged dimer and the eightꢀmembered
ring dimer (D and E, respectively, Table 3), and the degradation of 4 into diborane species upon
1
8
heating. Nonetheless, the latter decomposition process and the stability of the dimer can
rationalize the lower catalytic activity of catalyst 4.
Energies of all intermediates and transition states for the proposed CꢀH bond activation
mechanism (Figure 1) were located by DFT and are represented in Figure 6 for 1ꢀMeꢀpyrrole and
Figure 7 for thiophene. To support this mechanism, the consumption of the aminoborane was
1
1
1
monitored using B{ H} NMR spectroscopy. In a typical experiment, a large excess of either 1ꢀ
methylpyrrole or thiophene (775, 1550, or 3100 ꢂM) was added to a known concentration of the
aminoborane 1 and 2 (38.8, 77.5, or 155 ꢂM) in chloroformꢀd. A glass capillary containing
HBpin was inserted in a quartz NMR tube as external standard. The rate of disappearance of the
starting material observed by NMR spectroscopy was compared to kinetic simulations using the
energies found computationally (Figures 4ꢀ5). It is important to note that this method allows
observing the impact of reagent concentration on rate, therefore allowing observing the trends in
consumption rather than the exact values. It cannot give a reliable time scale because of the
difficulty to find the preꢀexponential factor by only knowing the TS of a transformation (see ESI
for detailed explanations).
1
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59
60
ꢀ
1
Figure 4. Free energies in kcal mol for the CꢀH activation of 1ꢀmethylpyrrole with
aminoboranes 1 (Blue), 2 (Green), and 4 (Red) calculated at DFT/ωB97XD/6ꢀ31+G** (SMD,
chloroform) level of theory.
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TS1ꢀt
TS2ꢀt
‡
‡
H
R N
BH2
S
2
R N
B
2
H
S
H
H
2
2
7.7
6.8
0
1
2
3
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7
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0
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8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
22.7
dimer breakage
23.3
24.8
2
1.3
8.2
20.7
1
1
0.6
9
.6
9.1
7.1
5
.9
.2
3.9
1
R2N
BH2
2
1.8 1.6
0.0
H
S
S
S
R N
B
R N
B
H
2
R N
B
2
2
R N
BH2
2
H
H
H
for 2 and 4
Int2ꢀt
for 1
Int1ꢀt
ꢀ1
Figure 5. Free energies in kcal mol for the CꢀH activation of thiophene with aminoboranes 1
(
Blue), 2 (Green), and 4 (Red) calculated at DFT/ωB97XD/6ꢀ31+G** (SMD, chloroform) level
of theory.
As demonstrated previously by kinetic isotope effect studies, the rateꢀlimiting step in the CꢀH
activation of 1ꢀmethylpyrrole using bulky FLP 1 is the concerted CꢀH activation having an
ꢀ
1 9a
energy barrier of 24.5 kcal mol . The energy required to reach this TS can be broken down in
ꢀ1
the energy required to access the “opened” form (7.1 kcal mol ) and to cleave the C–H bond
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9
ꢀ1
ꢀ1
(
17.4 kcal mol ). The subsequent loss of H is easier with a barrier of 18.3 kcal mol . As
2
expected for such a mechanism, the rate of consumption of 1 is firstꢀorder in substrate. With a
concentration of 77.5 ꢂM of 1 and of 775 ꢂM of 1ꢀmethylpyrrole at 40 °C, half of the starting
material is consumed within 35 minutes, whereas increasing the concentration of pyrrole to 3100
ꢂM increased the rate by a factor of 3.5 (Figure 6A). As seen in Figure 6A’, these data correlate
well with the simulated rates using the energies found by DFT, supporting the proposed
mechanism.
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As explained above, the absence of catalytic activity in the borylation of thiophene is not related
ꢀ1
to the absence of CꢀH activation owing to the fact that the barrier of 27.7 kcal.mol for such
process is thermally accessible. Accordingly, it takes approximately 300 min for half of 1 to be
consumed using 20 equiv of thiophene when heated at 60 °C (Figure 6B). However, a striking
feature of this bond activation is the increase in the consumption rate of 1 as reaction goes along
rather than the expected logarithmic decay for a pseudoꢀfirst order reaction. Although we are not
able to propose a precise explanation for this behavior, it suggests that another side reaction is
taking place at the later stage of the process that is consuming 1. Interestingly, it was observed
that increasing the concentration of dimer 1 with a fixed concentration of the substrate led to a
slower rate of consumption of 1 for 1ꢀmethylpyrrole, as illustrated in Figure 7C. Once again,
such behavior is supported by kinetic simulations and is related to the presence of an equilibrium
favoring the formation of a dimeric species, which reduces the concentration of the “opened”
form relative to the dimeric species at higher concentrations. In the case of thiophene, the
mismatch between the experimental and simulated values once again presume the presence of an
unidentified side reaction (Figure 7D).
1
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2
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Catalyst 2 follows a similar mechanism as 1 for 1ꢀmethylpyrrole activation (Figure 5), but the
energies differ drastically from those observed for 1. The most striking feature is the CꢀH
ꢀ1
ꢀ1
activation step reduced by about 6 kcal mol , with a TS at 18.4 kcal mol , even if the active FLP
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
intermediate for the smaller catalyst lies higher in energy (9.6 kcal mol ) when compared with 1
ꢀ1
(7.1 kcal mol ). Accounting only for the energy required to cleave the C–H bond from the active
ꢀ1
FLP intermediate, the smaller analogue 2 requires only 8ꢀ9 kcal mol compared to the 17 kcal
ꢀ1
mol required by 1, firmly suggesting that reducing the steric bulk of the FLP leads to a more
active catalyst. It is logical to assume that with less steric hindrance, the Lewis pair is more
accessible for incoming substrates. However, the energy cost for the extrusion of H is more
2
ꢀ1
important in 2 requiring 23.5 kcal mol . It should be noted that such an increase is a
consequence of the relatively lower stability of the zwitterionic intermediate 2-Int1p, which is
ꢀ1
ꢀ1
located at 8.0 kcal mol rather than 4.3 kcal mol for 1-Int1p. By normalizing these values for
, 2, and 4, it was found that all zwitterionic intermediates require approximately 12ꢀ15 kcal
1
ꢀ1
mol to release H . Notwithstanding, none of these barriers exceed the energy required to
2
dissociate the dimer with 1ꢀmethylpyrrole. This behavior is supported experimentally since there
is no influence of pyrrole concentration on the CꢀH activation rate, as illustrated in Figure 8E.
Indeed, half of 2 was consumed within 10 minutes when varying the concentration of 1ꢀ
methylpyrrole from 775 ꢂM to 3100 ꢂM. However, the CꢀH activation of thiophene is more
ꢀ1
challenging by about 6 kcal mol and is now rate determining; the reaction rates are again
affected by thiophene concentration (Figure 8F). All these experimental values are in line with
the simulated kinetic data observed when inputting the energies located by DFT (Figures 8ꢀ9).
Energies of each step of the mechanism proposed in Figure 1, including the possible additional
CꢀH activation of a substrate, are illustrated in Figures S50ꢀS53 of the supporting information.
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The energies found for the metathesis step are all in accordance with our original report and was
2
0b
previously discussed in more detail.
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59
60
Figure 6. Left: Consumption of a 77.5 ꢂM solution of aminoborane 1 in chloroformꢀd at various
concentrations (775 ▲, 1550 ● and 3100 ■ ꢂM) of 1ꢀmethylpyrrole at 40°C (top row) or
thiophene at 60°C (bottom row). Right: Simulated rate of consumption according to DFT data.
2
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8
9
0
1
2
3
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8
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Figure 7. Left: Consumption of a solution of aminoborane 1 at various concentrations (38.8 ▲,
77.5 ● and 155 ■ ꢂM) in chloroformꢀd with a 1550 ꢂM concentration of 1ꢀmethylpyrrole at 40°C
(top row) or thiophene at 60°C (bottom row). Right: Simulated rate of consumption according to
DFT data.
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Figure 8. Left: Consumption of a 77.5 ꢂM solution of aminoborane 2 in chloroformꢀd at various
concentrations (775 ▲, 1550 ● and 3100 ■ ꢂM) of 1ꢀmethylpyrrole at 40°C (top row) or
thiophene at 60°C (bottom row). Right: Simulated rate of consumption according to DFT data.
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Figure 9. Left: Consumption of a solution of aminoborane 2 at various concentrations (38.8 ▲,
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(top row) or thiophene at 60°C (bottom row). Right: Simulated rate of consumption according to
DFT data.
Discussion
Although several observations have surfaced in the past few years supporting that FLP type
17
transformations are possible from stable Lewis pairs, this report is the first to clearly
demonstrate that smaller steric congestion can lead to an increase in catalytic activity.
Analogously to transition metal catalysis, an unhindered Lewis pair favors the interaction of the
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active site with incoming substrates but increases the chance of aggregation and deactivation
modes. This is supported by the increased reactivity of (1ꢀPipꢀ2ꢀBH ꢀC H ) (2) in the C–H bond
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4 2
activation compared to bulkier (1ꢀTMPꢀ2ꢀBH ꢀC H ) (1), even if 2 requires approximately 21
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kcal mol to reach the active and “opened” FLP intermediate where both the Lewis base and
acid are available. However, it is important to mention that faster reactivity might ensue when
only one of the Lewis pair components is required for a reaction to take place, such as in the
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interaction of a BꢀH with a protic reagent. Recently, a computational study was reported
proposing that smaller FLPs could yield more active catalysts for the hydrogenation reaction,
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notably using analogues 2 and 4. Our experimental results support such hypothesis for the C–H
bond activation process, but also illustrate the care that needs to be taken when doing
computational design. Indeed, the authors proposed 3ꢀcentersꢀ2ꢀelectrons resting states (Table
3
C) for 2 and 4 rather than the experimentally characterized BꢀH bridged dimers (Table 3D). As
ꢀ1
such, the TS are in reality 5 kcal mol higher than proposed and dimer dissociation should
remain rate limiting under such reaction conditions.
It is quite surprising that the energy required to cleave the CꢀH bond of 1ꢀmethylpyrrole from the
ꢀ
1
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opened” FLP intermediate is only 8.8 kcal mol with 2. For comparison, it was found that the
barrier for concerted metalationꢀdeprotonation using [(PR )Pd(Aryl)(C(O)R)] was over 12 kcal
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mol with the most active substrate being C F H. Although significant energy is required in
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order to access this FLP intermediate, strategies could be introduced to prevent dimerization and
access an active FLP state without requiring extra bulk, such as immobilization on solid
supports.
FLPs are better known as hydrogenation catalysts. Although it has been stipulated by some that
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the cleavage of H by a FLP is a barrierꢀfree process, the same cannot be said about the release
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of H from ambiphilic molecules. It was previously demonstrated that this transformation was an
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important driving force in the formation of diboranes and in the intramolecular C ꢀH bond
sp3
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cleavage by aminoboranes.
With aminoboranes, it can also be stated that loss of H can be
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rate determining in the overall CꢀH activation process, if we exclude the dissociation of the
dimer. As shown by the absence of catalytic activity with thiophene, it now becomes evident that
σꢀbond metathesis needs to be enhanced in order to increase the reactivity of this system.
Notwithstanding the exceptional activity of the smaller derivatives which are about 15 times
more active than the TMP analogues, yielding faster reactions and higher selectivity, this metalꢀ
free system has another significant advantage, notably for largeꢀscale applications. Indeed, the
diethylamineꢀ and piperidylboranes are significantly cheaper and much easier to synthesize. It is
possible to isolate fluorideꢀprotected analogues such as 2F on 100 gram scale for less than three
dollars a gram. Since these precatalysts are airꢀ and moistureꢀstable, they can be stored for
several months without significant loss in activity. Although these catalysts do not provide the
same wide and general versatility observed with the best transition metal catalysts, notably in the
presence of protic functional groups, they do provide a convenient and cheap alternative with
several substrates.
Conclusion
In this report, we demonstrated that FLPs with small amines, such as (1ꢀPipꢀ2ꢀBH ꢀC H ) (2),
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4 2
and their fluoride protected salts are extremely active catalysts for the borylation of heteroarenes,
surpassing in activity the TMP analogues. Not only these results suggest that steric hindrance is
not required for FLP transformations to take place, but also that small congestion actually leads
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to higher reactivity. As demonstrated by DFT and kinetic measurements, the rate limiting step
with smaller amines become the dissociation of the dimer and the extrusion of H . This better
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understanding of the operating mode of FLP in CꢀH activation process is critical for the synthesis
of more active and robust catalysts for commercial applications. We are currently investigating
the wide range of substrates that can be borylated using this procedure, exploiting notably the
green and economical advantages that are gained using solventꢀfree conditions. We hope that
additional design might lead to catalysts that can borylate other functional groups, such as CꢀO
and CꢀN bonds.
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Supporting Information
Experimental procedures, Xꢀray crystallographic data, and computational details including other
calculated reaction pathways, Cartesian coordinates, free energies and enthalpies. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
E-mail: frederic.fontaine@chm.ulaval.ca
ORCID ID
Julien L. Lavergne : 0000ꢀ0002ꢀ7062ꢀ9491
Arumugam Jayaraman : 0000ꢀ0001ꢀ7116ꢀ4174
Luis C. Misal Castro :
Étienne Rochette :
FrédéricꢀG. Fontaine : 0000ꢀ0003ꢀ3385ꢀ0258
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
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This work was supported by the National Sciences and Engineering Research Council (NSERC)
of Canada and the Centre de Catalyse et Chimie Verte (Quebec). We acknowledge BASF for the
gift of HBpin. E.R. and J.L.L. acknowledge NSERC, FRQNT and Vanier CGS for scholarships.
We acknowledge Compute Canada (Calcul Québec) for computation time. We acknowledge S.
Johnson and W. D Jones for helpful discussions and P. Audet for his help with NMR
experiments.
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Chirik, P. J. J. Am. Chem. Soc. 2017, 139, 2825ꢀ2832. Nickel catalyzed: j) T. Furukawa, T.;
Tobisu, M.; Chatani, N. Chem. Commun. 2015, 51, 6508–6511; k) Zhang, H.; Hagihara, S.;
Itami, K. Chem. Lett. 2015, 44, 779ꢀ781.
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