Selective C?N Borylation of Alkyl Amines Promoted by Lewis Base

Article abstract of DOI:10.1002/anie.201809608

An efficient method for the metal-free deaminative borylation of alkylamines, using bis(catecholato)diboron as the boron source, to directly synthesize various alkyl potassium trifluoroborate salts is introduced. The key to this high reactivity is the utilization of pyridinium salt activated alkylamines, with a catalytic amount of a bipyridine-type Lewis base as a promoter. This transformation shows good functional-group compatibility (e.g., it is unimpeded by the presence of a ketone, indole, internal alkene, or unactivated alkyl chloride) and can serve as a powerful synthetic tool for borylation of amine groups in complex compounds. Mechanistic experiments and computations suggest a mechanism in which the Lewis base activated B₂cat₂ unit intercepts an alkyl radical generated by single-electron transfer (SET) from a boron-based reductant.

Full text of DOI:10.1002/anie.201809608

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Accepted Article
Title: Lewis Base Promoted Selective C-N Borylation of Alkyl Amines
Authors: Zhuangzhi Shi, Jiefeng Hu, Guoqiang Wang, and Shuhua Li
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10.1002/anie.201809608
Angewandte Chemie International Edition
C-N Borylation
C−N Bond Activation
Lewis Base Promoted Selective C-N Borylation of Alkyl Amines
Jiefeng Hu+, Guoqiang Wang+, Shuhua Li*, and Zhuangzhi Shi*
Abstract: An efficient method for metal-free deaminative borylation
of alkylamines using bis-(catecholato)diboron as the boron source
to directly synthesize various alkyl potassium trifluoroborate salts is
introduced. The key to this high reactivity is the utilization of
pyridinium salt-activated alkylamines, with a catalytic amount of a
bipyridine-type Lewis base as a promoter. This transformation
shows good functional group compatibility (e.g., being unimpeded
by the presence of a ketone, indole, internal alkene, or unactivated
alkyl chloride) and can serve as a powerful synthetic tool for
borylation of amine groups in complex compounds. Mechanistic
experiments and computations suggest a mechanism in which the
Lewis-base activated B2cat2 unit intercepts an alkyl radical
generated by single-electron transfer (SET) from a boron-based
reductant.
Boronic acids and their derivatives play important roles in a variety
of fields ranging from material science to drug discovery and
organic synthesis.[1] They are usually prepared by either lithium
compounds or Grignard reagents, processes which are not
compatible with many functional groups.[2] The Miyaura-type[3] and
radical-mediated[4] borylation methods developed over the past
decades have enabled efficient approaches to build these useful
compounds, which features a broad substrate scope and good
functional group compatibility. Specifically, the selective borylation
of unreactive chemical bonds has shown promise because it confers
the synthetic versatility of inert functional groups.[5] However, these
methods are usually well appreciated in the construction of
arylboronic esters, and applying these strategies to synthesize
alkylboronic esters[6] has yet to be broadly recognized. Very recently,
Baran and coworkers reported the Ni-catalyzed decarboxylative
borylation of alkyl N-hydroxyphthalimide esters from alkyl
carboxylic acids with bis(pinacolato)diboron (B2pin2) to alkyl
boronic esters through alkyl radical intermediates.[7] Later,
Aggarwal et al. also uncovered that this transformation could also be
promoted by visible light at room temperature in the presence of
bis(catecholato)diboron (B2cat2).[8] Similar to alkyl carboxylic acids
in terms of natural abundance, alkylamines have received less
attention, and their deaminative borylation has been virtually
unexplored.
Figure 1. Selective borylation of alkylamine C-N bonds.
arylamines with B2pin2 via the Sandmeyer reaction process.[9] In
2014, Tobisu and Chatani developed Ni-catalyzed borylative
cleavage of sp2 C-N bonds in N-aryl amides and carbamates.[10] In
2016, we and other groups also reported Ni-catalyzed aryl and
benzyl C-N bond borylation via ammonium salts under mild
conditions (Figure 1a).[11] Inspired by recent progress from
Watson[12] and Glorius[13] groups, the Katritzky salts[14] generated
from alkylamines can act as alkylating agents in radical induced
deaminative arylation (Figure 1b). Moreover, we[15] first uncovered
the B-B bond cleavage by a Lewis base, 4-cyanopyridine, to
produce a pyridine-stabilized boryl radical.[16] We envisioned that if
the transient alkyl radical generated from Katritzky pyridinium salts
and the stabilized boryl radical were formed in one reaction system,
selective cross-coupling of these two species might build sp3 C-B
bonds.[17] Herein, we report our results on the utilization of
pyridinium salt-activated alkylamines as the electrophilic
component in a Lewis base-promoted deaminative borylation
reaction (Figure 1c).
Amines are known to be poor electrophiles because of the
resonance stability of the C-N bond. Therefore, the selective break
the C-N bond of an amine to build C-B bond is a very valuable
transformation in organic chemistry. In 2010, Wang et al. developed
a novel metal-free method for the synthesis of arylboronates from
We began the investigations by monitoring the reactivity of the
pyridinium salt 1b derived from a primary amine 1a with B2cat2.
The reaction was found to be facile, with 1.5 equiv of B2cat2 in the
presence of a Lewis base, dtbpy (10 mol %), in DMA after 6 h at
100 °C. Since the catechol boronate product is not stable, the crude
product can transfer to potassium trifluoroborate salt 1c with KHF2
in 62% yield by trituration with hot acetone or transesterification
with pinacol to boronic ester 1c' in 72% yield (entry 1).
Significantly, dtbpy can accelerate the C-N borylation process
(entries 2-4) and other Lewis bases, such as py and bpy, were also
effective for this transformation albeit with lower yields (entries 5-
6). Other diboron reagents, such as B2pin2, did not provide the
corresponding carboboration product (entry 7). The use of Lewis
basic solvents, such as DMA or DMF (entry 8), was required for the
reaction, and using toluene as a solvent led to a very low yield (entry
9). At a lower temperature (80 °C), the results were found to be
slightly inferior to those observed under the optimal conditions
[]
Jiefeng Hu[+], and Prof. Dr. Zhuangzhi Shi
State Key Laboratory of Coordination Chemistry, School of
Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, China
E-mail: shiz@nju.edu.cn
Guoqiang Wang[+], and Prof. Dr. Shuhua Li
Key Laboratory of Mesoscopic Chemistry of Ministry of
Education, Institute of Theoretical and Computational
Chemistry, School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing 210093, China
E-mail: shuhua@nju.edu.cn
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification
number(s) for the author(s) for this article can be found under
http://www.angewandte.org.
1
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10.1002/anie.201809608
Angewandte Chemie International Edition
Table 1. Reaction development.[a]
Table 2. Substrate scope.[a]
Yield of 1c'
Entry
Variation from the standard conditions
(%)[b]
1
2
none
84 (72[c], 62[d]
)
without Lewis base
without Lewis base, 12 h
without Lewis base, 24 h
using py instead of dtbpy
using bpy instead of dtbpy
B2pin2 instead of B2cat2
DMF
28
41
49
39
69
0
3
4
5
6
7
8
67
17
78
34
80
9
toluene
10
11
12
at 80 °C
at room temperature, 48 h
in the dark
[a] Reaction conditions: 1b (0.40 mmol), B2cat2 (0.60 mmol), 10 mol%
of dtbpy in DMA (1.0 mL), 100 °C, 6 h, under Ar. [b] Determined by
crude 1H NMR analysis based on 1c'. [c] Isolated yield of 1c'. [d]
Isolated yield of 1c. dtbpy = 4,4'-di-tert-butyl-2,2'-bipyridine; py =
pyridine; bpy = 2,2'-bipyridine.
(entry 10), and the reaction at room temperature resulted in poor
conversion, even with a prolonged time period (entry 11). Finally,
the reaction could be conducted well in the dark, indicating it is not
a visible-light-driven borylation (entry 12).
With the optimized reaction conditions in hand, we then
examined the scope of this transformation (Table 2). To facilitate
purification, we converted most products to the corresponding
potassium trifluoroborate salts. Deaminative borylation of primary
amine derivatives 2-10b with different aryl moieties on the carbon
chain proceeded smoothly. It should be noted that the
chemoselectivity of the C-N borylation process was not affected by
halo substituents such as F (5c), Cl (6c) and Br (7c) on the
substrates, highlighting the potential of this process in combination
with subsequent cross-coupling transformations. The couplings of
substrates with heterocyclic aromatic motifs, such as thiophene
(11c') and indole (12c'), were also tolerable. Borylation of
substrates containing ether (13b) and amide groups (14b) generated
products 13c' and 14c in modest yields. Notably, substrate 15b, with
a primary alkyl chloride motif, was also found to be compatible with
the reaction conditions. Amino acid derivative 16b produced
product 16c' in 61% yield. Substrate 17b with an internal alkenyl
motif worked well under the optimized procedure. Furthermore, (R)-
2-phenyl-1-propylamine (18a) with a preexisting stereocenter was
[a] Reaction conditions: A mixture of compound b (0.40 mmol), B2cat2
(0.60 mmol), and 10 mol% of dtbpy in THF (1 mL) was stirred for 6 h
at 100 °C under Ar, for product c: saturated KHF2 (4.5 M) at 0 °C, 3 h,
isolated yields by trituration with hot acetone; for product c': pinacol
(1.2 mmol), Et3N (1.0 mL),
1 h, isolated yields by column
chromatography. Yields given within parentheses were determined by
1HNMR analysis of crude product c'.
To showcase the utility of the transformation for diversifying
natural-product amines, we prepared a diverse collection of
Katritzky pyridinium salts and subjected them to the optimized
reaction conditions. For example, the reaction of cyclic substrate
24b only gave 24c' in high diastereoselectivity. Product 25c' is
derived from a commercially available drug baclofen, a medication
used to treat spasticity. Leelamine derivative 26b could undergo C-
N borylation with B2cat2 to produce product 26c in 54% yield.
Steroids 27-28b were also readily transformed into boronates 27-
28c' in 67-73% yields. In addition, a vitamin E derivative 29b was
borylated with excellent chemoselectivity.
preserved during the reaction (18c).
A range of secondary
alkylamines were also efficiently transformed into the
corresponding potassium trifluoroborate salts 19-22c. Importantly,
tertiary amine 23b could also be converted into the desired product
23c in modest yield. Unfortunately, pyridinium salts from sterically
hindered tertiary amines such as adamantyl amine can’t be prepared.
To further explore functional group compatibility of this method, an
additive-based robustness screen was also performed (see Scheme
S4 in SI for details).[18] The screen indicated the tolerance of the
reaction to alcohols, epoxides, acetals, ketones, carboxylic acids,
secondary amines, lactams, pyridines, silanes, internal alkynes and
α,β-unsaturated esters. Aldehydes, terminal olefins, and alkynes as
well as aziridines that likely underwent boron addition under the
reaction conditions were predicted to be unsuitable substrates.
To investigate the reaction mechanism, we explored a radical
clock experiment by performing the reaction on a cyclopropyl-
containing substrate 30. Under the standard conditions, we obtained
ring-opening products 32 and 33[19], and normal borylation product
31 was not detected (Scheme 1a). Additionally, the cross coupling
of 34, prepared from (S)-2-aminooctane, resulted in racemic 35
2
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10.1002/anie.201809608
Angewandte Chemie International Edition
(Scheme 1b). These results indicate that this deaminative borylation
undergo a radical-mediated pathway. In our system, we isolated a
symmetrical tetraorganoborate complex 37, likely by homolytic
cleavage of the B–B bond, which was confirmed through X-ray
(Scheme 1c). However, this complex could not transfer to the
desired product, confirming that it was not a viable intermediate in
this deaminative borylation process (Scheme 1d).
Figure 3. 11B NMR studies of the reaction intermediates.
As shown in Figure 4, the homolytic cleavage of the B-N bond in
Int3 could generate the radical species dtbpy-Bcat (Int3′′) and
DMAc-Bcat (Int4), which is predicted to be only endergonic by 3.7
kcal mol-1, suggesting that this process is also possible. It has been
reported that the Lewis base-stabilized boron centered radicals can
16a]
be considered as strong single-electron reductants.[6u,
The
Scheme 1. Mechanistic experiments.
calculated HOMO energy of Int3′′ and Int4 is -4.7 ev and -5.6 ev,
respectively. Thus, we proposed that the resulting Lewis base
stabilized boron radical could also react with Katritzky salts via the
SET process to form the alkyl radical b'. Hence, the in situ
generated bipyridinylidene analogue (Int3) using dtbpy and B2cat2,
or its fragmented species (Int4, Int3′′), might be possible for single
electron donors to initiate this radical process for subsequent
borylation reaction. It has been demonstrated that alkyl N-
hydroxyphthalimide ester could form an alkyl radical with B2cat2-
DMAc adduct to trigger a SET process via a thermal or
photochemical event.[8] However, the calculated HOMO energy of
B2cat2-DMAc complex is -6.7 ev, which indicates that this complex
is a weaker single electron reductant compared with Int3. These
results are in accord with the experimental result that in the absence
of dtbpy, the borylation product was obtained in a lower yield. The
generated alkyl radical b' could couple with Int4 to form the desired
boronic ester c[16a]. Alternatively, radical b' could also react with
B2cat2 to generate the final product c. [6u]
It is worth noting that dtbpy is crucial to accelerate the reaction of
Katritzky salts and B2cat2. Therefore, we performed the density
functional theory (DFT) calculations using the M06-2X
functional[20] (see SI for details) to investigate the role of dtbpy in
this radical process (Figure 2). The association of two N atoms of
dtbpy with
Figure 2. Gibbs free energy profile for the dtpby induced cleavage
of the B-B bond of B2cat2 (all energies are given in kcal mol-1).
B2cat2 forms a Lewis adduct Int1, which is exergonic by 2.5 kcal
mol-1. Then, the cleavage of B-B in Int1 generates the
bipyridinylidene intermediate Int2, and the corresponding barrier is
27.8 kcal mol-1 (with respect to separated B2cat2 and dtbpy). The
Int2 could be associated with the solvent DMAc to provide DMAc-
Int2 adduct (Int3). The formation of Int3 is exergonic by 6.5 kcal
mol-1, suggesting the generation of Int3 is possible under the
experimental conditions. As demonstrated by 11B NMR, the
calculated 11B NMR chemical shift (δB = 22.0 ppm) of Int2 is in
good agreement with the experimental 11B NMR shift at ~20 ppm
found in a 1:1 mixture of dtbpy and B2cat2 (Figure 3), which
indicates that the association of Int2 and DMAc is reversible at 100
°C. The bipyridinylidene derivative has recently been demonstrated
to be a strong organic single electron reductant.[21] The calculated
HOMO energy of Int3 (-4.9 ev) is comparable to the
bipyridinylidene derived from 4-DMAP[20] (-4.6 ev) (see Scheme S8
in SI for details). Thus, the species Int3 may act as an electron
donor. We speculate that SET from Int3 to Katritzky salts (a) leads
to the C-N fragmentation, generating the alkyl radical. This pathway
is exergonic by 1.7 kcal mol-1 (see Scheme S9 in SI for details).
Figure 4. Plausible mechanism.
In summary, we have developed an efficient transitionary, metal-
free system that can activate the C–N bonds of Katritzky pyridinium
salts derived from diverse alkylamines via a deaminative process to
produce a series of alkyl potassium trifluoroborate salts. In view of
the widespread amine group and its precursors in chemicals, this
method offers a meaningful tool to enable them as valuable building
blocks. This transformation showed exceptional functional group
tolerance, high efficiency and excellent chemoselectivity. Due to
these advantages, this reaction should be of high synthetic value.
Acknowledgments
3
This article is protected by copyright. All rights reserved.

10.1002/anie.201809608
Angewandte Chemie International Edition
We thank the “1000-Youth Talents Plan” from the NSF of China
(Grants 2167020084 and 21673110) for their financial support and
the “Innovation & Entrepreneurship Talents Plan” of Jiangsu
Province. Parts for the calculations that were performed using
computational resources on an IBM Blade cluster system from the
High-Performance Computing Center (HPCC) of Nanjing
University.
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Keywords: metal-free ·borylation ·alkylamine ·radical ·C-N
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Entry for the Table of Contents (Please choose one layout)
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C-N Borylation
Jiefeng Hu, Guoqiang Wang, Shuhua
Li*, and Zhuangzhi Shi*___ Page –
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Lewis Base Promoted Selective C-N
Borylation of Alkyl Amines
N to B: A mild catalytic system was developed for the preparation of alkyl
potassium trifluoroborate salts via C-N bond cleavage. This method has good
functional group compatibility and can serve as a powerful synthetic tool for late-
stage borylative cleavage C-N bonds in complex compounds.
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