Metal-Free Directed C?H Borylation of Pyrroles

Article abstract of DOI:10.1002/anie.202016573

Robust strategies to enable the rapid construction of complex organoboronates in selective, practical, low-cost, and environmentally friendly modes remain conspicuously underdeveloped. Here, we develop a general strategy for the site-selective C?H borylation of pyrroles by using only BBr₃ directed by pivaloyl groups, avoiding the use of any metal. The site-selectivity is generally dominated by chelation and electronic effects, thus forming diverse C2-borylated pyrroles against the steric effect. The formed products can readily engage in downstream transformations, enabling a step-economic process to access drugs such as Lipitor. DFT calculations (wB97X-D) demonstrate the preferred positional selectivity of this reaction.

Full text of DOI:10.1002/anie.202016573

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 8500–8504
International Edition:
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doi.org/10.1002/anie.202016573
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À
C H Borylation
À
Metal-Free Directed C H Borylation of Pyrroles
Zheng-Jun Wang+, Xiangyang Chen+, Lei Wu, Jonathan J. Wong, Yong Liang, Yue Zhao,
Kendall N. Houk,* and Zhuangzhi Shi*
Dedicated to Professor Pierre Dixneuf on the occasion of his 80th birthday
Abstract: Robust strategies to enable the rapid construction of
complex organoboronates in selective, practical, low-cost, and
environmentally friendly modes remain conspicuously under-
developed. Here, we develop a general strategy for the site-
C2 and C5 positions constitutes a prototypical example of
À
such an issue. As one of the most notable advances in C H
functionalization, C H borylation[7] has been conducted with
À
pyrroles[5a,8] by transition metal catalysis.[9] To the best of our
À
À
selective C H borylation of pyrroles by using only BBr3
knowledge, only one example of the C H borylation of a C3-
directed by pivaloyl groups, avoiding the use of any metal.
The site-selectivity is generally dominated by chelation and
electronic effects, thus forming diverse C2-borylated pyrroles
against the steric effect. The formed products can readily
engage in downstream transformations, enabling a step-eco-
nomic process to access drugs such as Lipitor. DFT calcu-
lations (wB97X-D) demonstrate the preferred positional
selectivity of this reaction.
substituted pyrrole containing an ester group has been
recently reported with an iridium catalyst, in which the
regioselectivity is preferentially located at the less hindered
C5 position (Figure 1a).[10] The introduction of a directing
group at the N-atom can position the metal catalyst near
a particular C H bond through cyclometallation.[11] The steric
À
hindrance around the coordination site on the transition
metals leads to strong repulsion at the C2 position with C3-
substituted pyrroles, thus leading to the C5 selectivity (Fig-
ure 1b).[12] Despite the broad utility of this approach, the
state-of-the-art method prevents the functionalization of the
M
olecules containing a diversely substituted pyrrole nuclei
feature are prevalent in pharmaceuticals, bioactive molecules,
natural products and agrochemicals.[1] As a result, the
development of efficient strategies for the rapid generation
of such skeletons is of commercial value. Many well-
established classical methods are now available by de novo
construction, but changing the substituent groups used in
these methods typically needs considerable synthetic effort.[2]
Strategies that enable late-stage modification of complex
À
sterically hindered C H bonds.
Given the economic and toxicity concerns, there is
À
a significant interest in the development of metal-free C H
functionalization to mimic the transition metal systems.[13]
Recently, we and Houk et al. uncovered a general strategy
À
for the directed aromatic C H borylation using BBr3 as both
a reagent and catalyst, in which C7 and C4-borylated indoles
were generated with broad functional group compatibil-
ity.[14,15] Based on this discovery, we herein disclose a highly
À
molecules by C H functionalization have become desirable
in both academia and industrial settings.[3] In this context,
À
À
numerous synthetic procedures based on the selective C H
efficient BBr3-mediated approach for the C H borylation of
functionalization of heteroarenes[4] and involving pyrroles[5]
with transition metal catalysts in an atom- and step-econom-
ical mode have been explored by many research groups.
pyrroles under metal-free conditions (Figure 1c). The instal-
lation of a pivaloyl group at the N atom of the pyrroles
selectively delivers the boron species to the sterically
À
À
Due to the presence of the multiple C H bonds of
pyrroles (C2 to C5 positions) that possess different steric and
hindered C2 position and allows for subsequent C H
borylation without any metal, showing an excellent site-
electronic properties, controlling the site-selectivity repre-
[6]
À
sents a key challenge for C H functionalization strategies.
Especially for C3-substituted pyrroles, the selectivity of the
[*] Dr. Z.-J. Wang,[+] L. Wu, Prof. Dr. Y. Liang, Dr. Y. Zhao, Prof. Dr. Z. Shi
State Key Laboratory of Coordination Chemistry, Chemistry and
Biomedicine Innovation Center (ChemBIC), School of Chemistry and
Chemical Engineering, Nanjing University
Nanjing 210093 (China)
E-mail: shiz@nju.edu.cn
Dr. X. Chen,[+] J. J. Wong, Prof. Dr. K. N. Houk
Department of Chemistry and Biochemistry, University of California
Los Angeles, CA 90095 (USA)
E-mail: houk@chem.ucla.edu
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016573.
À
Figure 1. Site-selective C H functionalization of pyrroles.
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selectivity to generate mono-borylated products. The down-
motifs such as Br (12a) and I (13a) were compatible. A
stream transformation of the formed boronates to drug
scaffolds demonstrates the potential utility of this strategy.[16]
Owing to the prevalence of 3-aryl substituted pyrroles in
known pharmaceuticals, we started our studies by focusing on
this motif, for which the C2-selectivity was not well-solved by
transition metal catalysis. The reactivity of N-pivaloyl 3-
phenyl pyrrole (1a) in the presence of BBr3 was first explored
(Scheme 1). The treatment of pyrrole 1a with a slightly
excessive of BBr3 (1.1 equiv) in dry CH2Cl2 for 4 hours at
room temperature afforded the borane complex 1b,[17] which
was facile to convert to the pinacol boronate ester 1c in an
excellent isolated yield. Notably, isomers including pyrrole C4
and C5 borylation products were not detected. Without
chelation assistance, the N-H-free pyrrole I-1a was failed for
this reaction, and the N-Me pyrrole II-1a afforded a mixture
of borylated products II-1c and II-1c’ (C2/C4 = 1.4/1) in 33%
yield. Other directing groups such as N-Bz (II-1a) were also
effective for this transformation, albeit with a lower reactivity.
Further exploration showed that substrates bearing the
common protecting groups like N-Ts (IV-1a), N-Ac (V-1 a),
and N-Boc (VI-1a) were failed.[18] These results confirmed
the selection of the N-Piv moiety for realizing a high reactivity
and selectivity, which was determined by both chelation and
electronic effects.
range of the electronically diverse 3-aryl substituted pyrroles
14–19a also worked well, affording the desired products in
good to excellent yields. While demethylation of the methoxyl
group with BBr3 was well documented, pyrrole 19a bearing
a methoxy group was tolerable in our system. In addition,
treatment of naphthyl-substituted substrate 20a could afford
20c in a 79% yield under the standard reaction conditions.
Pyrroles 21–23a with different alkenyl substituents provided
adducts 21–23c without any hydroboration byproducts. Sub-
jecting compound 24a containing two methyl groups at the C3
À
and C4 positions could undergo C H borylation at the C2
position. Furthermore, treatment of the unsymmetrical sub-
À
strates 25–26a allowed for the selective C H borylation at the
sterically crowded C2-position adjacent to the phenyl group.
Likewise, tetrahydroindole 27a was converted to the corre-
sponding product 27c in a 62% yield with an excellent C2
selectivity as well. However, C2-borylation of pyrrole 28a
became sluggish, in which the steric hindrance between the
directing group and the phenyl group at the C5 position
affected the chelation ability, thus leading to poor conversion.
In addition, noted that the current reaction conditions do not
allow access to pyrroles containing electron-withdrawing
substituents such as cyano, ester and nitro groups at C3-
position.
À
The scope of the C H borylation reaction was then
The metal-free strategy described above presents unique
opportunities to access boryl-substituted pyrroles via more
convergent synthetic routes. To further show the potential
synthetic applications of this strategy, we next applied it to the
rapid construction of the pyrrole subunit of Lipitor, a choles-
terol-lowering drug (Scheme 2).[20] The gram-scale synthesis
of 1c without a notable decrease in yield under the standard
conditions proved the practicality of this method. Subjecting
of the formed benzoates 1c with bromoarene 29 to palladium-
catalyzed Suzuki–Miyaura coupling conditions could afford
the 2,3-diaryl substituted N-H free pyrrole 30 directly in
investigated under the developed reaction conditions
(Table 1). To our delight, when simple N-pivaloylpyrrole
(2a) was treated with BBr3, the product 2c was obtained in
81% yield without any isomers. Pyrroles bearing primary (3–
5a), secondary (6–9a), tertiary (10a) alkyl substituents and
benzyl group (11a) at C3 position underwent facile borylation
and afforded the corresponding C2-borylation products 3–11c
in 43–97% yields. Among them, compound 8a containing
a cyclopropyl substituent did not provide the borylative ring-
opening byproduct.[19] In particular, halogen-containing
Scheme 1. Investigation of the N-substituted groups of pyrroles. Reac-
tion conditions: 1a (0.20 mmol), BBr3 (0.22 mmol) in 1.0 mL CH2Cl2
at room temperature (rt), 4 hours, under Ar; then Et3N (2.0 mmol)
and pinacol (0.30 mmol) were added to the mixture, and the temper-
ature was increased from 08C to rt over 1 hour, isolated yields. The
ratios of isomers were measured by analysis of 1H NMR spectra of the
unpurified mixtures. Bpin=boronic acid pinacol ester.
Scheme 2. Concise route to drug precursor through metal-free directed
À
C H borylation. Dppf=1,1’-bis(diphenylphosphino)ferrocene;
DMF=dimethylformamide.
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Table 1: Substrate scope of pyrroles.[a]
[a] Reaction conditions: substrates 2–28a (0.20 mmol), BBr3 (0.22 mmol) in 1.0 mL CH2Cl2 at rt, 4 hours, under Ar; then, Et3N (2.0 mmol) and pinacol
(0.30 mmol) were added to the mixture, and the temperature was increased from 08C to rt over 1 hour, isolated yields.
a good yield, in which the removal of
the directing group from the product
was readily achieved by Cs2CO3
during the reaction. Then, the intro-
duction of an isopropyl moiety at the
C5 position of 30 through a Friedel–
Crafts reaction with 2-chloropropane
(31) and mediated by AlCl3 furnished
the alkylation product 32, which was
a known synthetic precursor of Lip-
itor achieved through C4 amidation
and N-substitution.[21]
To establish the site-selectivity of
À
this directed C H borylation pro-
cess,[22] density functional theory
(DFT) calculations were performed
with wB97X-D/6–311 ++ G(d,p) and
SMD = CH2Cl2//wB97X-D/6-31G(d)
for the reaction of 3a and BBr3. Based
2
À
on our previous study, a Wheland
intermediate-involved pathway is pro-
posed.[14] As shown in Figure 2, the
complexation of pyrrole 3a with the BBr3 dimer is endergonic
by 6.2 kcalmolÀ1. Ionization to the borenium cation inter-
mediate IN2 leads to subsequent attack of C2 or C5 to give
Figure 2. Free energy profiles for C H borylation of 3a and the optimized structures of TSII
(264i cmÀ1) and TSII5 (312i cmÀ1). Bond lengths are in [ꢀ].
very stable Wheland intermediates. Attack at C2 via TSII2 is
favored and occurs with a barrier of 15.9 kcalmolÀ1. Electro-
philic attack at C5 through TSII5 is less favorable than attack
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at C2 via TSII2 and has a free energy barrier of 17.6 kcal
molÀ1.[23] This is consistent with our experimental observation
that 3b5 is not observed. The subsequent deprotonation by
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BBr4 through TSIII2 has a free energy barrier of 14.9 kcal
À
molÀ1. Based on the free energy profile, the borenium cation
attack step is the rate-determining step.[24] The site-selectivity
À
of the C H borylation in pyrroles at the C2 position over the
C5 position is a result of the direct stabilization of the
Wheland intermediate by the electron-donating methyl
group, in which IN32 is 5 kcalmolÀ1 more stable than IN35.
In addition, the stabilization of IN3 with phenyl substituent in
pyrrole 1a increases to 10.5 kcalmolÀ1 (see supporting
information).
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À
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À
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We would like to thank the National Natural Science
Foundation of China (Grant 22025104, 21972064, and
21672097), the National Natural Science Foundation of
Jiangsu Province (Grant BK20170632), the Excellent Youth
Foundation of Jiangsu Scientific Committee (Grant
BK20180007), and the “Innovation & Entrepreneurship
Talents Plan” of Jiangsu Province for their financial support.
Conflict of interest
The authors declare no conflict of interest.
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À
Keywords: C H borylation · DFT calculations ·
metal-free reactions · pyrroles · site-selectivity
À
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À
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Manuscript received: December 14, 2020
Revised manuscript received: January 12, 2021
Accepted manuscript online: January 15, 2021
Version of record online: March 5, 2021
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