Regioselective Functionalization of 7-Azaindole by Controlled Annular Isomerism: The Directed Metalation-Group Dance

Article abstract of DOI:10.1002/anie.201901724

The regioselective functionalization of 7-azaindole by controlled annular isomerism employing a directed metalation-group migration is reported. The N7 carbamoyl azaindoles undergo regioselective metalation and quenching with an electrophile to furnish C6-substituted derivatives which, in the presence of a catalytic amount of ClCONR₂ promotes a carbamoyl group shift or dance from N7 to N1. A second directed metalation/electrophile quench sequence leads to 2,6-substituted azaindoles. Optimization of the metalation conditions for C2 and C6, separately and iteratively, is presented. Using the directed metalation group dance strategy, a late-stage deuteration of an antipsychotic drug is described. Overall, the controlled migration of the carbamoyl directing group allows multiple functionalization events of the bioactive azaindole scaffold.

Full text of DOI:10.1002/anie.201901724

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Accepted Article
Title: The Directed Metalation Group Dance. Regioselective Iterative
Functionalization of 7-Azaindole by Controlled Annular Isomerism
Authors: Victor Snieckus, Jignesh Patel, Matthew Kitching, Michael
Dalziel, Jennifer Cosman, and Meagan Kaye
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901724
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The Directed Metalation Group Dance. Regioselective Iterative
Functionalization of 7-Azaindole by Controlled Annular
Isomerism
Michael E. Dalziel[a], Jignesh J. Patel[a], Meagan K. Kaye[a], Jennifer L. Cosman[a], Matthew O.
Kitching*[b], Victor Snieckus*[a]
Ted Taylor In Memoriam, a man for all heterocycles
Abstract: The regioselective functionalization of 7-azaindole by
controlled annular directed metalation group isomerism is reported.
The N-7 carbamoyl azaindoles 2a–b undergo regioselective
metalation and electrophile quench to furnish C-6 substituted
derivatives 3 which, in the presence of catalytic amount of ClCONR2
afford products 4 by an N-7 to N-1 carbamoyl group dance. A second
directed metalation-electrophile quench sequence leads to 2,6-
substituted azaindoles 5. Optimization of metalation conditions for C-
2 and C-6, separately and iteratively, is presented. Using the directed
metalation group dance strategy, a late-stage deuteration of an
antipsychotic drug is described. Overall, the controlled annular
isomerism of
a
carbamoyl directing group allows multiple
functionalization events of the bioactive azaindole scaffold.
Azaindoles occupy a prominent position in drug discovery
research due to their diverse bioactivities, especially in the area
of protein kinase inhibition for the development of anti-cancer
therapies. Among the four isosteres, the 7-azindole scaffold, also
present in a rare class of natural products,[1] has emerged as the
key heterocycle for structural modification for provision of new
bioactive molecules (Figure 1, A).[2] Among the synthetic routes
for 7-azaindoles, metalation-based methodologies have achieved
dominance over classical processes due to advantages of
regioselectivity, multiple substitution and ready modification of the
prototype nucleus.[3,4] In previous efforts, we have demonstrated
the power of the directed ortho metalation (DoM) reaction in new
halogen dance strategies,[5] anionic ortho-Fries rearrangement
processes,[6] latent directed metalation group (DMG) protocols,[7]
and, as demonstrated on the 7-azaindole framework, “walk-
around-the-ring” sequences.[4a,4b,8] Whilst synthetically powerful,
these metalation based approaches involve several steps: DMG
introduction, its use to direct the functionalization event, and its
subsequent removal or modification.
[a]
M. E. Dalziel, Dr. J. J. Patel, M. K. Kaye, J. L. Cosman, Prof. V.
Snieckus
Department of Chemistry
Queen’s University
Kingston, Ontario, K7L 3N6 (Canada)
E-mail: snieckus@chem.queensu.ca
Figure 1. A) 7-Azaindole in natural and bioactive molecules and drugs with
azine and azole ring functionalization. B) Selective iterative functionalization
through DMG controlled annular isomerization. C) Regioselective introduction
and migration studies on 7-azaindole.
[b]
Dr. M. O. Kitching
Department of Chemistry
Durham University
Durham, England, DH1 3LE (UK)
E-mail: matthew.o.kitching@durham.ac.uk
Inspired by the work of Sames on silyl migration,[9] we
hypothesized that the N-7 DMG azaindoles 2 would undergo
DoM-mediated C-6 functionalization (Figure 1, B) and, by azine
to azole ring DMG dance to the thermodynamically more stable
Supporting information for this article is given via a link at the end of
the document.
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isomer (34), would allow C-2 functionalization to afford 2,6-
With conditions for the introduction and migration of the
DMG in place, selective functionalization of each ring in the
azaindole scaffold was undertaken. Firstly, the DoM route to 2-
substituted 7-azaindoles 7 was investigated (Figure 2). After
considerable optimization (see SI), treatment of 6b with LDA
using an inverse addition protocol led to efficient C-2 metalation
affording 7a (90% d1 by 1H NMR). A comprehensive study of the
reaction scope was undertaken, leading to the preparation of a
variety of carbon, halogen, sulfur, and phosphorus 2-substituted
derivatives 7b–l. Of particular note is the oxidative conversion of
the B(OR)2 derivative into the azaoxindole 7i[14] and the availability
of substrates for further useful metalation (7e, f, h, j) and cross-
coupling (7b–d, g, i, j, l) chemistry.
With conditions for C-2 functionalization in hand,
investigation of the C-6 metalation process was conducted (Table
1, A). Metalation of 2a using s-BuLi/TMEDA or LDA followed by
CD3OD quench resulted in product with undetectable d-
incorporation, suggesting lower C-6 H acidity compared to that of
the pyridine C-2 acidity.[15] Using Barbier conditions
(LDA/TMSCl)[16] led to quantitative conversion to 3 (E = TMS) by
GC-MS analysis of crude product (entry 4) but normal aqueous
work-up resulted in desilylation to starting material 2a. Switching
to anhydrous work-up conditions resulted in formation of products
3 (E = TMS and Bpin) in excellent conversion by 1H NMR (entries
5 and 6) but subjection to normal work-up also resulted in isolation
of starting material 2a, undoubtedly the result of ipso-
protodesilylation and ipso-protodeboronation.[17] In view of the
limited electrophile-base compatible combinations for the Barbier
and Martin procedures, we returned to examine C-6 metalation of
2b using inverse addition-electrophile quench procedures.
Gratifyingly, 2.5 equiv of LDA under inverse addition conditions
gave product 3a with modest d-incorporation (entry 7, 73% d1).
Switching to the more sterically hindered LiTMP and modification
of reaction temperature improved the level of anion formation
considerably (entries 8 and 9, 90% and 93% d1, respectively).
Under the optimized conditions, the C-6 DoM chemistry of
2b was generalized (Table 1, B). As shown, the methodology
allows the synthesis of halogen containing 3b–d, carbon-based
disubstituted azaindoles 5. Such a migration sequence
Figure 2. Regioselective synthesis of C-2 substituted 7-azaindoles. Reactions
were performed on a 0.41 mmol scale. Reaction conditions: 6b (0.41 mmol, 1.0
equiv), LDA (0.90 mmol, 2.2 equiv), THF (0.10 M), –78 °C, 1 h; then E+ (1.0–3.7
mmol, 2.5–9.0 equiv), –78 °C (1 h) to 23 °C (12 h). Yields of isolated products.
circumvents the removal and introduction of the DMG and would
allow the same group to direct functionalization at a new, remote
location. In continuing efforts to invent new DoM-founded
chemistry,[10] we now report the successful attainment of the
DMG dance concept (34), which establishes a regioselective
route to 7-azaindoles bearing diverse C-2 (Table 1) and C-2 and
C-6 (Figure 3) substitution patterns.
In order to test the DMG dance concept, the regioisomeric
N-7 (2a,b) and N-1 (6a,b) carbamoyl azaindoles were prepared
(Figure 1, C, for optimization see SI).[11] The choice of the CONR2
as DMG was dictated by its previous efficacy in DoM
chemistry.[4b,12] Although N-1 DMG 7-azaindoles have been
synthesized previously,[4b,13] to the best of our knowledge, N-7
DMG-bearing 7-azaindole isomers are unknown. The identity of
the two isomers was unambiguously confirmed by X-ray
crystallography. To assess the expected thermodynamically
driven DMG dance, compound 2b was subjected to a catalytic
quantity of di-isopropyl carbamoyl chloride which led, under
optimized conditions (see SI, Table 1), to the isomeric derivative
6b in 95% yield.
3e–g, and heteroatom-based 3h azaindole derivatives.
A
potentially useful finding is the observation of controlled mono-
/bis-iodination of 2b simply by modification of the I2 stoichiometry
(3c vs 3d). Although high levels of conversion (>92%) were
observed in all cases (1H NMR analysis), yields of isolated
products were compromised due to their instability to column
chromatography. Fortunately, simple exposure of the crude
reaction products to the optimized DMG dance conditions
afforded 6-substituted azaindoles
4 which proved readily
separable. In this manner, methyl, carbamoyl, carbinol, and
sulfide substituted products 4a–h (Table 1, C) were readily
accessible in good to excellent yields.
To fully establish the DMG dance strategy for general
regioselective C-2 and C-6 functionalization of the 7-azaindole
scaffold, C-2 DoM reactions of substrate 4 were undertaken.
Application of the optimized C-2 metalation conditions on 4,
followed by electrophile quench, afforded products
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Table 1. Optimization of C-6 metalation, substrate scope and DMG migration from N-7 to N-1. A: [a] All reactions were performed on a 0.41 mmol scale. [b] Entries
1–6: 2a as starting material; entries 7–9: 2b as starting material. [c] % deuteration / conversion was determined by 400 MHz 1H NMR analysis on the crude reaction
mixture. [d] Aqueous workup. [e] Anhydrous work up. [f] The reaction was stirred at –78 °C for 30 mins before being warmed to –40 °C for 10 min. Electrophile was
added at –78 °C, and the reaction was stirred for 1.5 h at this temperature. [g] LiTMP was prepared using 1.6 equiv 2,2,6,6-tetramethylpiperidine and 1.5 equiv t-
BuLi in THF solution. B: [h] Reaction conditions: 2b (0.41 mmol, 1.0 equiv), LiTMP (0.62 mmol, 1.5 equiv), THF (0.10 M), –78 °C (30 min) to –40 °C (10 min); then
E+ (0.43–4.1 mmol, 1.05–10.0 equiv), –78 °C, 1.5 h. [i] All % yields represent conversion as determined by 400 MHz 1H NMR on the crude reaction mixture. C: [j]
Reaction conditions: 2b (0.41 mmol, 1.0 equiv), LiTMP (0.62 mmol, 1.5 equiv), THF (0.10 M), –78 °C (30 min) to –40 °C (10 min); then E+ (0.43–4.1 mmol, 1.05–
10.0 equiv), –78 °C, 1.5 h. After subsequent work-up: 3 (assumed 0.41 mmol, 1.0 equiv), ClCONiPr2 (0.10 mmol, 25 mol%), MeCN (0.04 M), 95 °C, 12 h. [k] All %
yields are of isolated products over the two steps (i.e. from 2b)
5a–j in good yields (67–89%) (Figure 3). Of particular note, the
presence of the powerful N-1 DMG overrides any competitive
metalation at C-5 aided by the potential DMGs present at C-6
(5j,k) including the powerful amide directing groups (5l). Given
the prevalence of bioactive 2-arylated 7-azaindole variants (e.g.
GSK 1070916, Figure 1, A), we explored the feasibility of the
cross-coupling of 5j with 4-nitrophenylboronic acid, two
expectedly proficient coupling partners.[18] In a preliminary
encouraging study, Suzuki-Miyaura coupling resulted in the
formation of product 8 in good yield.
In consideration of the interest in deuterated molecules as
new drug entities,[19] we undertook a deuteration study of the
antipsychotic agent L-745870 (9, Figure 4). Thus, compound 10,
prepared (see SI) and subjected to deuteration using the standard
LDA protocol afforded 12 (88% yield, 74% d1). Subjecting the
isomeric N-7 carbamoyl derivative 11 to the LiTMP/D2O
conditions as previously optimized (Table 1, A) followed by the
catalytic DMG dance procedure afforded deuterated material 13
in 37% yield over two steps (79% d1).
In summary, we have demonstrated a new DMG dance
concept and developed it for a general and highly regioselective
synthesis of 2- and 6- and combined 2,6-substituted 7-azaindole
derivatives. In addition, we have illustrated an application of this
annular DMG isomerism concept in the regioselective synthesis
of deuterated antipsychotic agent L-745870, a result which may
anticipate late-stage derivatization of other commercial drugs.
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Figure 4. Regioselective deuteration of antipsychotic agent L-745870.
[8]
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NSERC Canada is warmly acknowledged for consistent support
via the Discovery Grant (DG) program (VS) as is the Royal
Society for a University Research Fellowship (MOK). We thank Dr.
Francoise Sauriol for expert NMR assistance, Dr. Gabriele
Schatte for X-ray analysis and Adrian Bailey for DFT calculations.
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Keywords: Azaindole • DMG Dance • Iterative metalation •
Regioselectivity • Lithiation
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Michael E. Dalziel[a], Jignesh J. Patel[a],
Meagan K. Kaye[a], Jennifer L.
Cosman[a], Matthew O. Kitching*[b],
Victor Snieckus*[a]
Page No. – Page No.
The Directed Metalation Group
Dance. Regioselective Iterative
Functionalization of 7-Azaindole by
Controlled Annular Isomerism
Text for Table of Contents
The Directed Metalation Group Dance
A new Directed Metalation Group (DMG) dance concept is disclosed on the 7-azaindole framework. Azine selective (N-7) incorporation
of the carbamoyl DMG allows C-6 functionalization via directed ortho metalation. The controlled annular DMG dance N-7 to N-1
generates the azole (N-1) DMG derivative. Second and iterative DoM reactions allow the synthesis of 2,6-substituted azaindoles in
good yields. The DMG dance methodology is demonstrated in site selective deuteration of a drug scaffold.
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