Dedicated to Prof. Donald S. Matteson on the 60th anniversary of the reaction that bears his name.
Key words
boron - catalysis - chemoselectivity - homologation - diversity-oriented synthesis
Scheme 1 (a) General catalytic strategies towards C(sp2)–C(sp2) and C(sp2)–X bond formation. (b) General strategies towards benzylic C–C, C–N, and C–O bond
formations. (c) This work: a diversity-oriented approach towards benzylic C–C, C–N,
and C–O bonds via a catalytic arylboronic acid homologation using a halomethyl Bpin
reagent.
Diarylmethanes, benzyl ethers, and benzyl amines are common motifs found in bioactive
molecules. Typical organometallic approaches towards the synthesis of diarylmethanes
involve nucleophilic displacement of benzylic halides or the reduction of acetophenones/benzhydrols;[1] however, reactions are often limited to the availability of the organometallic reagent
or the preparation of symmetric diarylmethane products. Catalytic approaches – including
Suzuki–Miyaura couplings[2] – are known using either benzylic halides and arylboron reagents[3]
[4] or aryl (pseudo)halides and typically benzylic BF3Ks,[5,6] although other organoborons have been used.[7] Among other Pd-catalyzed methods,[8]
[9]
[10]
[11]
[12]
[13] Shibata has reported the synthesis of unsymmetrical diarylmethanes using diborylmethane
and 10 mol% Pd(P-tBu3)2.[14] These methods are supplemented by similar Ir- or Ni-catalyzed processes.[15]
[16] Classical alkylation or reductive amination reactions to prepare benzylic ethers
or amines often require harsh conditions and limit functional group compatibility
(Scheme [1b]).[17] Catalytic approaches towards C–X bond formation, including Buchwald–Hartwig,[18] Ullmann–Goldberg,[18] and Chan–Lam couplings,[19] have traditionally focused on C(sp2)–X bond formation (Scheme [1a]). C(sp3)–X bond formations using Buchwald–Hartwig and Chan–Lam approaches are becoming more
common but can require the use of bespoke ligands or long reaction times. [18]
[19]
While historically utilized in C(sp2)–C(sp2) cross-coupling reactions, contemporary work has employed C(sp3)–B organoboron reagents as a method to prepare more C(sp3)-rich scaffolds for improved biological characteristics in medicinal chemistry.[20] As such, both the preparation and utilization of C(sp3)–B bonds remains a strategic focal point within academic and industrial research
settings. Several benzyl boronic acids are known; however, very few are commercially
available likely due to their propensity to degrade (protodeboronation).[21] Approaches to prepare the respective benzylic boronic esters typically require the
use of stochiometric organometallic reagents from halides,[1]
[22] hydroboration,[1,23] C–H activation,[24] or photoredox[25] methods. As a conceptual alternative to the classical Matteson homologation,[26] which inserts a metalated carbenoid into an organoboron reagent,[27] we have recently disclosed an approach using Pd catalysis, arylboronic acids, and
a halomethylboronic acid pinacol ester.[28]
Scheme 2 Example scopes. Yields determined by 1H NMR spectroscopy using an internal standard, isolated yields in brackets. a) ArB(OH)2 (1 equiv), BrCH2BPin (1.5 equiv), Pd(PPh3)4 (1.5 mol%), K3PO4 (3 equiv), H2O (10 equiv), DCE, Ar, 60 °C, 24 h. b) Arylbromide (1 equiv), BnBpin (3 equiv), Pd(dppf)Cl2 (1 mol%), K3PO4 (3 equiv), H2O (50 equiv), PhMe, Ar, 90 °C, 24 h. c) Aq. H2O2/2 N aq. NaOH/THF (3:2:1), air, 0 °C to rt, 15 min. d) BnBpin (1 equiv), alcohol (5
equiv), Cu(OAc)2 (2 equiv), (t-BuO)2 (2 equiv), PhMe, Ar, 100 °C, 16 h. e) BnBpin (1 equiv), amine (4 equiv), Cu(OAc)2 (2 equiv), Cs2CO3 (0.5 equiv), MeOH/pyridine (4:1), Ar, 50 °C, 16 h.
Based on this, we sought to deliver a unified approach towards the synthesis of unsymmetrical
diarylmethanes, benzyl amines, and benzyl ethers using benzylic Bpins as common synthetic
precursors via a series of Suzuki–Miyaura and Chan–Lam couplings. Oxidation of the
Bpin would also provide a convenient method for the synthesis of benzyl alcohols (Scheme
[1c]). This divergent strategy would lead to an array of C(sp3)–X products from a commercially abundant pool of arylboronic acids, without the requirement
for stoichiometric metalation.
Table
[
1
] Summary of Reaction Development
|
|
Entry
|
Product
|
Conditions
|
Yield (%)a
|
|
|
Suzuki–Miyaura Benzylation
|
|
|
1
|
4
|
Pd(dba)2 (8 mol%), PPh3 (96 mol%), Ag2O (2 equiv), THF, 70 °C
|
19
|
|
2
|
4
|
Pd(dppf)Cl2 (1 mol%), K3PO4 (3 equiv), H2O (50 equiv), PhMe, 90 °C
|
99 (99)b
|
|
3
|
4
|
entry 2, Pd(PPh3)4 instead of Pd(dppf)Cl2
|
30
|
|
|
Chan–Lam Etherification
|
|
|
4
|
5
|
Cu(OAc)2 (5 mol%), (tBuO)2 (2 equiv), PhMe, 100 °C
|
22
|
|
5
|
5
|
entry 4, 2 equiv Cu(OAc)2
|
63 (62)b
|
|
|
Chan–Lam Amination
|
|
|
6
|
6
|
see entry 5
|
4
|
|
7
|
6
|
Cu(OAc)2 (2 equiv), Cs2CO3 (0.5 equiv), MeOH/pyridine (4:1), 50 °C
|
75 (71)b
|
|
|
Methanolation
|
|
|
8
|
7
|
H2O2/NaOH, THF, rt
|
99 (93)b
|
a Determined by 1H NMR analysis using an internal standard (see the Supporting Information for details).
b Isolated yield. dppf, 1,1′-bis(diphenylphosphino)ferrocene; rt, room temperature.
We established benchmark systems for the development of a Suzuki–Miyaura benzylation,
Chan–Lam etherification, and Chan–Lam amination using benzyl Bpins prepared via Pd-catalyzed
formal homologations of arylboronic acids (Table [1]). Suzuki–Miyaura cross-coupling of 3-Me and bromobenzene was contingent on controlling the hydrolysis of the Bpin ester to
generate limiting quantities of the unstable benzyl boronic acid. Yields were improved
using a K3PO4/stoichiometric H2O system,[29] rather than Ag2O,[7] and low loadings of Pd catalyst (1 mol%) were operative (entries 1 and 2). The switch
from Pd(PPh3)4 to Pd(dppf)Cl2 was essential (entry 3). A Chan–Lam etherification of benzyl Bpin with seven phenols
has been reported by Kuninobu;[30] however, in our hands these conditions were ineffective (entry 4) and required stoichiometric
quantities of Cu(OAc)2 for an efficient reaction (entry 5, see the Supporting Information for full details).
These conditions provided a more diverse range of phenols (vide infra) but did not translate to the analogous amination reaction (entry 6); however, conditions
reported by Partridge were effective (entry 7),[31] with further optimization delivering no further improvement (see the Supporting
Information for details). Oxidation of the homologated intermediate under Brown conditions
provided the desired benzyl alcohol in quantitative yield (entry 8).
With conditions for the homologation/C–X bond formation platform in place, the generality
of the four diversifications was assessed using a variety of boronic acids, bromides,
amines, and alcohols (Scheme [2]). For the Suzuki–Miyaura benzylation (top left), a variety of electronic and steric
substitution was tolerated at very good to excellent yields. Of note was the tolerance
towards heterocycles from either the Bpin (e.g., 9, 17) or bromide (15) counterparts, and the tolerance towards functional groups such as aldehyde (e.g.,
12, 18), ester (14), and sulfonate (16). Electrophile chemoselectivity was observed, leading to chloroarene products, useful
for onward cross-coupling (e.g., 17, 19). Substitution at the ortho position was well tolerated (e.g., 4, 12, 16, 17), although o-vinyl was a notable exception (see the Supporting Information for other limitations).
All oxidation reactions proceeded smoothly (bottom left), and the yields generally
reflected the homologation reaction, with more sensitive functional groups (e.g.,
23) unaffected. Upon examining the Chan–Lam amination (top right), primary (32, 35, 37) and secondary anilines (33, 38) and secondary aliphatic amines (6, 34, 36) were accommodated. From the Bpin ester component, ortho substitution was generally poor throughout (e.g., 29 and 38, for other examples see the Supporting Information) although the substituted pyridine
36 was an exception. Assessing the corresponding Chan–Lam etherification (bottom right),
the reaction was effective with electron-withdrawing (e.g., 5, 39–41) or neutral (e.g., 42) phenols; however, electron-rich substrates (e.g., 44) tended to give lower yields along with a series of unidentified side products. While
benzyl alcohol was tolerated to deliver product 43, this was generally an exception and other alkyl alcohols were recalcitrant at either
stoichiometric loading or when used as the solvent (see the Supporting Information
for full limitations).
The developed homologation–benzylation Suzuki–Miyaura process uses low loadings of
widely available and simple Pd catalysts, which we envisioned would serve as a straightforward
route to nonsymmetrical diarylmethane pharmacophores. These chemotypes are found extensively
throughout medicinal chemistry,[1] such as bifonazole, meclizine, fenofibrate, and bedaquiline (Scheme [3], top). To highlight the utility of this process, we undertook an SAR-style derivatization
of meclizine (Scheme [3], bottom).
The homologation–benzylation process provided intermediate 51, which was brominated to yield 52.[31] This could be used without purification for alkylation reactions to afford the meclizine
core (57) or ‘scaffold hopping’[32] alternatives appropriate for further SAR investigation in generally excellent yields
(57–60).
Scheme 3 Top: selected examples of substituted diarylmethanes in medicinal chemistry. Bottom:
derivatization of meclizine. Yields determined by 1H NMR spectroscopy using an internal standard, isolated yields in brackets. a) 53 (5 equiv), K2CO3 (3 equiv), MeCN, 80 °C, 12 h. b) 54 (3 equiv), Pd(dppf)Cl2 (1 mol%), K3PO4 (3 equiv), H2O (50 equiv), PhMe, Ar, 90 °C, 24 h. c) 55 (5 equiv), K2CO3 (3 equiv), MeCN, 80 °C, 12 h. d) 56 (5 equiv), K2CO3 (3 equiv), MeCN, 80 °C, 12 h. NBS, N-bromosuccinimide; AIBN, azobisisobutyronitrile. For full experimental details, see
the Supporting Information.
In summary, a diversity-oriented approach towards the platform synthesis of unsymmetrical
diarylmethanes and benzylic ethers, alcohols, and amines has been developed via a
catalytic formal homologation of arylboronic acids. These processes give straightforward
access to a range of C(sp3)–C(sp2) and C(sp3)–X scaffolds from a previous synthetic bottleneck of benzyl Bpin esters and where
stoichiometric metalation is avoided. All Pd-catalyzed manipulations take place at
very low catalyst loadings, and complex ligand systems were avoided. The synthetic
potential was further evaluated via an SAR-style derivatization of meclizine.[33]
