1,3-Difunctionalizations of [1.1.1]Propellane via 1,2-Metallate Rearrangements of Boronate Complexes

Article abstract of DOI:10.1002/anie.201914875

1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are valuable bioisosteres of para-substituted aromatic rings. The most direct route to these structures is via multicomponent ring-opening reactions of [1.1.1]propellane. However, challenges associated with these transformations mean that difunctionalized BCPs are more commonly prepared by multistep reaction sequences with BCP-halide intermediates. Herein, we report three- and four-component 1,3-difunctionalizations of [1.1.1]propellane with organometallic reagents, organoboronic esters, and a variety of electrophiles. This process is achieved by trapping intermediate BCP-metal species with boronic esters to form boronate complexes, which are versatile intermediates whose electrophile-induced 1,2-metallate rearrangement chemistry enables a broad range of C?C bond-forming reactions.

Full text of DOI:10.1002/anie.201914875

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Accepted Article
Title: 1,3-Difunctionalizations of [1.1.1]Propellane via 1,2-Metallate
Rearrangements of Boronate Complexes
Authors: Songjie Yu, Changcheng Jing, Adam Noble, and Varinder
Kumar Aggarwal
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1
,3-Difunctionalizations of [1.1.1]Propellane via 1,2-Metallate
Rearrangements of Boronate Complexes
†
†
[a]
Songjie Yu, Changcheng Jing, Adam Noble, and Varinder K. Aggarwal*
Abstract: 1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are
valuable bioisosteres of para-substituted aromatic rings. The most
direct route to these structures is via multi-component ring-opening
reactions of [1.1.1]propellane. However, challenges associated with
these transformations mean that difunctionalized BCPs are more
commonly prepared via multistep reaction sequences with BCP-
halide intermediates. Herein, we report three- and four-component
intermediates 2 are relatively stable to oligomerization with 1 and
can be intercepted in palladium- or nickel-catalyzed cross-
couplings,[
10]
copper-catalyzed alkylations,
[11]
or acylation
reactions (Scheme 1c).[10b,10d,11] We were intrigued by the
possibility of intercepting BCP-Grignards 2 with boronic esters to
form BCP-boronate complexes 3 (Scheme 1d). These versatile
intermediates can be utilized in a wide range C–C bond forming
reactions via 1,2-metallate rearrangements,[12] therefore providing
1,3-difunctionalizations of [1.1.1]propellane with organometallic
reagents, organoboronic esters and a variety of electrophiles. This is
achieved by trapping intermediate BCP-metal species with boronic
esters to form boronate complexes, which are versatile intermediates
whose electrophile-induced 1,2-metallate rearrangement chemistry
enables a broad range of C–C bond-forming reactions.
a
significant expansion to the range of unsymmetrical
1,3-disubstituted BCP derivatives accessible in one step from 1.
Herein, we describe the successful realization of this approach in
a
organometallic reagents, [1.1.1]propellane, and organoboronic
esters. Furthermore, this strategy could be extended to a four-
component coupling by trapping alkenyl BCP-boronate
complexes with a range of electrophiles, enabling rapid access to
highly functionalized BCP-derivatives.
transition metal-free three-component coupling between
Bicyclo[1.1.1]pentane (BCP) is a highly valuable motif in drug
discovery.[1] Its size and conformational rigidity make
1
,3-disubstituted BCPs bioisosteres of para-substituted benzene
rings.[
2]
Structure activity relationships have shown that
3
incorporating these sp -rich surrogates of aromatic rings into drug
candidates often results in more favorable pharmacokinetic
properties, including improved aqueous solubility, increased
membrane permeability, and higher metabolic stability (Scheme
1
1
a).[3] Despite these desirable characteristics, application of
,3-disubstituted BCP derivatives in drug discovery has been
hindered by the limited number of concise synthetic routes to
these motifs, in particular carbon-substituted analogues. One of
the most powerful approaches to BCPs is via addition reactions
to [1.1.1]propellane (1),[4] where the central σ-bond can be
cleaved under both radical[5] and anionic pathways (Scheme
1
b).[6] However, these reactions typically give monofunctionalized
BCPs, or involve atom-transfer processes where, in addition to a
carbon substituent, a halide group is introduced. Therefore,
access to 1,3-disubstituted BCPs with two carbon substituents
requires additional manipulations of the halide.[5c–e,7]
Direct
transformation
of
1
into
unsymmetrical
1
,3-disubstituted BCP derivatives via three-component coupling
reactions is challenging because of competing oligomerization of
the intermediate BCP radicals or carbanions.[4d,8] This is
especially apparent for radical processes, of which there is only a
single report by Uchiyama and co-workers describing a three-
component aminoalkylation of 1.[9] In contrast, BCP-Grignard
[
a]
Dr. S. Yu, Dr. C. Jing, Dr. A. Noble, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
[†]
These authors contributed equally.
Scheme 1. Synthesis of 1,3-difunctionalized bicyclo[1.1.1]pentanes.
Supporting information for this article is given via a link at the end of
the document.
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Our initial studies focused on the reaction of BCP-Grignard
reagent 2 in Zweifel olefinations with alkenylboronic esters to
provide synthetically useful alkenyl-BCPs 4 (Scheme 2).[13] Using
conditions developed by Knochel and co-workers,[10d] BCP-
Grignard 2a was conveniently accessed from 2-tolylmagnesium
bromide (5a) and 1. Addition of 2-propenylboronic ester 6a formed
boronate complex 3a, which was subsequently reacted with
iodine and sodium methoxide to promote 1,2-migration and boron
elimination, yielding alkenyl-BCP 4a in 53% yield. A recent report
by Morken and co-workers found that boronate complex formation
between vinyl Grignard reagents and pinacol boronic esters was
greatly facilitated by LiCl,[14] which is known to increase the
reactivity of Grignard reagents.[15] Pleasingly, addition of LiCl to
BCP-Grignard 2a prior to 6a resulted in a much improved yield of
bisalkenyl BCPs 4ad and 4ae. To the best of our knowledge,
these two examples represent the first reports of ring-opening of
1 with alkenyl Grignard reagents.
Table 1. Scope of alkenylboronic esters.[a]
4
a of 89%.
Scheme 2. Initial results for the BCP formation via Zweifel olefination.
With high yielding conditions in hand, we subsequently
explored the scope of this three-component coupling (Table 1).
Analysis of a range of alkenylboronic esters demonstrated the
generality of the protocol, which could be used to access vinyl-
BCP 4b and a range of 1,1-disubstituted alkenes (4c–e) in good
to excellent yields. For E-configured β-substituted alkenylboronic
esters, Zweifel olefination leads to the corresponding Z-alkene
products.[13c] This allowed the synthesis of a wide range of Z-
alkenyl BCP derivatives (4f–g, 4i–m), all with >95:5 Z:E selectivity.
Conversely, using a Z-alkenylboronic ester provided E-alkenyl
BCP product 4h, again with excellent yield and stereocontrol
[
a] Yields are of isolated products. See Scheme 2 for reaction conditions.
Products 4f–4m and 4q–4r were formed with >95:5 stereoselectivity. [b] Using
(
Z)-hex-1-en-1-ylboronic acid pinacol ester.
Inspired by previous reports of alkylmetal additions to 1,[10b,16]
we sought to extend this methodology beyond aryl/alkenyl-
substituted BCP synthesis. Therefore, we investigated the
addition of a range of alkyllithium reagents to 1 and subsequent
Zweifel olefination of the resulting BCP-lithium intermediate
(
Table 2). Secondary and tertiary alkyllithiums reacted efficiently
(
>95:5 E:Z). The functional group tolerance of the reaction was
demonstrated by preparing alkenyl-BCPs containing silyl ethers
4j), halides (4k), cyclopropanes (4l), and complex natural
with 1 at –78 °C, with subsequent high yielding Zweifel olefination
giving alkyl BCP derivatives 7a–7c. On the other hand, primary
alkyllithiums (e.g., nBuLi) were unreactive at –78 °C and elevated
temperatures led only to polymerization of 1.[ Fortunately, the
use of primary alkyl Grignards circumvented this issue and
enabled formation of ethyl-BCP derivative 7d in high yield.
Grignard reagents could also be used for the introduction of
secondary alkyl (7e) and benzyl groups (7f). Finally, reaction of 1
with the “turbo amide” pioneered by Baran and co-workers
provided amino-BCP 7g in good yield.[6a]
(
product scaffolds, such as lithocholic acid derivative 4m.
Trisubstituted alkenes were also formed in high yields, including
both cyclic (4n–p) and acyclic (4q–r) examples, with the latter
being formed with excellent stereoselectivity (>95:5 Z:E). Finally,
the Zweifel olefination could also be applied to the high yielding
synthesis of tetrasubstituted alkenes (4s).
17]
We next examined the scope of the reaction with respect to
the organometallic reagent (Table 2). We were pleased to find that
a broad range of functionalized aryl Grignards provided aryl-BCP
products 4t–4ac in high yields. Alkenyl Grignards were also found
to be competent reagents for ring-opening of 1, providing 1,3-
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Table 2. Scope of alkylmetal reagents.
included tetrafluoroboric acid, providing tertiary boronic ester 12;
and phenylselenyl chloride and dimethyl(methylthio)sulfonium
tetrafluoroborate, which gave selenide 13 and sulfide 14,
respectively.[20] Boronate 3a was successfully alkylated with
Eschenmoser’s salt, tropylium tetrafluoroborate, and 1,3-
benzodithiolylium tetrafluoroborate, forming products 15–17.
Finally, alkylation of 3a with electron-deficient alkyl iodides was
possible using our previously reported photochemical
conditions,[ allowing incorporation of trifluoromethyl (18), ester
21]
(
19) and nitrile (20) groups. Importantly, this four-component
coupling reaction provides access to highly functionalized BCP-
derivatives containing vicinal quaternary centers; structures that
previously could only be accessed via multi-step synthesis.
[
1
a] Using 1 (1.2 mmol) and Grignard reagent (0.60 mmol) in Et
–2 h, then LiCl (0.60 mmol), 6b (0.30 mmol), I (0.30 mmol) and MeONa (0.90
mmol). [b] Using (4-(bis(trimethylsilyl)amino)phenyl)magnesium bromide. [c]
Using 1 (0.30 mmol) and alkyllithium (0.45 mmol) in Et O at –78 °C for 30 min,
then 6b (0.45 mmol), I (0.30 mmol) and MeONa (0.90 mmol). [d] Reaction of
Bn NMgBr•LiCl with 1 was at RT for 16 h.
2
O at 100 °C for
2
2
2
2
To extend the range of BCP-derivatives accessible using this
,2-metallate rearrangement strategy, we investigated the
1
reaction of BCP-Grignard 2a with a variety of other boronic ester
substrates (Scheme 3A). Reaction with pinacolborane provided
synthetically useful BCP-boronic ester 8 in moderate yield.[12,18]
The low yield is likely a result of the instability of 8 during
chromatographic purification, which is supported by isolation of
the corresponding alcohol in 95% yield after in situ oxidation.
Alkylation of 2a with chloromethylboronic acid pinacol ester gave
alkylboronic ester 9 via a Matteson homologation, and arylations
of 2a were possible using our previously reported transition metal-
Scheme 3. Multi-component reactions of BCP-boronate complexes. Reagents:
[
a] HBpin, aq. HCl, yield in parenthesis is of the corresponding alcohol after in
situ oxidation with NaOH/H ; [b] ClCH Bpin; [c] furan-2-yl-Bpin, NBS; [d]
pyridin-4-yl-Bpin, ClCO CH CCl , NaOH/H ; [e] 6a, HBF ; [f] 6a, PhSeCl; [g]
a, MeSSMe BF [h] 6a, CNMe I; [i] 6a, tropylium BF [j] 6a, 1,3-
benzodithiolylium BF ; [k] 6a, CF I•2DMSO, blue LEDs; [l] 6a, ICH CO Et, blue
LEDs; [m] 6a, ICH CN, blue LEDs.
O
2 2
2
2
2
3
2
O
2
4
6
2
4
;
H
2
2
4
;
free couplings, forming BCP-furan 10 and BCP-pyridine 11 in
good yields.[19]
4
3
2
2
2
To further demonstrate the diversity of BCP-boronate
chemistry for the synthesis of functionalized BCP-derivatives, we
extended our approach to four-component coupling reactions
The synthetic utility of the three-component coupling process
was demonstrated through scaling up the synthesis of 4a to 3.0
mmol without loss in efficiency (Scheme 4a). Furthermore, high-
yielding derivatizations of 4a provided alcohol 21, via reductive
ozonolysis; and boronic ester 22, through an enantioselective
(
Scheme 3B). Alkenyl BCP-boronate complex 3a, formed from
aryl Grignard 5a, 1, and alkenyl boronic ester 6a, was found to
undergo efficient electrophile-induced 1,2-metallate
rearrangement with a range of heteroatom- and carbon-based
electrophiles under both polar and radical pathways. Electrophiles
[22]
hydroboration. Finally, BCP-boronic ester 8 was homologated
via a lithiation–borylation reaction with enantioenriched carbenoid
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COMMUNICATION
2
3 to give boronic ester 24 in 99% ee (Scheme 4b).[23] The
O’Sullivan, K. J. DiRico, W. S. McDonald, A. Won, P. H. Dorff, C. E.
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Scheme 4. Synthetic utility of the BCP-derivatives.
In summary, we have developed
a
synthesis of
1
,3-disubstituted BCP derivatives through a three-component
coupling reaction of [1.1.1]propellane with organometallic
reagents and organoboronic esters. By taking advantage of the
versatile C–C bond forming reactions that are possible via 1,2-
metallate rearrangements of boronate complexes, this approach
could be applied to the synthesis of alkenyl-, alkyl-, and aryl-BCP
derivatives. Furthermore, the strategy was extended to a four-
component coupling reaction to access tertiary boronic ester-
substituted BCPs containing contiguous quaternary centres. This
powerful multi-component reaction strategy, with up to three
points of diversification, provides a highly modular approach for
the preparation of libraries of structurally diverse BCPs.
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Keywords: [1.1.1]Propellane • Bicyclo[1.1.1]pentanes • Multi-
Component Reactions • Borylation • Zweifel Olefination
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COMMUNICATION
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COMMUNICATION
COMMUNICATION
A modular synthesis of 1,3-
difunctionalized
Songjie Yu, Changcheng Jing, Adam
Noble, Varinder K. Aggarwal*
bicyclo[1.1.1]pentanes has been
achieved through multi-component
couplings between organometallic
reagents, [1.1.1]propellane, and
organoboronic esters. By uitilizing the
versatile 1,2-metallate rearrangement
chemistry of in situ generated
boronate complexes, a range C–C
bond-forming reactions could be
carried out without the need for
transition metal catalysis.
Page No. – Page No.
1,3-Difunctionalizations of
[1.1.1]Propellane via 1,2-Metallate
Rearrangements of Boronate
Complexes
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