Nickel-Catalyzed Regioselective Hydroalkylation and Hydroarylation of Alkenyl Boronic Esters

Article abstract of DOI:10.1002/anie.201907045

Metal hydride catalyzed hydrocarbonation reactions of alkenes are an efficient approach to construct new carbon–carbon bonds from readily available alkenes. However, the regioselectivity of hydrocarbonation remains challenging to be controlled. In nickel hydride (NiH) catalyzed hydrocarbonation, linear selectivity is most often obtained because of the relative stability of the linear Ni–alkyl intermediate over its branched counterpart. Herein, we show that the boronic pinacol ester (Bpin) group directs a Ni-catalyzed hydrocarbonation to occur at its adjacent carbon center, resulting in formal branch selectivity. Both alkyl and aryl halides can be used as electrophiles in this hydrocarbonation, providing access to a wide range of secondary alkyl Bpin derivatives, which are valuable building blocks in synthetic chemistry. The utility of the method is demonstrated by the late-stage functionalization of natural products and drug molecules, the synthesis of an anticancer agent, and iterative syntheses.

Full text of DOI:10.1002/anie.201907045

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Accepted Article
Title: Nickel-Catalyzed Regioselective Hydroalkylation and
Hydroarylation of Alkenyl Boronic Esters
Authors: Srikrishna Bera and Xile Hu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907045
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10.1002/anie.201907045
Angewandte Chemie International Edition
COMMUNICATION
Nickel-Catalyzed Regioselective Hydroalkylation and
Hydroarylation of Alkenyl Boronic Esters
Srikrishna Bera and Xile Hu*
Abstract: Metal hydride catalyzed hydrocarbonation of alkenes is an
efficient approach to construct new carbon-carbon bonds employing
readily available alkenes. However, the regioselectivity of
hydrocarbonation remains challenging to control. In nickel hydride
(NiH) catalyzed hydrocarbonation, linear selectivity is most often
obtained due to the relative stability of the linear Ni-alkyl intermediate
over its branch counterpart. Here we show the boronic pinacol ester
(Bpin) group directs Ni-catalyzed hydrocarbonation at its adjacent
carbon center, resulting in formal branch selectivity. Both alkyl and
aryl halides can be used as electrophiles in this hydrocarbonation,
providing access to a wide range of secondary alkyl Bpin derivatives,
which are valuable building blocks in synthetic chemistry. The utility
of the method is demonstrated in late-stage functionalization of
natural products and drug molecules, synthesis of an anticancer agent,
and iterative synthesis.
indeed be achieved via NiH catalysis employing both alkyl and
aryl halides as electrophiles (Scheme 1d). A large array of
secondary alkyl Bpin derivatives, which are versatile synthetic
intermediates in medicinal and materials chemistry, can be
synthesized in a streamlined manner.[9] While some of the
products might be accessed by alternative methods such as
hydroboration of styrenes[10], cross-coupling or reductive coupling
of α-halo boronic esters[11]
, difunctionalization of alkenyl
boronates through 1,2-metalate shifts[12], as well as three-
component coupling of terminal alkynes, pinacolborane, and aryl
halides[1j], our method offers ample advantages such as a new
disconnection, wide availability of reagents, mild conditions,
broad scope, and high regioselectivity.
Hydrocarbonation of alkenes[1,2] via metal hydride[3]
insertion followed by cross-coupling of in-situ generated
organometallic intermediates offers an attractive alternative to
traditional cross-coupling, which employed pre-formed, often
reactive, stoichiometric organometallic reagents.[1,4] Building upon
the progress of Ni-catalyzed cross-coupling[5], nickel-catalyzed
hydrocarbonation of alkenes is undergoing
a
rapid
development.[2] Addition of NiH to a terminal alkene may yield two
isomeric products: a linear Ni-alkyl species and a branched Ni-
alkyl species (Scheme 1a). The linear species is typically
favoured.[6] Addition of NiH to an internal alkene often leads to
isomerization and chain walking of the alkenyl moiety to the
terminal position.[7] Thus, Ni-catalyzed hydrocarbonation of both
terminal and internal alkenes is linear selective (Scheme 1b). To
achieve branch selectivity in NiH-mediated alkene
functionalization, an aryl directing group next to the alkenyl moiety
is required (Scheme 1c).[2e,2f,2g,8] The aryl group cannot be easily
removed and offers
a
limited opportunity for further
functionalization. We reasoned that if a boryl group, particularly
the synthetically versatile boronic pinacol ester (Bpin) group,
could serve as a directing group similar to an aryl group, formal
branch-selective hydrocarbonation could be achieved upon
transformation of the boryl group, for example, in Suzuki coupling.
Both the formation of an α-boryl organonickel intermediate and its
coupling with an organic electrophile, however, were unknown.
Here we show that by judicious choices of catalysts and
conditions, hydrocarbonation of alkenyl Bpin derivatives can
Scheme 1. Selectivity of NiH-catalyzed hydrofunctionalization of alkenes. a)
Selectivity of NiH addition to terminal alkenes. b) Linear selective
hydrocarbonation of internal and terminal alkenes. c) Branch selective
hydrofunctionalization of alkenes using an aryl directing group. d) This work: Ni-
catalyzed hydroalkylation and hydroarylation of alkenyl boronic esters to
achieve formal branch selectivity.
The initial investigations of the target hydrocarbonation
were conducted using the commercially available alkenyl Bpin
derivative 1a as alkene, 1-iodo-3-phenylpropane 2a as an
alkylating agent, and diethoxy-methylsilane (DEMS) as a hydride
source (Table 1). The optimized reaction conditions were
NiBr2.diglyme (10 mol%) as Ni source, a Pyr-Ox L4 (12 mol%) as
ligand, KF as base, DMA as solvent, and room temperature.
Under these conditions, the desired hydroalkylation product 3aa
was obtained in 80% GC yield (75% isolated yield) as a single
[*]
Dr. S. Bera, Prof. Dr. X. L. Hu
Laboratory of Inorganic Synthesis and Catalysis
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne (EPFL)
ISIC-LSCI, BCH 3305, Lausanne 1015 (Switzerland)
E-mail: xile.hu@epfl.ch
Homepage: http://lsci.epfl.ch
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201907045
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Polymethylhydrosiloxane; THF
methylsilane.
= Tetrahydrofuran; DEMS = Diethoxy-
regio isomer (entry 1, Table 1). The influence of different reaction
parameter in the outcome of the reaction is described in Table
S1–S5, SI. A concise summary of key observations is shown in
Table 1. Structurally related 2,2'-bipyridine (L1 and L2) and 1,10-
phenanthroline (L3) ligands were not efficient in this
transformation (entries 2-4, Table 1). Other nickel sources such
as NiBr2 and Ni(acac)2 (acac = acetylacetonate) gave lower yields
(entries 5 and 6, Table 1). Replacement of KF by K2CO3 also
diminished the yield (entry 7, Table 1). PMHS (PMHS =
polymethylhydrosiloxane) was another competent hydride source
(entry 8, Table 1). THF was not a suitable solvent (entry 9, Table
1). The hydroalkylation also worked using an alkyl bromide, 1-
bromo-3-phenylpropane (2b), as the alkylating agent, but 20
mol% KI was needed as an additive for the in-situ Br/I exchange
(entry 10, Table 1). When trans-1-hexenyl boronic acid 1a' was
used as substrate instead of 1a, the hydroalkylation product
underwent protodeborylation to yield an alkane (SI). When trans-
1-octenyl boronic acid neopentylglycol ester 1o was used as
substrate, the hydroalkylation product 3ob' was obatined in 50%
yield (SI). The reaction protocol also worked for hydroarylation
using iodobenzene 4a (2.0 equiv.) as the arylating agent (entry
11, Table 1). The hydroarylation was further improved using 20
mol% KI as additive (entry 12, Table 1).
The optimal reaction conditions were then applied to explore
the scope of the hydroalkylation (Table 2). The scope of alkyl
halides was first probed using 1a as a representative alkene
partner. A wide range of primary alkyl iodides and bromides were
suitable alkylating agents, leading to hydroalkylation products in
good yields (3aa-3an). For the reactions with alkyl bromides, a
longer reaction time (40 h instead of 24 h) and 20 mol% KI was
necessary for high yields (3ad-3ag and 3ak-3am). The formation
of a secondary-secondary C(sp3)–C(sp3) bond in hydroalkylation
is challenging due to steric congestion in the product as well as
the general difficulty in cross-coupling of secondary alkyl
halides.[13] To our delight, the hydroalkylation protocol also
worked when secondary alkyl iodides were used as alkylating
agents. Cyclic iodoalkanes containing a four, five, six, and even
eight-membered carbocyclic or heterocyclic ring reacted smoothly
to give the corresponding alkyl boronic ester (3ao-3az). Thus, the
method provides a facile access to alkyl boronic ester containing
small ring systems privileged in medicinal chemistry such as
oxetane, azetidine and spiro-cyclobutane (3av, 3ax and 3ay). No
isomerization was observed in the alkyl fragment (e.g., 3ar-3ay).
This result was surprising because Ni-H was widely reported to
catalyze isomerization of secondary alkyl halides.[14] An acyclic
secondary alkyl iodide with a pendant alkene moiety was also a
viable reaction partner, resulting in chemo- and regioselective
hydroalkylation (3az).
Table 1. A summary of the influence of key reaction parameters in the outcome
of the hydrocarbonation reactions of 1a.a
The hydroalkylation protocol was applicable to a wide range
of alkenyl boronic estersresulting in a diverse set of alkyl boronic
esters (3ba-3lg'). The alkylation was always regioselective at the
carbon -to the Bpin group. An exception was the hydroalkylation
reaction with vinylboronate 1m, which gave a 2:1 regio mixture of
products favoring 3ma. The alkenyl boronic esters can contain an
ester (3da', 3eb'), ether (3hd', 3ie') and protected alcohol (3gc',
3jh, 3kf'), or nitrile group (3lg'). The generality of the
hydroalkylation method was further illustrated by the successful
reactions with alkyl halides derived from drug molecules and
natural products. Thus, alkyl Bpin derivatives of ibuprofen (3ah'),
cintronellol (3ai'), and lithocholic acid (3ij') were prepared in good
yields.
Entry
1
deviation from standard conditions
none
Yield (%)
80 (75)b
2
L1 instead of L4
17
nr
3
L2 instead of L4
The hydroalkylation protocol exihibited high functional group
tolerance. Ester (3ad, 3af, 3da', 3eb' and 3gc'), nitrile (3ae, 3kf'
and 3lg'), acetal (3an), various amides including phthalimide and
Weinreb amide (3ah, 3al, and 3am), various heterocyclic groups
such as furan (3ai), thiophene (3hd') and indole (3lg'), and alkene
(3az and 3ai') were all compatible with the reaction conditions.
The reactions were chemoselective so that alkyl chloride (see 3ac,
3ca'), aryl chloride (3aj), aryl fluoride (3ak), and even
pinacolboronic ester (3ie') groups, which are potential leaving
groups in cross-coupling reactions, remained intact. This feature
reserves a possibility of facile sequential functionalization of the
corresponding hydroalkylation products.
4
L3 instead of L4
7
5
NiBr2 instead of NiBr2.diglyme
Ni(acac)2 instead of NiBr2.diglyme
K2CO3 instead of KF
63
6
10
7
51
8
PMHS instead of DEMS
THF instead of DMA
75
9
nr
10c
11d
12e
1-bromo-3-phenylpropane instead of 2a
iodobenzene (4a) instead of 2a
4a plus 20% KI instead of 2a
74
84
91(85)b
The scope of hydroarylation was then examined (Table 3).
First, various aryl iodides were reacted with 1a. The reactions
were largely insensitive to the electronics of the aryl moieties, as
electron-donating, neutral, and withdrawing substituents at para-
and meta-positions were all compatible (5aa-5ah). Various
heteroaryl iodides were also suitbale reaction partners.
a See the SI for experimental details; all reactions were carried out in 0.1 mmol
scale with respect to 1a; corrected GC yields using n-dodecane as an internal
b
c
standard were reported Isolated yield is shown in the parenthesis. with 20
d
mol% KI as additive and the reaction time was 36 hours.
iodobenzene. e 20 mol% KI. DMA = Dimethyacetamide; RT = room temperature;
hour. nr no reaction; acac acetylacetonate; PMHS =
2.0 equiv.
h
=
=
=
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Hydroarylation using 3-iodopyridine had a relatively low yield
(32% NMR yield ), probably due to inhibition of the Ni catalyst by
the pyridinyl group. The product was prone to an immediate
protodeborylation, preventing isolation. These problems were
alleviated by using iodopyridines with a substituent at the C-2
position, which likely hindered the binding of the Ni catalyst by the
pyridinyl N-atom. Thus, hydroarylation with these substrates was
achived in good yields (5ai–5ak). Likewise, reactions of
substrates derived from 2-methoxypyrimidine and 2-quinoline
gave the desired products (5al and 5am) in reasoable yields
without suffering much from catalyst inhibition. The hydroarlyaiton
also worked well with Boc-protected 3-iodoindole and 3-iodo-N-
methylpyrazole (5an and 5ao).
Table 2. Scope of hydroalkylationa
a All reactions were performed with NiBr2.diglyme (10 mol%), L4 (12 mol%), alkenyl Bpin (0.2 mmol), alkyl halides (0.3 mmol), DEMS (0.5 mmol), KF (0.4 mmol)
b
c
d
and DMA (0.6 mL) at 25 °C for 24-40 hours. Alkyl bromide with 20 mol% KI was used and the reaction time was 40 hours. 1:1 Diastereomeric ratio. 1.3:1
Diastereomeric ratio. e Regioisomeric ratio 2:1 (NMR yield of major isomer is represented). PMP = paramethoxyphenyl. Phth = phthalimide.
Table 3. Scope of hydroarylationa
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a All reactions were performed with NiBr2.diglyme (10 mol%), L4 (12 mol%), alkenyl Bpin (0.2 mmol), aryl halides (0.4 mmol), DEMS (0.5 mmol), KF (0.4 mmol), KI
(20 mol%) and DMA (1.0 mL) at 25 °C for 24-36 hours. b Regioisomeric ratio 12:1. c Regioisomeric ratio 7:1. d Regioisomeric ratio 11:1. e Bromoarene was used,
and the reaction time was 36 h. f Regioisomeric ratio 15:1. g Diastereomeric ratio 1:1. h Regioisomeric ratio 10:1 (branch/linear). i dr was not determined.
The scope of alkenyl boronic ester in the hydroarylation was
broad (5bb-5nr). Substrates containing a chloro, ester, ether, and
nitrile groups were all viable. Vinylboronate 1m, which was a
problamtic substrate in hydroalkylation (see above), reacted well
in the hydroarylation to give the product (5mb) in 51% yield and
10:1 b/l selectivity. The hydroarlytion protocol was successfully
The details of the mechanism of this hydrocarbonation
reaction is subjected to a future study, so only a preliminary
hypothesis is provided here. The reaction proceeds via the
formation of a NiH species from the Ni catalyst and silane,
followed by insertion of the NiH into the alkene.[19,6d,7c] The
insertion is selective at the carbon α to the boryl group probably
due to an electronic stabilization. The resulting Ni-alkyl species
can engage in alkyl-alkyl and alkyl-aryl coupling reactions, similar
to Ni-catalyzed cross-coupling of alkyl nucleophiles.[4,5b,20] To
probe whether the insertion of NiH into the alkene is reversible, a
hydroalkylation reaction was conducted using a deuterated silane
as the hydride source (Scheme 3). More than 90% deuterium
incorporation at the carbon β to the boryl group was observed,[21]
indicating that NiH addition was largely irreversible. This result
suggests that the α-boryl group stabilizes the Ni-alkyl species
against -H elimination. To compare the rates of alkylation and
arylation by the same Ni-alkyl intermediate, a competition
experiment was conducted using an equal amount of 2a and 4a
(SI). Only the hydroarylation product 5aa, but not the
hydroalkylation product, 3aa, was obtained. This result suggests
that the α-boryl stabilized Ni-alkyl species preferentially reacts
with an aryl iodide over an alkyl iodide.
applied to susbtrates derived from
a natural sugar and
dehydroepiandrosterone, an endogenous steroid hormone[15]. In
both cases, the products were obtained in very good yields with
excellent regio- and chemoselectivity (5ep and 5iq). In general,
the hydroarylation was chemo- and regio-selective and exhibited
high functional group tolerance, as ester (e.g., 5ac, 5db, 5eb),
aldehyde (5ag), Bpin (5af), nitrile (5la), heterocycles (5ai-5ao),
ketone (5iq), and even free alcohol (5ah) groups were all
compatible.
The utility of the hydrocarbonation methodology in organic
synthesis was illustrated by the synthesis of 6[16], a potential anti-
breast cancer agent (Scheme 2a). Starting from a commercially
available boronic ester (1n) and 2-iodonatpthalene (4r) and using
the optimized hydroarylation protocol, the Bpin intermediate (5nr)
was obtained in 67% yield. 5nr was easily converted to 6 in 65%
yield (Scheme 2a).[17] The hydrocarbonation methodology also
enabled a new type of iterative synthesis. For example, a first
hydroalkylation reaction using 1a and 2a gave the secondary alkyl
Bpin product 3aa, which was easily converted to the secondary
alkyl iodide 7 following a reported protocol (Scheme 2b).[18]
Compound 7 was susceptible to a second hydroalkylation
reaction, to give a new secondary alkyl Bpin product (8 or 9).
Scheme 3. D-Labelling experiment.
In summary, a general methodology for hydrocarbonation of
alkenyl boronic esters has been developed. In this method, the
Bpin group is exploited as a directing group for regioselective
insertion of NiH into alkene. The method works well for both
hydroalkylation and hydroaralytion, providing easy access to a
wide range of secondary alkyl boronic esters, which are valuable
synthetic intermediates. The reactions are regioselective and
highly tolerant to functional groups. Applications in late-stage
functionaliazation of natural products and drug molecules,
synthesis of bio-active compounds, and iterative synthesis are
demonstrated.
Acknowledgements
We thank the Swiss National Science Foundation for financial
support.
Scheme 2. Examples of synthetic utility. a Reaction was conducted in 0.2 mmol
scale following standard reaction conditions as in Table 3 and 48 hours of
reaction time. b Reaction conditions: NiBr2.diglyme (10 mol%), L4 (12 mol%), 1a
(2.0 mmol), 2a (3.0 mmol), DEMS (5.0 mmol), KF (4.0 mmol), DMA (10 mL) at
25 °C for 48 hours. c Reactions were conducted in 0.1 mmol scale with respect
to 1e and 1j, respectively, using similar reaction condition as in Table 2.
Keywords: alkenes • hydroarylation • nickel hydride • boron
compounds • hydroalkylation
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same reason diastereomeric ratio was not determined.
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10.1002/anie.201907045
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
S. Bera, Xile Hu*
Page No. – Page No.
Nickel-Catalyzed Regioselective
Hydroalkylation and Hydroarylation
of Alkenyl Boronic Esters
Highly regio- and chemoseletive nickel-catalyzed hydroarylation and hydroalkylation
of alkenes is achieved using Bpin (pin = boronic acid pinacol ester) group as a
directing group.
This article is protected by copyright. All rights reserved.