Nickel-catalyzed difunctionalization of allyl moieties using organoboronic acids and halides with divergent regioselectivities

Article abstract of DOI:10.1039/c7sc03149a

Efficient difunctionalization of alkenes allows the rapid construction of molecular complexity from simple building blocks in organic synthesis. We present herein a nickel-catalyzed dicarbofunctionalization of alkenes using readily available organoboronic acids and organic halides in a three-component fashion. In particular, an unprecedented regioselectivity of the 1,3-dicarbofunctionalization of N-allylpyrimidin-2-amine is achieved when aryl and methyl iodides are utilized. In contrast, the use of alkyl bromides with β-hydrogens results in 1,3-hydroarylation or oxidative 1,3-diarylation. Preliminary mechanistic studies suggest an isomerization involving nickel hydride in the 1,3-difunctionalization reactions. On the other hand, the use of alkenyl or alkynyl halides promotes alternative regioselectivities to deliver 1,2-alkenylcarbonation or intriguing 2,1-alkynylcarbonation products. Such 2,1-alkynylarylation is also applicable to N-allylbenzamide as a different class of substrates. Overall, this nickel-catalyzed process proves to be powerful in delivering versatile difunctionalized compounds using readily available reagents/catalysts and a simple procedure.

Full text of DOI:10.1039/c7sc03149a

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Nickel-catalyzed Difunctionalization of Allyl Moieties Using
Organoboronic Acids and Halides with Divergent
Regioselectivities
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
DOI: 10.1039/x0xx00000x
Wanfang Li, Jie Kang Boon, and Yu Zhao *
www.rsc.org/
Efficient difunctionalization of alkenes allows the rapid construction of molecular complexity from simple building blocks in
organic synthesis. We present herein a nickel-catalyzed dicarbofunctionalization of alkenes using readily available
organoboronic acids and organic halides in a three-component fashion. In particular, an unprecedented regioselectivity of
1
,3-dicarbofunctionalization of N-allylpyrimidin-2-amine is achieved when aryl and methyl iodides are utilized. In contrast,
the use of alkyl bromides with β-hydrogens results in 1,3-hydroarylation or oxidative 1,3-diarylation. Preliminary
mechanistic studies suggest an isomerization involving nickel hydride in the 1,3-difunctionalization reactions. On the other
hand, the use of alkenyl or alkynyl halides promotes alternative regioselectivities to deliver 1,2-alkenylcarbonation or
intriguing 2,1-alkynylcarbonation products. Such 2,1-alkynylarylation is also applicable to N-allylbenzamide as a different
class of substrates. Overall, this nickel-catalyzed process proves to be powerful in delivering versatile difunctionalized
compounds
using
readily
available
reagents/catalysts
and
a
simple
procedure.
1
. Introduction
herein the first example of dicarbofunctionalization of terminal
alkenes substituted with a 2-aminopyrimidine unit using
readily available organoboronic acids and halides. This nickel-
catalyzed process turns out to be versatile. Depending on the
choice of organic halides, divergent regioselectivities are
achieved, including the unprecedented 1,3-diarylation and 2,1-
alkynylcarbonation (Scheme 1c).
The identification of new strategies for building up molecular
complexity from simple chemical feedstocks represents an
important goal in organic synthesis and application to
medicinal and material chemistry. Towards this target,
transition-metal-catalyzed
dicarbofunctionalization
of
1
-3
4
alkenes and alkynes by the introduction of one carbon
electrophile and one carbon nucleophile has attracted much
attention. In particular, the three component reaction using
readily available and easy-to-handle organic boronic acids and
organic halides for these transformations provides great
practical advantages. A few elegant examples for alkyne
difunctionalization using these reagents have been
a) 1,2-dicarbofunctionalization of alkenes
Nu
[
M]
[Pd]: Sigman, Gong
[Ni]: Zhang, Baran
+
El
+
Nu
El
R
R
Suzuki: R–R'
very challenging
to suppress:
R1–X
2
R -B(OH)
2
1
R
Heck:
R
b) Remote dicarbofunctionalization
R
5
documented. For the corresponding difunctionalization of
R'
[
M]
+
RX
+
R'-B(OH)
2
Unknown
alkenes, on the other hand, how to suppress the classical Heck
and Suzuki couplings poses formidable challenges (Scheme 1a).
The few successful examples along these lines require the use
n
R
R
n
R'
Ar(Me)
c) This work:
1
a-b
Ar–I or MeI
,3-
of either strained alkene substrates or are limited to special
3
(i)
1
DG
DG
b
alkyl halide electrophiles.
The development of
dicarbofunctionalization of alkenes that tolerates a variety of
organic boronic acids and halides will be highly desired.
Br
3
1
R'–B(OH)
R' = Ar, alkenyl
Ni(0)
L
R
+
2
DG
(ii)
1,2-
R'
2
R
In
a
related area of research, remote alkene
functionalization, which selectively installs a functionality
distal to the initial alkene moiety via metal catalyzed C=C bond
isomerization (“chain walking”), has also attracted much
R'
DG
R
Br
(iii)
2,1-
6
R
attention. Such a process greatly expands the chemical space
Scheme 1 TM-catalyzed difunctionalization of alkenes.
accessible from readily available alkenes. However, a remote
dicarbofunctionalization of alkenes using boronic acids has
never been documented before (Scheme 1b). We report
Our group has been interested in carbofunctionalization of
7
alkenes under base metal catalysis. We became particularly
interested in the development of
a general alkene
dicarbofunctionalization reaction using organic boronic acids
and halides. Compared to palladium catalysis, we envisioned
that the use of nickel catalyst might be better suited for these
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e
challenges considering that nickel has distinct reactivities in Deallylation was the major side reaction. AlMe
3
(20 mol%) was added for
f
8
the elementary steps of cross-coupling. Indeed, nickel
the reduction of Ni((II) to Ni(0). The Suzuki product biphenyl and the
deallylation product 2-aminopyrimidine were the major side products.
n.r.= no reaction. n.d. = not determined.
catalysis has shown great promise for related functionalization
9
4
of alkenes and alkynes, and the use of nickel catalyst is also
attractive for the promotion of economical and sustainable
chemical synthesis.
yield of Suzuki coupling side product. A screening of common
phosphine ligands was carried out, from which dppm provided
the optimal 47% isolated yield (entry 9 vs. 7-8). Here again,
Suzuki cross-coupling consumed the reagents to a large extent
(
40% yield of biphenyl). Intriguingly, the product was
determined to be a mixture of 2f and an unexpected 1,3-
difunctionalization product 2f’ which represents an
2
Results and discussion
2
.1 Initial discovery and optimization
We initiated our investigation
dicarbofunctionalization of simple alkenes such as allylbenzene
1a and N-allyl aniline 1b using iodobenzene and
,
unprecedented regioselectivity in alkene difunctionalization.
Gratifyingly, when 1g bearing 2-aminopyrimidine was
examined next, the 1,3-diarylation product 2g’ was isolated
exclusively with an improved yield of 68% (entry 10).
Moreover, the undesired Heck and Suzuki products were
minimized to 5% and 15% respectively. Other substrates
bearing related directing groups (1h-j) were also examined,
which suffered from either low conversion or deallylation of
the substrate (entries 11-13). Different metal precursors were
also examined under the optimized conditions. Ni (II) species
in the presence of reductant proved to be much less effective
with
the
(
)
(
)
phenylboronic acid. Under various nickel-catalyzed conditions,
unfortunately, no diarylation product was detected at all
(entries 1-2, Table 1). This prompted us to turn our attention
to alkenes with a coordinative directing group. While the use
of amides (1c and 1d) or ester (1e) as the directing group
proved futile (entries 3-5), we were excited to observe the
formation of desired diarylation product in 23% isolated yield
by the use of 1f (entry 6), together with 42%
(entries 14-15). Importantly, the use of palladium catalyst
a
Table 1 Optimization of Ni-catalyzed diarylation.
resulted in the deallylation of the substrate and undesired
Suzuki coupling without any difunctionalization (entry 16).
2
.2 Scope of 1,3-dicarbofunctionalization
With the optimal conditions in hand, we moved on to examine
the substrate scope of this 1,3-difunctionalization reaction.
Initial efforts were focused on the variation on the substitution
pattern of the alkene substrate. Unfortunately, various
Yield (%)
2S
r.r.
2/2’
--
Entry
1
[M]
Ligand
a
b
internal alkenes including 1k, 1l and 1m (Table 1) all failed to
2
H
2’
1
2
3
4
5
6
7
8
9
1a Ni(COD)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
PPh
PPh
PPh
PPh
PPh
PPh
3
3
3
3
3
3
<2
<5
<2
<2
<2
13
5
<2
n.r.
participate in this three-component difunctionalization
reaction. Even under more forcing conditions (15% catalyst
loading, 110 °C, 36 h), only Heck and Suzuki products were
obtained in moderate yield. This provided serious limitation
and prompted us to focus on the reaction with terminal
alkenes. On the other hand, as shown in Scheme 2, various aryl
iodides bearing para-, meta- and ortho-substituents of
1b Ni(COD)
<5
<2
<2
<2
42
12
27
40
15
<5
<2
<2
17
41
25
trace
n.r.
--
1c
Ni(COD)
--
1d Ni(COD)
1e Ni(COD)
n.r.
--
n.r.
--
c
1f
1f
1f
1f
Ni(COD)
Ni(COD)
Ni(COD)
Ni(COD)
23
n.d.
n.d.
n.d.
3/2
1/>20
--
PEt
3
10
28
dppf
dppm
dppm
dppm
dppm
dppm
dppm
dppm
dppm
5
electron-withdrawing
or
electron-donating
character
c
5
47
c
successfully participated in this reaction to produce 3a-k in
moderate to high yields. This method showed a high tolerance
of functional groups including cyano (3e), alkene (3g), ester
1
1
1
1
0
1
2
3
1g Ni(COD)
1h Ni(COD)
<5
<5
<2
<2
<5
<5
<5
68
d
<1
d
1i
1j
Ni(COD)
Ni(COD)
<1
--
(
3f) and ketone (3h). Higher temperature was required for the
ortho-substituted aryl iodides probably due to steric hindrance
3i and 3j). In the case of 4-iodo-benzonitrile, a lower
n.r.
29
--
e
1
4
5
1g Ni(COD)
1g Ni(acac)
1/6
n.d.
--
e
1
16
f
(
1
6
1g Pd
2
(dba)
3
0
temperature of 85 °C proved to be important to produce 3d in
a good 65% yield, while higher temperature led to much
decomposition. Unfortunately, heteroaryl iodides like 2-iodo
thiophene, pyridine, pyrimidine gave only trace amount of
desired product. A wide range of aryl boronic acids bearing
bromo, vinyl, fluoro and trifluoromethyl substituents could
also be used to deliver a range of diarylation products 3l-u in
good efficiency. Notably, alkenyl boronic acids could also be
employed under the same conditions to afford the
arylalkenylation products 4a-e in good to high yields, which
a
1
(0.2 mmol), PhI (34 µL, 0.3 mmol), PhB(OH)
2
(36.5 mg, 0.3 mmol). GC-
dramatically
expanded
the
scope
of
this
1,3-
yield determined by using n-hexadecane as the internal standard. The yield
b
1
c
d
of biphenyl was based on PhI. Determined by H NMR. Isolated yield.
dicarbofunctionalization of alkenes. However, heteroaryl
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boronic acids (2-thienyl, 2-furyl and 5-quinolinyl boronic acids) decomposition of these boronic acids under the diarylation
led to only trace amount of products owing to the conditions.
Scheme
2
Scope
of
1,3-diarylation/arylalkenylation.
2.3 Mechanistic studies. To shed some light on the reaction
Based on these data, we proposed a domino Heck-
mechanism, we first examined the effect of radical trapping isomerization-Suzuki reaction pathway for the 1,3-diarylation
reagents such as BHT (2,6-di-tert-butyl-p-cresol) or α- as shown in Scheme 4. Oxidative addition of Ni(0) to aryl
cyclopropylstyrene
Scheme 3a). As it turned out, the efficiency of the diarylation intermediate
remained constant in the presence of these additives. In reduced the rate for the
8
on the difunctionalization reaction iodide followed by carbonickelation of the substrate produces
. The chelation from the substrate presumably
-hydride elimination to deliver the
(
B
β
addition, the additives also remained unchanged after the Heck side product. On the other hand, B could undergo
reaction. This suggested that the diarylation likely did not transmetalation directly to yield a 1,2-difunctionalization
involve a radical process. Although at this point we can not product. Instead of that,
rule out the possibility of radical formation followed by a very hydride elimination and reinsertion to form a five-membered
fast trapping by Ni within the solvent cage. chelation complex . Transmetalation of with organoboronic
We were curious whether a chain-walking mechanism was acid then yields , which undergoes reductive elimination to
B is isomerized to D through β-
D
D
E
operating for this 1,3-difunctionalization process. To probe produce the diarylation product and regenerate Ni(0) catalyst.
that possibility, deuterium labelling of the substrate was
examined (Scheme 3b). When 3,3’-deuterium-labeled 1g was
subjected to the standard conditions, a clean transfer of one
deuterium to the 2-position was observed, which is consistent
with the chain-walking mechanism. For the small amount of
Heck side product 2g’’, on the other hand, the deuterium
labelling remained at the 3-position, suggesting the transfer
proceeded after the proposed carbometallation step.
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Scheme 3 Mechanistic investigations.
Scheme 5 Scope of 1,2-alkenylcarbonation.
It is worth noting that while the ratio of 1,2 vs 1,3-
difunctionalization (rr) for most products was >10/1 (as
5
determined by GC-MS), the electronic property of the styryl halides
had a significant influence on the regioselectivity. As shown by the
3
comparison of 5c and 5d, the change of electron-withdrawing CF to
electron-donating OMe increased the ratio from 7.7/1 to >100/1.
We assumed that this 1,2-regioselectivity for alkenylarylation could
be attributed to the coordinating effect of the alkenyl unit on nickel
(
Scheme 6). Once intermediate B is formed from alkenylnickelation
of 1g with A, the C=C bond from the electrophile would coordinate
to nickel and suppress the isomerization. When an electron-
deficient alkenyl halide is used, it presumably does not coordinate
to nickel so effectively, leading to higher ratio of isomerization and
1
0
in turn 1,3-difunctionalization.
Scheme 4 Plausible mechanism for 1,3-dicarbofunctionalization.
2.4 1,2-Alkenylcarbonation
When alkenyl bromides were examined under the same
conditions, the related alkenylarylation proceeded smoothly,
but with an interesting switch to the 1,2-regioselectivity
(Scheme 5). Under the standard conditions, a range of alkenyl
bromides bearing various substituted arenes including
heterocycle such as thiophene as well as unsubstituted vinyl
bromide were all applicable for this 1,2-alkenylaryaltion (5a-f).
Besides, dialkenylation could also be realized to deliver 5g
.
Scheme 6 Proposed mechanism of 1,2-Alkenylcarbonalization.
2
.5 Alkynylcarbonation
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well-tolerated. Alkenylboronic acids also worked well to yield
and 6g in good yield.
6f
This catalytic system, however, showed a narrow scope of the
alkynyl reagents. Other than electron-neutral aryl-substituted
alkynyl bromides (59% yield for 6h), the perturbation of the
electronic property of aryl-alkynyl bromides, the use of alkyl-
substituted alkynyl bromide all resulted in no conversion to
the desired product. While the previous 1,3- and 1,2-
dicarbofunctionalization necessitates the use of pyrimidine.
directing group, we were curious whether the 2,1-
alkynylarylation could overcome this limitation. To our
excitement, simple N-allylbenzamide 1c was identified to be a
suitable substrate for this reaction. As shown in Scheme 7d,
the 2,1-difunctionalized product 7 was obtained in a good yield
of 56% at slightly higher temperature. Further exploration of
the scope of this transformation is ongoing.
It is noteworthy that in the previous 1,3-diarylation and 1,2-
alkenylcarbonation reactions, a small amount of Heck product
was isolated as the side product. In contrast, no Heck product
was observed in the 2,1-alkynylcarbonation. Instead, a small
amount of Suzuki product was detected. This observation was
further confirmed in the attempted two-component couplings
under standard conditions (Scheme 8a): the alkynyl bromide
underwent Suzuki coupling but not Heck reaction. Taking this
observation and the intriguing reverse regioselectivity into
consideration, we propose the reaction mechanism shown in
Scheme 8b. Instead of reacting with the alkene, the oxidative
addition
intermediate
A
preferentially
underwent
, which was featured
a
b
Scheme 7 2,1-Alkynylcarbonation
c
.
Reaction in toluene. Reactions in toluene transmetalation with R-B(OH) to form
B
with two distinct carbanion ligands on nickel. Selective
2
with PCy
3
.
Reactions in dioxane with dppm.
insertion of 1g into the aryl/alkenyl-nickel bond led to the
Alkynyl halides are versatile and powerful reagent for the
formation of intermediate
alkynylarylation products through reductive elimination. The
on the success in the dicarbofunctionalization of 1g with key chemo-selectivity in the carbonickelation step was likely
C
,
which delivered the 2,1-
1
1
introduction of alkynyl groups into organic molecules. Based
various
aryl and alkenyl halides, a three-component reaction between than the Ni-aryl and Ni-alkenyl counterparts.
due to the fact that nickel-alkynyl bonds are much stronger
1
2
2
1g, (bromoethynyl)benzene and PhB(OH) was tested under
the previously optimized conditions (Scheme 7a). A moderate
isolated yield of 56% was obtained for the difunctionalization
2
product 6a using Ni(COD) /dppm. The use of alkynyl chloride
and iodide also yielded 6a, albeit in lower yields. To our great
surprise, both NMR and X-ray structure analysis confirmed an
unexpected reverse regioselectivity. In contrast to the 1,2-
alkenylaryaltion in Scheme 5, the alkynyl group was added on
to the internal position of the C=C bond while phenyl groups
on to the terminal. To further optimize this intriguing
transformation, various bisphosphine, monophosphine,
phosphite and bipyridine ligands were screened (Scheme 7b).
3
The yield of 6a could be improved to 85% by using PCy as the
ligand and toluene as the solvent. It is noteworthy that a good
yield of 77% could be obtained for 6a even in the absence of
ligand in dioxane (<2% in toluene). The coordinative solvent
presumably played an important role in stabilizing the nickel
species in this case. On the other hand, the combination of
3
Ni(II) precursors with PCy or the use of Pd complex were
much less effective for this 2,1-alkynylarylation (<11% for 6a).
The scope of this 2,1-alkynylation was extended to various
alkynyl bromides and boronic acids under optimized conditions
(Scheme 7c). Bromo (6b), trifluoromethyl (6c), acetyl (6d) and
chloro (6e) substituents on the phenylboronic acids could be
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diarylation (Scheme 4) or 1,2-dialkenylation (Scheme 6) as
discussed in previous sections.
Scheme 8 Proposed mechanism for alkynylarylation.
2.6. Reaction with alkyl halides.
Alkyl halides are usually poor electrophiles in transition-metal
catalyzed cross-coupling reactions due to their slow oxidative
1
3
addition and facile β-hydride elimination. As shown in
Scheme 9a, when methyl iodide was used for
dicarbofunctionalization of 1g, 1,3-methylarylation (8a) or 1,3- Scheme 9 Difunctionalization using alkyl halides.
methylalkenylation product (8b) could be obtained in 41% and
When alkyl halides bearing β-hydrogen such as ethyl
bromide were employed (See SI for other alkyl bromides), a
complete switch of reactivity was observed. 1,3-
Hydroarylation of the terminal alkene 1g proceeded smoothly
to yield 9a in a high yield of 85% (Scheme 10a). In this
3
9% yield by using phenyl or styryl boronic acid, respectively.
In addition, an unexpected oxidative diarylation product (2g’
)
was also obtained.
When methyl iodide was replaced by benzyl bromide,
interestingly, only trace amount of the desired product (8c
)
was detected from GC-MS, while 2g’ was obtained as the transformation, the nickel hydride intermediate is presumably
major product in 35% yield (Scheme 9b). By the use of a known generated from nickel (0) precursor/alkyl bromide and
5
i
oxidant 1,2-dibromoethane, the yield of 2g’ could be improved
to 75%.
undergoes the following hydrofunctionalization. This 1,3-
hydroarylation or hydroalkenylation proved to be general to
deliver 9b-d in good
This transformation thus represents a novel oxidative 1,3-
diarylation of this class of terminal alkenes.
yields. In this case, previously unreactive internal alkenes 1k
and 1l were able to participate in the 1,3-hydroarylation, albeit
with moderate reactivity (Scheme 10b).
An oxidative dialkenylation was also attempted under the
same conditions (Scheme 9c). It is intriguing to note that 1,2-
dialkenylation product 5h was formed selectively instead of
Importantly, other substrates such as allylsilane 1j could also
undergo 1,3-hydroarylation under the optimized conditions to
produce silane 9e in high yield (Scheme 10c). This greatly
expands the scope of this catalytic transformation.
1,3- difunctionalization. This also provided an important piece
of evidence for the reaction mechanism (Scheme 9d). Starting
from the Ni (0) catalyst, oxidative addition/β-bromide
elimination could produce Ni(II) dibromide (
B
) by the release
with organoboronic
acid then generated the key organo-nickel intermediate . The
To push the limit of this remote functionalization, a 1,4-
hydroarylation of N-homoallyl pyrimidineamine (1n) was
attempted under similar conditions. To our excitement, the
desired product 8a was successfully obtained, albeit in a
moderate yield (Scheme 10d). Unfortunately, the diarylation of
1
4
of ethylene gas. Transmetalation of
B
C
next steps will then follow the pathways for either 1,3-
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1n
and other internal alkene substrates was unsuccessful due In summary, we have realized the first nickel-catalyzed
dicarbofunctionalization of N-allyl 2-aminopyrimidine using
readily available organic boronic acids and halides. Divergent
regioselectivities were obtained based on the nature of
different hybridized organic halides. Aryl and methyl iodides
led to an intriguing 1,3-regioselectivity for the reaction
through a domino Heck-isomerization-Suzuki pathway. For
alkenyl halides, the C=C bond coordination helped to anchor
the Ni(II) intermediate, resulting less tendency towards
isomerization and the formation of 1,2-difunctionalization
instead. The reaction with alkynyl halides produced a reversed
to their low reactivity (see SI for details).
2,1-regioselectivity, presumably resulting from an alternative
sequence of transmetalation followed by selective C=C
insertion into the weaker Ni(II)-carbon bond. Alkyl halides with
β-hydrogen furnished the 1,3- or 1,4-hydrofunctionalization
product. In addition, dihaloethane worked as an oxidant under
the
same
conditions
to
form
the
oxidative
dicarbofunctionalization products. These methodologies can
be used to the synthesis of 2-aminopyrimidine motifs as
attractive pharmacophores. Current efforts in our laboratory
are directed towards the dicarbofunctionalization of more
diverse alkenes and enantioselective variants of these
transformations
.
Acknowledgements
We are grateful for the financial support from the Ministry of
Education of Singapore (R-143-000-613-112), Singapore
Economic Development Board and GlaxoSmithKline (R-143-
0
00-564-592) and National University of Singapore (R-143-000-
Scheme 10 1,3- and 1,4-Hydrocarbonation using alkyl halides bearing β- 605-112).
hydrogen.
2
.7 Application of the methodology
The 2-aminopyrimidine motif represents
pharmacophore in bioorganic and medicinal chemistry
Scheme 11), and has found many applications including
hypertension and congestive heart failure treatment as well as
Notes and references
a
universal
(
Notes and references
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