Intramolecular carbonickelation of alkenes

Article abstract of DOI:10.3762/bjoc.9.81

The efficiency of the intramolecular carbonickelation of substituted allylic ethers and amines has been studied to evaluate the influence of the groups borne by the double bond on this cyclization. The results show that when this reaction takes place, it affords only the 5-exo-trig cyclization products, viz. dihydrobenzofurans or indoles. Depending on the tethered heteroatom (O or N), the outcome of the cyclization differs. While allylic ethers are relatively poor substrates that undergo a side elimination and need an intracyclic double bond to proceed, allylic amines react well and afford indoline and indole derivatives. Finally, the synthesis of the trinuclear ACE core of a morphine-like skeleton was achieved by using NiBr₂bipy catalysis.

Full text of DOI:10.3762/bjoc.9.81

Intramolecular carbonickelation of alkenes
Rudy Lhermet, Muriel Durandetti* and Jacques Maddaluno*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 710–716.
Laboratoire COBRA, CNRS UMR 6014 & FR 3038, Université de
Rouen, INSA de Rouen, 1 rue Tesnières, 76821 Mont St Aignan
Cedex, France
doi:10.3762/bjoc.9.81
Received: 14 January 2013
Accepted: 14 March 2013
Published: 12 April 2013
Email:
Muriel Durandetti* - muriel.durandetti@univ-rouen.fr;
Jacques Maddaluno* - jmaddalu@crihan.fr
This article is part of the Thematic Series "Carbometallation chemistry".
Guest Editor: I. Marek
* Corresponding author
Keywords:
© 2013 Lhermet et al; licensee Beilstein-Institut.
License and terms: see end of document.
alkenes; carbometallation; carbonickelation; cyclization; Heck-type
reaction; nickel catalysis
Abstract
The efficiency of the intramolecular carbonickelation of substituted allylic ethers and amines has been studied to evaluate the influ-
ence of the groups borne by the double bond on this cyclization. The results show that when this reaction takes place, it affords only
the 5-exo-trig cyclization products, viz. dihydrobenzofurans or indoles. Depending on the tethered heteroatom (O or N), the
outcome of the cyclization differs. While allylic ethers are relatively poor substrates that undergo a side elimination and need an
intracyclic double bond to proceed, allylic amines react well and afford indoline and indole derivatives. Finally, the synthesis of the
trinuclear ACE core of a morphine-like skeleton was achieved by using NiBr2bipy catalysis.
Introduction
Carbometalation is a reaction involving the addition of an thesis of pharmaceutical and agrochemical intermediates using
organometallic species to a nonactivated alkene or alkyne nonactivated olefins with high regio- and stereoselectivity [7].
to form a new carbon–carbon bond and generate a new Besides the typical intermolecular version, some intramolecular
organometallic entity, which may subsequently undergo syn- variants were developed leading to useful heterocycles [8-10].
thetic transformations [1,2]. Even though these reactions have Even if palladium is very efficient, nickel appears to be among
been known for over 85 years [3], they have emerged as prac- the most promising metallic substitutes [11]. However, the
tical organometallic tools only during the past forty years, in tedious preparation of Ni(0) complexes such as Ni(cod)2
particular through the development of palladium chemistry [4]. explains that nickel chemistry is hardly perceived as a realistic
The catalytic cycle starts with the oxidative addition of Pd(0) to alternative to palladium, except in electrochemical processes
generate a σ-arylpalladium(II), then a rapid insertion of a [12,13]. Nevertheless, some nickel-catalyzed Heck vinylations
double or triple bond takes place [5]. This method was particu- have been recently reported on activated olefins [14,15]. Some
larly applied in the “Mizoroki–Heck reaction” [6] for the syn- years ago, we showed that the in situ generation of Ni(0)
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Beilstein J. Org. Chem. 2013, 9, 710–716.
complexes in the presence of both the aromatic halide and the
electrophile [16] represents an interesting alternative to electro-
chemical processes. The main advantages of the method are the
use of an easily prepared Ni(II)bipy complex in combination
with manganese dust as a reducing agent, which is not air sensi-
tive, is compatible with fragile functions, and can be used in a
catalytic amount. We showed that this nickel catalysis applies to
cross-coupling reactions, efficiently leading to a variety of func-
tionalized 2-arylpyridines [17]. More recently, this nickel-
Scheme 1: Synthesis of substrates 1a–c.
catalyzed reaction provided a convenient and mild method for a 0.2 equiv of NiBr2bipy and 2 equiv of finely grown manganese
one-pot synthesis of substituted benzofurans, chromans and in DMF containing trace amounts of trifluoroacetic acid at
indoles by carbonickelation of alkynes [18]. We finally decided 50 °C (Table 1). Disappointingly, using 1a the major new pro-
to extend the scope of this heterocyclization reaction to various duct recovered was the dimer 4a, obtained with trace amounts
nonactivated olefins in a nickel-catalyzed intramolecular base- of several other byproducts (Table 1, entry 1). The formation of
free Heck-type coupling.
this symmetrical dimer suggests that: (i) the oxidative addition
of Ni(0) into the carbon–iodine bond leads to 1a-Ni, which trig-
gers a 5-exo-trig carbonickelation on the terminal olefin; (ii) the
resulting 2a-Ni does not undergo the expected Ni–H elimina-
Results and Discussion
Scope of the reaction
We applied the Nickel-catalyzed intramolecular base-free Heck- tion but probably evolves by disproportionation [20] leading to
type coupling to two model substrates, assumed to provide alkyl2Ni and NiBr2bipy [21,22]. The subsequent reductive elim-
either a benzofuran or an indole core. Our first study involved ination of alkyl2Ni would explain the formation of the dimer 4a.
the cyclization of allyl moieties such as allyl ether 1a or N-allyl
protected anilines 1b–c, easily prepared by quantitative allyla- In contrast, the carbonickelation of 1b led to an equimolar mix-
tion of o-iodophenol and o-iodoanilines using allyl bromide in ture of the expected 3-methylindole 2b’ (3-methyleneindoline
DMF (Scheme 1).
2b rearranging into 3-methylindol 2b’, probably during work-
up) and 3-methylindoline 3b in an overall good 60% isolated
Following the protocol optimized for the carbonickelation of yield (Table 1, entry 2). The formation of 3 is probably due to
triple bonds [19], we exposed 1a–c to a mixture containing the sluggishness of the NiH elimination, which allows for the
Table 1: Carbonickelation of compound 1a–c.
entry
ArI
Z
ratio 2/2’/3/4a
1
1a
1b
1c
1c
O
ε/ε/ε/100 (26%b)
0/50/50/0 (60%)
61/26/13/0 (60%c)
40/22/38/0 (69%c)
2
N-Boc
N-Ms
N-Ms
3
4d
aDetermined by NMR, isolated yield between brackets; btrace amounts of 2a, 2a’ and 3a were identified as well as several other byproducts; cNMR
yield with respect to an internal standard, based on initial aryl iodide 1c; dreaction run with 1 equiv of NiBr2bipy.
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Beilstein J. Org. Chem. 2013, 9, 710–716.
competitive protonation of the fragile intermediate alkylnickel
2-Ni. While the Pd-catalyzed reductive Heck reaction promoted
by a hydride generated in situ is well known [23,24], the nickel-
catalyzed process is likely to occur through a radical hydrogen
transfer from the DMF [20,25]. The N-allylaniline 1c gives the
same good yield added to an attractive (2c + 2c’)/3c ratio of
87/13 (Table 1, entry 3). Formation of the 3-methylindoline 3 is
therefore disfavored when a mesyl protecting group is used
instead of a carbamate. When this reaction is run with stoichio-
metric amounts of nickel, the reductive pathway affording indo-
line 3c is slightly increased, and a (2c + 2c’)/3c ratio of 62/38 is
observed (Table 1, entry 4).
Scheme 3: Cyclization of substrate 5a and 5c.
In conclusion to the first part of this study, the formation and
cyclization of arylnickel intermediates 1-Ni is observed in all
cases. Afterward, the stability of the exo-methylene-nickel 2-Ni the major products isolated being compounds 8a and 9a. For-
seems to govern the formation of the cyclized product. Particu- mation of these unexpected products could result from the
larly, the dimerization of 2-Ni threatens the synthetic utility of consecutive intermolecular reactions between 5a and the alkyl-
this reaction, as observed in the case of 1a. In an effort to nickel 7a-Ni or the arylnickel 5a-Ni, respectively (Scheme 4).
escape this pathway, we tried to stabilize 2-Ni by using allyl This reactivity is not unexpected: allyl ethers are known to be
moieties that would provide secondary alkylnickel intermedi- good allylating agents in the presence of nickel-bipyridine
ates. Crotyl and cyclohexenyl ethers and amines were thus complexes [26,27]. In addition, the electroreductive allylation
employed instead of the allyl. Compounds 5 and 6 were easily of aromatic or heteroaromatic halide and allylic acetate [28,29]
prepared by a Mitsunobu condensation involving 2-iodophenol was successfully carried out using nickel-bipyridine complexes
or 2-iodo-N-mesylaniline and crotyl alcohol or cyclohex-2-enol as catalysts in DMF. More recently, Weix noted that the same
(Scheme 2). An N-mesyl derivative was retained, with a lesser reaction could be achieved under chemical conditions, always
amount of indoline 3 being obtained above when this protecting using bi-(or ter-)pyridine nickel catalysts [30]. These data
group was employed.
explain the formation of 9a. Finally, the 8a/9a ratio suggests
that 5a-Ni can undergo two competitive pathways: the 5-exo-
trig cyclization leading to 7a-Ni, and the aromatic allylation
affording 9a. Based on the figures we conclude that 5a-Ni
reacts more rapidly with the allyl derivative than it cyclizes.
Under the same conditions, N-mesylaniline 5c is more efficient
(Scheme 3), and the expected cyclized product 7c is obtained as
the major product (60% GC yield, 31% isolated yield due to the
instability of the exocyclic double bond during the purification)
[31].
In the cyclohexenyl series, we were pleased to observe that
ether 6a affords only the benzofuran 10a, but the conversion is
limited (30% of the starting material 6a is recovered) and the
yield modest (36% isolated, 51% based on recovered material,
Scheme 2: Synthesis of substrates 5a, 5c, 6a and 6c.
The carbonickelation protocol was applied to the cyclization of Scheme 5).
crotyl derivatives 5 (Scheme 3).
Interestingly, the intracyclic character of the double bond in 6
When applied to ether 5a, as expected, the substitution of the appears to influence the relative kinetics of the competing reac-
allyl moiety at the terminal position by a methyl tends to tions in favor of both the carbonickelation and the β-elimina-
disfavor the dimerization of the alkylnickel intermediate, and tion (thus the Heck-type coupling) over the formation of a
type-4 dimers are no longer observed. However, the expected π-allyl complex that would afford allylation products such as 8
cyclized compound 7a is obtained only in trace amounts, with or 9. In the aniline series, the indole 10c (50% GC yield, 28%
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Beilstein J. Org. Chem. 2013, 9, 710–716.
Scheme 4: Proposed mechanism involving π-allylnickel formation.
junction. This pattern is found in important natural products
such as morphine whose ACE ring system exhibits a tetrahy-
drodibenzofuran motif with an angular ethylamino chain on
C13. We thought that the nickel-catalyzed intramolecular
carbometalation reaction could help to tackle the problem of the
central ring (E) closure. To validate this hypothesis, we retained
substrate 13 as a simplified working model. If ether 13 is little
functionalized, it bears the methylvinyl moiety that is essential
to the construction of the quaternary ring junction. Substrate 13
was prepared by a simple Mitsunobu condensation between
2-methylcyclohex-2-enol (12), a known compound prepared in
three steps from commercially available 2-methylcyclohexa-
none and 2-iodophenol (Scheme 6). The carbonickelation
protocol applied to 13 led in one hour to the expected (and sole)
Scheme 5: Cyclization of substrate 6a and 6c.
isolated yield) is obtained together with the indoline 11c, in an tricyclic product 14 in 52% isolated yield, resulting from a
indol/indoline 10c/11c ratio of 80/20.
nickel-catalyzed intramolecular base-free Heck-type coupling
and exhibiting an all-carbon quaternary center at a cis-ring junc-
tion (as established by NOESY experiments). This result, added
to that obtained above with aryl ether 6a, underlines that the
Creation of an all-carbon quaternary center at
a ring junction
The success of the above experiments prompted us to conduct endocyclic character of the unsaturation is essential to favor the
this reaction with trisubstituted olefins, in an effort to construct Heck coupling. The carbonickelation process leads to a second-
tricyclic skeletons with an all-carbon quaternary center at a ring ary alkylnickel intermediate, which is sufficiently stabilized to
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Beilstein J. Org. Chem. 2013, 9, 710–716.
Scheme 6: Synthesis and carbometalations of 13.
avoid the side reactions observed above. Actually, the carbo- Conclusion
nickelation remains the rate-determining step as suggested by In this work, we have shown that the NiBr2bipy complex can be
an experiment in which allyl acetate was mixed with 13 before used to catalyze an intramolecular Heck-type reaction in the
the addition of the catalyst (Barbier conditions). In this case, the absence of any additional base. This glove-box-free procedure
only product was the allylated aryl derivative 17, recovered in occurs using 20% of NiBr2bipy and does not require the
comparable yields, suggesting that in the presence of a good handling of air- or moisture-sensitive reagents. Thus, this single
allyl donor, the σ-arylnickel undergoes an intermolecular allyla- process gives access to a simplified model of the trinuclear
tion quicker than the intramolecular carbonickelation.
ACE core of morphine. Beyond the appeal of the possible
replacement of expensive palladium by cheap nickel, the
From a synthetic point of view, it is interesting to note that 14 absence of post-coupling isomerization of the double bond
was obtained as only one isomer, the double bond remaining at seems particularly worthy of note.
the location imposed by the nickel hydride elimination. In order
Experimental
to compare the Ni-catalyzed version to the Pd(0) one, the same
General procedure for the intramolecular
carbonickelation of alkenes
reaction was run following the protocol recently described by
Fukuyama [32] in the key-step of his total synthesis of
morphine. Under these conditions, the cyclization took place in
an excellent 82% yield after 3.5 h, but a mixture of the three
regioisomers 14–16 was recovered (Scheme 6). By contrast,
under Larock’s conditions [33] [Pd(OAc)2 (5 mol %), Na2CO3,
DMF, 80 °C], an even higher yield (90% after 2 days) was
returned but consisted of a 1:1:1 mixture of the same three
products 14–16. Replacing sodium carbonate by silver
carbonate avoids these post-cyclization isomerizations [34,35],
but the yield (52% after 16 h) was not higher than with nickel.
Thus, this study suggests that a Heck-coupling reaction relying
on a carbonickelation step can be considered as a useful tool in
the total synthesis.
To a solution of aryliodide (0.5–1 mmol, 1 equiv) in anhydrous
DMF (5 mL) under argon atmosphere at 50 °C is added
manganese (2 equiv) followed by NiBr2bipy (0.2 equiv) then
rapidly TFA (20 μL). The medium is vigorously stirred at
50 °C, and disappearance of the starting material is monitored
by gas chromatography. The mixture is hydrolyzed with water
(10 mL), diluted with Et2O (10 mL), and then filtered through
celite. The aqueous layer is extracted with Et2O (2 × 10 mL),
and then the combined organic layers are washed with water
(3 × 10 mL) and brine (2 × 10 mL), dried over anhydrous
MgSO4, and concentrated. The crude is purified by flash chro-
matography.
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Beilstein J. Org. Chem. 2013, 9, 710–716.
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Supporting Information
Supporting Information File 1
Experimental procedures and compound characterization.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-81-S1.pdf]
doi:10.1007/978-3-642-28123-5
Radical intermediates have been proposed in case of alkylnickel.
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RL is grateful to the Région de Haute-Normandie and CNRS
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