Ni-catalyzed cascade cyclization-kumada alkyl-alkyl cross-coupling

Article abstract of DOI:10.1002/chem.201300882

Suggesting novel disconnections: A powerful Ni-catalyzed cascade reaction involving cyclization followed by cross-coupling allows the formation of up to three alkyl-alkyl bonds in a single operation by using alkene-containing alkyl iodides and Grignard reagents (see scheme; acac=acetylacetonate; TMEDA=N,N′,N′-tetramethyl ethylenediamine). Mechanistic experimental and computational studies suggest a Ni^I-Ni^II-Ni ^III catalytic cycle and the intermediacy of radicals. Copyright

Full text of DOI:10.1002/chem.201300882

COMMUNICATION
DOI: 10.1002/chem.201300882
Ni-Catalyzed Cascade Cyclization–Kumada Alkyl–Alkyl Cross-Coupling
Manuel Guisꢀn-Ceinos, Rita Soler-Yanes, Daniel Collado-Sanz, Vilas B. Phapale,
Elena BuÇuel, and Diego J. Cꢀrdenas*[a]
3
(sp3) bonds by cross-coupling reac-
Table 1. Ligand survey for the alkyl–alkyl cross-coupling reaction.
À
Formation of C
(sp ) C
tions has experienced an important development in recent
years.[1] The intrinsic limitations associated with these kind
of couplings, mainly the more difficult oxidative addition of
alkyl electrophiles and the fast b-elimination of hydrogen in
the alkyl–metal intermediates,[2] have been overcome in a
variety of ways. Thus, in the Negishi and Suzuki cross-cou-
pling reactions,[3] the use of bulky and highly donating lig-
ACHTUNGTRENNUNGands, such as trialkyl phosphines and nitrogen heterocyclic
Entry Ligand (mol%)
Yield [%][a] Yield [%][b]
carbene (NHC) ligands, has led to efficient Pd-catalyzed
alkyl–alkyl cross-couplings by both acceleration of the oxi-
dative addition and precluding elimination.[3c,4] The use of
Ni catalysis in Suzuki- and Negishi-type couplings has un-
covered novel mechanisms.[5] Most cases involve radical
pathways,[1n,5,6] in contrast to the well-established mechanism
for Pd-catalyzed reactions. On the other hand, recently,
Kumada-type couplings are becoming more and more inter-
esting and versatile due to the discovery of novel methods
for the preparation of functionalized Grignard reagents,[7]
and to the finding of active catalysts able to afford fast cou-
plings at low temperature, in the presence of functional
groups. The use of first-row transition metals (Ni,[8] Co,[9]
Cu,[10] and Fe[11]) has proven to be key in this kind of re-
search. Since the initial report by Knochel,[5f–i] Ni catalysis
has been demonstrated to be highly convenient for the per-
formance of alkyl–alkyl couplings. Some years ago, we pub-
lished a cascade cyclization and Negishi couplings in the
presence of functional groups, by using substrates capable to
experience cyclization prior to coupling.[5n,12] In this Com-
munication, we report our recent advances on Ni-catalyzed
cascade cyclization–coupling reactions for the formation of
up to three alkyl–alkyl bonds involving Grignard reagents
and provide insight into the reaction mechanism through
experimental and computational studies.
1
2
3
4
5
6
7
8
bipyridine (10)
35
40
47
40
30
49
–
–
–
–
40[c]
45[c]
56
terpyridine (10,[a] 6[b]
)
(S)-sBu-Pybox[e] (10,[a] 6[b]
)
o-phenanthroline (10,[a] 6[b]
Ph2P(CH2)2PPh2 (dppe, 10)
)
15
ACHTUNGTRENNUNG
Me2N
Me2N
Me2N
U
80(90)[c]
73[d]
55[d]
9
10
A
U
20
38[c]
[a] Fast addition of Grignard reagent (4 equiv), 10 mol% [Ni]. Reaction
time: 0.5 h. [b] Slow addition (over 10 h) of Grignard reagent (2 equiv),
5 mol% [Ni]. Overall reaction time: 11 h. [c] Yield calculated by GC
analysis. [d] Contains traces of an inseparable unknown impurity.
[e] 2,6-bis[(S)-4-(s-butyl)-4,5-dihydrooxazol-2-yl]pyridine.
N ligands were the most effective ones. In the present case,
both sBu-Pybox and N,N’,N’-tetramethylethylenediamine
(TMEDA) afforded the best results when the reaction was
performed by mixing all the reagents at the same time. Nev-
ertheless, we found a strong influence of the addition rate of
the Grignard reagent on the reaction yield. Slow addition
makes the yield increase from 49 up to 80% yield (90% by
GC analysis) when using TMEDA as the ligand
(Table 1, entry 6).
We initially chose the model reaction shown in Table 1 to
screen a variety of ligands and conditions. Our previous
study on the Negishi reaction demonstrated that tridentate
Noticeably, yields do not significantly increase for pyri-
dine-based ligands (Table 1, entries 1–4) or phosphine deriv-
atives (entries 5 and 10). The use of other trialkylamino che-
lating ligands with different bite angles (N,N,N’,N’-tetrame-
thylmethylenediamine (TMMDA) and N,N,N’,N’-tetrame-
thylpropylenediamine (TMPDA)) also afforded lower yields
(entries 7 and 8) under slow addition conditions. Tridentate
[a] M. Guisꢀn-Ceinos, R. Soler-Yanes, D. Collado-Sanz,
Dr. V. B. Phapale, Dr. E. BuÇuel, Prof. D. J. Cꢀrdenas
Departamento de Quꢁmica Orgꢀnica, Facultad de Ciencias
Universidad Autꢂnoma de Madrid (UAM)
Cantoblanco, 28049, Madrid (Spain)
ligand [Me2NACTHUNTRGNE(UNG CH2)2]2NMe led to a sluggish 20% yield. The
influence of the addition rate has been previously reported
for other couplings involving organomagnesium reagents as
nucleophiles.[10c,11c,13] The analogous bromide and tosylate
were tested as alternative electrophiles. Bromide gave no re-
Fax : (+34)914973966
E-mail: diego.cardenas@uam.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300882.
Chem. Eur. J. 2013, 19, 8405 – 8410
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8405

couplings.[5n] Sequential forma-
tion of two alkyl–alkyl carbon
bonds could be achieved
(Table 3). This cascade reaction
is very powerful from a synthet-
ic point of view, since it can be
applied to a wide variety of
substrates, in the presence of
several functional groups, and
provides structurally complex
Table 2. Scope of the alkyl–alkyl cross-coupling.
À
products. Moreover, the C C
bonds formed are not the ones
usually thought about when ret-
rosynthetic analysis is per-
formed on the kind of products
obtained. Acetals, sulfonamide
(4k), and again ester groups
(4l) are tolerated. Iodo ketals,
which are usually employed in
radical Ueno–Stork cyclization
reactions, afforded good results
(4a–e, 4h, 4i, 4n). The five-
membered-ring-containing re-
agents gave higher stereoselec-
tivities (Table 3, 4a–d). In con-
trast, six-membered-ring ketals
[a] Reaction was carried out by slow addition of the Grignard reagent (2 equiv, 10 h, 0.081 mmolhÀ1) to a THF
solution of alkyl iodide (0,41 mmol), [NiACTHNUTRGNEUNG(acac)2] (5 mol%) and TMEDA (10 mol%), under Ar at 258C. Over-
all reaction time: 11 h. [b] Reaction was carried out by dropwise addition of the nucleophile over 10 min
(1.5 equiv). Reaction time: 0.5 h. [c] 2.5 equiv of nucleophile. Isolated with 9% of 2-phenylethanol (probably
formed by oxidation of the Grignard reagent).
action at all, whereas tosylate afforded a 20% yield of cou-
pling product. Regarding the Ni source, the use of NiCl2,
(4e) and ethers (4 f–g) afforded mixtures of diasteromers. In
all cases, cis fusion is observed for both diatereoisomers, and
mixtures correspond to epimers on the alkyl carbon atom
coming from the internal position of the starting alkene.
Functionalized acyclic starting iodides gave the correspond-
ing monocyclic products (4j–l) Finally, the use of a 1,6-diene
allowed an impressive double cyclization prior to the cross-
coupling, leading to the formation of three new alkyl–alkyl
bonds in a single operation, albeit with low stereoselectivity
(4m).
Experiments involving radical clock precursors as electro-
philes were performed (Scheme 1). The reaction of iodo-
methyl cyclopropane led exclusively to 5, derived from ring
opening prior to coupling, which suggests the intermediacy
of carbon radicals. On the other hand, 6-iodohexene, afford-
NiBr2, [NiCl2(py)4] (py=pyridine), and [Ni
acetylacetonate) provided similar results. The less hygro-
scopic [Ni(acac)2] was selected as the most convenient Ni
ACHTUNGTERN(NUNG acac)2] (acac=
ACHTUNGTRENNUNG
precatalyst. Optimal catalyst loading was determined to be
5%. Lower catalyst loadings led to lower yields. The opti-
mal ligand/metal ratio was found to be 2:1. A variety of sub-
strates containing different functional groups were subjected
to the optimized reaction conditions. Results are summar-
ized in Table 2. Both primary and secondary alkyl iodides
gave the expected products in moderate to excellent yields
when coupled to alkyl- and ketal-containing magnesium re-
agents. As can be seen, the reaction is effective in the pres-
ence of several functional groups, such as acetal and carba-
mate (3m). More interestingly,
esters and nitriles afforded fair
to good yields (3e, 3 f, and 3j).
The alkoxide group does not in-
terfere either (3c), although an
extra equivalent of Grignard
reagent is of course necessary.
Once we demonstrated the
utility of this catalytic system
for the efficient Ni-catalyzed
Kumada cross-coupling, we
tried to perform cascade cycli-
zation–coupling reactions, by
using alkyl iodides containing
an alkene functionality, as in
our previous study on Negishi Scheme 1. Experimental evidence of a radical pathway for the alkyl–alkyl cross-coupling reaction.
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Ni-Catalyzed Cascade Cyclization
COMMUNICATION
Table 3. Cascade cyclization-coupling reaction.[a]
the stationary points in THF, by
using the PCM solvation model
(unless otherwise stated). Previ-
ous studies by several groups,
including ours, led to the con-
clusion that alkyl–Mg or alkyl–
Zn reagents reduce precatalysts
to formally NiI complexes,
which are the actual catalytical-
ly active species. This proposal
comprises Kumada and Negishi
couplings of alkyl and aryl hal-
ides involving neutral bi- and
tridentate
ands,[1 h,5n,6a–e,14] and Suzuki cou-
plings with diamines as lig-
AHCTUNGTRENNUNG
ands.[6a] The NiI complexes pro-
N-based
lig-
AHCTUNGTRENNUNG
posed as intermediates in these
catalytic reactions have the
usual square-planar structure
expected for d8 NiII derivatives.
Molecular orbital studies clear-
ly indicate that the unpaired
electron is not located on the
metal atom, but on the p* orbi-
tals of the polydentate aromatic
ligand.[5n,6] Therefore, although
the formal oxidation state of Ni
is I, these species are better de-
scribed as NiII complexes with
one anionic polydentate ligand,
as if an intramolecular electron
transfer from Ni to the ligand
took place upon complex for-
mation. In the present case,
support for the formation of a
NiI radical species was also
found when performing the re-
action in the presence of
[a] All products were isolated by column chromatography (racemic). Major diastereomers depicted. [b] Slow
addition (0.081 mmolhÀ1) of the Grignard reagent (2 equiv) to a THF solution of alkyl iodide (0.41 mmol),
[NiACHTUNGTRENNUNG
(acac)2] (5 mol%) and TMEDA (10 mol%), under Ar at 258C. [c] Dropwise addition (4.88 mmolhÀ1) of
the Grignard reagent (1.5 equiv). [d] Diastereomeric ratio calculated by NMR spectroscopy. [d] Mixture of
1
stereoisomers (as shown by H NMR spectroscopy) that could not be separated. [e] Two diastereoisomers in a
2:1 ratio (GC analysis). Stereochemistry could not be determined.
ed a mixture of both possible coupling products (linear 6
and cyclic 7). Partial cyclization of the intermediate
6-hexen-1-yl radical, which cyclizes at a lower rate relative
to the ring opening of the cyclopropylmethyl radical, ex-
plains these results. Interestingly, the reaction yield is much
lower in THF (20%) relative to benzene (80%), which sug-
gests radical reduction by the solvent in the former case.
Additionally, a higher cyclic–linear coupling product ratio is
observed in benzene, in which intermediate radicals would
be longer lived. In this solvent, 1 equivalent of TMEDA is
necessary for the reaction to be
TEMPO (see the Supporting Information).
These studies support an initial transmetalation on a NiI
halide to give an alkyl–NiI complex, which in turn activates
the electrophile affording a diorgano–NiIII species. C–C re-
ductive elimination completes the catalytic cycle. Initially,
the oxidative addition of 2-iodopropane to [Ni(Me)-
AHCTUNGTREG(NNUN TMEDA)] (I) was studied (Scheme 2). Association com-
plex (I’) is formed prior to oxidative addition. This interac-
tion is thermoneutral from an enthalpic point of view.
effective, due to the lower solu-
bility of the catalytic system.
We have performed a DFT
study on the reaction mecha-
nism. Calculations have been
carried out with the B3LYP
Scheme 2. Calculated activation and reaction free energies for the oxidative addition and subsequent C–C
hybrid functional, optimizing reductive elimination (in THF, kcalmolÀ1). [a] Values in the gas phase (see the Supporting Information).
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D. J. Cꢀrdenas et al.
Complex I’ evolves by C–I
homolytic cleavage showing a
low activation energy (10.4 kcal
molÀ1). Subsequent reaction of
the radical with the NiII com-
plex II to afford dialkyl Ni de-
rivative III is also fast (Ea =
14.3 kcalmolÀ1). Although coor-
dination of the radical to the
NiII–halide intermediate II is
slightly endoergic, the overall
oxidative addition occurs down-
hill to give pentacoordinate III
(À7.1 kcalmolÀ1). Fast C–C re-
ductive elimination leads to the
Figure 2. Calculated reaction pathways for the evolution of the secondary radical (G values in THF,
formation of the reaction prod- kcalmolÀ1).
uct and NiI complex IV. Trans-
metalation of model IV with
Grignard reagent to afford I was calculated to be a feasible
and fast process, as expected in accordance to the high nu-
cleophilicity of Grignard reagents, and the similar result ob-
tained for the transmetalation of alkylzinc halides previously
studied (see the Supporting Information).[6b,13]
of this radical with NiII complex II. We were pleased to find
that 5-exo radical cyclization is both faster and more favor-
AHCTUNGTRENNUNG
As has been explained above, the electronic structure of
the usual polydentate formally NiI complexes shows the un-
paired electron on the orbitals p* of the ligand,[5n,6] which
cannot occur for TMEDA. For the former, complexes are
better described as NiII complexes with anionic polydentate
ligands. A natural bond orbital (NBO) study of the key cata-
lyst I (Figure 1) shows that the unpaired electron is located
on the metal, according to the spin density values. Molecular
orbital calculations show the SOMO pointing towards the
ACHTUNGTRENNUNG
served stereoisomer is a result of kinetic control: radical VII
is less stable than VIII, but it is formed through the most
stable transition state. As expected, 6-endo cyclization is
much slower (not shown; see the Supporting Information).
After cyclization, primary radicals VII and VIII coordinate
to NiII and evolve by reductive elimination to the products
and IV, completing the catalytic cycle.
The above results allow us to depict the mechanistic ra-
tionale shown in Scheme 3. {Ni-XACTHUNTGRNEUNG(TMEDA)} (A) transmeta-
lates with the Grignard reagent to afford an electron-rich
NiI alkyl derivative B. This complex is able to homolytically
cleave the alkyl halide to give a primary radical and NiII spe-
cies C. Coordination of the radical to this complex is slow
enough to allow 5-exo radical cyclization. Subsequent coor-
dination of the resulting secondary radical provides diorga-
Figure 1. SOMO of NiI complex I calculated at the MP2 level.
vacant coordination site in which interaction of the electro-
phile takes place, according to the structure of intermediate
I’. In contrast, complex IV, shows a more symmetrical struc-
ture reminiscent of a trigonal planar coordination with the
SOMO located mainly on the I atom, with lower participa-
tion of Ni. Spin-density calculations clearly indicate that the
unpaired electron is again located on Ni (see the Supporting
Information). Therefore, stabilization of formally NiI com-
plexes by polydentate N-based ligands with p* orbitals, is
not necessary. In the present case, true NiI species can be
formed, according to our calculations.
Regarding the cascade cyclization–coupling reaction, we
calculated the activation and reaction energy for the cycliza-
tion of the secondary radical resulting from a model iodo-
A
Scheme 3. Proposed reaction mechanism.
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Ni-Catalyzed Cascade Cyclization
COMMUNICATION
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cade cyclization–coupling was performed with sBuMgCl,
isomerization of the alkyl group to nBu took place
(Scheme 4), which suggests b-elimination of hydrogen, fol-
lowed by hydrometalation of the resulting alkene with the
opposite regioselectivity. Interestingly, the acyclic secondary
iodide shown in Scheme 4, gave no isomerization of the
alkyl chain coming from the electrophile. According to the
most likely mechanism, isomerization involving the alkyl
group coming from the electrophile could only occur on the
diorgano–NiIII intermediate (such as model III, Scheme 2),
and this does not seem to be the case. Therefore, formation
of the observed linear coupling product when using
sBuMgCl suggests that b-elimination of hydrogen has to
take place on NiI or NiII intermediates, prior to coordination
of the carbon chain of the halide to the metal complex.
In summary, we have developed a catalytic system for
both simple Ni-catalyzed alkyl–alkyl Kumada reactions and
cascade cyclization–coupling for the formation of two alkyl–
alkyl bonds. The reaction is general and tolerates several
functional groups, including esters, carbamates, nitriles, alk-
oxides and ketals. The use of N-heterocycles is not mandato-
ry for these reactions to proceed. Mechanistic studies
strongly suggest the intermediacy of radical species, and
point to a NiI–NiII–NiIII catalytic cycle. Calculations are in
accord with the reaction outcome and with the stereoselec-
tivity observed for the cyclic coupling products observed.
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Acknowledgements
This work was supported by the MICINN (CTQ2010-15927) and CAM
(AVANCAT PPQ-1634). We thank the UAM for a FPU-UAM fellowship
to M.G.-C., the MINECO for a FPI fellowship to R. S.-Y, the MEC for a
FPU fellowship to D. C.-S., the AECI-MAE for a fellowship to V.B. Pha-
pale, and the CCC-UAM for computation time.
À
Keywords: C C coupling
homogeneous catalysis · nickel · radical reactions
·
Grignard reactions
·
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Received: March 7, 2013
Published online: May 15, 2013
8410
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