Ni(I)-Catalyzed Reductive Cyclization of 1,6-Dienes: Mechanism-Controlled trans Selectivity

Article abstract of DOI:10.1016/j.chempr.2017.07.010

A Ni-catalyzed reductive cyclization of 1,6-dienes affords 3,4-disubstituted cyclopentane and pyrrolidine derivatives with high trans diastereoselectivity. This cyclization reaction enables the efficient synthesis of trans-3,4-dimethyl gababutin, a pharma

Full text of DOI:10.1016/j.chempr.2017.07.010

Article
Ni(I)-Catalyzed Reductive Cyclization of 1,6-
Dienes: Mechanism-Controlled trans
Selectivity
Yulong Kuang, David Anthony,
Joseph Katigbak, Flaminia
Marrucci, Sunita Humagain,
Tianning Diao
diao@nyu.edu
HIGHLIGHTS
Reductive coupling of dienes
gives a trans diastereoselectivity
An efficient synthesis of a
gababutin derivative for treating
neuropathic pain
A classic organometallic
mechanism is mediated by Ni(I)
and Ni(III) intermediates
The mechanistic basis for the
chemoselectivity and
diastereoselectivity
Diao and coworkers have developed a reductive coupling reaction to convert 1,6-
dienes into cyclic molecules with trans-vicinal disubstituents. This method is
readily applicable to the syntheses of biologically active molecules with high
efficiency. Mechanistic studies revealed that the reaction proceeds via a classic,
two-electron transfer mechanism mediated by paramagnetic Ni(I) and Ni(III)
intermediates. The identification of the well-defined Ni(I) catalyst and elucidation
of the mechanism will facilitate future development of Ni-catalyzed cross-coupling
reactions.
Kuang et al., Chem 3, 268–280
August 10, 2017 ª 2017 Elsevier Inc.
http://dx.doi.org/10.1016/j.chempr.2017.07.010

Article
Ni(I)-Catalyzed Reductive
Cyclization of 1,6-Dienes:
Mechanism-Controlled trans Selectivity
Yulong Kuang,1 David Anthony,1 Joseph Katigbak,1 Flaminia Marrucci,1 Sunita Humagain,2
and Tianning Diao1,3,
*
SUMMARY
The Bigger Picture
Modern pharmaceutical and
chemical synthesis calls for new
catalytic methods of accessing
intricate molecules with high
efficiency. Ni-catalyzed cross-
coupling reactions have emerged
as an appealing method for the
construction of C–C bonds. The
complex mechanisms of these
reactions often involve single-
electron transfer and radical
intermediates. Here, we used a
well-defined Ni(I) complex to
catalyze a trans-selective
A Ni-catalyzed reductive cyclization of 1,6-dienes affords 3,4-disubstituted
cyclopentane and pyrrolidine derivatives with high trans diastereoselectivity.
This cyclization reaction enables the efficient synthesis of trans-3,4-dimethyl
gababutin, a pharmaceutical lead for treating neuropathic pain, and trans-3,4-
dimethylpyrrolidine, a precursor to drug candidates and pesticides. The trans
selectivity distinguishes this reaction from relevant precedents that proceed
via hydrogen-atom transfer and lead to cis products. Mechanistic investigation,
including kinetic, spectroscopic, and radical clock studies, attributes the trans
diastereoselectivity to a classic, organometallic catalytic cycle mediated by
Ni(I) and Ni(III) intermediates. The electron-rich Ni(I) intermediate, stabilized
by a redox-active a-diimine ligand, is responsible for the chemoselectivity to-
ward reductive cyclization as opposed to the redox-neutral cycloisomerization
observed with previous Ni(II) catalysts.
reductive coupling of dienes,
which led to the efficient synthesis
of biologically active molecules.
The reaction proceeds via a
classic, two-electron transfer
pathway mediated by
INTRODUCTION
Contemporary nickel-catalyzed cross-coupling reactions have found widespread ap-
plications in organic synthesis.1,2 The mechanisms of these reactions frequently
invoke single-electron transfer steps and Ni(I) and Ni(III) intermediates.3,4 In contrast
to radical pathways, the mechanism for Ni(0)-catalyzed reductive coupling of unsat-
urated molecules, developed by Montgomery and colleagues,5 proceeds through
classic oxidative cycloaddition of Ni(0) to form Ni(II) metallocycles. Although these
reactions provide an appealing way to functionalize alkynes, similar reactivity has
not been observed with unactivated alkenes. Here, we report a reductive cyclization
of dienes that proceeds via a mechanism distinct from those of previous reports.
A well-defined Ni(I) intermediate mediates two-electron transfer pathways via a
Ni(I)-Ni(III) catalytic cycle, without single-electron transfers and organic radical
intermediates.
paramagnetic Ni(I) and Ni(III)
intermediates. This mechanism
distinguishes this work from
previous reactions and accounts
for the observed trans
diastereoselectivity and the
chemoselectivity for reductive
coupling. The characterization of
this mechanism and the
Alkenes are versatile functional groups in organic synthesis. Catalytic functionaliza-
tion of alkenes represents one of the most powerful synthetic strategies in contem-
porary pharmaceutical synthesis. Cyclization reactions of olefins can rapidly
construct cyclic molecules and have been practiced extensively. Among a variety
of approaches, ring-closing metathesis is the most widespread, giving rise to unsat-
urated ring systems (Scheme 1A).6,7 In addition, [2 + 2] cycloaddition and ene reac-
tions provide access to a variety of cycles.8,9 A number of catalytic conditions have
been developed to carry out the cycloisomerization of dienes to form exo-methyle-
necyclopentanes (Scheme 1B).10,11 In particular, Widenhoefer and DeCarli12 and
introduction of the Ni(I) catalyst
precursor are anticipated to
inspire catalyst design in the field
of Ni catalysis.
268 Chem 3, 268–280, August 10, 2017 ª 2017 Elsevier Inc.

Scheme 1. Cyclization Reactions of
1,6-Dienes
A
B
C
Perch et al.13 used Pd(II) catalysts to perform cyclization of dienes, followed by a tan-
dem coupling with silanes to afford trans-disubstituted silylated products. A recent
report by Crossley et al.14 shows that Co catalyzes cycloisomerization via hydrogen
atom transfer (HAT) to afford cis-3,4-disubstituted cyclopentanes. Reductive
coupling of unactivated alkenes can install two adjacent stereocenters at once,
but such reactivity has been historically challenging (Scheme 1C).15–17
trans-3,4-Disubstituted cyclopentane18 and pyrrolidine motifs are commonplace in
natural products and pharmaceutical leads.19,20 Synthesis of trans-3,4-disubstituted
five-membered rings, however, often requires multiple steps21,22 or stoichiometric
metal reagents.23 Using the Ni(I)/Ni(III)-mediated two-electron mechanism, we
developed a reductive cyclization of 1,6-dienes, which provides trans-3,4-disubsti-
tuted cyclopentane and pyrrolidine derivatives (Scheme 1C). The trans diastereose-
lectivity depicted here complements previous reductive olefin coupling methods
reported by Molander and Hoberg24 and Baran and colleagues,25–27 which proceed
through organolanthanide and radical intermediates, respectively. Our mechanistic
studies reveal that the unique two-electron mechanism and the radical nature of the
Ni(I) catalyst are responsible for the high reductive chemoselectivity and trans
diastereoselectivity.
RESULTS
Catalyst Development
Our catalyst optimization focused on dimethyl malonate-derived 1,6-heptadiene 1
as the substrate (Figure 1). The combination of Fe(acac)3 and PhSiH3 has been re-
ported to reductively couple activated olefins.25 This condition led to reductive
cyclization of 1 to form a mixture of cis and trans diastereoisomers, with the cis iso-
mer as the major product (entry 1). Conditions based on a Co catalyst developed by
Crossley et al.14 were ineffective for the cyclization of 1 (entry 2). (a-Diimine)Ni com-
plexes have been developed for olefin polymerization and oligomerization.28 We
anticipated that catalysts of this class could effect intramolecular coupling of
alkenes. In the presence of Et2SiH2, (Ara-diimine)NiBr2 3 (Ar = 2,6-diisopropylphenyl)
catalyzed reductive cyclization of 1 in hexafluoroisopropanol (HFIP) to generate
trans-3,4-dimethylcyclopentane 2 in 50% yield (entry 3). The reaction did not pro-
duce the cis diastereomer as a by-product. This exquisite selectivity for the trans dia-
stereomer prompted us to investigate different catalyst precursors in order to
improve the yield. (a-Diimine)NiMe2 4 failed to activate and resulted in no product
formation (entry 4). The extensive participation of Ni(I) and Ni(III) intermediates in
1Department of Chemistry, New York University,
100 Washington Square East, New York, NY
10003, USA
2Department of Physics and Astronomy, Hunter
College, 695 Park Avenue, New York, NY 10065,
USA
3Lead Contact
*Correspondence: diao@nyu.edu
http://dx.doi.org/10.1016/j.chempr.2017.07.010
Chem 3, 268–280, August 10, 2017 269

Figure 1. Catalyst Development for Reductive Cyclization of 1,6-Diene, 1
catalysis4 led us to evaluate Ni(I) precursors. Indeed, [(a-diimine)Ni(m-Br)]2 5 ex-
hibited the highest reactivity (Figures S7 and S8),29 giving rise to 2 in 79% yield
(entry 5). A similar Ni(I) precursor, [(a-diimine)Ni(m-H)]2 6,30 afforded 2 in a slightly
lower yield (entry 6).
To probe the effect of ligands on this reaction, we prepared less hindered (Bna-dii-
mine)NiBr2 7, in which the 2,6-diisopropylphenyl substituents of 5 were replaced
by benzyl groups. With an increased catalyst loading of 10 mol %, we achieved a
good yield of 2 with catalyst 7 (entry 7). Notably, catalyst 7 is synthetically more acces-
sible than 5 because it requires no glovebox manipulations. [(dtbpe)Ni(m-Br)]2 831 ex-
hibited substantially lower reactivity than (a-diimine)Ni complexes (entry 8). Evalua-
tion of other reductants revealed that tertiary silanes (entry 9) and hydrogen were
inactive (entry 11), whereas primary silanes afforded some 2 accompanied by satu-
rated molecules resulting from the reduction of the substrate (entry 10).
Scope
With the reaction conditions optimized, we investigated the scope of the reduc-
tive cyclization. A number of electronically unbiased 1,6-dienes (Figures S7–S20) un-
derwent cyclization in good yields (Figure 2; see also Figures S21–S65). In all cases,
270 Chem 3, 268–280, August 10, 2017

Figure 2. Substrate Scope
Isolated yields: unless specified, only 3,4-trans-product was observed. Solvent for 11, 18–21, and
23–25: acetone/iPrOH (5/1). Catalyst loading for 10, 20, 22, and 25 = 5 mol %. Catalyst loading for
21 = 10 mol %. NMR yield for 11 and 14: side products from the reduction and decomposition of the
substrates were not separated from the cyclized product. 25: after reduction with H2 in the
presence of Pd/C.
Chem 3, 268–280, August 10, 2017 271

A
B
Scheme 2. Synthetic Applications of trans-Selective Reductive Cyclization
(A) Derivation of trans-dimethyl-pyrrolidine 18 to pesticide 27 and selective estrogen receptor modulator 28.
(B) Synthesis of dimethyl gababutin derivative 36 via Ni-catalyzed reductive cyclization.
only trans-3,4-disubstituted products were observed. The substrate scope generally
resembles that of classic cycloisomerization reactions.10,11 The Thorpe-Ingold effect
is crucial to assist in the formation of cyclopentane derivatives.32 The conditions
tolerate a number of functional groups, including esters, acetals, and amines.
When a crotyl-substituted malonate was used, the cyclization proceeded with
slightly reduced reactivity to afford 14 in 59% yield. Substituents at the allylic posi-
tion could give rise to 2,3-diastereo-isomers on the basis of the relative positions of
the substituent and the methyl groups formed. This diastereoselectivity was depen-
dent on the size of the substituent, favoring 2,3-anti-diastereomers (15–17).
Cyclization of diallylamines was best performed in a mixture of acetone and iPrOH as
the solvent, giving rise to a variety of pyrrolidine derivatives (18–25). 3,4-Dimethyl-
pyrrolidine 18 formed in 15:1 diastereoselectivity, favoring the trans product. Substi-
tution on the olefin exhibited a modest inhibitory effect. Cyclization of a crotyl
substrate afforded pyrrolidine 19 in high yield, whereas bulkier substituents led to
reduced yields (20–22). In the preparation of pyrrolidine 21, both cis- and trans-
alkenes gave the desired product, but the cis-alkene exhibited higher reactivity.
Cyclization of a dicrotyl substrate generated trans-diethyl pyrrolidine 23 in 31%
yield, suggesting more difficult cyclization with two internal olefins. Cyclization of
a geminal-disubstituted olefin proceeded to afford trisubstituted pyrrolidine 24
with a quaternary carbon in 47% yield. When a cyclohexene derivative was used
as the substrate, the standard conditions gave a mixture of reductive and redox-
neutral cyclization products in a 1:1 ratio, which was then converted to the single dia-
stereomer 25 upon hydrogenation.
Applications
The current reductive coupling reaction found appealing applications in preparing
bioactive molecules. trans-Dimethyl-pyrrolidine product 18 can be readily depro-
tected to generate trans-3,4-dimethylpyrrolidine 26, which serves as the precursor
to pesticide 2733 and selective estrogen receptor modulator 28 (Scheme 2A).19 Pre-
vious methods to prepare 18 require multiple steps from the commercially available
dimethylmaleic anhydride 29, and give a mixture of cis and trans diastereomers.34 In
contrast, our cyclization reaction provides exclusive access to the trans diaste-
reomer. The volatile nature of 26 prompted us to treat it with acid after deprotection
272 Chem 3, 268–280, August 10, 2017

Figure 3. Kinetic Profile of the Cyclization of 1 to Form 2
Data were collected with 1H NMR spectroscopy. Conditions: [1]0 = 167 mM, [Et2SiH2]0 = 333 mM,
[5] = 8.3 mM (5 mol %), solvent = acetone-d6 (0.5 mL) + iPrOH-d8 (0.1 mL), temperature = 50ꢀC,
internal standard = mesitylene.
and purify it via recrystallization (Figures S66 and S67). Resolution methods are
readily available to separate the two enantiomers of 26.34
The (R,R) enantiomer of gababutin derivative 36 exhibits superior efficacy toward
relieving neuropathic pain and anxiety in in vivo models (Scheme 2B).18 The previous
synthesis required 13 steps with less than 14% overall yield. The chiral centers were
established in the first step with (À)-menthol as a chiral auxiliary.18 Our reductive
cyclization enables the construction of the 3,4-dimethyl cyclopentane structure 32
from the easily accessible a,a-diallyl-butyrolactone 31 in 78% yield. Ring opening
of the lactone 32 with ammonia gives amide 33 in 68% yield (88% yield on the basis
of the recovered starting material). The 1,3-amino alcohol 34 undergoes dehydro-
genative amide formation in the presence of a 10% Ru catalyst35 to form pyrrolidone
35 in 93% yield. Alternatively, straightforward protection of the amine by Boc2O,
followed by oxidation of the alcohol by pyridinium dichromate (PDC) and deprotec-
tion of the amine, gives 35 in 86% yield over three steps (Figures S68–S79). The ring
opening of 35 by acid to form 36 has been established in the previous synthetic
work.18 We anticipate that racemic 36 could be readily resolved to provide both
enantiomers, which are both valuable for drug discovery.36
Mechanistic Studies
Catalyst 5 displays a high chemoselectivity for reductive cyclization, as opposed to
redox-neutral cycloisomerization. In addition, the reaction exhibits high diastereo-
selectivity favoring formation of the trans-disubstituted products. We conducted
studies in order to elucidate the mechanistic reasons for this observed selectivity.
Monitoring the conversion of 1 to 2 by in situ 1H nuclear magnetic resonance
(NMR) spectroscopy resulted in a linear time course (Figure 3), revealing that the re-
action rate was independent of [1] and [Et2SiH2]. We attempted to determine the
kinetic isotope effect with Et2SiD2, but the measurements were complicated by
H/D scrambling of the silane reagent with the protic solvent and the isopropyl
groups of the ligand via cyclometallation, resulting in partial deuterium incorpora-
tion to the methyl groups of 2 (Figures S2 and S3). Such cyclometallation is
commonplace in transition-metal-catalyzed hydrogenation and hydrosilylation
reactions.37
Chem 3, 268–280, August 10, 2017 273

Figure 4. X-Band EPR Spectrum of the Reaction Mixture of 1 Catalyzed by 5
Temperature = 10 K, solvent = acetone/iPrOH (5/1). Spectroscopic parameters: gx = 2.38, gy = 2.34,
gz = 2.00, Axx = 5 MHz, Ayy = 93 MHz, Azz = 11 MHz. Microwave frequency = 9.380 GHz, power = 0.25
mW, modulation amplitude = 1 mT/100 kHz.
During the course of the reaction, we observed broad 1H resonances corresponding
to the catalyst resting state. When the catalytic reaction was frozen, the electron
paramagnetic resonance (EPR) spectrum showed a Ni-centered radical (Figure 4).
The reaction catalyzed by (Bna-diimine)NiIIBr2 7 (Figure 3, entry 7) also displayed a
Ni radical signal upon freezing (Figure S1). Analyzing the crude reaction mixture re-
vealed that Et2SiH(OCH(CF3)2) and Et2SiH(OiPr) were the resulting silane products
when reactions were conducted in HFIP and an acetone/iPrOH mixture, respectively.
The presence of S = 1/2 Ni species, as characterized by EPR spectroscopy, prompted
us to isolate possible paramagnetic Ni intermediates. We reasoned that a Ni(I)-alkyl
complex could be present. We prepared (a-diimine)Ni(I)Bn 37 by taking advantage
of stabilization by a cyclohexyl backbone.38 Addition of Et2SiH2 to complex 37 re-
sulted in an immediate formation of toluene (Figure 5A). When Et2SiD2 was used,
the reaction resulted in mono-deuterated toluene. An alternative pathway for
product formation involves the protonation of Ni(I)-alkyl species by protic solvents
to form toluene and a Ni-alkoxyl complex. To verify this pathway, we dissolved com-
plex 37 in a mixture of acetone-d6 and iPrOH-d7 in a 5/1 ratio. At 50ꢀC, no toluene
was formed in 30 min (Figure 5A).
Single-crystal X-ray diffraction established that complex 37 was stabilized by the
h3-coordination of the benzyl ligand (Figure 5B). Density functional theory (DFT)
calculations on the electronic structure of 37 with the use of the ORCA package39
suggest that the majority of the spin density is delocalized on the a-diimine ligand
(Figure 5C). This assignment is corroborated by its EPR spectrum, which exhibits
an isotropic signal at 22ꢀC with a giso value of 2.00 (Figure 5D). The superhyperfine
splitting patterns are due to the coupling of the radical with the N (I = 1) and a-H
(I = 1/2) atoms of the ligand. Thus, the electronic structure of 37 is best described
by its valence tautomer 38, featuring a Ni(II) center with a radical delocalized on
the redox-active a-diimine ligand (Figures 5A).40,41
274 Chem 3, 268–280, August 10, 2017

Figure 5. Isolation and Characterization of Possible Ni(I) Intermediate 37
(A) Reactivity of 37 toward Et2SiH2.
(B) Single-crystal X-ray structure of 37. Atom thermal ellipsoids were shown at the 50% probability level. Hydrogen atoms are omitted for clarity.
(C) Mulliken spin-density plot of 37 according to DFT calculations.
(D) X-band EPR spectrum of 37 at 22ꢀC. Spectroscopic parameters: giso = 2.003, A(N) = 14.5 MHz, A(H) = 23.5 MHz. Microwave frequency = 9.720 GHz,
power = 0.63 mW, modulation amplitude = 1 mT/100 kHz.
Gaussian DFT calculations on possible Ni(III) intermediates converged to square
pyramidal complex 39 (Figure 6), in which the hydride and silyl groups are trans to
each other. The spin-density plot calculated with the ORCA package39 clearly shows
a Ni-centered radical. Calculation of the EPR spectrum of complex 39 resulted in g
tensors of gx = 2.29, gy = 2.24, and gz = 2.03 and an Aiso value of 32.2 MHz.
In order to distinguish two-electron pathways from an HAT mechanism, we prepared
radical clock 40 (Figures S80–S87).42 Reductive cyclization of 40 generated the cy-
clized product 41 in 30% isolated yield, accompanied by reduced products 42 and
43 (Figure 7A; see also Figures S4, S5, and S88–S93). We attribute this side reaction
to the steric hindrance created by the cyclopropyl substituent that inhibited cycliza-
tion. Importantly, the cyclopropyl group underwent no ring opening, even when the
adjacent C=C double bond was reduced in 43. It is also possible that the reductive
coupling proceeds via a classic cycloisomerization, followed by reduction of the un-
saturated intermediate. We prepared the correspondingly exo-methylene product
45 and subjected it to our standard conditions (Figure 7B). In HFIP, internal cyclopen-
tene was formed as the major product via migration of the C=C double bond, and
cyclopentanes formed in a 2:1 cis/trans mixture as minor products via reduction
(Figure S6). In a mixture of acetone and iPrOH, no reaction was observed.
DISCUSSION
Origin of trans Diastereoselectivity
Several reasonable pathways can be proposed for the reductive cyclization of dienes
(Scheme 3). Tandem cycloisomerization and reduction is expected to generate the
Chem 3, 268–280, August 10, 2017 275

Figure 6. Geometry Optimization and Spin-Density Plot of Possible Ni(III) Intermediate 39
According to DFT Calculations
cis product (Scheme 3A). A control experiment in which the cycloisomerization prod-
uct 45 was subjected to the reductive conditions led to olefin migration as the major
product (Figure 7B) and ruled out this pathway. Cycloaddition of the diene with Ni
forms a metallocycle, followed by reduction with Et2SiH2 to afford the reductive cycli-
zation product (Scheme 3B). This cycloaddition mechanism, however, would give rise
to the cis diastereomer, as determined previously with Ni43 and other metals.8
HAT pathways via organic radical intermediates have been invoked in recent olefin
coupling reactions.14,25,44 Cyclization of diene 1 with Fe led to a mixture of cis and
trans diastereomers, with a preference for the cis isomer (Figure 1, entry 1). The
formation of the cis product with Fe corroborates previous studies of radical cycliza-
tion14,45 and provides circumstantial evidence to exclude a radical cyclization
pathway for this Ni system (Scheme 3C). In addition, results from radical clock 40
confirmed the absence of an organic radical intermediate (Figure 7A). Formation
of the reduced products 42 and 43 suggests that hydride transfer occurs prior to
cyclization, as opposed to formation of a radical intermediate. The observed trans
diastereoselectivity is consistent with a classic, organometallic pathway proceeding
via hydride insertion,46 followed by reinsertion to the second olefin and reductive
cleavage of the Ni–C bond by Et2SiH2 (Scheme 3D). Previous studies in the context
of cycloisomerization reveal that the hydride insertion pathway favors formation of
trans products.47,48
Figure 7. Mechanistic Study of Ni-Catalyzed Reductive Cyclization
(A) Reaction of radical clock 40 under standard conditions.
(B) Control experiment of cycloisomerization product 45 under reductive cyclization conditions.
276 Chem 3, 268–280, August 10, 2017

A
B
C
D
Scheme 3. Mechanistic Pathways for Ni-Mediated Reductive Cyclization of 1,6-Diene
Proposed Catalytic Cycle
The trans diastereoselectivity and the radical clock experiment described above pro-
vide support for a classic, organometallic mechanism. Our experimental data are
consistent with the catalytic cycle shown in Scheme 4, in which formal oxidation
states of the Ni intermediates are shown for clarity. Activation of the dimeric catalyst
5 by Et2SiH2 gives rise to Ni-H 46, which inserts into the diene substrate, followed by
reinsertion to form Ni(I)-alkyl intermediate 48. Oxidative addition of Et2SiH2 gener-
ates a Ni(III) intermediate 39, which undergoes reductive elimination to form the 3,4-
disubstituted cyclic product and Ni-silyl 49. Ni(I)-H 46 is regenerated by the reaction
of Ni-silyl intermediate 49 with the protic solvent, HFIP or iPrOH. The formation of
the silyl ether by-product is evident after the reaction by NMR spectroscopy.
Analysis of the electronic structure of Ni(I) complex 37 suggests that the a-diimine
ligand is redox active, giving a Ni(II) center with an organic radical delocalized to
the a-diimine ligand. This assignment is consistent with the EPR spectrum of 37,
showing an organic radical at 22ꢀC (Figure 5C). In contrast, the frozen catalytic reac-
tion displays an S = 1/2 Ni species as a rhombic signal at 10 K (Figure 4). The features
of the EPR spectrum resemble that of the Ni(III) complexes reported previously49–53
and are consistent with the calculated EPR spectrum of Ni(III) intermediate 39 (Fig-
ure 6). Comparing the EPR spectrum of the catalyst resting state with those of known
compounds suggests that the catalyst resting state is a Ni(III) species. This assign-
ment is corroborated by the zero-order kinetic dependence on [diene] and [Et2SiH2].
Thus, the turnover-limiting step is the reductive elimination of Ni(III) 39 that occurs
after the insertion of the diene and addition of Et2SiH2. When (Bna-diimine)NiBr2 7
was used, the frozen reaction mixture exhibits a Ni radical (Figure S1), suggesting
Chem 3, 268–280, August 10, 2017 277

Scheme 4. Proposed Catalytic Cycle of Ni(I)-Catalyzed Reductive Cyclization of 1,6-Dienes
that the Ni(II) precursors can be activated to access Ni(I) intermediates during the re-
action. Such a catalyst activation process has been observed recently in the context
of hydrosilylation.54
Origin of Chemoselectivity for Reductive Cyclization
The chemoselectivity of reductive cyclization in relation to cycloisomerization arises
from the Ni(I)/Ni(III) catalytic cycle. The electron-rich, formal Ni(I) intermediate 48 un-
dergoes rapid oxidative addition with Et2SiH2, which outcompetes b-H elimination
to form the unsaturated cycloisomerization product 51 (Scheme 4). This chemoselec-
tivity sharply distinguishes the Ni(I) catalyst from previous Ni(II) catalysts,10,11 which
favor b-H elimination rather than reaction with silanes. In addition, the lack of b-H
elimination prevents possible olefin isomerization, which could lead to scrambling
of the stereocenters.10,11 Characterization of the electronic structure of 37 reveals
that the redox-active a-diimine ligand plays an important role in stabilizing Ni(I) in-
termediates, such as 48, by forming its valence tautomer 50. The dtbpe ligand lacks
conjugated p* orbitals to delocalize the radical on Ni and therefore exhibits lower
reactivity than a-diimine ligands (Figure 1, entry 8).
Conclusion
We developed a Ni-catalyzed reductive cyclization reaction of 1,6-dienes and diallyl-
amines to form trans-3,4-disubstituted cyclopentane and pyrrolidine derivatives
with high diastereoselectivity. This cyclization reaction has found applications in
the preparation of biologically active molecules. The trans diastereoselectivity arises
from a classic organometallic catalytic cycle mediated by Ni(I) and Ni(III) intermedi-
ates. The trans diastereoselectivity distinguishes this reaction from HAT and cyclo-
addition pathways, which favor cis products. The electron-rich Ni(I) intermediate is
278 Chem 3, 268–280, August 10, 2017

stabilized by the redox-active a-diimine ligand, and is responsible for the chemose-
lectivity toward reductive cyclization, as opposed to redox-neutral cycloisomeriza-
tion observed with previous Ni(II) catalysts. The distinct reactivity of (a-diimine)
Ni(I) highlights the power of ligand control in achieving unprecedented selectivity
in organic transformations.
EXPERIMENTAL PROCEDURES
Detailed experimental procedures are provided in the Supplemental Information.
ACCESSION NUMBERS
Crystallographic data have been deposited in the Cambridge Crystallographic Data
Center (CCDC) under accession numbers CCDC: 1548657 for 5 and 1548656 for 37.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, 93 fig-
ures, and 2 data files and can be found with this article online at http://dx.doi.org/10.
1016/j.chempr.2017.07.010.
AUTHOR CONTRIBUTIONS
Y.K., D.A., and F.M. performed the experiments. J.K. conducted the DFT calcula-
tions of intermediate 39. S.H. performed the EPR characterization of compound
32. T.D. supervised the project and wrote the manuscript.
ACKNOWLEDGMENTS
We thank Nadia Leonard (Chirik lab, Princeton University) and Prof. Steven Greenbaum
(Hunter College) for assisting with recording EPR spectra, Dr. Chunhua Hu for solving
the crystal structures of 5 and 37, and Prof. Carsten Milsmann (University of West Vir-
ginia) for helpful discussions. Financial support was provided by the American Chemical
Society Petroleum Research Fund (56568-DNI3) and New York University.
Received: May 17, 2017
Revised: June 24, 2017
Accepted: July 20, 2017
Published: August 10, 2017
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