The discovery of [Ni(NHC)RCN]2 species and their role as cycloaddition catalysts for the formation of pyridines

Article abstract of DOI:10.1021/ja3075924

The reaction of Ni(COD)₂, IPr, and nitrile affords dimeric [Ni(IPr)RCN]₂ in high yields. X-ray analysis revealed these species display simultaneous η¹- and η²-nitrile binding modes. These dimers are catalytically competent in the formation of pyridines from the cycloaddition of diynes and nitriles. Kinetic analysis showed the reaction to be first order in [Ni(IPr)RCN]₂, zeroth order in added IPr, zeroth order in nitrile, and zeroth order in diyne. Extensive stoichiometric competition studies were performed, and selective incorporation of the exogenous, not dimer bound, nitrile was observed. Post cycloaddition, the dimeric state was found to be largely preserved. Nitrile and ligand exchange experiments were performed and found to be inoperative in the catalytic cycle. These observations suggest a mechanism whereby the catalyst is activated by partial dimer-opening followed by binding of exogenous nitrile and subsequent oxidative heterocoupling.

Full text of DOI:10.1021/ja3075924

Article
pubs.acs.org/JACS
The Discovery of [Ni(NHC)RCN]2 Species and Their Role as
Cycloaddition Catalysts for the Formation of Pyridines
Ryan M. Stolley, Hung A. Duong, David R. Thomas, and Janis Louie*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850, United States
S
* Supporting Information
ABSTRACT: The reaction of Ni(COD)2, IPr, and nitrile
affords dimeric [Ni(IPr)RCN]2 in high yields. X-ray analysis
revealed these species display simultaneous η1- and η2-nitrile
binding modes. These dimers are catalytically competent in the
formation of pyridines from the cycloaddition of diynes and
nitriles. Kinetic analysis showed the reaction to be first order in
[Ni(IPr)RCN]2, zeroth order in added IPr, zeroth order in nitrile, and zeroth order in diyne. Extensive stoichiometric
competition studies were performed, and selective incorporation of the exogenous, not dimer bound, nitrile was observed. Post
cycloaddition, the dimeric state was found to be largely preserved. Nitrile and ligand exchange experiments were performed and
found to be inoperative in the catalytic cycle. These observations suggest a mechanism whereby the catalyst is activated by partial
dimer-opening followed by binding of exogenous nitrile and subsequent oxidative heterocoupling.
INTRODUCTION
■
Because of the prevalence of pyridine-containing molecules in
nearly all aspects of the chemical sciences,1 the ability to
selectively synthesize structurally diverse pyridine-containing
molecules is paramount. Transition-metal catalyzed methods to
prepare pyridine cores have become a significant synthetic
route as they hold the potential to access highly functionalized
pyridines in a simplistic and atom-economical fashion.2
A
handful of transition metals have demonstrated the ability to
cocyclize alkynes and nitriles to make pyridines catalytically.
Specifically, Co,3 Ru,4 and Rh5 have received considerable
attention. More recently, we and others have developed new
Ni,6 Fe,7 and Ir8 complexes that are able to catalyze pyridine
formation.
Our discovery that a Ni/NHC (NHC = N-heterocyclic
carbene) catalyst couples alkynes and nitriles to afford
pyridines6a is remarkable for a number of reasons: (1) Ni
complexes readily catalyze the trimerization of alkynes (even in
the presence of excess nitrile, eq 1);9 (2) Ni complexes readily
A cursory look into the possible mechanism of Ni-catalyzed
cycloaddition raises even more questions. Of the above-
mentioned transition metals, the cobalt-catalyzed mechanistic
pathway is the most thoroughly studied and is believed to
proceed through a homocoupling pathway, that is, Co
undergoes oxidative homocoupling of the two alkynes before
inserting the nitrile, with subsequent reductive elimination
affording the desired product (Scheme 1).3,12 While consid-
erably less studied, the reactions catalyzed by Ru and Rh are
believed to undergo a similar homocoupling mechanis-
m.4a,b,5a,12 In contrast, Ni-mediated pyridine formation appears
to follow a different route. Stoichiometric reactions of alkynes
and azanickelacycles (prepared from transmetalation between
an azazirconacyclopentenone and Ni(PPh3)2Cl2)13 afford
highly substituted pyridines suggesting that heterocoupling
between a nitrile and an alkyne, rather than homocoupling of
two alkynes, is the initial step (eq 4). Yet, the oxidative coupling
of an alkyne and a nitrile is sluggish at best for Ni,9 and an
isolable azanickelacycle has yet to be discovered (unlike other
heteronickelacycles).
undergo oxidative addition of R−CN bonds (eq 2);10 (3) Ni
complexes are known to cause homodimerization of nitriles;9
and, perhaps most intriguingly, (4) Ni complexes catalyze a
completely different reaction between alkynes and nitriles,
namely, the carbocyanation of alkynes (eq 3).11 Despite these
potential obstacles, the Ni/NHC catalyst efficiently converts a
variety of nitriles and diynes into pyridines in generally high
yields.
Further anecdotal evidence of an alternate oxidative
heterocoupling pathway in the nickel-catalyzed system arises
Received: August 1, 2012
Published: August 23, 2012
© 2012 American Chemical Society
15154
dx.doi.org/10.1021/ja3075924 | J. Am. Chem. Soc. 2012, 134, 15154−15162

Journal of the American Chemical Society
Article
resulting from the stoichiometric reaction between Ni(NHC)
complexes and nitrile. Herein, we report the synthesis and
characterization of these Ni dimers and their role in catalytic
pyridine formation.
Scheme 1. Divergent Pathways for Alkyne/Nitrile
Cycloaddition
RESULTS
■
Synthesis of [Ni(IPr)RCN]2 Species. The reaction of
Ni(COD)2, IPr, and acetonitrile (1:1:1 equiv) in C6D6 was
observed in situ by H NMR spectroscopy and revealed clean
1
displacement of the COD ligands by IPr and nitrile to form a
new complex (IPr = 1,3-bis-(2,6-diisopropylphenyl)imidazol-2-
1
ylidene). Interestingly, relative intensities of H resonances
indicated a complex in which the ratio of IPr to acetonitrile was
1:1. A larger scale reaction between equivalent amounts of
Ni(COD)2, IPr and acetonitrile in hexane or pentane at room
temperature afforded 3a as a red precipitate in 76% yield (eq
5).
from the observed regioselectivity of the nickel-catalyzed
cycloaddition of unsymmetrical diynes and nitriles (Scheme
2).6 If a homocoupling pathway were operative, the observed
Scheme 2. Observed Regioselectivity in Ni/SIPr Catalyzed
Cycloaddition
A single-crystal X-ray structure of 3a was obtained (Figure 1)
wherein 3a was found to be an unexpected dimeric species in
which one nitrile is bound to two Ni atoms in both η1- and η2-
binding modes. Importantly, an N−C bond length of 1.226(3)
Å was observed. This, along with a stretching frequency of 1757
cm−1, is indicative of an N−C double bond of an η2-bound
nitrile.10,17 The Ni−N and Ni−C bond lengths are similar to
regiochemistry would dictate that insertion of the nitrile would
require insertion from the sterically least-accessible face of
intermediate 1. Alternatively, in order to minimize negative
substrate/ligand steric interaction, heterocoupling of the bulky-
substituted alkyne with the nitrile would result in the observed
regioselectivity (intermediate 2). This regioselectivity trend has
also been observed in the Ni/NHC-catalyzed coupling of
alkynes and aldehydes14 (as well as isocyanates15). Using DFT
studies, Montgomery and Houk found that regioselectivity is
primarily controlled by the steric hindrance at the region of the
ligand closest to the alkyne. Analysis of steric contour maps of
NHC ligands demonstrated that the regioselectivities are
directly affected by the shape and orientation of the N-
substituents on the ligand.16
Figure 1. Ortep plot of 3a at the 30% probability level. Hydrogen
atoms omitted for clarity. Pertinent bond lengths include: Ni(1)−
C(28): 1.854 Å, Ni(1)−C(15): 1.8677 Å, Ni(1)−N(3): 1.9523 Å,
Ni(1)−N(3)_3: 1.9951 Å, N(3)−C(28): 1.226 Å. Pertinant bond
angles include: C(28)−Ni(1)−C(15): 120.29°, C(28)−Ni(1)−N(3):
37.37°, C(15)−Ni(1)−N(3)_3: 132.83°,N(3)−Ni(1)−N(3)_3:
95.37°, N(3)−C(28)−C(29): 134.6°.
Given the ambiguity surrounding the success of Ni-catalyzed
pyridine formation, we initiated a mechanistic investigation of
these cycloaddition reactions of alkynes and nitriles. We
discovered an interesting nitrile-bound Ni(NHC) dimer
15155
dx.doi.org/10.1021/ja3075924 | J. Am. Chem. Soc. 2012, 134, 15154−15162

Journal of the American Chemical Society
Article
those of analogous phosphine bound nickel−nitrile complex-
es.17b,c However, the Ni−C15 bond length of 3a is significantly
shortened (1.8677 vs 2.1−2.2 Å) compared to previously
reported Ni−NHC bonds.18 Interestingly, the double hapticity
of the nitriles has been observed with only select transition
metals17a and, to the best of our knowledge, has only been
observed for nickel in tetranuclear species.17 Importantly,
Signer analysis19 confirmed that 3a exists as a dimer in solution
(MW = cald. 978.7; obsd 961.9 100) as well as the solid state.
Dimers 3b−3e were prepared in a similar synthetic protocol
from the requisite nitrile. The structure of 3c is shown in Figure
2. Not surprisingly, the Ni−C and N−C bond lengths are
Stoichiometric [2 + 2+2] Cycloadditions. In contrast to
the high yields observed in dimer catalyzed reactions,
stoichiometric reactions between equimolar amounts of Ni
dimers and diynes produced pyridines in unexpectedly low
yields. However, when free nitrile was added, increased product
yields were observed. For example, when 1 equiv of diyne 4 was
added to dimer 3a, pyridine 5a was formed in 30% yield (eq 7,
Table 1. Pyridine Yields from Stoichiometric Cycloaddition
a
Reactions
yield of 5 (no
b
yield of 5 (w/1 equiv
b
entry
R
added RCN)
RCN added)
1
2
3
4
5a, R = Me
30%
34%
35%
31%
64%
91%
96%
63%
5b, R = Ph
5c, R = 4-CF3-C6H4
5d, R = 4-MeO-C6H4
a
Dimer 3 (1 equiv), diyne 4 (1 equiv), w/and w/out nitrile, C6D6, 23
Figure 2. Ortep plot of 3c. Hydrogen atoms are omitted for
clarity.Pertinent bond lengths include: Ni(1)−C(28): 1.857 Å, Ni(1)−
C(15)-1.895 Å, Ni(1)−N(3): 1.974 Å, Ni(1)−N(4): 1.982 Å, N(3)−
C(28): 1.223 Å. Pertinant bond angles include: C(28)−Ni(1)−C(15):
119.48°, C(28)−Ni(1)−N(3): 37.08°, C(15)−Ni(1)−N(4): 109.50°,
N(3)−Ni(1)−N(4): 93.93°, N(3)−C(28)−C(29): 136.1°.
b
1
°C. Yields determined by H NMR spectroscopy.
Table 1, entry 1). Yet, when diyne 4 (1 equiv) was added to
dimer 3a in the presence of MeCN (1 equiv), pyridine 5a was
formed in 64% yield. The same phenomenon was observed in
reactions with dimer 3b and PhCN (34% vs 91% yield, entry
2), 3c and 4-CF3C6H4CN (35% vs 96%, entry 3), and 3d with
4-MeOC6H4CN (31% vs 63% yield, entry 4). Again, all yields
obtained in the presence of free nitrile compare favorably to
those obtained in our parent Ni(COD)2/SIPr catalyst system.6
Stoichiometric Cross-Cycloaddition Reactions. The
stoichiometric reaction of dimer 3a, diyne 4, and CD3CN
was also performed (eq 8). Surprisingly, the major pyridine
product (5ad) resulted from incorporation of CD3CN, the
exogenous nitrile, rather than the already bound acetonitrile.
similar to those seen in 3a; only the Ni−N bond was slightly
shorter (1.982 vs 1.995 Å). Attempts to form a dimer from
isobutyronitrile and other bulky nitriles were unsuccessful and
resulted in complex reaction mixtures.
[Ni(IPr)RCN]2-Catalyzed [2 + 2+ 2] Cycloadditions.
When dimers 3 were employed as catalysts for the cyclo-
addition of diynes and nitriles, the expected pyridine products
were obtained in good to excellent yields. Specifically, when
diyne 4 and acetonitrile were subjected to 5 mol % dimer 3a,
clean formation of pyridine 5a occurred (eq 6). Similarly, when
Other cross-cycloaddition combinations were evaluated to
determine whether preferred incorporation of the exogenous
nitrile was a general trend (eq 9). These results are summarized
aryl dimers 3b, 3c, and 3d were used as catalysts with PhCN, 4-
CF3C6H4CN, and 4-MeOC6H4CN, respectively, pyridines 5b−
5d were obtained. Importantly, all yields compare favorably to
those obtained in our parent Ni(COD)2/SIPr catalyst system
(SIPr = 1,3-bis-(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-
ylidene).6a
15156
dx.doi.org/10.1021/ja3075924 | J. Am. Chem. Soc. 2012, 134, 15154−15162

Journal of the American Chemical Society
Article
in Table 2. Upon examination, the exogenous, rather than the
dimer-bound (i.e., endogenous or internal), nitrile was the most
bound PhCN) was observed after full consumption of both
diyne and nitrile (entry 1). In the cases where MeCN was
supplied in heavy excess (10 equiv), significant amounts of
other Ni species were present as indicated by unknown
resonances in the 1H NMR spectrum (entries 3 and 7).
Presumably, these resonances can be attributed to a mixed Ni
dimer species (such as 3ab), although attempts to isolate these
mixed species thus far have been unsuccessful.
Table 2. Pyridine Yields and Product Ratios from
a,b
Stoichiometric Cross-Cycloaddition Reactions
yield of 5
(R1:R1)
postreaction dimer
species
entry dimer 3
R2CN (equiv)
1
2
3a
3b
3b
3b
3b
3c
3c
3C
3d
3d
PhCN (1)
84% (1:27)
74% (1:1.6)
67% (1:2.9)
93% (1:4.5)
95% (1:4)
3a
3b
Kinetic Analysis of the [Ni(IPr)MeCN]2-Catalyzed [2 +
2 + 2] Cycloaddition of Diyne 4 and MeCN. Using the
cycloaddition of diyne 4 and MeCN catalyzed by dimer 3a as a
model, pseudo-first-order kinetic analyses were used to
determine the substrate dependence of dimer, diyne, nitrile,
MeCN (1)
c
3
MeCN (10)
4-CF3-C6H4 (1)
4-MeO-C6H4 (1)
MeCN (1)
3b/3a
c
4
3b/3d
5
3b
c
6
63% (1:1.4)
91% (1:1.9)
96% (1:4.3)
69% (1:2.1)
99% (1:11)
3c
1
and IPr. All kinetic evaluations were performed via H NMR
c
c
,d
7
MeCN (10)
PhCN(1)
3c
3c
spectroscopy at 0 °C in toluene-d8 using either ferrocene or
1,3,5-trimethoxybenzene as an internal standard. Clean kinetics
revealed the reaction to be first-order in 3a and zeroth-order in
4, MeCN, and IPr (Figure 3).
8
9
MeCN (1)
3d
3d
10
PhCN (1)
a
Dimer 3 (1 equiv), diyne 4 (1 equiv), nitrile (1 equiv), C6D6, 23 °C.
b
Yields, product ratios, and postreaction dimer species determined by
c
1H NMR spectroscopy with ferrocene as an internal standard. Traces
of unknown Ni species were detected. Complex mixture of Ni
d
products were formed.
widely incorporated into the product. However, it is also worth
noting that the dimer-bound nitrile was incorporated into a
significant amount of product in some cases. Specifically, when
dimer 3b reacted with exogenous MeCN and diyne 4, 45%
pyridine product 5b, which incorporates the internal, Ni-bound
benzonitrile, was formed (entry 2). Notably, when the
exogenous MeCN was supplied in heavy excess (10 equiv),
the ratio of products changed only slightly (entry 2 vs entry 3,
1:1.6 vs 1:2.9). Similar trends were observed in reactions with
other aryl nitrile-bound dimers and exogenous MeCN (entries
6−7 and 9). Conversely, when exogenous PhCN reacted with
diyne 4 and dimer 3a, PhCN was almost exclusively
incorporated into the product (entry 1).
Figure 3. Plots of [3a] vs time, kobs vs [IPr], and kobs vs [MeCN] for
the cycloaddition of 4 at 0 °C in C7D8.
The stoichiometric cross-cycloaddition of diyne 4 and dimer
3b, which is ligated with PhCN, with electronically dissimilar 4-
CF3-PhCN and 4-MeO-PhCN were also carried out (entries 4
and 5). Surprisingly, the yields and product distributions were
nearly identical. That is, in both cases, the exogenous nitrile is
preferentially incorporated and afforded a mixture of pyridines
in ∼95% yield and in a 1:∼4 ratio (internal vs exogenous nitrile
incorporation). The high yields of pyridines 5c−5d obtained in
these cross-cycloaddition reactions are in stark contrast to the
individual catalytic and stoichiometric yields for these
respective nitriles (eq 7) where pyridine 5d was formed in
lower yields (31−63%). In almost every case where MeCN was
used as the exogenous nitrile, overall pyridine yields were
modest (compared to those employing only aryl nitriles) and
agreed with the pyridine yield from Ni(COD)2/SIPr-catalyzed
cycloaddition of 4 and MeCN. The one exception to this
observation was when 10 equiv of MeCN was used in the
reaction with 4 and 3c; a considerably higher yield was
observed (91%, entry 7). In addition to lower yields, lower
selectivity for the exogenous nitrile was observed when MeCN
was used as the exogenous nitrile.
Dimer Crossover and Ligand Exchange Experiments.
When equimolar amounts of 3a and 3b were combined in a
solution of benzene-d6 at room temperature, no detectable
amount of mixed dimer (i.e., 3ab)13 was observed after 1 h at
room temperature (eq 10).14
In contrast, a possible mixed-dimer species formed when a
sterically- and electronically equivalent nitrile was added to
dimer 3a (eq 11). That is, upon exposure of 3a to one
equivalent of CD3CN, 50% consumption of 3a was observed in
addition to the free, unligated MeCN after 1 h at room
temperature. The nature of the deuterated exchange-product
(3ac or 3ad) is unknown. Similar nitrile exchange was observed
when the more electrophilic benzonitrile was added to dimer 3a
(eq 12). Within minutes, 3b, 3a, and free acetonitrile, along
with resonances corresponding to an unknown species
Also summarized in Table 2, the identity of the dimer at the
end of the reaction was predominately the dimer that was
initially employed for the reaction. That is, when dimer 3a,
diyne 4, and PhCN were reacted (to form predominately
pyridine 5b), only dimer 3a (not dimer 3b which possesses
1
(presumably 3ab), were observed by H NMR spectroscopy
in the reaction of 3a with free benzonitrile at room
temperature. Complete exchange occurred in roughly an hour
15157
dx.doi.org/10.1021/ja3075924 | J. Am. Chem. Soc. 2012, 134, 15154−15162

Journal of the American Chemical Society
Article
Scheme 3. Possible Mechanistic Pathways for
[Ni(IPr)RCN]2-Catalyzed Cycloadditions
and a half. Conversely, a solution of 3b and acetonitrile
exhibited no exchange under the same conditions and the same
reaction time scale (eq 13), although a complex mixture was
observed after 3 h.
Unlike the nitrile exchange reactions, dimers 3a and 3b
displayed analogous reactivity toward free IPr ligand. When
either 3a or 3b were exposed to excess IPr-d2 in C6D6 at room
temperature, no ligand exchange was observed even after 3 h.
Similarly, no ligand exchange was observed in the reaction of
dimer 3a or 3b, excess IPr-d2, and 1 equiv of free nitrile
(acetonitrile or benzonitrile, respectively, eq 14). The
stoichiometric reaction of 3a, diyne 4, and MeCN was also
carried out in the presence of IPr-d2 (1−5 equiv) Upon
completion of the cycloaddition reaction, no ligand exchange
was observed (eq 15).
reductive elimination. Alternatively, in order to generate an
open coordination site, IPr ligand could occur (pathway B or
C). Pathway B involves initial alkyne binding followed by
partial dimer dissociation and oxidative coupling of the
proximal nitrile thereby generating an open dimeric species
3LL. Nitrile and/or IPr-facilitated reductive elimination then
regenerates the dimer. Pathway C, on the other hand, involves
initial nitrile binding subsequent to ligand loss. This externally
bound nitrile (i.e., of an exogenous nitrile) then undergoes
oxidative coupling and insertion on the “outside” of the dimer
DISCUSSION
■
At the onset of our research, four reasonable and relatively
simplistic mechanisms were proposed (Scheme 3). The most
straightforward pathway, A, begins with an initial dimer
dissociation to an active monomeric form 3mon. Following
dissociation, we envision alkyne binding followed by sub-
sequent oxidative coupling, alkyne insertion, and, finally,
15158
dx.doi.org/10.1021/ja3075924 | J. Am. Chem. Soc. 2012, 134, 15154−15162

Journal of the American Chemical Society
Article
species (3out). In an entirely different process, an alternative
pathway (pathway D) is initiated by an incomplete dissociation
or dimer opening (3open). Alkyne binding onto the open dimer
followed by IPr loss then leads to oxidative coupling with an
internally bound nitrile. Nitrile/IPr facilitated reductive
elimination then regenerates the dimer.
Scheme 5. Modified Pathway A″
Systematic Evaluation of the Proposed Mechanistic
Pathways. Pathway A. Mechanistically, we initially surmised
pathway A was the operative pathway as it is the most simplistic
and straightforward. However, the kinetic evaluation of the
cycloaddition of 4 and MeCN catalyzed by 3a revealed the rate
of cycloaddition depended solely on the concentration of dimer
(i.e., a first-order dependence of dimer 3a). This data reveals
that the dimer must be on the catalytic pathway (otherwise
autocatalytic behavior would be observed). Thus, in a modified
pathway A′ (Scheme 4), the dimer is the catalyst resting state
Scheme 4. Modified Pathway A′
with diyne 4 to afford 5b. Once pyridine 5b is formed, the only
reactants left are MeCN, and possibly free IPr. As such, dimer
3a or Ni(IPr)n would be formed in a detectable amount (i.e.,
∼14%). Yet, upon completion of the reaction, the only carbene
species present is from 3b, not 3a; no other species were
present. Generally, of the Ni-species present postreaction,
nitrile exchange products that arise through diyne-free nitrile
exchange were the only other observed products (eq 12 and
13).
The cross-cycloaddition of 3b with diyne 4 and both 4-CF3-
PhCN and 4-MeO-PhCN (Table 2, entries 4 and 5) provides
more evidence against a negligible amount of dimer
dissociation/degradation product as the active catalyst. Both
of these cross-cycloaddition reactions afforded comparable
pyridine yields and product ratios (i.e., similar amount of
exogenous nitrile incorporation). However, catalytic cyclo-
addition of 4-CF3-PhCN is higher yielding than 4-MeO-
PhCN (eq 6). As such, a small concentration of active 3bmon
catalyst would have produced higher amounts of 5c than 5d, in
agreement with the catalytic reactions, rather than the similar
yields observed. A similar phenomenon is observed in the
discrepancy between the observed effects of increasing the
equivalents of applied nitrile. In the cycloaddition of 3b, 4, and
10 equiv of MeCN (Table 2, entry 3), a mild decrease in yield
and a 2-fold increase in selectivity for MeCN were observed.
This is contrary to the cycloaddition of 3c, 4, and 10 equiv of
MeCN (Table 2, entry 7) where a significant increase in yield
and only mild increase in selectivity were observed.
Lastly, if a negligible amount of dimer 3 degrades into an
active catalyst (e.g., not necessarily 3mon), the incorporation of
exogenous nitrile would be directly related to the stability of the
dimer. That is, faster dimer degradation would result in more
exogenous nitrile incorporation. Thus, product ratios would
suggest a dimer stability trend of 3a < 3d < 3b ≈ 3c where 3a is
the least stable since it incorporates the most exogenous nitrile
(Table 2). However, qualitative measurement of the decom-
position of the dimers displayed the opposite relative stabilities
(3a ≫ 3d > 3b ≈ 3c) where 3a was the most stable to
decomposition.
and dimer dissociation is rate limiting. The observed
irreversibility may be attributed to the high activity of the
monomer (3mon). However, as seen in the stoichiometric
reactions of dimers 3a−3d with diyne 4, added nitrile is
required for optimal yield (Table 1, eq 7). If dissociation were
operative, one would expect complete consumption of dimer
and high pyridine yields without the need for additional nitrile.
In addition, each of these stoichiometric cycloaddition reactions
(without added nitrile, eq 7) afforded pyridines in comparable
yields despite considerable differences in their reactivity (i.e., 3a
< 3b) suggesting that catalyst degradation products that may
facilitate homodimerization of diyne 4 (at a faster rate than
cycloaddition)20 do not account for the added nitrile
requirement. Furthermore, if dimer to monomer dissociation
were operative, dimer crossover would be expected, yet no
cross over is observed even in trace amounts (eq 10).
An alternative possibility that still includes dimer-to-
monomer dissociation involves generation of a small amount
of catalytically active monomer from catalytically inactive dimer
(Pathway A″, Scheme 5). At first glance, assuming dimer
degradation to monomer 3mon was first order and much slower
than cycloaddition, such a mechanism would account for (1)
the lack of dimer crossover observed (eq 10), (2) the observed
dimer species at the end of the cycloaddition reaction (i.e., the
original dimer is almost always observed), and (3) the selective
incorporation of the exogenous nitrile. However, several
stoichiometric cross-cycloaddition reactions rule out this
possibility. For example, the reaction of dimer 3b, diyne 4,
and MeCN affords the phenyl-substituted pyridine 5b in 28%
yield (Table 2, entry 2). To accommodate this yield, at least
14% of the applied dimer 3b must dissociate to 3bmon and react
Taken together, our data suggest the dissociative pathway A
(or A′) is not operative.
Pathways B and C. Just as with pathway A, pathways B and
C are also straightforward to envision. With exclusive first-order
dependence in dimer for the cycloaddition reaction, IPr loss
must be rate-determining if either pathway (B or C) were
operative. However, when both 3a and 3b were individually
15159
dx.doi.org/10.1021/ja3075924 | J. Am. Chem. Soc. 2012, 134, 15154−15162

Journal of the American Chemical Society
Article
treated with IPr-d2 (eq 14), no ligand exchange was observed.
Additionally, no ligand exchange occurred when either 3a or 3b
were treated with IPr-d2 in the presence of the requisite nitrile.
Furthermore, no ligand exchange occurred when 3a or 3b were
used in the cycloaddition of diyne 4 and nitrile in the presence
of excess IPr-d2 (eq 15). As such, the lack of observable ligand
exchange in conjunction with our kinetic data rule out pathways
B and C.
than almost exclusive formation of 5b (Table 2, entry 1). Our
other cross-cycloaddition reactions further highlight this
discrepancy. If incorporation of the exogenous nitrile were
explained solely through nitrile exchange, a higher incorpo-
ration of 4-CF3-PhCN relative to 4-MeO-PhCN (since 4-CF3-
PhCN exchanges more readily than 4-MeO-PhCN) would be
expected. Instead, equal ratios of pyridine products are
observed when 3b, diyne 4, and either 4-CF3-PhCN or 4-
MeO-PhCN are reacted (Table 1, entries 4 and 5). As such, the
last of the initial mechanisms, pathway D, can be ruled out.
Pathway E. Although delineating a detailed mechanism of a
reaction with an early rate-determining step is difficult, our data
suggest a mechanism that does indeed involve partial dimer
opening. However, rather than subsequent reaction with alkyne,
nitrile binding immediately follows dimer opening since,
regardless of electronic bias, the exogenous nitrile is selectively
incorporated. Our kinetic data and all of our stoichiometric
reactions suggests a nitrile cycloaddition mechanism past dimer
opening that involves the following:
Pathway D. Given the congested nature of dimers 3, rate-
limiting partial dimer opening would allow for subsequent
substrate binding and reaction and would agree with our kinetic
data. Subsequent to rate-determining dimer opening, a
mechanism involving oxidative coupling and insertion of the
diyne followed by nitrile-assisted reductive elimination agrees
with not only with our kinetic data but our stoichiometric
analyses which showed the requirement of added nitrile for
high pyridine yield (eq 6). Nevertheless, our stoichiometric
cross-cycloaddition reactions rule out pathway D since this
pathway would provide pyridine products that incorporate the
internally bound nitrile, rather than the exogenous nitrile. For
example, in the reaction of MeCN-bound dimer 3a, diyne 4,
and PhCN, pyridine 5b (which incorporates exogenous PhCN)
is formed almost exclusively. However, in the reaction of
PhCN-bound dimer 3b, diyne 4, and MeCN, pyridines 5a
(which incorporates exogenous MeCN) and 5b are formed in
almost equally with a moderate preference for 5b (1:1.6, Table
2, entry 2). Furthermore, to account for these product
distributions, the reactivity of a mixed dimer intermediate
(3ab) would react one way in the first reaction (3abPh) but in
the opposite way in the latter reaction (3abMe, Scheme 6).
Alternatively, if we were to explain the exclusive formation of
5b through nitrile exchange, another contradiction would
occur. That is, initial nitrile exchange of 3a and PhCN would
result in the formation of 3b and MeCN. Yet, reaction of 3b
and MeCN (and diyne) afforded a mixture of products rather
1. Both of the initially bound, endogenous nitriles must
remain coordinated to the active catalyst throughout the
entire reaction. Upon dimer opening, two unique Ni-
coordination environments are formed (eq 16). One is a
two-coordinate (Ni2) and the other three-coordinate (Ni3).
Coordination of the external nitrile to Ni3 would occur in an η1-
fashion, owing to the congested steric-environment. As such, a
hapticity-shift would need to occur in the exogenous nitrile in
order for subsequent oxidative heterocoupling. This is
problematic in that selectivity for the exogenous nitrile would
then be lost; and product distributions would be dictated by
relative reactivities of the different nitriles, which is inconsistent
with the observed product ratios.
Scheme 6. Contradictory Reactivities of 3ab Required by
Pathway D to Account for Observed Product Ratios
Alternatively, coordination of exogenous nitrile would occur
at the less saturated Ni2 (eq 17). In this case, the internal (i.e.,
precoordinated) nitrile is in a unique η2 -μ-binding motif,
,1
which renders it inaccessible and/or unreactive. Thus, the
exogenous nitrile remains in a coordination environment
distinct from the internal nitrile. At this point, alkyne binding
leads to subsequent cycloaddition with the only reactive nitrile
available, namely the exogenous nitrile, thereby resulting in the
observed product distribution.
2. The catalyst maintains a bimetallic (or higher) motif.
To accommodate the required continuous coordination of both
initially bound, endogenous nitriles, a bimetallic complex is
necessary. As previously mentioned, if the dissimilar nitriles
ever occupy an equivalent coordination environment, either
simultaneously or stepwise, the reactivity would be dictated by
the relative reactivities of the nitriles themselves. In this context,
15160
dx.doi.org/10.1021/ja3075924 | J. Am. Chem. Soc. 2012, 134, 15154−15162

Journal of the American Chemical Society
Article
Notes
if the catalyst split into a monomeric form, all nitrile
coordination-modes, and subsequent product distribution,
would be dependent on the individual nitrile reactivities.
Only through secondary coordination (aside from direct
reaction) could nitrile resolution occur, in this case by
effectively tying-up the internal nitrile.
3. There may be competing pathways. Binding of an
exogenous nitrile appears to follow dimer opening followed by
cycloaddition. To account for the consistent incorporation of
the internal nitrile, however, a competing pathway(s) must also
be operative. Most likely, this arises through minimal nitrile
exchange to facilitate the required coordination chemistry for
cycloaddition.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH (GM076125) and NSF (0911017) for
financial support of this work. We thank Drs. J. Muller and A.
Arif for providing HRMS and X-ray spectroscopic data,
respectively.
REFERENCES
■
(1) For leading sources see: (a) Jones, G. Pyridines and Their
Benzoderivatives: Synthesis. In Comprehensive Heterocyclic Chemistry
II; Katritzky, A., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon:
Oxford, 1996; Vol. 5, p 167. (b) Alford, P. E. Six-Membered Ring
Systems: Pyridines and Their Benzo Derivatives. In Progress in
Heterocyclic Chemistry; Gribble, G. W., Joule, J. A., Eds.; Elsevier:
Oxford, 2011; Vol. 22, p 349. (c) Gonzalez-Bello, C.; Castedo, L. Six-
Membered Heterocycles: Pyridines. In Modern Heterocyclic Chemistry;
Alvarez-Builla, J., Vaquero, J. J., Barluenga, J., Eds.; Wiley-VHC:
Weinheim, 2011; Vol. 3, p 1431.
Taken together, a mechanism (Pathway E) that includes
these requirements is summarized in Scheme 7.
Scheme 7. Proposed Mechanism of [Ni(IPr)RCN]2-
Catalyzed Cycloaddition
(2) (a) Varela, J. A.; Saa,
Hapke, M. Chem. Soc. Rev. 2007, 36, 1085. (c) Henry, G. D.
Tetrahedron 2004, 60, 6043. (d) Varela, J. A.; Saa, C. Chem. Rev. 2003,
103, 3787.
́
C. Synlett 2008, 17, 2571. (b) Heller, B.;
́
(3) (a) Weng, C.-M.; Hong, F.-E. Organometallics 2011, 30, 3740.
(b) Dahy, A. A.; Koga, N. J. Organomet. Chem. 2010, 695, 2240.
(c) Kase, K.; Goswami, A.; Ohtaki, K.; Tanabe, E.; Saino, N.;
Okamoto, S. Org. Lett. 2007, 9, 931. (d) Wakatsuki, Y.; Yamazaki, H. J.
Chem. Soc., Chem. Comm. 1973, 8, 280. (e) Wakatsuki, Y.; Yamazaki,
H. J. Chem. Soc. Dalton 1978, 10, 1278. (f) Bonnemann, H.;
Brinkmann, R.; Schenkluhn, H. Synthesis. 1974, 8, 575. (g) Naiman, A.;
Vollhardt, K. P. C. Angew. Chem. 1977, 89, 758.
(4) (a) Yamamoto, Y.; Kinpara, K.; Ogawa, R.; Nishiyama, H.; Itoh,
K. Chem.Eur. J. 2006, 12, 5618. (b) Yamamoto, Y.; Kinpara, K.;
Saigoku, T.; Takagishi, H.; Okuda, S.; Nishiyama, H.; Itoh, K. J. Am.
Chem. Soc. 2005, 127, 605. (c) Yamamoto, Y.; Kinpara, K.; Nishiyama,
H.; Itoh, K. Adv. Synth. Catal. 2005, 347, 1913. (d) Yamamoto, Y.;
Ogawa, R.; Itoh, K. J. Am. Chem. Soc. 2001, 123, 6189. (e) Yamamoto,
Y.; Okuda, S.; Itoh, K. Chem. Commun. 2001, 1102. (f) Varela, J. A.;
In summary, a new class of Ni/nitrile/NHC dimers have
been isolated and characterized in an investigation of the
unique reactivity of Ni/NHC systems with nitriles. These
dimers were found to be catalytically competent in the [2 + 2 +
2]-cycloaddition of nitriles and diynes to form pyridines. While
initial hypotheses focused on a dimer-to-monomer dissociative
pathway, a first-order dependence solely on dimer, lack of
dimer-crossover, and poor stoichiometric yields in the absence
of free nitrile instead suggest a cycloaddition mechanism
involving partial dimer opening as the rate-determining step.
Immediate binding of an exogenous nitrile and subsequent
reaction with diyne led to pyridine product as deduced from
product ratios from competition reactions, ligand exchange
reactions, and final outcome of the nickel species post-
cycloaddition. Future work on this system will be focused on
computational experiments, which may aid in determining the
coordination environment of the Ni intermediates that form
after the rate-limiting step. In addition, recent success in in situ
mass spectrometric methods may also help elucidate the
structure of some complex intermediates.21
́
Castedo, L.; Saa, C. J. Org. Chem. 2003, 68, 8595.
(5) (a) Diversi, P.; Ermini, L.; Ingrosso, C.; Lucherini, A. J.
Organomet. Chem. 1993, 447, 291. (b) Tanaka, K.; Suzuki, N.; Nishida,
G. Eur. J. Org. Chem. 2006, 3917. (c) Tanaka, K.; Hara, H.; Nishida,
G.; Hirano, M. Org. Lett. 2007, 9, 1907. (d) Wada, A.; Noguchi, K.;
Hirano, M.; Tanaka, K. Org. Lett. 2007, 9, 1295.
(6) (a) McCormick, M. M.; Duong, H. A.; Zuo, G.; Louie, J. J. Am.
Chem. Soc. 2005, 127, 5030. (b) Tekavec, T. N.; Zuo, G.; Simon, K.;
Louie, J. J. Org. Chem. 2006, 71, 5834. (c) Stolley, R. M.; Maczka, M.
T.; Louie, J. Eur. J. Org. Chem. 2011, 3815. (d) Kumar, P.; Prescher, S.;
Louie, J. Angew. Chem., Int. Ed. 2011, 50, 10694.
(7) (a) D’Souza, B. R.; Lane, T. K.; Louie, J. Org. Lett. 2011, 13,
2936. (b) Wang, C.-X.; Li, X.-C.; Wu, F.; Wan, B.-S. Angew. Chem., Int.
Ed. 2011, 50, 7162. (c) Knoch, F.; Kremer, F.; Schmidt, U.; Zenneck,
U. Organometallics 1996, 15, 2713.
(8) (a) Weding, N.; Jackstell, R.; Jiao, H.; Spannenberg, A.; Hapke,
M. Adv. Synth. Catal. 2011, 353, 3423. (b) Onodera, G.; Shimizu, Y.;
Kimura, J.-N.; Kobayashi, J.; Ebihara, Y.; Kondo, K.; Sakata, K.;
Takeyuchi, R. J. Am. Chem. Soc. 2012, 134, 10515.
ASSOCIATED CONTENT
* Supporting Information
Full experimental details, spectral data, and X-ray data for 3a
and 3c. This material is available free of charge via the Internet
at http://pubs.acs.org.
(9) Eisch, J. J.; Ma, X.; Han, K. I.; Gitua, J. N.; Kruger, C. Eur. J. Inorg.
Chem. 2001, 1, 77.
(10) (a) García, J. J.; Jones, W. D. Organometallics 2000, 19, 5544.
(b) García, J. J.; Brunkan, N. M.; Jones, W. D. J. Am. Chem. Soc. 2002,
■
S
124, 9547. (c) García, J. J.; Arev
Organometallics 2004, 23, 3997. (d) Atesi
García, J. J.; Jones, W. D. Organometallics 2008, 27, 3811. (e) Schaub,
T.; Doring, C.; Radius, U. Dalton Trans. 2007, 20, 1993. (f) Wilting, J.;
́
alo, A.; Brunkan, N. M.; Jones, W. D.
̧
n, T. A.; Li, T.; Lachaize, S.;
AUTHOR INFORMATION
Corresponding Author
louie@chem.utah.edu
■
̈
Muller, C.; Hewat, A. C.; Ellis, D. D.; Tooke, D. M.; Spek, A. L.; Vogt,
̈
D. Organometallics 2005, 24, 13.
15161
dx.doi.org/10.1021/ja3075924 | J. Am. Chem. Soc. 2012, 134, 15154−15162

Journal of the American Chemical Society
Article
(11) (a) Nakao, Y.; Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2004, 126,
13904. (b) Nakao, Y.; Yada, A.; Ebata, S.; Hiyama, T. J. Am. Chem. Soc.
2007, 129, 2428. (c) Nakao, Y.; Yukawa, T.; Hirata, Y.; Oda, S.; Satoh,
J.; Hiyama, T. J. Am. Chem. Soc. 2006, 128, 7116.
(12) Dazinger, G.; Torres-Rodrigues, M.; Kirchner, K.; Calhorda, M.
J.; Costa, P. J. J. Organomet. Chem. 2006, 691, 4434.
(13) (a) Takahashi, T.; Tsai, F.-Y.; Kotora, M. J. Am. Chem. Soc.
2000, 122, 4994. (b) Takahashi, T.; Tsai, F. Y.; Li, Y.; Wang, H.;
Kondo, Y.; Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc.
2002, 124, 5059.
(14) (a) Tekavac, T. N.; Louie, J. Org. Lett. 2005, 7, 4037.
(b) Tekavac, T. N.; Louie, J. J. Org. Chem. 2008, 73, 2641.
(15) Duong, H. A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004,
126, 11438.
(16) (a) Liu, P.; Montgomery, J.; Houk, K. N. J. Am. Chem. Soc.
2011, 133, 6956. For related DFT studies of Ni(0)/Phosphine
systems see: (b) Liu, P.; McCarren, P. R.; Cheong, P. H.-Y.; Jamison,
T. F.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 2050. (c) McCarren, P.
R.; Liu, P.; Cheong, P. H.-Y.; Jamison, T. F.; Houk, K. N. J. Am. Chem.
Soc. 2009, 131, 6654.
(17) (a) Michelin, R. A.; Mozzon, M.; Bertani, R. Coord. Chem. Rev.
1996, 147, 299. (b) Bassi, I. W.; Benedicenti, C.; Calcaterra, M.;
Intrito, R.; Rucci, G.; Santini, C. J. Organomet. Chem. 1978, 144, 225.
(c) Walther, D.; Schonberg, H.; Dinjus, E. J. Organomet. Chem. 1987,
334, 377.
(18) (a) Matsubara, K.; Miyazaki, S.; Koga, Y.; Nibu, Y.; Hasimura,
T.; Matsumoto, T. Organometallics 2008, 27, 6020. (b) Danopoulos, A.
A.; Pugh, D. Dalton Trans. 2008, 30.
(19) (a) Signer, R. Liebigs Ann. Chem. 1930, 478, 246. (b) Zoellner,
R. W. J. Chem. Educ. 1990, 67, 714.
(20) Homodimerization of diyne 4 was observed in the crude
reaction mixture.
(21) (a) Takats, Z. W.; Wiseman, J. M.; Gologan, B.; Cooks, R. G.
Science 2004, 306, 471. (b) Perry, R. H.; Splendore, M.; Chien, A.;
Davis, N. K.; Zare, R. N. Angew. Chem., Int. Ed. 2011, 50, 250.
(c) Johansson, J. R.; Norden
2186.
́
, B. Proc. Natl. Acad. Sci. U.S.A. 2012, 109,
15162
dx.doi.org/10.1021/ja3075924 | J. Am. Chem. Soc. 2012, 134, 15154−15162