Reversible C-N Bond Formation in the Zirconium-Catalyzed Intermolecular Hydroamination of 2-Vinylpyridine

Article abstract of DOI:10.1021/acs.organomet.8b00904

The intermolecular hydroamination of alkenes with alkylamines has been a long-standing challenge in catalysis, partially due to the near-thermoneutral nature of this transformation. Consistent with this understanding, we report the direct observation of reversible C-N bond formation in hydroamination. A bis(ureate) zirconium complex catalyzed the intermolecular hydroamination of 2-vinylpyridine. Reversible C-N bond formation was characterized by variable-temperature NMR spectroscopy, and thermodynamic parameters were determined using van't Hoff plots. Isolated intermediates support an aza-Michael-addition mechanism. Sensitivity to steric bulk in the C-N bond forming step provided further evidence for the kinetically accessible but limited thermodynamic driving force for this transformation.

Full text of DOI:10.1021/acs.organomet.8b00904

Communication
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Reversible C−N Bond Formation in the Zirconium-Catalyzed
Intermolecular Hydroamination of 2‑Vinylpyridine
Samuel E. Griffin, Javier Pacheco, and Laurel L. Schafer*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada V6T 1Z1
*
S Supporting Information
ABSTRACT: The intermolecular hydroamination of alkenes
with alkylamines has been a long-standing challenge in
catalysis, partially due to the near-thermoneutral nature of
this transformation. Consistent with this understanding, we
report the direct observation of reversible C−N bond
formation in hydroamination. A bis(ureate) zirconium
complex catalyzed the intermolecular hydroamination of 2-
vinylpyridine. Reversible C−N bond formation was charac-
terized by variable-temperature NMR spectroscopy, and
thermodynamic parameters were determined using van’t
Hoff plots. Isolated intermediates support an aza-Michael-
addition mechanism. Sensitivity to steric bulk in the C−N
bond forming step provided further evidence for the kinetically accessible but limited thermodynamic driving force for this
transformation.
ydroamination, the 100% atom-economical addition of
Scheme 1. (A) Initial Stoichiometric Studies with Alkenes
and (B) Synthesis of Intermediate 4
H
an N−H bond across a C−C unsaturation, is an efficient,
1
catalytic method of synthesizing amines. While this trans-
1
−8
formation has been extensively investigated,
the intermo-
9
lecular variant with alkenes remains a challenge in catalysis.
This is primarily due to the reaction’s ergoneutral nature and
high kinetic barrier. Nevertheless, numerous strategies have
10
1
been developed to circumvent the lack of driving force in
intermolecular alkene hydroamination. One powerful strategy
is to activate the amine using photocatalysis to overcome
1
1
thermodynamic barriers. Other methods include using
12,13
directing groups to overcome kinetic and entropic barriers
or employing activated amine derivatives in formal hydro-
5
,14−21
amination reactions.
Experimental insights into C−N
bond formation in direct hydroamination inform the synthetic
community in devising new catalysts for this transformation.
Direct evidence for insertion of an alkene into a M−N bond
2
2−30
is rare,
making it difficult to study the bond-forming
processes relevant to alkene hydroamination in detail.
Previously, we reported bis(ureate) zirconium precatalysts 1
(Scheme 1) and 2, the related dibenzyl zirconium complex
(
Scheme S1A), for the intermolecular hydroamination of
alkynes and intramolecular hydroamination of alkenes with
primary and secondary amines.
the Zr−N bond of 1 was observed, providing direct evidence
for a σ-insertive mechanism for alkyne substrates. In contrast,
kinetic and computational investigations have shown 1 to
catalyze intramolecular hydroamination of alkenes via a
Considering the mechanistic diversity of precatalysts 1 and 2
and precedent for observing efficient catalytic C−N bond
formation using either primary or secondary amines with both
alkynes and aminoalkenes, we aimed to gain insight into C−N
bond forming processes toward intermolecular alkene hydro-
amination. Herein we report the first example of stoichiometric
31,32
Insertion of an alkyne into
33
3
1,34
proton-assisted mechanism.
It should be noted that
precatalysts 1 and 2 generate the same catalytically active
Received: December 14, 2018
bis(amido) species upon reaction with amine substrate.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00904
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
and catalytic anti-Markovnikov intermolecular hydroamination
using a group 4 catalyst. Mechanistic investigations revealed an
aza-Michael type reaction, and reversible C−N bond formation
has been directly observed in an isolated catalytic intermediate.
Recently, Schulz and co-workers disclosed the anti-
Markovnikov hydroamination of styrenes with secondary
vinylpyridine to a toluene solution of 3 resulted in a color
change to orange once again. Cooling for several days afforded
orange crystals of complex 4 suitable for X-ray diffraction. The
solid-state molecular structure of 4 (Figure 1) shows a seven-
35
amines using an yttrium binaphthylamido catalyst. Therein,
-vinylpyridine was found to be a very active substrate,
2
achieving full conversion at room temperature in 5 min in the
reaction with pyrrolidine. This high activity was attributed to
35
coordination of the pyridyl nitrogen. In our zirconium
system 1, we proposed that the highly ionic nature of the
ureate ligand generates a very electropositive metal center,
thereby promoting increased reactivity akin to that of rare-
3
2,36−39
earth metals.
It was thus hypothesized that 1 and 2
would also promote intermolecular hydroamination of the
reactive 2-vinylpyridine substrate.
Figure 1. ORTEP representation of complex 4 with ellipsoids shown
at 50% probability and hydrogen atoms omitted for clarity. Selected
bond lengths (Å): C1−C2, 1.370(2); C2−C3, 1.431(3); C3−C4,
First, the catalytic activity of the tethered bis(ureate)
zirconium complex was established (Scheme S1B). Pyrrolidine
35
1
.360(3); C4−C5, 1.461(2); C5−C6, 1.368(2); C6−C7, 1.497(2);
was chosen as the amine substrate. Dibenzyl precatalyst 2
was used to avoid the potential formation of hydroamination
products resulting from both dimethylamine and pyrrolidine,
which could occur with the use of 1. Gratifyingly, the reaction
between 2-vinylpyridine and pyrrolidine with 5 mol % of 2
Zr1−N1, 2.3558(12); Zr1−N2, 2.4401(12); N2−C7, 1.513(2); N1−
C5, 1.413(2); N1−C1, 1.3691(19); Zr1−N3, 2.0962(12). Selected
bond angle (deg): N1−Zr1−N3, 169.62(5).
proceeds to completion at room temperature within 6 h
coordinate complex with pseudo-C symmetry and distorted-
s
1
(
Scheme S1B). This reaction can be monitored by H NMR
pentagonal-bipyramidal geometry. This structure results from
nucleophilic attack of the equatorial amido ligand on
coordinated 2-vinylpyridine to realize C−N bond formation
in an aza-Michael-addition reaction (Figure S3). While a
proton-assisted mechanism cannot be excluded under catalytic
conditions, it cannot be the only mechanistic route, as we show
that C−N bond formation occurs in the absence of a proton
trigger.
spectroscopy (Figure S12), in which the olefinic resonances
disappear and two new multiplets at 2.97 and 2.84 ppm,
corresponding to the new methylene protons of the product,
are observed. Having shown zirconium to be proficient in
catalyzing this transformation, we conducted stoichiometric
experiments to gain mechanistic information.
Numerous mechanisms have been proposed for alkene
hydroamination by metal-based catalysts, and they vary greatly
Notably, the pyridine ring has been dearomatized and a six-
membered zirconacycle has formed. The alternating C1−C2,
C2−C3, C3−C4, and C4−C5 bond lengths (1.370(2),
1.431(3), 1.360(3), and 1.461(2) Å, respectively) show limited
delocalization within the ring. These alternating short and long
bond lengths are consistent with a study by Rosenthal et al., in
which a five-membered zirconacycle involving a dearomatized
pyridine ring was synthesized from 2-vinylpyridine and
1
depending on the nature of the metal. For example, σ-
4
0,41
31,42
insertive
or proton-assisted
pathways are often
proposed for early-transition-, rare-earth-, alkaline-earth-, and
alkali-metal catalysts. Computational work supports the σ-
insertive mechanism in several systems, invoking reversible C−
43−48
N bond formation for the insertion step.
Despite these
predictions, evidence for reversible C−N bond formation has
23,49−54
58
2
scarcely been reported
and reversible C−N bond
Cp Zr(thf)(η -Me SiC SiMe ). Additionally, the depiction
2 3 2 3
formation has not been observed directly. With 2-vinylpyridine
as the alkene substrate, an aza-Michael-addition mechanism is
another viable pathway. Indeed, the addition of amines to 2-
vinylpyridine via an aza-Michael addition has been achieved by
of C5−C6 as a double bond and C6−C7 as a single bond is
further supported by bond metrics (1.368(2) and 1.497(2) Å,
59
respectively). The fact that the Zr1−N1 bond length in 4
(2.3558(12) Å) is much shorter than that of the corresponding
5
5−57
31
various Lewis acid catalysts.
Given the number of
bis(dimethylamido) pyridine complex (2.508(3) Å) supports
pathways possible for this transformation, we sought to gain
mechanistic insight into this group 4 catalyzed hydroamination
reaction.
Expecting the stoichiometric reaction of 1 and 2-vinyl-
pyridine to cleanly afford the dimethylamine-containing
its assignment as an amido ligand. Furthermore, the Zr1−N2
bond distance is consistent with that of a neutral amine donor
(2.4401(12) Å). While there are many examples of metal
60−64
complexes with a dearomatized pyridine ligand,
they are
most often generated via precoordination of the neutral
pyridine followed by deprotonation with a strong base. In this
case, C−N bond formation triggers the dearomatization of the
pyridine ring.
hydroamination product, 1 was dissolved in toluene-d and
8
2
-vinylpyridine was added to the solution, causing a change
from colorless to orange not observed in the catalytic reaction
1
(Scheme 1A). The H NMR spectrum showed diagnostic
Spectroscopic solution-phase characterization of isolated 4
revealed a complex chemical environment. First, the tethered
ureate ligand has reduced symmetry; the geminal methyl
methylene signals at 2.90 and 2.65 ppm for the expected
product (Figure S13). However, a multitude of other new
ligand-based resonances were present, consistent with new
metal-containing species being formed in solution.
1
groups produce two separate resonances in the H NMR
spectrum (1.22, 0.90 ppm), as do the methylene protons (3.44,
3.25 ppm) and isopropyl methyl protons (1.25, 1.17 ppm).
To prevent catalytic turnover, the previously reported
dimeric complex 3, which does not contain neutral dimethyl-
3
3
This is consistent with reduced flexibility in the ureate ligand.
3
1
13
amine, was synthesized (Scheme 1B). Addition of 2-
The C NMR resonance for the carbonyl carbon (167.3 ppm)
B
DOI: 10.1021/acs.organomet.8b00904
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
is also shifted slightly upfield relative to that of bis(amido)
complex 3 (170.8 ppm). For the N,N-chelate resulting from
C−N bond formation and dearomatization of the pyridyl ring,
Scheme 2. Synthesis of Pyrrolidine Aza-Michael-Addition
Intermediate 7
1
the resonances in the H NMR spectrum appear upfield in
comparison to those of 2-vinylpyridine; for example, the C−H
proton next to the pyridyl nitrogen appears at 8.48 ppm in 2-
vinylpyridine and 7.06 ppm in 4. Additionally, an upfield shift
of the methyl protons in the N,N-chelate (2.61 ppm) relative
to the amido protons in 3 (3.39 ppm) is consistent with
conversion of the equatorial amido ligand in 3 to a more
weakly donating amino ligand in 4.
Interestingly, signals for 2-vinylpyridine and unreacted 3 are
also observed in the NMR spectrum of dissolved crystalline 4.
Hypothesizing that these species were in equilibrium, variable-
temperature NMR spectroscopy was used to probe the
solution-phase dynamics (Figure 2). The doublet of doublets
Surprisingly, the solution-phase behavior of 7 is strikingly
different from that of 4. When 7 is dissolved in solution,
insoluble poly(vinylpyridine) immediately begins precipitating
out. Electrophilic metal complexes are known to polymerize 2-
35,66−70
1
vinylpyridine under similar conditions.
From the H
NMR spectrum, 7 decomposes readily to give 6 and various
unidentified species. Forming 7 in situ gives resonances
analogous to those of 4 and the same unidentified impurities.
Characterization of in situ generated 7 by variable-temperature
NMR spectroscopy reveals the same reversible C−N bond
formation observed in 4 (Figure S18). Thus, as free 2-
vinylpyridine forms from C−N bond cleavage in 7, it may
irreversibly polymerize. This process is much slower when 7 is
formed in situ, likely due to the dilute conditions. Thermal
parameters for these equilibria, determined using van’t Hoff
plots (Figures S1 and S2), change slightly between complexes
(
ΔH° = −113 ± 5 kJ/mol, ΔS° = −380 ± 20 J/(mol K) for 4;
ΔH° = −127 ± 7 kJ/mol, ΔS° = −460 ± 30 J/(mol K) for
7
in this system is subtly affected when switching from
dimethylamido to pyrrolidido as the nucleophile.
71
). The thermodynamics of reversible C−N bond formation
1
Figure 2. Variable-temperature H NMR spectra of 4, focusing on the
Without a clear electronic rationale for the disparity in
solution-phase behavior between 4 and 7, the propensity for
solutions of 7 to undergo C−N bond cleavage and further
react to form poly(vinylpyridine) over time was hypothesized
to be due to the different steric effects imposed by the
dimethylamido versus pyrrolidido ligands. To test this
hypothesis, the even larger bis(piperidido) complex 8 was
olefinic region (400 MHz in toluene-d8).
signals due to the olefin protons of 2-vinylpyridine at 6.33 and
.27 ppm (H and H , respectively; see Scheme 1B) decrease
in intensity as the temperature is lowered, until they disappear
at −30 °C. Concomitant with this phenomenon is the increase
in intensity of the signals at 6.12 ppm (H , H ) and 5.10 ppm
H ) of 4, respectively. At −9 °C, the doublet of doublets
signal originating at 6.12 ppm begins to split into multiple
signals as H and H become distinguishable. Both the
5
a b
72
synthesized. Interestingly, 8, unlike 3 and 6, is monomeric
both in solution and in the solid state. Reacting 8 with 2-
vinylpyridine results in no coordination or C−N bond
d
e
(
c
65
1
formation, as observed by H NMR spectroscopy (Figure
d
e
isopropyl methine and methyl signals for 3 also decrease in
intensity at lower temperature. Thus, complex 4 forms
preferentially at low temperature while 2-vinylpyridine and 3
are favored at higher temperature. Altogether, reversible C−N
bond formation is observed directly in this variable-temper-
ature experiment.
To observe this phenomenon using other amido precursors,
analogous experiments were conducted using pyrrolidine. The
stoichiometric reaction of 2-vinylpyridine with the seven-
coordinate complex 5 afforded the hydroamination product;
the corresponding bis(amido) dimer 6 is also clearly observed
as the only byproduct (see the Supporting Information). This
contrasts with the analogous reaction with 1 (vide supra), in
which incomplete product formation and multiple metal-
containing species are observed. Next, 6 was synthesized
independently and reacted with 2-vinylpyridine, affording the
aza-Michael intermediate 7 (Scheme 2). The solid-state
molecular structure is analogous to that of 4, with only
minor differences in the bond lengths and angles (Figure S22).
S15). Furthermore, after a few days at room temperature, all of
the 2-vinylpyridine polymerizes. These results demonstrate
extreme sensitivity to steric effects in C−N bond formation
73
with this system.
In summary, we have shown that zirconium, a group 4 metal,
can mediate intermolecular hydroamination of 2-vinylpyridine
with pyrrolidine. Stoichiometric experiments resulted in
isolation of reactive intermediates consistent with C−N bond
formation occurring by an aza-Michael-addition reaction,
resulting in dearomatization of the pyridine ring. Furthermore,
we have discovered a system in which reversible C−N bond
formation can be directly observed by variable-temperature
NMR spectroscopy. Consequently, thermodynamic parameters
for C−N bond formation could be experimentally determined
in two related systems. Here we show that minor changes in
substrate can cause large changes in reactivity, as steric bulk
was observed to play an important role in the reversibility and
degradation of these intermediates in solution. These results
are consistent with challenges associated with developing a
C
DOI: 10.1021/acs.organomet.8b00904
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
general catalyst for intermolecular hydroamination of simple
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CCDC 1849489−1849493 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Buchwald, S. L.; Liu, P. Ligand−Substrate Dispersion Facilitates the
Copper-Catalyzed Hydroamination of Unactivated Olefins. J. Am.
Chem. Soc. 2017, 139, 16548−16555.
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*
Corresponding Author
E-mail for L.L.S.: schafer@chem.ubc.ca.
(
16) Shi, S.-L.; Wong, Z. L.; Buchwald, S. L. Copper-Catalysed
ORCID
Enantioselective Stereodivergent Synthesis of Amino Alcohols. Nature
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Amines with Remote Stereocentres by Enantioselective CuH-
Catalysed Reductive Relay Hydroamination. Nat. Chem. 2016, 8,
Samuel E. Griffin: 0000-0001-7358-9424
Laurel L. Schafer: 0000-0003-0354-2377
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
Regiocontrolled Hydroamination of Unactivated Alkenes via Proto-
■
depalladation. J. Am. Chem. Soc. 2016, 138, 5805−5808.
Funding from NSERC is gratefully acknowledged. S.E.G.
thanks the NSERC (CGSM) and UBC (4YF, Laird) for
scholarships. Dawson Beattie, Dr. Sorin Rosca, and Dr. Jason
Brandt are thanked for helpful discussions. Dr. Brian Patrick is
thanked for helping with structure refinement. This work was
partially supported through a Canada Research Chair in
Catalyst Development for L.L.S.
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F
DOI: 10.1021/acs.organomet.8b00904
Organometallics XXXX, XXX, XXX−XXX