Diverse Reactivity of Diazatitanacyclohexenes: Coupling Reactions of 2 H-Azirines Mediated by Titanium(II)

Article abstract of DOI:10.1021/acs.organomet.8b00522

2H-Azirines are versatile coupling partners for the synthesis of N-heterocycles. Herein, we present our studies on the reactivity of Cp₂Ti(BTMSA) (1; BTMSA = bis(trimethylsilyl)acetylene) with a variety of azirines. In all the cases examined, the initial organometallic products formed are diazatitanacyclohexenes, presumably formed via oxidative addition of Ti(II) into the C-N bond of the azirine to form an azatitanacyclobutene intermediate, followed by C=N insertion of a second equivalent of azirine into the Ti-C bond to form the observed products. Diazatitanacyclohexene 3, bearing phenyl substituents and derived from 2,3-diphenyl-2H-azirine, fragments to form an azabutadiene and nitrile, which is shown to be catalytic in the presence of excess 2,3-diphenyl-2H-azirine. H-substituted complex 8, derived from 3-phenyl-2H-azirine, decomposes via protonolysis of the Cp ligands. In contrast, the methyl-substituted diazatitanacyclohexene 10, derived from 2-methyl-3-phenyl-2H-azirine, is thermally robust. Attempts to trap the putative azatitanacyclobutene intermediate with an alkyne were unsuccessful, resulting instead in the formation of titanacyclopentadiene (12) from coupling of alkyne with BTMSA. Initial reactivity studies found that 10 could be protonolyzed with AcOH to form mixtures of pyrrole and aziridine products, whereas reacting 10 with MeOH results solely in the formation of 2,4-dimethyl-3,5-diphenyl-1H-pyrrole.

Full text of DOI:10.1021/acs.organomet.8b00522

Communication
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Diverse Reactivity of Diazatitanacyclohexenes: Coupling Reactions
of 2H‑Azirines Mediated by Titanium(II)
Addison N. Desnoyer, Xin Yi See, and Ian A. Tonks*
Department of Chemistry, University of MinnesotaTwin Cities, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United
States
S
* Supporting Information
ABSTRACT: 2H-Azirines are versatile coupling partners for the synthesis of N-heterocycles. Herein, we present our studies on
the reactivity of Cp2Ti(BTMSA) (1; BTMSA = bis(trimethylsilyl)acetylene) with a variety of azirines. In all the cases examined,
the initial organometallic products formed are diazatitanacyclohexenes, presumably formed via oxidative addition of Ti(II) into
the C−N bond of the azirine to form an azatitanacyclobutene intermediate, followed by CN insertion of a second equivalent
of azirine into the Ti−C bond to form the observed products. Diazatitanacyclohexene 3, bearing phenyl substituents and
derived from 2,3-diphenyl-2H-azirine, fragments to form an azabutadiene and nitrile, which is shown to be catalytic in the
presence of excess 2,3-diphenyl-2H-azirine. H-substituted complex 8, derived from 3-phenyl-2H-azirine, decomposes via
protonolysis of the Cp ligands. In contrast, the methyl-substituted diazatitanacyclohexene 10, derived from 2-methyl-3-phenyl-
2H-azirine, is thermally robust. Attempts to trap the putative azatitanacyclobutene intermediate with an alkyne were
unsuccessful, resulting instead in the formation of titanacyclopentadiene (12) from coupling of alkyne with BTMSA. Initial
reactivity studies found that 10 could be protonolyzed with AcOH to form mixtures of pyrrole and aziridine products, whereas
reacting 10 with MeOH results solely in the formation of 2,4-dimethyl-3,5-diphenyl-1H-pyrrole.
external chloride.11 Motivated by the dearth of reports in the
ue to their high strain energy and structural diversity,
D2H-azirines are attractive coupling partners for the
literature on the reactivity of early metals with azirines, we set
synthesis of larger N-heterocyclic rings.1 For example, Lu
out to examine the fundamental organometallic reactivity of
titanium14−17 with these N-heterocycles. Herein, we present
and Xiao have demonstrated the coupling of azirines and
electron-deficient alkynes in the presence of a photocatalyst to
form highly functionalized pyrroles (Figure 1).2 Notably,
azirine addition to the alkyne in this instance occurs through
cleavage of the C−C bond of the azirine. Historically,
transition-metal catalysts have been commonly utilized for
coupling reactions of azirines through C−N bond cleavage.3,4
Alper and co-workers have shown that the C−N bond of
azirines is susceptible to oxidative addition with low-valent
palladium to form azaallyl intermediates.5 Subsequent carbon-
ylation with CO and attack by a second equivalent of
azaallylpalladium results in the formation of β-lactams.
Many of the coupling reactions involving azirines are
facilitated by late transition metals, including rhodium,6−8
nickel,9 and silver.10 In contrast, examples of azirine
functionalization using early metals are much rarer and
typically involve group 6 carbonyl complexes as coupling
partners.11−13 In the sole example using titanium reported to
date, Alper and co-workers demonstrated that TiCl4 can
coordinate azirines, activating them to nucleophilic attack from
our preliminary findings on the reactivity of a family of azirines
with a well-defined titanium(II) synthon and their subsequent
reactivity to form an array of different products depending on
the azirine substituents.
Reaction of equimolar amounts of the Rosenthal complex
Cp2Ti(BTMSA)18 (1; Cp = cyclopentadienyl, BTMSA =
bis(trimethylsilyl)acetylene) with 2,3-diphenyl-2H-azirine (2)
in C6D6 resulted in an instant color change from golden brown
1
to dark red-purple. H NMR spectroscopic analysis revealed
the presence of approximately equimolar amounts of residual 1
and a new organometallic complex (3). Addition of a second
equivalent of 2 results in full consumption of 1 and the
1
formation of 3 in 66% NMR yield (Figure 2). The H NMR
Special Issue: Organometallic Complexes of Electropositive Ele-
ments for Selective Synthesis
Received: July 24, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.organomet.8b00522
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Complex 3 is unstable in solution, decomposing overnight at
room temperature to form (relative to 3) the products of
formal 2H-azirine disproportionation: the azabutadiene N-
(1,2-diphenylvinyl)-1-phenylmethanimine (5)19 in 87% yield
and benzonitrile (6) in 77% yield (Figure 3). While 6 could
Figure 1. Examples of coupling reactions of azirines.
Figure 3. (top) Decomposition of 3 into 5 and 6. (bottom) Catalytic
1
2H-azirine disproportionation. Legend: (a) H NMR yield; (b) GC-
FID yield.
clearly be seen by GC/MS and GC/FID analysis, we observed
1
only broadened resonances for it in the H NMR spectrum of
the crude reaction mixtures. This is likely the result of a
dynamic equilibrium process with Ti in solution. There is only
one other example of this type of formal azirine disproportio-
nation in the literature, catalyzed by Ni0.20 In this previous
study, the authors propose that the nitrile is formed via retro [2
+ 2] cycloreversion of an azanickelacyclobutene. If the
titanium system described here is operating by the same
mechanism, it would require that the insertion of the second
equivalent of 2H-azirine into 4 to form 3 be reversible.
Preliminary mechanistic experiments of the decomposition of
3 indicate that the rate of decomposition of 3 is relatively
unaffected by the presence of excess 2. This argues against
reversible elimination of 2 from 3 followed by [2 + 2]
cycloreversion from 4. Instead, direct ejection of the observed
products from 3 via a more complicated electrocyclic
mechanism appears to be more plausible. Notably, we do
not detect any products of nitrile coupling in these reactions,
which has recently been reported for group 4 metallocenes.17,21
Given that release of the azabutadiene fragment 5 should
formally regenerate titanium(II), we sought to probe whether
this disproportionation could be rendered catalytic. Addition
of 10 mol % of 1 to a solution of 2 in C6D6 resulted in an
immediate color change to dark brown-red. The solution was
stirred at room temperature for 16 h before being analyzed by
1H NMR and GC-FID, revealing the formation of 5 (27%
yield) and 6 (33% yield). Although these yields are not ideal,
they demonstrate that catalytic turnover is feasible within this
system. More broadly, these preliminary results show that
titanium(II) is competent for the catalytic functionalization of
2H-azirines, a process which has not been reported to date.
1
Figure 2. (top) Synthesis of diazatitanocyclohexene 3, with the H
NMR yield given in parentheses. (bottom) Partial 1H NMR spectrum
(400 MHz, C6D6, 25 °C) of 3.
spectrum of 3 displays two singlets in the Cp region (δ 6.02
and 5.93) that each integrate to five protons, indicating that
the complex is asymmetric. In addition, resonances at δ 5.00
and 3.71 (both singlets integrating to 1) demonstrate that the
two incorporated azirine moieties are in distinct environments.
Although we were unable to grow crystals of 3 for X-ray
diffraction studies, we assigned the structure as the
diazatitanacyclohexene shown in Figure 2, where the titanium
is bound by imidyl and aziridinyl ligands. We propose that 3 is
formed by oxidative addition of titanium(II) into the C−N
single bond of 2 to form the azatitanacyclobutene intermediate
4, which then undergoes rapid insertion of the CN bond of
another equivalent of 2 into the Ti−C bond to form 3.
Complex 3 is formed as a single diastereomer, which was
assigned by 2D NOESY spectroscopy (vide infra).
B
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We then sought to explore the 2H-azirine coupling scope,
hypothesizing that bulkier 2H-azirine substituents may hinder
the insertion of a second equivalent of azirine into the putative
azatitanacyclobutene 4. Unfortunately, reactions of 1 with 2,2-
dialkyl-3-phenylazirines ultimately resulted in mixtures of
decomposition products (see ESI). In contrast, reaction of 1
with 3-phenyl-2H-azirine (7) resulted in rapid formation of
diazatitanacyclohexene 8, which was characterized in solution
by a variety of NMR spectroscopic methods (Figure 4).
cleave the coupled organic fragment from the metal center
(Figure 6). Washing a benzene solution of 10 with 2 M
1
Figure 6. Reactivity of 10 with acids, with H NMR yields given in
parentheses.
1
Figure 4. Synthesis of 8 and 10, with the H NMR yield given in
parentheses. Legend: (a) 52% isolated yield.
HCl(aq) resulted in an immediate color change from purple to
red-orange. 1H NMR spectroscopic analysis revealed the
formation of Cp2TiCl2 as the main organometallic species.22
Using weaker acids with less nucleophilic conjugate bases such
as 1 M AcOH(aq) instead resulted in mixtures of pyrrole 1323,24
(26% yield) and aziridine 14 (45% yield), as determined by 1H
NMR spectroscopy. Satisfyingly, dissolving 10 in MeOH
resulted solely in the formation of 13 (48% yield by 1H NMR)
from the coupled azirine moieties, along with CpH. These
transformations are remarkably selective given the relatively
simple metal scaffold utilized here and demonstrate that 2H-
azirines can indeed be useful coupling partners for the selective
formation of N−H pyrroles and other N-heterocycles using
titanium.
Finally, we then sought to examine whether it would be
possible to trap the putative azatitanacyclobutene intermediate
with an organic substrate other than azirine. Our initial
approach involved premixing 2H-azirine 9 and various
amounts of p-tolylacetylene (11) before addition to complex
1. While the resulting NMR spectra showed complicated
mixtures of products indicative of 2H-azirine + acetylene
coupling (see the Supporting Information), a major product of
the reaction was direct coupling of 1 with 11 to form 12
(Figure 7). Upon scaling up these reactions, we were able to
Complex 8 decomposed on standing at room temperature over
several hours and was thus unisolable in our hands.
Interestingly, the main observable product of decomposition
of 8 was not an azabutadiene such as 5 but rather
cyclopentadiene (CpH).
Addition of 1 to a solution of 2-methyl-3-phenyl-2H-azirine
(9) resulted in an instant color change from brown to purple.
1H NMR spectroscopy revealed the clean formation of
diazatitanocyclohexene 10, which was found to be thermally
robust (Figure 4). Indeed, in contrast to 3 and 8, 10 was stable
in refluxing C6D6 for several days. Cooling a saturated solution
of 10 in Et2O overnight at −35 °C allowed for the growth of
large red crystals suitable for X-ray diffraction studies, and the
solid-state structure of 10 is shown in Figure 5. Notably, both
Figure 5. Thermal ellipsoid diagrams of 10 (left) and 12 (right) (50%
probability ellipsoids). Most H atoms are omitted for clarity. Relevant
bond distances (Å): for 10, Ti1−N1 1.944(1), N1−C1 1.268(2),
Ti1−N2 1.975(1), N2−C3 1.479(2); for 12, Ti1−C1 2.185(4), C1−
C2 1.373(5), C2−C3 1.481(4), C3−C4 1.344(4), Ti1−C4 2.145(3).
Figure 7. Synthesis of 12 from 1 and 11, with the isolated yield given
in parentheses.
isolate brown crystals of 12 (see Figure 5 for the solid-state
structure). The titanacyclopentadiene moiety is clearly shown
by the short C1−C2 (1.373(5) Å) and C3−C4 (1.344(4) Å)
bonds and the long C2−C3 (1.481(4) Å) bond. Remarkably,
the only other reported example of cyclization of an alkyne
with 1 uses acetylene as a substrate;25 typically, BTMSA is
considered as an innocent spectator in reductive coupling
reactions.26,27 Other efforts to use CO and isocyanides as
trapping agents for the azatitanacyclobutene intermediate have
so far been unsuccessful.
the NMR data and the crystallographic data indicate that 10 is
formed as a single diastereomer. Both Ti−N bonds are similar
in length. The six-membered titanacycle is remarkably flat, with
the second equivalent of azirine inserting such that the methyl
group of the aziridinyl moiety is pointing away from the
ancillary Cp ligand.
To further probe the reactivity of 10, we undertook
protonolysis experiments with a variety of acids in order to
C
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ASSOCIATED CONTENT
* Supporting Information
CCDC 1857649−1857650 contains the supplementary
crystallographic data for this paper. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.organomet.8b00522.
■
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compounds, and X-ray crystallographic data (PDF)
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propenyl)-2H-azirine Derivative with Molybdenum Carbonyl Com-
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C-H activation of N-methylanilines at ambient temperature. Angew.
Chem., Int. Ed. 2015, 54, 4383−7.
(15) Manßen, M.; Lauterbach, N.; Woriescheck, T.; Schmidtmann,
M.; Beckhaus, R. Reactions of Secondary Amines with Bis(η5:η1-
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Accession Codes
CCDC 1857649−1857650 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.
AUTHOR INFORMATION
Corresponding Author
*E-mail for I.A.T.: itonks@umn.edu.
ORCID
Ian A. Tonks: 0000-0001-8451-8875
Notes
The authors declare no competing financial interest.
■
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ACKNOWLEDGMENTS
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Financial support was provided by the National Institutes of
Health (1R35GM119457) and the Alfred P. Sloan Foundation
(I.A.T. is a 2017 Sloan Fellow). Equipment for the Chemistry
Department NMR facility was supported through a grant from
the National Institutes of Health (S10OD011952) with
matching funds from the University of Minnesota.
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