Facile C-H, C-F, C-Cl, and C-C Activation by Oxatitanacyclobutene Complexes

Article abstract of DOI:10.1021/acs.organomet.5b00470

Aryl ketones react readily with oxatitanacyclobutenes bearing pentamethylcyclopentadienyl ligands to form unique titanocene complexes resulting from Cp modification and C-H activation. An intermediate in this reaction is intercepted with various functional groups to form carbonyl insertion, C-F activation, and cyclopropane ring-opening products.

Full text of DOI:10.1021/acs.organomet.5b00470

Communication
pubs.acs.org/Organometallics
Facile C−H, C−F, C−Cl, and C−C Activation by Oxatitanacyclobutene
Complexes
Trang T. Nguyen, Jeffery A. Bertke, Danielle L. Gray, and Kami L. Hull*
Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, United
States
S
* Supporting Information
ABSTRACT: Aryl ketones react readily with oxatitanacyclobu-
tenes bearing pentamethylcyclopentadienyl ligands to form
unique titanocene complexes resulting from Cp* modification
and C−H activation. An intermediate in this reaction is
intercepted with various functional groups to form carbonyl
insertion, C−F activation, and cyclopropane ring-opening
products.
bismethoxybenzophenone to a solution of 1a in C6D6 resulted in
an immediate color change, from green to dark red, and complete
conversion to a new complex was observed after 10 min at room
temperature (Scheme 2). Analysis of the crude reaction mixture
xa- and azametallacycles of group IV metals are important
Ointermediates in a number of metal-mediated reactions,
including hydroamination,1,2 reductive cyclization,3,4 vinyl
cyclopropane ring opening,5 aldehyde−alkyne coupling,6 and
aldehyde−imine coupling.7 The key step in many of these
reactions involves insertion of the substrate’s unsaturated bond
into the metal−carbon bond of the metallacycles. This reactivity
has been extensively studied in the cases of azametallacycles,
generated from titanium and zirconium imido complexes, and
more recently with oxazirconacyclobutenes.6 On the other hand,
the reactivity of analogous oxatitanacyclobutenes toward
unsaturated organic substrates has not been reported. In order
to develop analogous catalytic cycles with Ti−oxo complexes, it
is key to understand their fundamental reactivity and probe the
decomposition pathways for these compounds. The results
described herein probe the reaction between oxatitanacyclobu-
tenes and carbonyl-containing compounds.
Scheme 2. Reaction of Oxatitanacyclobutenes with
Benzophenone
1
by H NMR spectroscopy revealed that a single product was
formed in near-quantitative yields. The 1H NMR spectrum had
an interesting pattern in the Cp* methyl region, with a singlet
integrating to 15 hydrogen atoms and 5 singlets each integrating
to 3 hydrogen atoms, indicating desymmetrization of one of the
Cp* ligands. Additionally, a singlet, corresponding to the vinylic
proton, had moved from 7.60 to 4.62 ppm. These observations
were consistent with reductive elimination between a Cp* ligand
and the Ti−C bond of the oxatitanacyclobutene; a related
reaction was recently reported by Chirik for reductive
elimination from complexes bearing the 2,3,4,5-tetramethyl-1-
(trimethylsilyl)cyclopentadienyl ligand.11 Further, the AA′BB′
spin system of the (p-methoxy)phenyl of the aryl ring in 1a
became a ABC spin system and a new singlet at 6.56 ppm was
It is known that aldehydes and aldimines insert into the [M]−
C bond of azazirconacyclobutenes,7a,b,8 oxazirconacyclobu-
tenes,6,9 and azatitanacyclobutenes;7c,d however, the insertion
of aldehydes into oxatitanacyclobutenes has not been reported.
Treatment of titanocene complex 1 with aldehyde resulted in
rapid consumption of the starting materials. The aldehyde
1
insertion product was not detected by H NMR spectroscopy
(Scheme 1); rather, a complex mixture of products was
observed.10
To gain insight into the reactions of 1 with carbonyl
compounds, the less reactive benzophenone was chosen to
probe its reactivity. Interestingly, addition of 1 equiv of 4,4′-
1
observed. On the basis of the H and 13C NMR spectra the
structure was proposed to be titanacycle 2a. The new [Ti]−C
bond is between the aryl from 1a and the [Ti]; the hydride has
transferred to the ketone, resulting in the formation of an
alkoxide ligand.
Scheme 1. Proposed Aldehyde Insertion into a Ti−C Bond
Received: June 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.5b00470
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To confirm the structural assignment, X-ray-quality crystals
were grown by slow diffusion of pentane into a THF solution of
2a. The structure of 2a·THF is shown in Figure 1. The titanium is
Scheme 3. Proposed Mechanism for C−H Activation
titanium inserts into the carbonyl CO bond and the modified
Cp* ligand dissociates from the metal, forming the proposed
intermediate B. Titanium−ketone intermediates have been
proposed in the reaction of bis(cyclopentadienyl)-
titanacyclobutane with tetrakis(trifluoromethyl)-
cyclopentadienone17 and the cyclization reaction of enones.3a
With the phenyl ring now proximal, C−H activation occurs to
form a stable five-membered metallacycle and an alkoxide ligand,
generating product 2b.
The proposed mechanism is supported by deuterium labeling
experiments. Three isotopically labeled isomers of 1b, prepared
from Cp*2TiO(pyr) and the corresponding alkynes, were
combined with 4,4′-bismethoxybenzophenone in C6D6 (Scheme
4). Deuteration at the alkene carbon in metallacycle 1c (Scheme
Figure 1. X-ray crystal structure of 2a·THF. Hydrogen atoms and THF
carbons are omitted for clarity. Oxygen O6 is from THF. Ellipsoids are
drawn at the 50% probability level.
in a pseudo-square-pyramidal environment, and all of the atoms
of the titanacycle are coplanar. The acyclic Ti−alkoxide (Ti1−
O3) bond length of 1.8351(12) Å is shorter than the cyclic Ti−
alkoxide (Ti1−O1) bond length of 1.9273(11) Å, consistent
with a larger Ti−O3−C20 bond angle of 143.86(11)° in
comparison to the Ti−O1−C1 bond angle of 123.33(10)°.
Carbonyl compounds are known to insert into the metal−
carbon bond of titanacyclobutenes bearing the unsubstituted Cp
ligand to form six-membered metallacycles in good yields.12 The
difference in reactivity between those complexes and titanacycles
1 is explained by the increased steric interactions at the metal
center. Interestingly, benzophenone imine undergoes a similar
reductive elimination reaction, while no reaction was observed
when other Lewis basic groups, including triphenylphosphine,
tributylphosphine, triphenylphosphine oxide, 4-dimethylamino-
pyridine, benzonitrile, ethyl benzoate, and N,N-dimethylbenza-
a
Scheme 4. Labeling Study
10
1
mide, were added to a solution of 1 in C6D6 by H NMR.
Analogous oxazirconacyclobutenes bearing a Cp* ligand have a
larger Cp*−Ti−Cp* bond angle9 in comparison to that of 1,13
suggesting a less crowded metal center. These complexes form
six-membered metallacycle insertion products6,9 and have been
reported to undergo C−H activation to form a five-membered
metallacycle similar to 2;14 however, this transformation is only
affected at temperatures exceeding 150 °C. The details of such
conversion are not known, but various intermediates, including
zwitterion, diradical, and free zirconium−oxo, have been
invoked.
In Chirik’s recent report, it was concluded that the silyl group
was essential to the transformation, as an oxatitanacyclobutene
complex with all-alkyl-substituted Cp ring did not exhibit the
same reactivity.11 While complexes 1a,b are stable for extended
times in solution at up to 60 °C, the addition of the ketones is
important to trigger this transformation.
a
1
In situ yield determined by H NMR spectroscopy and comparison
to an internal standard.
A tentative mechanism for this transformation is illustrated in
Scheme 3. In the first step, due to the high oxophilicity of
titanium, coordination of the carbonyl oxygen to 1b promotes
the reductive elimination between the Cp* ring and the Ti−C
bond, to afford intermediate A. Reductive elimination of the
unsubstituted Cp ligand in titanocene complexes has also been
previously reported.15 The presence of a Ti−vinyl linkage may be
crucial for this reactivity, as a Ti−vinyl bond is slower to insert
into hindered carbonyls, relative to a Ti−alkyl bond.16 From A,
4a) results in labeling of the alkene proton in 2c, supporting the
direct reductive elimination between one Cp* ligand and a Ti−C
bond. Further, as Scheme 4b illustrates, one of the ortho C−D
bonds is transferred selectively to form the new Ti−OCD(Ph)2
bond of 1d. Interestingly, when only one ortho position was
deuterated, as in 1e (Scheme 4c), a very large intramolecular KIE
of >9 was observed, as determined by integration in the 1H NMR
spectrum.10
B
DOI: 10.1021/acs.organomet.5b00470
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Communication
It was hypothesized that blocking the ortho positions in
oxametallacycle 1 would inhibit C−H activation and allow for the
direct observation of intermediate B. However, reactions of
titanocene−oxo with 2,6-difluorophenylacetylene and 2,4,6-
trimethoxyphenylacetylene generated hydroxyacetylide com-
plexes instead of the desired titanacycles. The selective formation
of the hydroxyacetylides over oxatitanacyclobutenes is attributed
to the increased steric repulsion between the Cp* and the ortho
substituents.13 Meta substituents are also known to slow the rate
of C−H activation;18 1f was synthesized and treated with 4,4′-
bismethoxybenzophenone (Scheme 5). Excitingly, 50% con-
form pinacol-type product 3. These intriguing results suggested
the possibility of a more general C−X activation (Scheme 6),
Scheme 6. Intramolecular Trapping of B with an Adjacent
Reactive C−X Bond
Scheme 5. Formation of Double-Insertion Product
providing that the C−X bond activation from B is faster than C−
H activation and carbonyl insertion. Trifluoromethyls are known
to undergo C−F activation with titanocene complexes via an
intermediate similar to B.17 Reaction of 1a with 1 equiv of
trifluoroacetophenone (Scheme 7) resulted in an immediate
Scheme 7. Reaction of Oxatitanacyclobutene with
a b
,
CX3COPh
version to reductive elimination was seen by 1H NMR
spectroscopy; the metallacycle and Ti−alkoxide resulting from
C−H activation were not observed. When 2 equiv of the
benzophenone was added to a solution of 1f in C6D6, quantitative
conversion to product 3 was observed by 1H NMR spectroscopy.
The proposed mechanism for the formation of 3 is that, upon the
formation of intermediate B, another 1 equiv of the ketone
undergoes rapid insertion into the Ti−C bond, as the C−H
activation is slowed by the proximal CF3 groups.
a
b
Isolated yield. Reaction run in pentane.
X-ray-quality crystals of 3 were obtained from a toluene
solution layered with pentane. As seen in Figure 2, the solid-state
1
color change from green to yellow. H NMR spectroscopy
reveals the same pattern expected from reductive elimination of
Cp*, as observed in Scheme 1; however, the phenyl ring bearing
the methoxy group remains symmetric, suggesting that C−H
activation did not occur. In addition, 19F NMR spectroscopy
shows two doublets at −99.96 and −116.07 ppm, suggesting the
presence of an olefinic CF2 group. Analogous reactivity was
observed with 2,2,2-trichloroacetophenone, which afforded 4b in
51% isolated yield. The formation of 4a,b is consistent with the
mechanism outlined in Scheme 6. The driving force for this
process could be the formation of a strong Ti−X bond. The
ketone plays an important role, as treatment of 1a with ethyl
trifluoroacetate or octafluorotoluene19 resulted in no reaction.
Single crystals suitable for X-ray crystallography were grown
by slow diffusion of pentane into a toluene solution of 4a. As
depicted in Figure 3, 4a has a piano-stool geometry, with the
three leg positions occupied by one fluorine and two alkoxide
ligands. One of the alkoxides results from reductive elimination
of Cp* and the ring carbon from 1a; the other results from C−F
activation of the reactive trifluoromethyl. Both of these ligands
show strong deviation from sp2 geometry with Ti−O1−C11 and
Ti−O2−C19 angles of 156.06(14) and 167.36(14)°, respec-
tively, suggesting the multiple-bonding nature of the Ti−O
linkages.
Figure 2. X-ray crystal structure of 3. Hydrogen atoms are omitted for
clarity. Ellipsoids are drawn at the 50% probability level.
structure of 3 shows a five-membered metallacycle with two
molecules of ketone having undergone a pinacol coupling. The
metal is in a three-legged piano-stool geometry, with a slightly
puckered metallacycle. The acyclic alkoxide oxygen has an almost
linear geometry, with the Ti−O7−C31 angle of 171.44(11)°
suggesting a four-electron alkoxide ligand. Complex 2a, in
comparison, has a bent alkoxide with a Ti−O3−C20 angle of
143.86(11)°.
Next, the ability of B to undergo C−C bond activation was
studied with phenyl cyclopropyl ketone. The proposed trans-
formation in Scheme 6 would result in the formation of an
oxatitanacyclohexene complex. Related oxatitanacyclohexenes
generated via carbonyl insertion into the Ti−C bonds of
titanacyclobutenes are known to be stable.12,16b Indeed,
treatment of 1a with 4-methoxyphenyl cyclopropyl ketone
Formation of complexes 2 demonstrates the ability of
titanocenes 1 to undergo C−H activation. When C−H activation
is slow, as with 1f, intermediate B reacts with a second ketone to
C
DOI: 10.1021/acs.organomet.5b00470
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ACKNOWLEDGMENTS
■
The authors thank the University of Illinois, Urbana−
Champaign, and the Petroleum Research Fund for their
generous support.
REFERENCES
■
(1) (a) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc.
1992, 114, 1708. (b) McGrane, P. L.; Livinghouse, T. J. Org. Chem.
1992, 57, 1323. (c) Haak, E.; Bytschkov, I.; Doye, S. Angew. Chem., Int.
Ed. 1999, 38, 3389. (d) Johnson, J. S.; Bergman, R. G. J. Am. Chem. Soc.
2001, 123, 2923. (e) Cao, C.; Ciszewski, J. T.; Odom, A. T.
Organometallics 2001, 20, 5011. (f) Tillack, A.; Castro, I. G.; Hartung,
C. G.; Beller, M. Angew. Chem., Int. Ed. 2002, 41, 2541. (g) Ong, T.-G.;
Yap, G. P. A.; Richeson, D. S. Organometallics 2002, 21, 2839.
(h) Bytschkov, T.; Doye, S. Tetrahedron Lett. 2002, 43, 3715. (i) Li, C.;
Thomson, R. K.; Gillon, B.; Patrick, B. O.; Schafer, L. L. Chem. Commun.
2003, 2462. For recent reviews see: (j) Severin, R.; Doye, S. Chem. Soc.
Rev. 2007, 36, 1407−1420. (k) Bytschkov, I.; Doye, S. Eur. J. Org. Chem.
2003, 2003, 935−946. (l) Hazari, N.; Mountford, P. Acc. Chem. Res.
2005, 38, 839−849. (m) Odom, A. L. Dalton Trans. 2005, 225−233.
(2) For other amino functionalization reactions, see: (a) Fairfax, D.;
Stein, M.; Livinghouse, T.; Jensen, M. Organometallics 1997, 16, 1523−
1525. (b) Kablaoui, N. M.; Hicks, F. A.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 5818−5819. Duncan, D.; Livinghouse, T. Organometallics
1999, 18, 4421−4428.
Figure 3. X-ray crystal structure of 4a. Hydrogen atoms are omitted for
clarity. Ellipsoids are drawn at the 50% probability level.
resulted in the formation of titanacycle 5 (Scheme 8). When
cyclobutyl phenyl ketone was used, an immediate color change
Scheme 8. Formation of Cyclopropane-Opened Product
(3) (a) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
3182−3191. (b) Sturla, S. J.; Buchwald, S. L. Organometallics 2002, 21,
739−748.
(4) For a recent review see: Micalizio, G. C. Early Transition Metal
Mediated Reductive Coupling Reactions. In Comprehensive Organic
Synthesis II, 2nd ed.; Knochel, P., Ed.; Elsevier: Amsterdam, 2014; pp
1660−1737.
(5) Macklin, T. K.; Micalizio, G. C. Nat. Chem. 2010, 2, 638−643.
(6) Kortman, G. D.; Orr, M. J.; Hull, K. L. Organometallics 2015, 34,
1013−1016.
from green to bright red was observed. The 1H NMR spectrum
indicated consumption of starting materials and formation of an
intractable mixture of products; the C−C activation product was
not observed.
(7) (a) Ruck, R. T.; Bergman, R. G. Organometallics 2004, 23, 2231−
2233. (b) Ruck, R.; Zuckerman, R. L.; Krska, S. W.; Bergman, R. G.
Angew. Chem., Int. Ed. 2004, 43, 5372−5374. (c) Basuli, F.; Aneetha, H.;
Huffman, J. C.; Mindiola, D. J. J. Am. Chem. Soc. 2005, 127, 17992−
17993. (d) Aneetha, H.; Basuli, F.; Bollinger, J.; Huffman, J. C.;
Mindiola, D. J. Organometallics 2006, 25, 2402−2404.
(8) (a) Hanna, T. A.; Baranger, A. M.; Walsh, P. J.; Bergman, R. G. J. J.
Am. Chem. Soc. 1995, 117, 3292−3293. (b) Hanna, T. A.; Baranger, A.
M.; Bergman, R. G. J. Org. Chem. 1996, 61, 4532−4541.
(9) Vaughan, G. A.; Hillhouse, I. P. G. L.; Rheingold, A. L. J. Am. Chem.
Soc. 1990, 112, 7994−8001.
(10) See the Supporting Information.
(11) Pappas, I.; Chirik, P. J. Angew. Chem., Int. Ed. 2014, 53, 6241−
6244.
In summary, aryl ketones promote facile reductive elimination
of the usually inert Cp* ligand, providing a rare example of this
reactivity in all-alkyl-substituted Cp-based ligands. Reactions
proceed with the formation of a highly reactive Ti−ketone
complex, capable of C−X activation (X = H, F, Cl, C). These
transformations proceed readily at room temperature to generate
a number of novel titanium complexes. In addition, these results
indicate potential catalyst decomposition pathways in titano-
cene-catalyzed reactions; coordination of a Lewis basic group,
e.g., a ketone, aldehyde, or imine, to the metal center could
promote the reductive elimination and thus catalyst deactivation.
(12) Meinhart, J. D.; Grubbs, R. H. Bull. Chem. Soc. Jpn. 1988, 61, 171−
180.
(13) Polse, J. L.; Andemen, R. A.; Bergman, R. G. J. Am. Chem. Soc.
1995, 117, 5393−5394.
(14) Carney, M. J.; Walsh, P. J.; Hollander, F. J.; Bergman, R. G. J. Am.
Chem. Soc. 1989, 111, 8751−8753.
(15) (a) Rosenthal, U.; Lefeber, C.; Arndt, P.; Tillack, A.; Baumann,
W.; Kempe, R.; Burlakov, V. V. J. Organomet. Chem. 1995, 503, 221−
223. (b) Tillack, A.; Baumann, W.; Ohff, A.; Lefeber, C.; Spannenberg,
A.; Kempe, R.; Rosenthal, U. J. Organomet. Chem. 1996, 520, 187−193.
(16) (a) Doxsee, K. M.; Mouser, J. K. M. Organometallics 1990, 9,
3012−3014. (b) Doxsee, K. M.; Mouser, J. K. M. Tetrahedron Lett. 1991,
32, 1687−1690. (c) Pappas, I.; Chirik, P. J. Polyhedron 2014, 84, 67−73.
(17) Burk, M. J.; Staley, D. L.; Tumas, W. J. Chem. Soc., Chem. Commun.
1990, 11, 809.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.5b00470.
Experimental procedures, characterization data, and
crystallographic data (PDF)
Crystallographic data for 2a, 3, and 4a (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail for K.L.H.: kamihull@illinois.edu.
(18) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149−4152.
(19) Bailey, B. C.; Huffman, J. C.; Mindiola, D. J. J. Am. Chem. Soc.
2007, 129, 5302−5303.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.organomet.5b00470
Organometallics XXXX, XXX, XXX−XXX