The epimetallation and carbonation of carbonyl and imino derivatives: Epivanadation route to 2-amino and 2-hydroxy acids

Article abstract of DOI:10.1016/j.jorganchem.2007.06.045

The feasibility of hydrocarboxylating carbonyl and imino derivatives by the two-step process of epimetallation and carbonation has been demonstrated with the model substrates of 9-fluorenone and 9-fluorenone anil. With lithium vanadium dihydride as the epimetallating agent, such hydrocarboxylation has led to a 75% yield of 9-hydroxy-9-fluorenecarboxylic acid and a 65% yield of 9-(N-phenylamino)-9-fluorenecarboxylic acid, respectively. Some initial success in extending the scope of this reaction to other substrates, such as benzophenone, has been achieved by using other epimetallating agents, like the presumed LiV(CH₃)₂ and Ti(OPrⁱ)₂. A brief review of the processes and organic synthetic applications of epimetallation and transfer epimetallation of C-C π-bonds is offered as background.

Full text of DOI:10.1016/j.jorganchem.2007.06.045

Journal of Organometallic Chemistry 692 (2007) 4647–4653
www.elsevier.com/locate/jorganchem
The epimetallation and carbonation of carbonyl and imino derivatives:
q
Epivanadation route to 2-amino and 2-hydroxy acids
a,
a
b
John J. Eisch *, Paul O. Fregene , John N. Gitua
a
Department of Chemistry, The State University of New York at Binghamton, Binghamton, NY 13902-6000, USA
b
Chemistry Department, Drake University, 207 University Avenue, Des Moines, Iowa 50311, USA
Received 29 March 2007; received in revised form 7 June 2007; accepted 7 June 2007
Available online 29 June 2007
Dedicated to Professor Gerhard Erker on the occassion of his 60th birthday.
Abstract
The feasibility of hydrocarboxylating carbonyl and imino derivatives by the two-step process of epimetallation and carbonation has
been demonstrated with the model substrates of 9-fluorenone and 9-fluorenone anil. With lithium vanadium dihydride as the epimetal-
lating agent, such hydrocarboxylation has led to a 75% yield of 9-hydroxy-9-fluorenecarboxylic acid and a 65% yield of 9-(N-phenyla-
mino)-9-fluorenecarboxylic acid, respectively. Some initial success in extending the scope of this reaction to other substrates, such as
benzophenone, has been achieved by using other epimetallating agents, like the presumed LiV(CH3)2 and Ti(OPri)2. A brief review of
the processes and organic synthetic applications of epimetallation and transfer epimetallation of C–C p-bonds is offered as background.
Ó 2007 Elsevier B.V. All rights reserved.
Keywords: Hydrocarboxylation; Epimetallation of C@E bond (E = O, N–R); Carbonation; Lithium vanadium(I) dihydride; Presumed lithium dimeth-
ylvanadate(I)
1. Introduction
to have on organic synthesis [3]. Ever since, every new
preparation or type of carbon–metal r-bond has been
seized upon by organic chemists, eager to learn what inser-
tions of p-bonded substrates could be achieved. The most
recent example of such stupendously successful research
has been Karl Ziegler’s synthesis of unsolvated aluminum
alkyls and his discoveries of the multi-insertions of olefins
and acetylenes into C–Al or into the ensuing carbon–tran-
sition metal bonds [4]. From these seemingly simple studies
of C–M bond insertions whole new vistas of organic syn-
thesis and polymerization processes have unfolded.
1.1. Leitmotiv of this festschrift and its relation to organic
synthesis with organometallics
The theme of this special issue dedicated to Gerhard
Erker, ‘‘Insertion Chemistry of the Metal–Carbon Bond’’,
celebrates both Professor Erker’s prominent research con-
tributions to this field, as well as this key reaction itself,
which has continually fascinated organic chemists since
the time of Frankland [1]. The studies of Frankland, Butle-
rov, Zelinsky, Reformatsky and their students with zinc
alkyls and carbonyl derivatives [2] had set the stage for
the revolutionary impact that the Grignard reagent was
1.2. Epimetallation of carbon–carbon p-bonds and the sigma
C–M bond character of such reaction products
q
Part 42 of the series, ‘‘Organic Chemistry of Subvalent Transition
Over the last two decades the ubiquitous transition
metal p-complexes (3) formed between subvalent transition
salts Mnt Lm (1) and C@C or C„C linkages (2) have come
to be recognized as varying in structure from principally
Metal Complexes; for the previous Part 41, see J.J. Eisch, J.N. Gitua,
Organometallics 26 (2007) 778 (Ref. [13b]).
*
Corresponding author. Tel.: +1 607 777 4261; fax: +1 607 777 4865.
E-mail address: jjeisch@binghamton.edu (J.J. Eisch).
0022-328X/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2007.06.045

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J.J. Eisch et al. / Journal of Organometallic Chemistry 692 (2007) 4647–4653
O
(8)
R
C
−
OMe
EtH
Et2Ti(OPri)2
Ti
6
(OPri)2
Ti(OPri)2
OMe
R
O
7
H3O+
i
−
MgBr(OPr )
2 EtMgBr (5)
Ti(OPri)4
OH
R
4
9
Scheme 1.
that of a p- or g2-complex (3a) to that of a metallacyclo-
propane or -cyclopropene ring with significant r C–M
bonding and an increase of the oxidation number of Mtn
toward Mnt þ2 (3b) (Eq. (1)). The relative importance of res-
onance structures 3a and 3b can be assessed in specific cases
by analyzing structural information for those complexes
that can be isolated or by determining the chemical proper-
ties of such complexes in solution. Such an analysis has
been carried for a number of nickel, titanium, zirconium,
chromium and vanadium complexes with the conclusion
that the metallacyclopropane (-cyclopropene) structure
(3b) is in better accord with the observed physical and
chemical properties [5,6].
Since in many of the cases of the complex formation
according to Eq. (1), with TiE2 [6], ZrCl2 [11], HfCl2 [11],
CrCl [12], VCl [13], Ni0 Æ Ln [14], LiCrH2 [15] and LiVH2
[13a], the adduct 3 has displayed the physical and chemical
properties of a three-membered metallocycle 3b, we have
proposed the term of epimetallation for the reaction of 1
with 2 to produce 3b [5]. This term has its origin and anal-
ogy with the reaction of epoxidation in organic chemistry,
by which a neutral O from O2 or a peroxyacid is added
across a carbon–carbon p-bond.
1.3. Epimetallations in organic synthesis
Impressed by the fundamental importance of epititana-
tions in the Kulinkovich cyclopropanol synthesis, we have
been motivated to explore epimetallations of olefins and
acetylenes with such diverse reagents as TiCl2, ZrCl2,
HfCl2, CrCl, VCl, LiCrH2 and most recently LiVH2, as
well as their R2MtE2 derivatives in transfer epimetallations
(for reviews, consult Ref. [5,16]). The generalized metalla-
cyclopropanes or -cyclopropenes arising from such epimet-
allations, 14, have been shown to undergo an impressive
array of high-yielding, often stereoselective insertions of
unsaturated substrates into the strained metal–carbon r-
bond. A ‘‘palette’’ of useful reactions is depicted in Scheme
3 (products after hydrolysis).
Mtn Lm
+
R
C
C
R
R
C
C
R
R
C
C
R
2
1
Mtn+2
Mtn
3a
3b
ð1Þ
The first experimental suggestion that a metallacyclo-
propane could be a critical intermediate in transition
metal-mediated organic synthesis was that of the Kulinko-
vich group in their report of an astonishing high-yielding
cyclopropanol synthesis [7] (Scheme 1). The interaction of
titanium(IV) isopropoxide (4) with two or more equiva-
lents of EtMgBr (5) at ꢀ78 °C was proposed to lead to
Et2Ti(OPri)2 (6), whose decomposition would provide 7,
the so-called Kulinkovich intermediate. Reaction of the
two C–Ti bonds of 7 with the ester 8 would produce ulti-
mately the cyclopropanol 9.
The likelihood of this mechanistic path was corrobo-
rated in our group by the synthesis of the presumed inter-
mediate 7 in an independent way [6], namely the transfer
epimetallation of ethylene by BuTi(OPri)2 with the loss of
the butyl groups (10 ! 7). (For the experimental evidence
supporting the occurrence of transfer epititanations, please
consult Ref. [8,9]). Proof that 7 has two distinct C–Ti
bonds follows from the successive reactions of two different
electrophiles, benzonitrile and CO2, to produce upon
hydrolysis keto acid 13, logically via 11 and 12. The final
product 13 is not explicable without the intermediacy of
7 [6,10] (see Scheme 2).
1.4. Epimetallations of carbonyl and imino groups
The aforementioned success with the epimetallation and
derivative formation of olefins and acetylenes has stimu-
lated us to apply such reactions to polar p-bonds, such as
C@O, C@N or C„N groups. Our earliest attempt to real-
ize such a process was with benzophenone (15) and
LiCrH2.1 Treatment of 15 with LiCrH2 and subsequent
treatment with D2O gave principally dideuterio 17. Thus
the main reaction was one of epichromation to produce
1
This first hydrocarboxylation, via epichromation and subsequent
carbonation, was achieved in 2000 by J.J. Eisch and F.A. Owuor,
subsequent to the publication of the preparation and properties of LiCrH2
in Ref. [15] and this work was cited in Ref. [5].

J.J. Eisch et al. / Journal of Organometallic Chemistry 692 (2007) 4647–4653
4649
Ph−C≡N
(1 equiv.)
CO2
Ti(OPri)2
Ph
O
Ph
Ti
N
N
O
(OPri)2
Ti
7
11
(OPri)2
12
−
2 Bu
H2C=CH2
H3O+
O
Bu2Ti(OPri)2
OH
Ph
10
O
13
Scheme 2.
R
R
R
R
R
R
H
CO2
R'−C N
≡
Mtn+2
Lm
H
C
O
O
C
R'
OH
14
→
O
Me3N
1 equiv.
R'−C
≡C−H
R
H
H
R
R
R
D2O
O
R'
R'
R
R
D
D
Scheme 3. Scheme 3 exemplifies such insertions with the generalized epimetallated product 14, although in actuality a specific transformation may have
been achieved via the epimetallation of any olefin or acetylene.
LiCrH2
2. Results and discussion
15
15
H2
Our recent synthesis and characterization of the analo-
gous lithium vanadium(I) dihydride, LiVH2 (21) as a birad-
ical vanadium reagent2 have shown it to have similar
epimetallating action to LiCrH2 but having much less the
tendency to cleave C–O bonds.3
In the present study we have explored the utility of lith-
ium vanadium(I) dihydride, LiVH2 (21), for the hydrocarb-
oxylation of carbonyl and imino derivatives in useful yields
and with minimal formation of deoxyacids. Our model
substrates for stepwise epivanadation and carbonation
have been 9-fluorenone (22) and 9-fluorenone anil (23), as
treated first with 2 equiv. of LiVH2 (21) and then with
CO2, as shown in Scheme 5. Epivanadation of either 22
Cr− Li+
O
Ph2C
Cr− H L i
+
O
Ph2C
H
16
18
1. CO2
2. H3O
D2O
O
+
D2O
O
O
Ph2C
Ph2C
Ph2C
OH
20
C
OH
D
D
H
D
19
17
Scheme 4.
2
The gasometric, infrared spectral and chemical characterization of 21
16 and not of hydrochromation to yield 18. Were 18 to
have been present, D2O treatment would have yielded 19,
a product not formed (Scheme 4). Carbonation of 16 at
low temperatures did provide benzilic acid (20), up to
65%, but always admixed with variable amounts of diphe-
nylacetic acid, i.e., deoxygenated 20.1
as having the empirical formula of LiCrH2 is given in Ref. [13a]. The
detailed EPR investigation of 21 establishing it as the lithium salt of the
linear biradical VH2 anion will also be described in the next publication in
this series (Ref. [13a]).
As a typical example, LiCrH2 cleaves dibenzofuran and, at a slower
rate, the solvent THF, so that o-phenylphenol and 1-butanol result upon
3
hydrolysis. Under similar conditions, LiVH2 cleaves neither ring.

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J.J. Eisch et al. / Journal of Organometallic Chemistry 692 (2007) 4647–4653
D (H)
D (H)
21
LiVH2 (
)
D2O
E
E
E
(H2O)
V −
H2
Li+
22
23
24
25
26
: E = O
: E =N
: E = O
: E = NPh
−Ph
1. CO2
2. H3O+
O
C
OH
EH
27
28
: E = O
−
: E = N Ph
Scheme 5.
Ph
C
Ph
Ph
LiVH2 (21)
?
O
V − H Li+
C
O
H
C
O
R
R
V −
Me
H2
Li
30
31
15 : R = Ph
29 : R = Me
1. CO2
2. H3O+
H2O
R
C
Ph
O
C
H
C
OH
Ph
OH
Me
32
OH
33a : R = Ph
33b : R = Me
Scheme 6.
or 23 and treatment of respective aliquots with D2O
showed that 9-fluorenol (25) and 9-(N-phenylamino)fluo-
rene (26) had formed in yields of 84% and 95%, respec-
tively, with the C9 center deuteriated in over 90%. Thus,
epimetallated intermediates of the type 24 had been suc-
cessfully formed and maintained in the reaction mixtures.
Subsequent carbonation and hydrolysis produced 75% of
27 and 65% of 28 in nonoptimized yields (Scheme 5).
Similar reactions between 2:1 molar mixtures of LiVH2
(21) and either benzophenone (15) or acetophenone (29)
gave up to 80% of the secondary alcohol, 32, upon hydro-
lysis but separate treatment of such reaction mixtures with
D2O revealed that 32 was about 50:50 mixtures of
PhRCD–OD and PhRCH–OH. That the crucial C–V bond
in the epimetallated intermediate 30 was largely lost, possi-
bly via 31, was confirmed by carbonation. With benzophe-
none benzilic acid (33a) was formed in only 28% yield and
9% of diphenylacetic acid was produced as a by-product.
With acetophenone the yield of 2-hydroxy-2-phenylprop-
ionic acid (33b) was decreased to 22% (Scheme 6).
The failure of this epivanadation–carbonation sequence
could be circumvented for benzophenone by using
LiV(CH3)2 (34) in place of LiVH2 (21). Having no H atoms
directly on the vanadium center, the intermediate involved

J.J. Eisch et al. / Journal of Organometallic Chemistry 692 (2007) 4647–4653
4651
here, similar to 30, should be less prone to the hydrogeno-
lytic rearrangement of 30–31. Indeed, this assumption
appears to be the case: the yield of benzilic acid now rose
to 65% with no contamination by any diphenylacetic acid.
However, a similar treatment of acetophenone with 34 fol-
lowed by carbonation did not increase the yield of 33b.
Hence, we have now begun to extend our studies to the
use of neutral metallating reagents, such as tributylvana-
dium, vanadium(I) chloride, titanium(II) isopropoxide and
dibutyltitanium diisopropoxide. We have thereby found
that titanium(II) isopropoxide can epititanate benzophe-
none quantitatively to give, upon hydrolysis, benzhydrol,
without producing any benzopinacol, the reductive dimer
[6]. This epimetallated product has now been shown to
undergo carbonation to yield benzilic acid cleanly and exclu-
sively in 40% yield. By employing other neutral vanadium or
titanium reagents for the epimetallation of benzophenone,
as well as for other carbonyl and imino derivatives, we aspire
to arrive at a more general process for producing 2-hydroxy-
or 2-amino acids from ketones or imines.
Packard instrument, model 4890, having a 30 m SE-30 cap-
illary column, respectively. Melting points were determined
on a Thomas–Hoover Unimelt capillary melting point
apparatus and are uncorrected.
The VCl3, VCl4, methyllithium in ethyl ether and n-
butyllithium in hexane were obtained from commercial
sources, as were 9-fluorenone and benzophenone, in at
least 97% purity. The 9-fluorenone anil, m.p. 88 °C, was
prepared from 9-fluorenone and aniline by a published
method [18].
4.2. Preparation of lithium vanadium(I) dihydride (21) from
vanadium(IV) chloride
Although LiVH2 (21) can be prepared from the interac-
tion of either VCl3 or VCl4 with appropriate equivalents of
n-butyllithium in THF and the resulting reagent 21 in solu-
tion has very similar properties, the reagent 21 resulting
from VCl4 is more stable upon solvent removal: samples
of 21 isolated by the VCl4-route consistently give
2.5 0.1 equiv. of H2 at STP by gasometric analysis with
glacial acetic acid, while solvent-free samples of 21 isolated
from the VCl3-method give considerably less hydrogen
upon such analysis (<2 equiv. H2). Therefore, the prepara-
tion of 21 by the VCl4-route is described here.
To a solution of VCl4 (920 mg, 4.8 mmol) in 30 mL of
THF at ꢀ78 °C was slowly added n-BuLi (14.9 mL,
23.8 mmol., 1.6 M in hexane) and the resulting mixture
allowed to stir for 30 min. The solution was then rapidly
brought to RT and stirred for 2 h, during which time the
color changed from reddish brown to black. A solution
of the desired carbonyl or imino substrate in THF was then
introduced.
3. Conclusion
We have demonstrated the feasibility of achieving the
hydrocarboxylation of a number of sterically substituted
ketones and an imine to give useful yields of 2-hydroxy
and 2-amino acids, respectively, by the two-step process
of epivanadating the C@E linkage (E = O, NR) with
LiVH2 or LiV(CH3)2 and then carbonating the vanadaoxa-
or vanadaazacyclopropane intermediate. Further studies
using vanadium(I) or titanium(II) complexes as the direct
epimetallating agent or dibutyltitanium diisopropoxide as
the transfer-epimetallating agent offer the possibility of
extending the applicability of such a hydrocarboxylation
process.
4.3. Preparation of lithium dimethylvanadate(I) (34)
4. Experimental
Anhydrous VCl3 (750 mg, 4.8 mmol) in 30 mL of THF
at ꢀ78 °C was admixed with methyllithium (11.9 mL,
19.1 mmol, 1.6 M in ethyl ether) and the mixture then stir-
red for 30 min. After being brought to RT and then stirred
for 2 h, the mixture turned from purple to black. Appropri-
ate gasometric analyses of reagent 34 have yet to be per-
formed and its suggested structure as lithium
dimethylvanadate(I) (34) is based upon the analogous reac-
tion of VCl3 with 4 equiv. of n-BuLi, where successively
LiV(n-Bu)4, then LiV(n-Bu)2 and finally LiVH2 would be
formed. With the methylated analog, LiV(CH3)2 would
be the final product, since this intermediate cannot undergo
b-hydride elimination. Also when admixed with ketones, 34
epimetallates the C@O group and does not insert the C@O
group into a V–CH3 bond.
4.1. Instrumentation, analysis and starting reagents
All reactions were carried out under a positive pressure
of anhydrous, oxygen-free argon. All solvents employed
with organometallic compounds were dried and distilled
from a sodium metal–benzophenone ketyl mixture prior
to use [17]. The IR spectra were recorded with a Perkin-
Elmer instrument, model 457 and samples were measured
either as mineral oil mulls or as KBr films. The NMR spec-
tra (1H and 13C) were recorded with a Bruker spectrometer,
model EM-360, and tetramethylsilane (Me4Si) was used as
the internal standard. The chemical shifts reported are
expressed in the d-scale and in parts per million (ppm) from
the reference Me4Si signal. The GC/MS measurements and
analyses were performed with a Hewlett–Packard GC
5890/Hewlett–Packard 5970 mass-selective detector instru-
ment. The gas chromatographic analyses were carried out
with a Hewlett–Packard instrument, model 5880, provided
with a 6 ft. OV-101 packed column or with a Hewlett–
4.4. Preparation of titanium(II) isopropoxide
To a solution of titanium(IV) isopropoxide (5.95 mL,
20 mmol) dissolved in anhydrous, deoxygenated THF
(30 mL) at ꢀ78 °C was added slowly n-butyllithium

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J.J. Eisch et al. / Journal of Organometallic Chemistry 692 (2007) 4647–4653
(25 mL in hexane, 40 mmol) whereupon the solution
turned light brown and then brown. The reaction mixture
was stirred overnight (18 h) as the reaction temperature
was allowed to rise to room temperature. At this point, a
black solution of titanium(II) isopropoxide (22) was
obtained [6].
9-Fluorenecarboxylic acid
1H NMR: 7.55 (d, 2H), 7.65 (d, 2H), 7.40–7.20 (m, 6H),
4.85 (s, 1H) ppm.
13C NMR: 171.6, 141.1, 140.7, 127.7, 127.1, 125.5,
119.9, 53.1 ppm.
4.5. Reaction of lithium vanadium dihydride (21) with 9-
fluorenone (22)
4.6. Reaction of lithium vanadium dihydride (21) with 9-
fluorenone anil (23)
4.5.1. Workup with D2O
When a 1:2 mole ratio of 22 and 21 was employed at
RT, the reaction led to the disappearance of any coupled
products and an increase in 25. Thus a solution of LiVH2
(21) (3.9 mmol) in 30 mL THF was allowed to react with
a solution of 9-fluorenone (22) (350 mg, 1.9 mmol) in
10 mL THF and allowed to stir for 12 h from ꢀ78 °C to
room temperature. Hydrolytic workup of the reaction mix-
ture yielded 690 mg of a pale yellow solid. The crude prod-
uct was then washed with pentane to give 30 mg of 12% of
fluorene and 4% of unreacted 9-fluorenone, while the pen-
tane-insoluble residue was found to be 9-fluorenol 25 (84%
yield).
4.6.1. Workup with D2O
The deuteriolytic workup of a 1:2 mixture of 23 and 21 in
THF, conducted analogously with the corresponding 9-flu-
orenone experiment (Section 4.5) showed that the 9-(N-phe-
nylamino)fluorene was 95% dideuteriated in the form of 26.
4.6.2. Workup with carbonation
A solution of 9-fluorenoneanil (23) (80 mg, 0.5 mmol) in
5 mL tetrahydrofuran was allowed to react with a solution
of LiVH2 (21) (1.0 mmol) in 5 mL tetrahydrofuran at room
temperature for 12 h. The resulting mixture was then car-
bonated with dry carbon dioxide at ꢀ78 °C and gradually
brought to room temperature over 12 h to give after hydro-
lytic workup 65% of 9-(N-phenylamino)-9-fluorenecarb-
oxylic acid (28). Structural elucidation of 28 was achieved
In a separate experiment designed to establish the source
of the benzhydryl C9–H in 25 a solution of LiVH2
(4.8 mmol) (21) in 40 mL was again allowed to react with
9-fluorenone (22) (440 mg, 2.4 mmol) in 10 mL THF at
room temperature for 12 h. Workup of both halves of the
reaction mixture, using ordinary water and deuterium
1
by H, 13C and, decisively, by electron-spray mass spec-
trometry, in order to observe the parent ion peak of 324
(301 + Na+ complex).
1
oxide, respectively, gave pale yellow solids. The H NMR
spectrum of the reaction solution worked up with D2O
showed the presence of 82% 9,O-dideuterio-9-fluorenol
(25).
1H (CDCl3) d: 7.81–7.98(d, 2H), 7.46–7.23(m, 8H),
6.83(t, 2H), 6.52(t, 1H), 6.07(d, 1H) ppm.
13C (CDCl3) d: 176.7, 143.6, 141.1, 134.7, 129.4, 128.6,
128.1, 123.7, 120.6, 118.1, 114.6, 70.9 ppm. MS (electro-
spray with NaI, m/e): 165.1, 181.1, 109.0, 210.1, 256.1,
302.1, 303.1, 324.1 (M+ + 23 of Na+).
4.5.2. Workup with carbonation
The presence of a carbon–vanadium bond in the oxava-
nadacyclopropane intermediate, established by incorpora-
tion of deuterium at the C9 carbon in 25, encouraged the
investigation of the reactivity of such bonds to carbon
dioxide. Thus a solution of LiVH2 (21) (8.9 mmol) in
120 mL THF was allowed to react with a solution of 9-flu-
orenone (22) (4.5 mmol, 810 mg) in 20 mL THF room tem-
perature for 12 h. The resulting reaction mixture was then
carbonated using a stream of dry carbon dioxide at ꢀ78 °C
and left to warm up to room temperature for 7 h to give
810 mg of a pale yellow solid after hydrolytic workup
and isolation from the aqueous layer. The 1H and 13C
NMR spectra recorded in DMSO-d6 showed the presence
of 75% 9-hydroxy-9-fluorenecarboxylic acid (27) and 6%
of 9-fluorenecarboxylic acid; these products were identified
by NMR spectral comparison with spectra of authentic
samples.
4.7. Epivanadations of benzophenone and acetophenone with
lithium vanadium(I) dihydride or lithium
dimethylvanadate(I)
These epivanadations and their workup by carbonation
were conducted analogous to the foregoing procedures for
9-fluorenone and 9-fluorenone anil. The benzilic acid and
2-hydroxy-2-phenylpropionic acid products were identified
by NMR spectral comparison with spectra of authentic
samples.
4.8. Epititanation of benzophenone with titanium(II)
isopropoxide (22) and subsequent carbonation
9-Hydroxy-9-fluorenecarboxylic acid (27)
A solution of 20 mmol of titanium(II) isopropoxide gen-
erated in 60 mL of THF–hexane (Section 4.4) and 10 mmol
of benzophenone (15) (10 mmol) was cooled to ꢀ78 °C and
treated with a steady stream of dry CO2 gas as the temper-
1H NMR: 7.1–7.6, (m, 4H); 7.8 (d, 2H).
13C NMR: 82.27, 120.09, 123.94, 125.66, 127.83, 140.26,
146.95, 173.91.

J.J. Eisch et al. / Journal of Organometallic Chemistry 692 (2007) 4647–4653
4653
[2] E. Krause, A. von Grosse, Die Chemie der metallorganischen
Verbindungen, Verlag Borntraeger, Berlin, 1937, pp. 61–68; 114–120.
[3] M.S. Kharasch, O. Reinmuth, Grignard Reactions of Nonmetallic
Substances, Prentice-Hall, New York, 1954, 1384pp.
[4] J.J. Eisch, in: E.W. Abel, F.G.A. Stone, G. Wilkinson (Eds.),
Comprehensive Organometallic Chemistry, vol. 1, Pergamon, 1982
(Chapter 6).
[5] J.J. Eisch, J. Organomet. Chem. 617–618 (2001) 148.
[6] J.J. Eisch, J.N. Gitua, P.O. Otieno, X. Shi, J. Organomet. Chem. 624
(2001) 229.
ature of the reaction mixture was raised to RT over 3 h.
Thereafter, the reaction mixture was carbonated continu-
ously as the solution was maintained at reflux for 3 h.
Hydrolytic workup with aqueous N–HCl yielded an
organic extract. This solution was extracted with aqueous
NaOH. The NaOH aqueous extract was acidified with
aqueous N–HCl to precipitate the pure benzilic acid, m.p.
148–150 °C. Two identical runs of this reaction gave yields
of 39% and 40% of this acid.
[7] O.G. Kulinkovich, S.V. Sviridov, D.A. Vasilevski, T.S. Prityckaja,
Zh. Org. Khim. 25 (1989) 2245.
[8] J.J. Eisch, J.N. Gitua, Organometallics 22 (2003) 24.
[9] J.J. Eisch, J.N. Gitua, Organometallics 22 (2003) 4172.
[10] J.J. Eisch, A.A. Adeosun, J.N. Gitua, Eur. J. Org. Chem. (2003)
4721.
[11] J.J. Eisch, Xi. Shi, F.A. Owuor, Organometallics 17 (1998) 5219.
[12] J.J. Eisch, J.R. Alila, Organometallics 18 (1999) 2930.
[13] (a) J.J. Eisch, P.O. Fregene, D.C. Doetschman, manuscript in
preparation;
Acknowledgements
The foregoing research was conducted with the financial
support of the Boulder Scientific Company and a Senior
Scientist Award to J.J.E. from the Alexander von Hum-
boldt Stiftung of Bonn, Germany for a sabbatical leave
spent at the Technische Universita¨t Munchen and in tour-
¨
(b) J.J. Eisch, J.N. Gitua, Organometallics 26 (2007) 778.
[14] J.J. Eisch, X. Ma, K.I. Han, J.N. Gitua, C. Kruger, Eur. J. Inorg.
¨
ing German universities during the spring of 2006 while lec-
turing on the organic chemistry of subvalent transition
metal complexes.
Chem. (2001) 77.
[15] J.J. Eisch, J.R. Alila, Organometallics 19 (2000) 1211.
[16] J.J. Eisch, A.A. Adeosun, S. Dutta, P.O. Fregene, Eur. J. Org. Chem.
(2005) 2657.
References
[17] J.J. Eisch, Organometallic Syntheses, vol. 2, Academic Press, New
York, 1981, pp. 3–37.
[18] G. Reddelien, Ber. Dtsch. Chem. Ges. 46 (1913) 2721.
[1] E. Frankland, Liebigs Ann. Chem. 71 (1849) 171.