Enantiopure chiral (2,4,6-triisopropylbenzoyl)oxy-[D1] methyllithium: Configurational stability, reactions, and mechanistic studies

Article abstract of DOI:10.1021/jo802625q

The configurational stability of enantiopure chiral (2,4,6- triisopropylbenzoyl)oxy-[D₁]methyllithium generated by a tin-lithium exchange was tested on the macroscopic time scale, employing trapping experiments with benzaldehyde. It was found t

Full text of DOI:10.1021/jo802625q

Enantiopure Chiral
(2,4,6-Triisopropylbenzoyl)oxy-[D1]methyllithium: Configurational
Stability, Reactions, and Mechanistic Studies
Dagmar C. Kapeller and Friedrich Hammerschmidt*
Institute of Organic Chemistry, UniVersity of Vienna, Wa¨hringerstrasse 38, A-1090 Vienna, Austria
friedrich.hammerschmidt@uniVie.ac.at
ReceiVed NoVember 27, 2008
The configurational stability of enantiopure chiral (2,4,6-triisopropylbenzoyl)oxy-[D1]methyllithium
generated by a tin-lithium exchange was tested on the macroscopic time scale, employing trapping
experiments with benzaldehyde. It was found to be configurationally stable for minutes at -78 °C and
to be an appropriate substitute for the carbamoyloxy-substituted analogue in terms of cleavage. Its addition
to several electrophiles was studied, leading to a protocol for the preparation of chiral primary deuterated
alcohols, exemplified by the synthesis of 2-phenyl-[1-D1]ethanol of 98% enantiomeric excess (ee).
Furthermore, the mechanisms of enantiomerization and decomposition of this aroyloxymethyllithium
were addressed by spectroscopic investigations of labeled substrates. It decomposed by formation of
ethylene (minor pathway) and homologation of n-BuLi by up to three methylene units, followed by an
exchange for a butyl group of Bu4Sn.
Introduction
Organolithiums of diverse structures are the most important
of all organometallic reagents, due to their easy availability,
secure handling, and high reactivity with many functional
groups. Their selectivity has led to multifold applications, made
even more attractive by the development of configurationally
stable species. The first to report on an enantiomerically enriched
organolithium was Letsinger, who described the preparation of
2-lithiooctane in 1951.1 The breakthrough came when Still and
Sreekumar found that R-oxy-substituted organolithiums were
configurationally stable up to -30 °C.2 They turned out to be
more configurationally stable than their nitrogen- and sulfur-
substituted analogues. Finally, Hoppe’s group discovered that
primary alcohols with a carbamoyl protecting group (e.g., Cbx,
Cby) based on an oxazolidine could be metalated highly
FIGURE 1. Known (2,4,6-triisopropylbenzoyl)oxy-substituted alkyl-
lithiums.
enantioselectively R to oxygen by using s-BuLi/(-)-sparteine.3,4
Beak et al. reported the synthesis of 2,6-disubstituted benzoates
of primary alcohols, their lithiation to dipole-stabilized carban-
ions such as 1 (Figure 1), their reaction with various electro-
philes, and their reductive cleavage with LiAlH4.5,6 Later studies
focused on the configurational stability and stereochemistry of
reactions of tertiary benzyllithiums 2,7,8 3,9 and 4,9 which proved
(1) Letsinger, R. L. J. Am. Chem. Soc. 1950, 72, 4842.
(2) Still, W. C.; Sreekumar, C. J. Am. Chem. Soc. 1980, 102, 1201–1202.
(3) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem. 1990, 102, 1457-1459;
Angew. Chem., Int. Ed. Engl. 1990, 29, 1422-1424.
(4) (a) Hoppe, D.; Hense, T. Angew. Chem. 1997, 109, 2376-2410; Angew.
Chem., Int. Ed. Engl. 1997, 36, 2282-2316. (b) Hoppe, D.; Christoph, G. In
The Chemistry of Organolithium Compounds, Rappoport, Z., Marek, I., Eds.;
John Wiley & Sons Ltd.: Chichester, U.K., 2004; Part 2, pp 1055-1164.
(5) Beak, P.; McKinnie, B. G. J. Am. Chem. Soc. 1977, 99, 5213.
(6) Beak, P.; Carter, L. G. J. Org. Chem. 1981, 46, 2363–2373.
(7) Hammerschmidt, F.; Hanninger, A. Chem. Ber. 1995, 128, 1069–1077.
2380 J. Org. Chem. 2009, 74, 2380–2388
10.1021/jo802625q CCC: $40.75 2009 American Chemical Society
Published on Web 02/20/2009

Chiral (2,4,6-Triisopropylbenzoyl)oxy-[D1]methyllithium
SCHEME 1. Preparation of Stannane Precursors 6 and
[D1]6a
SCHEME 2. Testing of Transmetalation/Quenching in the
Unlabeled Seriesa
a DIAD ) diisopropyl azodicarboxylate; Ar ) 2,4,6-(i-Pr)3C6H2.
a Ar ) 2,4,6-(i-Pr)3C6H2.
to be less configurationally stable than their (N,N-diisopropyl-
carbamoyl)oxy-substituted analogues.10,11
TABLE 1. Reaction Conditions and Yields of 7
To expand the scope of the chiral heteroatom-substituted
methyllithiums (XCHDLi), which so far include carbamoyl-
oxy,12 silyloxy-,13 germyloxy-,13 2-alkenyloxy-,13 and chloro-
substituted14 ones, we decided to prepare the (2,4,6-triisopro-
pylbenzoyl)oxy-substituted version [1-D1]1 as well.
Besides studying its macroscopic configurational stability and
reactions with several electrophiles, we wanted to explore its
potential for the preparation of enantiopure chiral primary
deuterated alcohols. Finally, we addressed its mechanisms of
enantiomerization and decomposition.
entry
solvent
temp (°C)
time (min)
yielda (%)
1
Et2O/TMEDA
Et2O/TMEDA
Et2O/TMEDA
THF
-78
-78
-50
-50
0
3
3
3
3
80
93
55
78
53
2b
3
4
5c
Et2O/TMEDA
a Determined from 1H NMR spectra of the chromatographed products
(contaminated with 1-phenylpentanol). b With MeOH as electrophile.
c Benzaldehyde (5 equiv) already present on addition of n-BuLi (5
equiv).
benzaldehyde. It did not matter here as the side product could
be removed at a later stage. To ensure that tin-lithium exchange
was complete before addition of benzaldehyde, the experiment
was repeated with methanol as the trapping agent to give methyl
ester 8 quantitatively (entry 2, Table 1). Otherwise, some
transmetalation could have occurred after the addition of
benzaldehyde. The overall result would then reflect a combina-
tion of macroscopic and microscopic configurational stability
in the labeled series.
When transmetalation and addition to benzaldehyde were
performed at -50 °C in Et2O/TMEDA or THF, the yield was
higher in the latter solvent, having a stabilizing effect on 1
(entries 3 and 4, Table 1). When the reaction temperature was
increased to 0 °C, no alcohol 7 could be isolated, because
carbanion 1 had already decomposed on addition of the
aldehyde. Therefore, the microscopic configurational stability
was addressed at 0 °C by intercepting the short-lived carbanion
with benzaldehyde, which was added before n-BuLi, each in
large excess (entry 5, Table 1). The yield of 7 was 53% and
indicated that the tin-lithium exchange was faster than the
addition of n-BuLi to benzaldehyde and that the carbanion was
long-lived enough at 0 °C to add to benzaldehyde before
chemical decomposition.
The experiments in the labeled series were performed
similarly. To determine the configuration at the deuterium
bearing carbon atom, benzoate [1-D1]7 derived from ester (R)-
[1-D1]6 was converted to diol [2-D1]9. The side product
1-phenylpentanol could now be removed easily by flash column
chromatography from the diol, which was esterified with (S)-
MTPACl to give the bis-(R)-Mosher ester for 1H NMR
spectroscopic analysis (Scheme 3).12 For the sake of clarity it
is more convenient here to give the enantiomeric excess (ee)
for each chiral center individually. As the addition of chiral
carbanion [1-D1]1 to benzaldehyde is not enantioselective, the
benzylic center of [2-D1]9 is always racemic, resulting in a
product with zero diastereomeric excess (de). However, the
configuration at C-2 of [2-D1]9 for entry 1 (Table 2) was mainly
(S) (>97%), resulting in an ee of 95%. Assuming that the
tin-lithium exchange proceeds with retention16 of configuration,
Results and Discussion
Macroscopic Configurational Stability of (2,4,6-Triiso-
propylbenzoyl)oxy-[D1]methyllithium. In analogy to previous
studies, we wanted to prepare enantiopure [1-D1]1 from the
corresponding tributylstannane precursor via tin-lithium ex-
change, easily accessible from enantiopure (99% enantiomeric
excess (ee)) (R)- and (S)-tributylstannyl-[D1]methanol ([D1]5).12
For the optimization of reaction conditions, unlabeled 5 was
reacted with 2,4,6-triisopropylbenzoic acid in a Mitsunobu
reaction15 (SN2) in almost quantitative yield (Scheme 1). The
esterification in the deuterated series proceeded with inversion
of configuration. To investigate the macroscopic configurational
stability of [1-D1]1, we intended to perform several experiments
involving the aging of the organolithium before trapping it with
benzaldehyde as an electrophile. This would allow a direct
comparison with the previously tested carbamoyloxy-substituted
analogue.12 But beforehand, the feasibility of transmetalation
and quenching was established in the unlabeled series (Scheme
2). Therefore, various conditions were tested by changing the
temperature and the solvent (Table 1). The first experiment was
performed in Et2O/TMEDA at -78 °C, and benzaldehyde was
added 3 min after the addition of n-BuLi, which gave racemic
alcohol 7 in an 80% yield. Unfortunately, monoprotected diol
7 could not be separated by flash chromatography from
1-phenylpentanol, which was formed from excess n-BuLi and
(8) Hammerschmidt, F.; Hanninger, A.; Vo¨llenkle, H. Chem.-Eur. J. 1997,
3, 1728–1732.
(9) Hammerschmidt, F.; Hanninger, A.; Peric Simov, B.; Vo¨llenkle, H.;
Werner, A. Eur. J. Org. Chem. 1999, 3511–3518.
(10) (a) Hoppe, D.; Carstens, A.; Kra¨mer, T. Angew. Chem. 1990, 102, 1455-
1456; Angew. Chem., Int. Ed. Engl. 1990 29, 1424-1425. (b) Carstens, A.;
Hoppe, D. Tetrahedron 1994, 50, 6097–6108.
(11) Derwing, C.; Frank, H.; Hoppe, D. Eur. J. Org. Chem. 1999, 3519–
3524.
(12) Kapeller, D.; Barth, R.; Mereiter, K.; Hammerschmidt, F. J. Am. Chem.
Soc. 2007, 129, 914–923.
(13) Kapeller, D. C.; Brecker, L.; Hammerschmidt, F. Chem.-Eur. J. 2007,
13, 9582–9588.
(14) Kapeller, D. C.; Hammerschmidt, F. J. Am. Chem. Soc. 2008, 130, 2329–
2335.
(15) (a) Reviews: Mitsunobu, O. Synthesis 1981, 1-28. (b) Hughes, D. L.
Org. Prep. Proc. Int. 1996, 28, 127–164.
J. Org. Chem. Vol. 74, No. 6, 2009 2381

Kapeller and Hammerschmidt
SCHEME 3. Testing of the Configurational Stability of [D1]1a
a Ar ) 2,4,6-(i-Pr)3C6H2.
TABLE 2. Reaction Conditions and Yields of [1-D1]7
SCHEME 4. Trapping of Oxymethyllithium [1-D1]1 with
Me3SnCl or Et3PbCl, Followed by Transmetalation and
Addition of the Regenerated [1-D1]1 to PhCHO, Starting
from (R)-[1-D1]1a
entry substrate
solvent
temp (°C)/time (min) yielda/ee (%)
1
2
3
4
5
6
(R)-[D1]6 Et2O/TMEDA
(S)-[D1]6 Et2O/TMEDA
(S)-[D1]6 Et2O/TMEDA
(R)-[D1]6 Et2O/TMEDA
(S)-[D1]6 THF
-78/3
-78/180
-50/3
0/-
-78/10
-78/180
88/95
75/73
70/78
59/86
76/98
70/50
(S)-[D1]6 THF
a Determined from 1H NMR spectra of the chromatographed products
(contaminated with 1-phenylpentanol).
benzoyloxymethyllithiums obtained from benzoates (R)-[1-D1]6
and (S)-[1-D1]6, should have (S) and (R) configurations,
respectively. As they are configurationally stable, they will have
to add to benzaldehyde with retention of configuration as proven
by entry 1 (Table 2). It was found that [1-D1]1 did not racemize
in Et2O/TMEDA and THF for short periods of time (3 and 10
min, respectively) at -78 °C (entries 1 and 5 in Table 2). When
the carbanion was aged for 3 h before adding benzaldehyde,
the yields were only slightly reduced, but the ee’s were
significantly lower, in THF even more so than in Et2O/TMEDA
(entries 2 and 6, Table 2). Raising the temperature to -50 °C
caused an erosion of the ee to 78% within only 3 min of aging
of the carbanion (entry 3, Table 2). When the transmetalation
was performed at 0 °C under microscopic conditions, the ee at
C-2 was still 86% (entry 4, Table 2), demonstrating that chiral
oxymethyllithium [1-D1]1 was microscopically configurationally
labile.
In summary, aroyloxy-substituted chiral [1-D1]methyllithiums
were found to be slightly less configurationally stable than their
N,N-diisopropylcarbamoyl analogues but could, under the
appropriate conditions, form monoprotected diols [2-D1]9 with
an ee of up to 98% at the deuterated center on addition to
benzaldehyde.
Trimethyltin and Triethyllead Chloride as Electrophiles.
The stereochemistry concerning the trapping of an organolithium
species is strongly influenced by the electrophile used.16
Aldehydes or H+ usually react under retention of configuration,
while inversion is observed with alkyl, acyl, or stannyl halides.
This effect is especially pronounced with benzyllithiums having
a flattened carbanion.16 In the case of benzaldehyde, we found
exclusive retention of configuration on reaction with (2,4,6-
triisopropylbenzoyl)oxy-[D1]methyllithium. Would this change
if a reagent known to prefer inversion of configuration was used,
even though our carbanion was not a stabilized one? To test
this, we decided to employ trimethyltin and triethyllead chloride
a Ar ) 2,4,6-(i-Pr)3C6H2.
TABLE 3.
Reaction Conditions and Yields of [1-D1]7 Prepared
via Stannane [1-D1]10 or Plumbane [1-D1]11
temp (°C)/time yielda/ee
entry substrate/intermediate
solvent
(R)-[D1]6/(R)-[D1]9 Et2O/TMEDA
(S)-[D1]6/(S)-[D1]9 THF
(S)-[D1]6/(S)-[D1]10 THF
(min)
(%)
1
2
3
-78/3
-78/10
-78/5
62/96
77/38
53/8
a Determined from 1H NMR spectra of the chromatographed products
(contaminated with 1-phenylpentanol).
as electrophiles in a two step reaction sequence (Scheme 4).
Thus, enantiopure stannane [1-D1]6 was transmetalated using
n-BuLi at -78 °C in the respective solvent, and the intermediate
oxymethyllithium [1-D1]1 was trapped with either trimethyltin
or triethyllead chloride (Table 3). To determine whether
retention or inversion of configuration had occurred, stannane
[1-D1]10 and plumbane [1-D1]11 were not isolated but im-
mediately transmetalated, and the oxymethyllithium formed was
quenched with benzaldehyde under conditions where no enan-
tiomerization had been observed before (-78 °C, 5 min). This
gave alcohols [1-D1]7, whose ee’s were secured by reductive
deprotection of [1-D1]7 and esterification of the diols with (S)-
Mosher chloride in pyridine (Scheme 3). Surprisingly, complete
overall retention of configuration (ee of 96%) was observed,
when Et2O/TMEDA was used as the solvent and trimethyltin
chloride as the electrophile, added 3 min after addition of n-BuLi
(entry 1 in Table 3). Consequently, stannylation followed a
retentive course, the same as addition of [1-D1]1 to benzalde-
hyde. Changing the solvent to THF, which was found to lower
the configurational stability of [1-D1]1, the ee of diol [1-D1]7
(16) (a) Reich, H. J.; Borst, J. P.; Coplien, M. B.; Phillips, N. H. J. Am.
Chem. Soc. 1992, 114, 6577–6579. (b) Clayden, J. Organolithiums: SelectiVity
for Synthesis; Tetrahedron Organic Chemistry Series; Pergamon (An imprint of
Elsevier Science): Oxford, 2002; Vol. 23.
2382 J. Org. Chem. Vol. 74, No. 6, 2009

Chiral (2,4,6-Triisopropylbenzoyl)oxy-[D1]methyllithium
SCHEME 5. Transmetalation/Alkylation Sequence with
Stannane 6a
SCHEME 7. Preparation of Enantiopure
2-Phenyl-[1-D1]ethanol-Xanthogenate Routea
a Ar ) 2,4,6-(i-Pr)3C6H2.
SCHEME 6. Transmetalation/Alkylation Sequence with
Heptyl Iodidea
a Ar ) 2,4,6-(i-Pr)3C6H2.
a Ar ) 2,4,6-(i-Pr)3C6H2.
was significantly reduced to 38% with aging of the carbanion
for 10 min (entry 2, Table 3). This result underlines that the
solvent has a significant influence on the configurational stability
of the intermediate oxymethyllithium. Anticipating later results,
we think that one reason for that might be the opening of the
five-membered chelate ring by the stronger lithium-coordinating
effect of THF rather than Et2O in combination with TMEDA,
which is a prerequisite for inversion of configuration of the
carbanion.17 When this experiment was repeated, except that
trimethyltin chloride was replaced by triethyllead chloride,
almost racemic monoprotected diol [1-D1]7 was formed having
an ee of 8% at the deuterium-bearing carbon atom with retention
still predominating slightly.
Preparation of Chirally Labeled Primary Alcohols. We
also envisaged the synthesis of enantiopure primary deuterated
alcohols of known configuration by alkylation of oxymethyl-
lithium [1-D1]1 with alkyl halides. In a preliminary experiment
benzyl bromide was used as a highly reactive electrophile
(Scheme 5).
isolated in a 57% yield. LiAlH4-mediated reduction finally gave
C-1 deuterated 1-octanol, whose ee could be determined via its
(R)-Mosher ester. Comparison of its 1H NMR spectra with those
reported in the literature13 revealed an ee of 29%, which was
probably mainly due to an interfering radical mechanism18 and
to a lesser extent to some enantiomerization on aging of the
enantiopure carbanion before alkylation.
These findings effectively ruled out the preparation of
enantiomerically pure primary deuterated alcohols by alkylation
of aroyloxy-[1-D1]methyllithium with alkyl halides and by
deprotection. To avoid alkylation, we thought of a sequence
involving addition of chiral oxymethyllithium [1-D1]1 to an
aldehyde, followed by deoxygenation to give the 2,4,6-triiso-
propylbenzoate of a primary deuterated alcohol. The most
promising route seemed to be the intermediate formation of a
xanthogenate in a one-pot reaction, reminiscent of the Barton-
McCombie protocol.19
To this end, stannane 6 and later (R)-[D1]6 were transmeta-
lated (THF, -78 °C, 5 min) and the intermediate carbanion was
trapped with benzaldehyde. The lithium alkoxide formed was
reacted with carbon disulfide and subsequently methyl iodide
to give xanthogenate (1S)-[1-D1]15 in an average yield of 79%
(Scheme 7).
But before optimizing deoxygenation, we checked if enan-
tiomerization had occurred at the deuterated center. Therefore,
xanthogenate (1S)-[1-D1]15 was quantitatively reduced with
LiAlH4 to deuterated 1-phenylethane-1,2-diol of 98% ee at C-2
as determined by 1H NMR spectroscopy of the bis-(R)-Mosher
ester.12 Then, unlabeled and labeled 15 were treated with
tris(trimethylsilyl)silane/AIBN20 in toluene at 90 °C to afford
esters 12 and (1S)-[1-D1]12 in 78% yield, which were in turn
deprotected to finally yield 2-phenylethanols (16) (Scheme 7).
At this stage we again determined the ee of deuterated (S)-
[1-D1]16 to rule out enantiomerization during the radical
When performing the transmetalation for 3 min in Et2O/
TMEDA with the nondeuterated stannane 6 and waiting with
the workup for 30 min after addition of benzyl bromide, we
isolated the desired benzyl ester 12 in merely 22% yield.
However, the main product (40%) was methyl ester 8, indicating
that alkylation of methyllithium was possibly slow and not yet
finished before aqueous workup. When THF was used as solvent
and the reaction time for alkylation extended to 3 h, the yield
of 2-phenylethyl benzoate 12 did not improve either (28%).
These disencouraging results induced us to try heptyl iodide as
an alternative electrophile with chiral oxymethyllithim [1-D1]1
(Scheme 6).
In an exploratory experiment with the unlabeled oxymeth-
yllithium, we were able to isolate 57% of unlabeled 13, which
seemed enough to repeat the reaction with labeled stannane (R)-
[D1]6. Transmetalation was performed at -78 °C in THF for
10 min as usual before addition of heptyl iodide, followed by
an aqueous workup 1 h later. The octyl ester [D1]13 could be
(18) Ashby, E. C. Acc. Chem. Res. 1988, 21, 414–421.
(19) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1
1975, 1574–1585. For a review see: (b) Hartwig, W. Tetrahedron 1983, 39,
2609–2645.
(17) Basu, A.; Thayumanavan, S. Angew. Chem., Int. Ed. Engl. 2002, 41,
717–738.
J. Org. Chem. Vol. 74, No. 6, 2009 2383

Kapeller and Hammerschmidt
SCHEME 8. Preparation of Labeled Octanol
(1S)-[1-D1]14-Xanthogenate Routea
1
FIGURE 2. Sections of H NMR spectra (400 MHz, toluene-d8) of
16·MTPA-(R) (top) and (1S)-[1-D1]16·MTPA-(R) (bottom).
a Ar ) 2,4,6-(i-Pr)3C6H2.
mediated step of deoxygenation. Again, the (R)-Mosher esters
were formed and investigated by 1H NMR spectroscopy.
Unlabeled 16·MTPA-(R) showed a tripletic AB system at δ )
4.13 (JAB ) 10.9 Hz, J ) 7.1 Hz). In the labeled series, a
broadened triplet at δ ) 4.10 (J ) 6.6 Hz) was found for the
CHD group. Decoupling of the neighboring CH2 group did not
bring any further information, as the peaks were too broad to
be well separated. No signal was found that could be attributed
to the diastereomeric Mosher ester, indicating that 2-phenyl-
[1-D1]ethanol was enantiomerically pure (Figure 2). This claim
was supported by calculating the relative chemical shifts for
the hydrogens of the AB system in the unlabeled series and
subtracting the deuterium induced isotope shift.21 Chemical
shifts of νA ) 4.123 ppm and νB ) 4.101 ppm were found, the
latter in good agreement with the 4.104 ppm of labeled (1S)-
[1-D1]16·MTPA-(R). There was no significant peak at 4.12 ppm
apart from resonances of the unlabeled compound (2-3%).
After our success with benzaldehyde, we wanted to test this
procedure on an aliphatic aldehyde as well and decided to use
heptanal, as we had a reference sample of the (R)-Mosher ester
for the resulting [1-D1]octanol.13 Thus, the same sequence was
repeated, except that benzaldehyde was replaced by heptanal
(Scheme 8). This time, the yield of xanthogenate 17 was lower
(55-60%) which could be likely due to the enolization of
heptanal by the oxymethyllithium, giving methyl ester 8 isolated
as well (16%). Believing that we did not have to determine the
ee of the xanthogenate directly after our success with 2-phe-
nylethanol, we immediately deoxygenated it, which gave octyl
ester 13 and its deuterated analogue in a 69% yield. Surprisingly,
the latter had an ee of 89% as determined by 1H NMR
spectroscopy of the (R)-Mosher ester of the respective 1-[1-D1]-
octanol {[1-D1]14} obtained after reductive removal of the 2,4,6-
triisopropylbenzoyl group (Scheme 6).
SCHEME 9. Synthesis of Labeled Octane-1,2-diol [1-D]18a
a Ar ) 2,4,6-(i-Pr)3C6H2.
We reasoned that perhaps in this instance the fault lay with
the deoxygenation. Thus, again a sample of xanthogenate (S)-
[D1]13 was reduced to (1S)-[1-D1]octane-1,2-diol, which was
converted to the bis-(R)-Mosher esters (1S,2RS)-[1-D1]18·[MTPA-
(R)]2 (Scheme 8). The Mosher esters diastereomeric at C-2 could
be separated by flash column chromatography. Additionally, we
prepared unlabeled and racemic deuterated reference samples
of diol 18. Therefore, methyl ester 8 was deprotonated with
s-BuLi/TMEDA and quenched with D2O to give 63% of a 5:4
mixture of [D1]8 and 8 (Scheme 9).
This mixture was again treated with s-BuLi and trapped with
heptanal (-78 °C, 2 h), yielding 30% of [1-D]19 (labeled/
unlabeled compound 5:4), which was reduced to diol [1-D]18,
a mixture of four stereoisomeric deuterated octane-1,2-diols and
racemic nondeuterated octane-1,2-diol, with LiAlH4 (see Scheme
8) and transformed into the bis-(R)-Mosher esters for recording
1
reference H NMR spectra. Comparison of these spectra with
those of the bis-(R)-Mosher ester of the 1,2-diol derived from
xanthogenate (1S)-[1-D1]17 allowed unequivocal assignment of
the peaks, especially after reducing the number of relevant
signals by irradiation at 2-H of the diol portion (Figure 3). The
(20) For a review see: (a) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 191–
194. (b) Schummer, D.; Ho¨fle, G. Synlett 1990, 705–706.
(21) Gu¨nther, H. NMR-Spektroskopie; Georg Thieme Verlag: Stuttgart, 1973,
163-165.
2384 J. Org. Chem. Vol. 74, No. 6, 2009

Chiral (2,4,6-Triisopropylbenzoyl)oxy-[D1]methyllithium
SCHEME 11. Synthesis of Regiospecificly 18O Labeled 6a
a Ar ) 2,4,6-(i-Pr)3C6H2.
SCHEME 12. Transmetalation of [18O1]6 and Quenching of
Intermediate Oxymethyllithium with AcOHa
FIGURE 3. Signals of CH2O/CHDO groups in the 1H NMR spectra
(400MHz,CDCl3)of[1-D]18·[MTPA-(R)]2 and(1S)-[1-D1]18·[MTPA-
(R)]2 derived from stannane (R)-[1-D1]6. (A) (1R/S,2R)-[D]18·[MTPA-
(R)]2. (B) (1R/S,2S)-[D]18 · [MTPA-(R)]2. (C) (1R/S,2R)-[D]18 · [MT-
PA-(R)]2 after irradiation at 4.3 ppm. (D) (1R/S,2S)-[D]18 · [MTPA-
(R)]2 after irradiation at 4.3 ppm. (E) (1S,2R)-[1-D1]18 · [MTPA-
(R)]2 of 85% ee at C-1 after irradiation at 4.3 ppm. (F) (1S,2S)-[1-
D1]18 · [MTPA-(R)]2 of 89% ee at C-1 after irradiation at 4.3 ppm.
a Ar ) 2,4,6-(i-Pr)3C6H2.
TABLE 4.
and Quenching of Carbanion with AcOH
Conditions and Yields for Transmetalation of [18O1]6
entry
solvent
temp (°C)
time
yield (%)
1
2
3
THF
Et2O/TMEDA
THF
-78
-50
-30
5 h
5 min
3 min
61
76
12
SCHEME 10. Proposed Mechanism for Enantiomerization
Of (R)-[1-D1]1a
ethylbenzene in a microwave reactor to give doubly 18O-labeled
benzoic acid22 in an 80% yield (79% [18O2], 17% [18O1], 4%
unlabeled, by MS) (Scheme 11).
Benzoic acid [18O2]20 was then coupled with tributylstan-
nylmethanol (5) in a Mitsunobu reaction to yield benzoate
[18O2]21. It was reduced with lithium triethylborohydride to
[18O1]5, which was esterified with 2,4,6-triisopropylbenzoyl
chloride in pyridine. This was followed by transmetalation,
aging, and trapping with acetic acid under various conditions
to yield methyl ester [18O1]8a(86% [18O1], Scheme 12, Table
4).
Mass spectroscopic analysis revealed in all three cases that
the isolated ester was only isotopomer [18O1]8a, thus the carbene
was excluded as an intermediate for enantiomerization of chiral
[D1]1, which is undoubtedly significant at -30 °C beside
chemical decomposition (entry 3, Table 4).
Mechanistic Studies toward the Decomposition of [1-D1]1.
Extensive experience with oxymethyllithium 1 proved it to be
a chemically labile compound. It started to decompose around
-50 °C and rapidly vanished at -30 °C. So far, we had no
conclusive explanation for the mechanism, although we strongly
suspected the formation of ethylene or insertion into the solvent
(e.g., THF), common pathways for the decomposition of
R-heteroatom-substituted organolithiums.23 The analytical method
of choice was 13C NMR spectroscopy. To ease the tracing of
the carbon atom in question, the starting stannane was 13C-
a Ar ) 2,4,6-(i-Pr)3C6H2.
ee of 85% at C-1 was found for (1S)-[1-D1]18·[MTPA-(R)]2,
proving that enantiomerization did not occur during radical
deoxygenation but evidently during addition of the carbanion
to heptanal. We do not have a plausible explanation for this
finding, as intermediate oxymethyllithium [D1]1 is configura-
tionally stable under these conditions. The mechanism that
initially comes to mind is a single electron transfer between
heptanal and oxymethyllithium, which caused enantiomerization
before radical combination. But if that was indeed the case, one
would expect even more enantiomerization with benzaldehyde
as the electrophile, which is not supported by our experiments.
Mechanistic Studies toward the Enantiomerization of
[1-D1]1. None of the mechanisms concerning enantiomerization
of organolithiums in the literature seemed to describe this
particular species, and thus we hypothesized that inversion of
configuration could involve the intermediate formation of lithium
2,4,6-triisopropylbenzoate and deuteromethylene, which could
recombine with either oxygen of the benzoate to give enanti-
omers of [1-D1]1 (Scheme 10).
To demonstrate that, regiospecificly 18O-labeled stannane 6
was prepared starting from oxygen-18 labeled water (87% 18O).
It was reacted with a mixture of benzonitrile and trichlorom-
(22) (a) Tanaka, N.; Araki, M. J. Am. Chem. Soc. 1985, 107, 7780–7781.
(b) Schwab, J. M.; Ray, T.; Ho, C.-K. J. Am. Chem. Soc. 1989, 111, 1057–
1063. (c) Wnuk, S. F.; Chowdhury, S. M.; Garcia, P. I., Jr.; Robins, M. J. J.
Org. Chem. 2002, 67, 1816–1819.
J. Org. Chem. Vol. 74, No. 6, 2009 2385

Kapeller and Hammerschmidt
SCHEME 13. Preparation of 13C-Labeled 6a
followed by an exchange of a butyl group of tetrabutyltin for the
[1-13C1]pentyl group. The time difference between disappearance
of [1-13C1]1 and formation of tributyl-[1-13C1]pentyltin was an
indication for the latter, as the exchange of substituents at tin
seemed to need a higher temperature than the formation of
[1-13C1]pentyllithium.
When we left the NMR tube at ambient temperature over
18 h, the signals of methyl ester [1-13C1]8 disappeared. The
contents of the NMR tube were worked up with dilute HCl and
the crude product was investigated by 13C NMR spectroscopy.
Besides the already expected tributyl-[1-13C1]pentylstannane
(10-30%, roughly estimated from the intensity of the peaks),
also some tributyl-[1,2-13C2]hexylstannane (approximately one-
third of the pentyl analogue) and traces of tributyl-[1,2,3-
13C3]heptylstannane could be detected (Figure 5). This is another
point in favor of the second pathway, as it would be easier
for pentyllithium to attack another molecule of [13C1]1 to
form hexyllithium than exchange for a butyl group of
tetrabutyltin. The products originating from the homologation
of n-BuLi and insertion into tetrabutyltin only accounted for
part of the 13C, most of it went undetected. However, a
mixture of stannanes and 2,4,6-triisopropylbenzoic acid could
be recovered quantitatively.
To study the influence of the alkyllithium on the product
distribution of the decomposition, two more test reactions with
MeLi instead of n-BuLi were performed in a flask. Stannane
[1-13C1]1 was treated with 2.0 and 1.2 equiv of MeLi at -60 °C,
and the reaction mixture was allowed to warm to -10 °C, before
it was worked up under acidic conditions. Surprisingly, the amount
of MeLi did not affect the outcome of the experiments. In analogy
to the results with n-BuLi, a resonance at δ ) 0.76 [J(117/119Sn) )
319.9, 305.2 Hz] was found in the 13C NMR spectrum, revealing
CH313CH2SnBu3 (in about a 5% yield). Again, we were faced with
the fact that most of the label was unaccounted for, about 10% of
it was recovered as methyl ester [1-13C1]8.
a Ar ) 2,4,6-(i-Pr)3C6H2.
labeled. Thus, 2,4,6-triisopropylbenzoic acid (22) was converted
to the potassium salt and alkylated with [13C1]methyl iodide.
The ester formed was metalated and stannylated to give the
required precursor [13C1]5 (Scheme 13).
A sample of 30 mg of this compound was transmetalated at
-78 °C in dry [D8]THF in an NMR tube under argon.
Afterward, NMR spectra (1H, 13C, HSQC, and HMBC) were
recorded at -70, -50, -30, and +20 °C. As expected, the
signal for O13CH2Li could be clearly seen at -70 °C (Figure
4) in the 13C NMR spectrum (100 MHz), where it resonated as
a broad singlet at δ ) 83.6 ppm, shifted to lower field by ∆δ
) 31.5 ppm compared with the unlithiated compound. The
signal at δ ) 52.1 ppm resulted from the methyl group of methyl
ester [1-13C1]8 formed by protonation of [1-13C1]1 due to traces
1
of residual water. The H spectrum showed a broad doublet at
δ ) 3.75 ppm with a rather small coupling constant J ∼ 109
Hz, only 0.05 ppm downfield of [1-13C1]8. To the best of our
knowledge, there are no comparable experimental values for
an aroyloxy-substituted organolithium found in the literature.
But there is an example from Boche et al., who reported that
the CH2O group of lithiated methyl N,N-diisopropyl carbamate
in Et2O resonated at 67.3 ppm, just shifted to a lower field by
7.0 ppm compared with the respective unlithiated species.24 This
rather small difference was attributed to the dipole-stabilized
lithium-containing chelate ring, which was assumed to be the
prevailing structure in Et2O.24 On the contrary, the shift
difference of 31.5 ppm found by us for aroyloxymethyllithium
1 and methyl ester 8 in THF corresponds better to an alkoxy-
substituted carbenoid than to a carbanion in a chelate ring. This
is another argument for the increasing lithium-coordinating
effect of THF to break down the chelate structure in favor of
the carbenoid nature of 1.
Following the course of the reaction in the NMR tube by 13C
NMR spectroscopy (Figure 4) revealed that the concentration of
the lithiated species decreased by going from -70 to -50 °C but
completely disappeared at -30 °C. The increasing signal at 123.5
ppm stemmed from ethylene,25 although its low intensity spoke
against this being the main decomposition pathway. Surprisingly,
another signal around 9 ppm was detected that steadily increased
in intensity at rising temperature. It was attributed to a 13CH2 group
bound to tin, when taking the satellites with large coupling constants
into account [J(117/119Sn) ) 314.0, 300.1 Hz]. There were two
possibilities for the formation of a stannane containing a Sn13CH2
group: First, direct insertion of [13C1]methylene into a Sn-C bond
of tetrabutyltin, which seemed unlikely, and second, the reaction
of excess n-BuLi with [13C1]1 to give [1-13C1]pentyllithium,
Conclusions
In summary, we demonstrated that enantiopure aroyloxy-
[D1]methyllithium [1-D1]1 was macroscopically configuration-
ally stable for minutes at -78 °C, as proven by trapping
experiments performed with benzaldehyde. When the organo-
lithium was aged for extended periods of time or at an elevated
temperature, partial enantiomerization occurred, which was more
pronounced in THF than in Et2O/TMEDA as the solvent.
Alkylation of [1-D1]1 with heptyl iodide afforded a partly
racemized product of 29% ee, while benzyl bromide reacted
too slowly to warrant further testing.
The usefulness of aroyloxymethyllithium [1-D1]1 as a general
synthon for the preparation of stereospecifically deuterated com-
pounds was demonstrated by the synthesis of chirally deuterated
primary alcohols in an aldehyde-addition/deoxygenation sequence.
It worked best for 2-phenyl-[1-D1]ethanol (98% ee) but less well
for [1-D1]octanol (ee of <90%) starting from benzaldehyde and
heptanal, respectively. Furthermore, the mechanism of racemization
and decomposition of [1-D1]1 was investigated via isotope labeling
and mass/NMR spectroscopic analysis. An intermediate carbene
could be ruled out, as well as its insertion into THF. Experiments
in the NMR tube followed by recording 13C NMR spectra at
increasing temperatures revealed that [1-13C1]1 decomposed with
formation of some ethylene and tetraalkylstannanes containing
13CH2Sn, (13CH2)2Sn, and (13CH2)3Sn fragments in decreasing
quantity. The high downfield shift of the CH2O signal of [1-13C1]1
(23) For a review see: (a) Boche, G.; Lohrenz, J. C. W. Chem. ReV. 2001,
101, 697–756. (b) Ko¨brich, G. Bull. Soc. Chim. Fr. 1969, 2712–2720. (c) Ko¨brich,
G.; Flory, K.; Fischer, H. R. Chem. Ber. 1966, 99, 1793–1804.
(24) Boche, G.; Bosold, F.; Lohrenz, J. C. W.; Opel, A.; Zulauf, P. Chem.
Ber. 1993, 126, 1873–1885.
(25) Sadykov, R. A.; Shishlov, N. M. J. Organomet. Chem. 1989, 369, 1–7.
2386 J. Org. Chem. Vol. 74, No. 6, 2009

Chiral (2,4,6-Triisopropylbenzoyl)oxy-[D1]methyllithium
FIGURE 4. 13C NMR spectra (100 MHz, THF-d8) at various time (addition of n-BuLi, t ) 0) and temperature intervals. The gray areas highlight
(from left to right) the formation of ethylene, the disappearance of [13C1]1, and the formation of 13CH2Sn.
Experimental Section
Tributylstannylmethyl 2,4,6-Triisopropylbenzoate (6), (S)-
[D1]6, and (R)-[D1]6. Tributylstannylmethanol (482 mg, 1.50
mmol), triphenylphosphine (472 mg, 1.80 mmol), and 2,4,6-
triisopropylbenzoic acid (447 mg, 1.80 mmol) were dissolved in
dry THF (6 mL) under argon. The solution was cooled to -20 °C,
before addition of DIAD (346 mg, 350 µL, 1.80 mmol), and
afterward stirred for 3 h (-20 °C f RT). Water (0.1 mL) was
added, and the crude product was concentrated on a rotary
evaporator and purified by flash chromatography (hexane/CH2Cl2
4:1, Rf 0.21) to yield benzoate 65 as a colorless oil (811 mg, 98%):
IR (Si) ν 2960, 2926, 1717, 1607, 1465, 1289, 1068 cm-1; 1H NMR
(400.13 MHz, CDCl3) δ 6.97 (s, 2Harom), 4.36 (s, J(117/119Sn) )
13.6 Hz, 2H), 2.86 (sept, J ) 6.8 Hz, 1H), 2.77 (sept, J ) 6.8 Hz,
2H), 1.55-1.46 (m, 6H), 1.29 (sext, J ) 7.3 Hz, 6H), 1.22 (d, J )
6.8 Hz, 6H), 1.21 (d, J ) 6.8 Hz, 12H), 0.98-0.92 (m, 6H), 0.87
(t, J ) 7.3 Hz, 9H); 13C NMR (100.61 MHz, CDCl3) δ 172.2, 149.9,
144.8 (2C), 131.0, 120.7 (2C), 55.1 (J(117/119Sn) ) 300.6, 286.0
Hz), 34.4, 31.6 (3C), 29.0 (J(117/119Sn) ) 21.4 Hz, 3C), 27.3 (J(117/
119Sn) ) 54.3 Hz, 3C), 24.2 (2C), 23.9 (2C), 13.7 (3C), 9.5 (J(117/
119Sn) ) 333.5, 319.7 Hz, 3C).
(S)-[D1]6: [R]20 +0.72 and [R]20 +2.76 (c 12.63, acetone).
D
365
The spectroscopic data were identical to those of 6, except for the
following:1H NMR (600.13 MHz, CDCl3) δ 4.34 (s, J(117/119Sn) )
13.2 Hz, 1H) with a deuterium induced upfield shift of 12.8 Hz;
13C NMR (150.90 MHz, CDCl3) δ 54.87 (t, J ) 21.2 Hz, 1C).
(R)-[D1]6: [R]20 -0.70 and [R]20 -2.66 (c 14.94, acetone).
FIGURE 5. 13C NMR spectrum (100.6 MHz, CDCl3) of the crude
product obtained from the reaction mixture in the NMR tube. Blue:
13C signals of tributyl-[1,2,3-13C3]heptylstannane. Red: 13C signals of
tributyl-[1,2-13C2]hexylstannane. Green: 13C signals of tributyl-[1-
13C1]pentylstannane. Black: signals of tetrabutyltin.
D
365
The spectroscopic data were identical to those of (S)-[D1]6.
(()-2-Hydroxy-2-phenylethyl 2,4,6-Triisopropylbenzoate (7),
(S)-[D1]7, and (R)-[D1]7. Macroscopic Conditions. Tributylstan-
nylmethyl 2,4,6-triisopropylbenzoate (132 mg, 0.24 mmol) and
TMEDA (55 mg, 72 µL, 0.48 mmol) were dissolved in dry solvent
(2 mL) under argon and cooled to the respective temperature.
n-BuLi (0.30 mL, 1.6 M solution in hexane, 0.48 mmol) was added,
compared with the CH3O of its unlithiated analogue (∆δ ) 31.5
ppm in the 13C NMR spectrum) underlines the high carbenoid
character of this aroyloxyorganolithium species.
J. Org. Chem. Vol. 74, No. 6, 2009 2387

Kapeller and Hammerschmidt
and after the respective time span, the reaction was quenched with
benzaldehyde (0.265 mL, 2 M solution in Et2O, 0.53 mmol). After
stirring for 30 min at bath temperature, a saturated aq solution of
NaHCO3 (3 mL) was added. The organic phase was separated and
the aq one extracted with Et2O (3 × 5 mL), dried (Na2SO4), and
concentrated under reduced pressure. The crude mixture was
purified by flash chromatography (hexane/EtOAc 7:1; TLC, hexane/
EtOAc 3:1, Rf 0.55) to yield an inseparable mixture of 1-phenyl-
1-pentanol and the product 7 that was once separated by recrys-
tallization from hexane (for results see Table 1 and 2).
Tributylstannylmethyl 2,4,6-Triisopropyl-[18O1]benzoate
([18O1]6). To a solution of [18O]tributylstannylmethanol (680 mg,
2.11 mmol) in dry pyridine (12 mL) was added 2,4,6-triisopropy-
lbenzoyl chloride (845 mg, 3.20 mmol) and DMAP (30 mg, 0.25
mmol) under argon. The reaction was stirred for 8 h at 50 °C, before
adding another portion of the acid chloride (280 mg, 1.10 mmol).
Two hours later pyridine was removed under reduced pressure, and
the residue dissolved in a mixture of EtOAc (15 mL) and 1 M HCl
(15 mL). The organic phase was separated and the aqueous one
extracted with EtOAc (3 × 10 mL). The combined organic layers
were washed with brine and dried (MgSO4), and the solvent was
removed on a rotary evaporator. Afterward, the crude product was
purified by flash chromatography (hexane/CH2Cl2 4:1, Rf 0.26) to
give benzoate [18O1]6 as a colorless oil (828 mg, 71%).
Microscopic Conditions. Tributylstannylmethyl 2,4,6-triisopro-
pylbenzoate (132 mg, 0.24 mmol), benzaldehyde (0.60 mL, 2 M
solution in Et2O, 1.2 mmol), and TMEDA (139 mg, 0.18 mL, 1.2
mmol) were dissolved in dry Et2O (2 mL) under argon and cooled
to 0 °C. n-BuLi (0.75 mL, 1.6 M solution in hexane, 1.2 mmol)
was added, and the solution stirred for 30 min before workup, which
was done according to the procedure for the macroscopic experiments.
7: mp 78-79 °C (hexane); IR (Si) ν 3470, 2962, 2930, 2871,
The spectroscopic data were identical to those of the unlabeled
compound (see above), except for the following: 13C NMR (100.61
MHz, CDCl3) δ 55.1 (J(117/119Sn) ) 307.2, 293.5 Hz), with an
oxygen-18 induced shift of 0.03 ppm to higher field.
1728, 1462, 1252, 1139, 1077 cm-1 1H NMR (400.13 MHz,
;
[13C1]Methyl 2,4,6-Triisopropylbenzoate ([13C1]8). To a mix-
ture of 2,4,6-triisopropylbenzoic acid (1.76 g, 7.10 mmol) and KOt-
Bu (797 mg, 7.10 mmol) in dry THF (20 mL) under argon was
added 13CH3I (1.00 g, 7.00 mmol, dissolved in 4 mL of dry THF).
The resulting white slurry was stirred for 2 days at RT. Water (20
mL) and Et2O (10 mL) were added, the organic phase was separated,
and the aq one extracted with Et2O (3 × 20 mL). The combined
organic layers were washed with a saturated aq solution of NaHCO3
(25 mL), dried (MgSO4), and concentrated under reduced pressure.
The crude product was purified by flash chromatography (hexane/
CH2Cl2 2:1, Rf 0.30) to yield [13C1]8 as colorless crystals (1.37 g,
75%, 99% 13C).
CDCl3) δ 7.45-7.41 (m, 2Harom), 7.39-7.28 (m, 3Harom), 7.00 (s,
2Harom), 5.04 (X-part of ABX-system, J ) 8.1, 3.4 Hz, 1H), 4.47
(AB-part of ABX-system, J ) 11.5, 8.1, 3.4 Hz, 2H), 2.88 (sept,
J ) 6.8 Hz, 1H), 2.81 (sept, J ) 6.8 Hz, 2H), 2.51 (br s, 1H), 1.23
(d, J ) 6.8 Hz, 1H), 1.21 (d, J ) 6.8 Hz, 12H); 13C NMR (100.61
MHz, CDCl3) δ 170.9, 150.4, 144.9 (2C), 139.6, 129.9, 128.6 (2C),
128.2, 126.2 (2C), 120.9 (2C), 72.3, 69.6, 34.4, 31.5 (2C), 24.1
(2C), 24.1 (2C), 23.9 (2C). Anal. Calcd for C24H32O3: C, 78.22; H,
8.75. Found: C, 78.05; H, 8.66.
1
[D1]7: H NMR data were identical to that of 7, except for the
following: 1H NMR (250.13 MHz, CDCl3) δ 5.04 (d, J ) 3.4 Hz,
1H, diastereomer A), 5.03 (d, J ) 8.1 Hz, 1H, diastereomer B),
4.50 (d, J ) 3.4 Hz, 1H, diastereomer A), 4.41 (d, J ) 8.1 Hz, 1H,
diastereomer B).
The spectroscopic data were identical to those of the unlabeled
compound, except for the following:1H NMR (400.13 MHz, CDCl3)
δ 3.86 (d, J ) 147.0 Hz, 3H); 13C NMR (100.61 MHz, CDCl3) δ
51.7 of 100-fold intensity. MS (EI): m/z 263 (37.1, M+), 248 (52.9,
Tributylstannylmethyl [18O2]Benzoate ([18O2]21). To a mixture
of [18O2]benzoic acid (330 mg, 2.50 mmol), tributylstannylmetha-
nol26 (883 mg, 2.75 mmol; prepared by addition of tributylstan-
nyllithium27 generated from hexabutylditin and n-BuLi at 0 °C to
paraformaldehyde and stirred for 2 h at 0 °C), and triphenylphos-
phine (721 mg, 2.75 mmol) in dry THF (10 mL) under argon was
added DIAD (0.54 mL, 2.75 mmol) at 0 °C. The reaction was stirred
overnight at RT and quenched with a few drops of water. The
solvent was then removed under reduced pressure, and the residue
was purified by flash chromatography (hexane/CH2Cl2 2:1, Rf 0.44)
to give ester [18O2]21 as a colorless oil (1.02 g, 95%).
M+
- -
13CH2), 230 (100.0, M+ 13CH3OH).
Tributylstannyl-[13C1]methyl 2,4,6-Triisopropylbenzoate
([13C1]6). [13C]Methyl 2,4,6-triisopropylbenzoate (790 mg, 3.0
mmol) and TMEDA (0.54 mL, 418 mg, 3.6 mmol) were dissolved
in dry THF (9 mL) under argon. s-BuLi (2.8 mL, 1.3 M solution
in cyclohexane, 3.6 mmol) was added at -78 °C, and the mixture
was stirred for 2 h at that temperature. Afterward, the reaction was
quenched with tributyltin chloride (1.22 g, 3.75 mmol in 2 mL of
dry THF). Stirring was continued for another 45 min before the
addition of a saturated aq solution of NaHCO3 (2 mL) and water
(10 mL). The organic phase was separated and the aq one extracted
with Et2O (3 × 15 mL). The combined organic layers were dried
(MgSO4), concentrated under reduced pressure, and purified by flash
chromatography (hexane/CH2Cl2 4:1, Rf 0.42) to yield [13C1]6 as a
colorless liquid (1.23 g, 74%).
1
IR (Si): ν 2956, 2944, 2921, 1680, 1315, 1285, 1091 cm-1. H
NMR (400.13 MHz, CDCl3): δ 8.00-7.96 (m, 2Harom), 7.54-7.48
(m, 1Harom), 7.43-7.37 (m, 2Harom), 4.41 (s, J(117/119Sn) ) 11.9 Hz,
2H), 1.56-1.46 (m, 6H), 1.27 (sext, J ) 7.3 Hz, 6H), 0.97-0.91
(m, J(117/119Sn) ) 51.8, 49.8 Hz, 6H), 0.85 (t, J ) 7.3 Hz, 9H). 13
C
NMR: (100.61 MHz, CDCl3) δ 167.6, 132.5, 130.6, 129.3 (2C),
128.3 (2C), 56.4 (J(117/119Sn) ) 305.9, 292.2 Hz), 29.0 (J(117/119Sn)
) 20.6 Hz, 3C), 27.3 (J(117/119Sn) ) 54.3 Hz, 3C), 13.7 (3C), 9.7
(J(117/119Sn) ) 333.5, 318.2 Hz, 3C).
The spectroscopic data were identical to those of the unlabeled
compound (see above), except for the following: 1H NMR (400.13
MHz, CDCl3) δ 4.36 (d, J(117/119Sn) ) 13.7 Hz, J ) 144.0 Hz,
2H); 13C NMR (100.61 MHz, CDCl3) δ 55.2 (J(117/119Sn) ) 306.7,
293.7 Hz) of 100-fold intensity.
[18O1]Tributylstannylmethanol ([18O1]5). To a solution of
tributylstannylmethyl [18O2]benzoate (1.00 g, 2.30 mmol) in dry
Et2O (23 mL) was added superhydride (5.06 mL, 1 M solution in
THF, 5.06 mmol) at 0 °C under argon. The reaction was stirred
for 1 h at RT and then quenched with acetone (2 mL). Furthermore,
water was added (15 mL), the organic layer was separated, and
the aq one extracted with Et2O (3 × 15 mL). The combined organic
layers were dried (MgSO4) and concentrated under reduced pressure,
and the residue was purified by flash chromatography (hexane/
EtOAc 10:1, Rf 0.36) to give stannylmethanol [18O1]5 as a colorless
oil (558 mg, 75%) that was spectroscopically identical to the
unlabeled compound.12
Acknowledgment. This work was supported by Grant No.
P19869-N19 from the FWF. We thank S. Felsinger for recording
the NMR spectra and Dr. L. Brecker for his help with their
interpretation. D.K. is grateful to the Austrian Academy of
Sciences for a DOC-FFORTE scholarship.
Supporting Information Available: All experimental pro-
cedures, analytical data, and spectra of selected compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(26) Kapeller, D.; Brecker, L.; Hammerschmidt, F. Chem.-Eur. J. 2007,
13, 9582–9588.
(27) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481–1487.
JO802625Q
2388 J. Org. Chem. Vol. 74, No. 6, 2009