Preparation and configurational stability of chiral chloro-[D 1]methyllithiums of 98% enantiomeric excess

Article abstract of DOI:10.1021/ja0779708

Enantiopure stannyl-[D₁]methanol was converted to chloro-[D ₁]methylstannane under complete inversion of configuration using Ph₃P/N-chlorosuccinimide in THF. It was transmetalated to stereospecifically give chloro-[D₁]methyllithium (ee up to 98%). Its microscopic configurational stability was tested by performing tin-lithium exchange in the presence of benzaldehyde as the electrophile under various conditions. The macroscopic configurational stability was addressed by using the same electrophile but by adding it 30 s after the addition of MeLi used for transmetalation. Chloro-[D₁]methyllithium is chemically very labile, however completely configurationally stable on both time scales up to the temperature of rapid decomposition (-78°C).

Full text of DOI:10.1021/ja0779708

Published on Web 01/25/2008
Preparation and Configurational Stability of Chiral
Chloro-[D1]methyllithiums of 98% Enantiomeric Excess
Dagmar C. Kapeller and Friedrich Hammerschmidt*
Institute of Organic Chemistry, UniVersity of Vienna, Wa¨hringerstrasse 38, 1090 Vienna, Austria
Received October 23, 2007; E-mail: friedrich.hammerschmidt@univie.ac.at
Abstract: Enantiopure stannyl-[D1]methanol was converted to chloro-[D1]methylstannane under complete
inversion of configuration using Ph3P/N-chlorosuccinimide in THF. It was transmetalated to stereospecifically
give chloro-[D1]methyllithium (ee up to 98%). Its microscopic configurational stability was tested by performing
tin-lithium exchange in the presence of benzaldehyde as the electrophile under various conditions. The
macroscopic configurational stability was addressed by using the same electrophile but by adding it 30 s
after the addition of MeLi used for transmetalation. Chloro-[D1]methyllithium is chemically very labile, however
completely configurationally stable on both time scales up to the temperature of rapid decomposition
(-78 °C).
in recent years have high level quantum-chemical calculations,1c,6
modern NMR techniques,7 and X-ray structure analyses8 at
Introduction
Organometallic compounds containing lithium and at least
one heteroatom, preferably a halogen, at the same carbon atom
[XC(R1)(R2)Li] are referred to as carbenoids.1 Depending on
the experimental conditions, they exhibit a diverse reactivity
spectrum. At low temperatures, these thermolabile species
behave as nucleophiles and can be trapped with a variety of
electrophiles. At higher temperatures, their electrophilic char-
acter comes into play. They either insert into C-H bonds, react
with RLi to give RC(R1)(R2)Li and LiX, form alkenes by
eliminative dimerization, or add to olefinic double bonds to
produce cyclopropanes.2 The versatility of carbenoids forms the
basis for their manifold synthetic applications.
The first to mention the term carbenoid was Closs and Closs
in 1962.3 They treated a mixture of dibromodiphenylmethane
and an alkene with methyllithium at -10 °C and isolated
tetraphenylethene and stereospecifically formed cyclopropanes.
Later, Closs and Moss proposed “the use of the term ‘carbenoid’
as a noun for the description of the intermediates which exhibit
reactions qualitatively similar to those of carbenes without
necessarily being free divalent carbon species”.4 Ko¨brich argued
that carbenoids are lithium halide complexed carbenes.5 Their
notorious instability complicated structural investigations. Only
low temperatures in combination with structural data in solution
and in the solid state allowed us to deduce their chemical
behavior.
The strongest argument to delineate the carbenoid nature of
R-haloalkyllithiums is the enhanced s-character of the C-Li
bond and the increased p-character of the other bonds as
demonstrated by NMR studies. The carbenoid 13C resonates at
a lower field than that of the non-lithiated species (e.g., ∆δ )
32.3 ppm for chloromethyllithium).6b,7b,c An X-ray structure
analysis of LiCHCl2‚3pyr supports these findings.8 Finally,
quantum-chemical calculations revealed that the methyl-
lithiums LiCH2X (X ) F, Cl, Br, I) have elongated C-X bonds
as compared to the non-metalated species, whereby the elonga-
tion decreases (F > Cl > Br > I) with increasing atomic weight
of the halogen.1c In the calculated most stable monomeric
structures, the lithium atom bridges the carbon and heteroatom.
Ko¨brich was one of the pioneers of carbenoid chemistry,
whose seminal work is still unparalleled.5 He prepared a number
of various R-bromo- and R-chloroalk(en)yllithiums, among them
the quite labile mono-,9 di-,10 and trichloromethyllithi-
(6) (a) Schleyer, P. v. R.; Clark, T.; Kos, A. J.; Spitznagel, G. W.; Rhode, C.;
Arad, D.; Houk, K. N.; Rondan, N. G. J. Am. Chem. Soc. 1984, 106, 6467-
6475. (b) Boche, G.; Bosold, F.; Lohrenz, J. C. W.; Opel, A.; Zulauf, P.
Chem. Ber. 1993, 126, 1873-1885. (c) Pratt, L. M.; Phan, D. H. T.; Tran,
P. T. T.; Nguyen, N. V. Bull. Chem. Soc. Jpn. 2007, 80, 1587-1596.
(7) (a) Siegel, H.; Hiltbrunner, K.; Seebach, D. Angew. Chem. 1979, 91, 845-
846; Ibid, Angew. Chem., Int. Ed. Engl. 1979, 18, 785. (b) Seebach, D.;
Siegel, H.; Gabriel, J.; Ha¨ssig, R. HelV. Chim. Acta 1980, 63, 2046-2053.
(c) Seebach, D.; Ha¨ssig, R.; Gabriel, J. HelV. Chim. Acta 1983, 66, 308-
337.
(1) Reviews: (a) Braun, M. In The Chemistry of Organolithium Compounds;
Rappoport, Z., and Marek, I., Eds.; Wiley-VCH: Chichester, 2004; Vol.
2, Lithium Carbinoids, pp 829-899. (b) Braun, M. In Houben-Weyl,
Methoden der Organischen Chemie; Carbanionen, E 19d; Hanack, M., Ed.;
Georg Thieme Verlag: Stuttgart, 1993; a-Hetero- und R,R-Dihetero-
carbanionen sowie Triheteromethyl-Anionen, pp 863-902. (c) Boche, G.;
Lohrenz, J. C. W. Chem. ReV. 2001, 101, 697-756.
(2) (a) Regitz, M. Houben-Weyl, Methoden der Organischen Chemie; Georg
Thieme Verlag: Stuttgart, 1989. (b) Hermann, H.; Lohrenz, J. C. W.; Ku¨hn,
A.; Boche, G. Tetrahedron 2000, 56, 4109-4115. (c) Ke, Z.; Zhao, C.;
Philips, D. L. J. Org. Chem. 2007, 72, 848-860.
(8) Mu¨ller, A.; Marsch, M.; Harms, K.; Lohrenz, J. C. W.; Boche, G. Angew.
Chem. 1996, 108, 1639-1640; Ibid, Angew. Chem., Int. Ed. Engl. 1996,
35, 1518-1520.
(3) Closs, G. L.; Closs, L. E. Angew. Chem. 1962, 74, 431; Ibid, Angew. Chem.,
Int. Ed. Engl. 1962, 1, 334-335.
(4) Closs, G. L.; Moss, R. A. J. Am. Chem. Soc. 1964, 86, 4042-4053.
(5) (a) Ko¨brich, G. Bull. Soc. Chim. Fr. 1969, 2712-2720. (b) Ko¨brich, G.
Angew. Chem. 1967, 79, 15-27; Ibid, Angew. Chem., Int. Ed. Engl. 1967,
6, 41-52.
(9) (a) Ko¨brich, G.; Fischer, R. H. Tetrahedron 1968, 24, 4343-4346. (b)
Tarhouni, R.; Kirschleger, B.; Rambaud, M.; Villieras, J. Tetrahedron Lett.
1968, 25, 835-838. (c) Einhorn, C.; Allavena, C.; Luche, J.-L. J. Chem.
Soc., Chem. Commun. 1988, 333-334.
(10) Ko¨brich, G.; Merkle, H. P. Chem. Ber. 1966, 99, 1793-1804.
9
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J. AM. CHEM. SOC. 2008, 130, 2329-2335
2329

A R T I C L E S
Kapeller and Hammerschmidt
ums,11 by either metalation with alkyllithiums or amides or
halogen/lithium exchange. He examined their stability and
reactivity, proving the latter to be different from classical
carbenes generated photochemically from diazo compounds. The
least stable species of the three chloromethyllithiums was
found to be monochloromethyllithium, which was prepared
from BrCH2Cl by halogen-lithium exchange with n-BuLi at
-110 °C and could be carboxylated in very low yield at that
temperature.9 Later, monochloromethyllithium proved to be a
useful reagent for homologations, similar to the more stable
bromomethyllithium.12 Because of their thermal instability,
however, these carbenoids had to be and were prepared in situ
and trapped with electrophiles such as carbonyl compounds,
boranes, borates, trialkylsilyl halides, and trialkyltin halides.
Ko¨brich was among the first to report the configurational
stability of carbenoids, of which there is still very little known.
He found that the epimers of 7-chloro-7-lithionorcarane rear-
ranged only slowly at -80 °C at a rate comparable to their
decomposition, attributed to the strained cyclopropane ring
resisting inversion of configuration at the carbanionic center.13
This result was supported by the finding that a variety of
R-bromo- and R-chlorocyclopropyllithiums were configuration-
ally stable below -78 °C but started to epimerize above that
temperature.14 Pioneering work by Hoffmann et al. demonstrated
that R-bromoalkyllithiums prepared by halogen-lithium ex-
change from geminal dihalides could form products of high
diastereoselectivity.15 Furthermore, they proved that acyclic
R-bromoalkyllithiums were configurationally stable at -110 °C
in the absence of their dibromo precursors.16
Scheme 1. Preparation of Tributyl(chloromethyl)stannane and
Tributyl(chloro-[D1]methyl)stannane via Appel Conditionsa
a (a) Ph3P, CCl4, CH3CN, 1 h, room temperature {93% for 2 and [D1]2}.
Scheme 2. Generation and Trapping of Chloromethyllithiums 3
and [D1]3: in Situ Methoda
a (a) PhCHO (5 equiv) followed by alkyllithium (5 equiv) (for yields of
4, see Table 1).
and the determination of its microscopic and macroscopic
configurational stability. Admittedly, the search for the smallest
configurationally stable methyllithium contributed to that inter-
est. Fluoromethyllithium, although even smaller, had been
reported to be chemically too unstable,1c and bromo- and
iodomethyllithium were anticipated to be configurationally too
labile.
As such, we envisioned preparing chiral chloro-[D1]-
methyllithium by tin-lithium exchange. We considered it the
method of choice as it allows for complete stereocontrol,
contrary to halogen-lithium exchange or deprotonation, the most
widely used methods for generating halomethyllithiums. There-
fore, enantiopure chloromethylstannane [D1]2 had to be syn-
thesized as a precursor from homochiral tributylstannyl-[D1]-
methanol {(R)-[D1]1} (Scheme 1). This was first performed with
the unlabeled compound, as all of the following reactions, to
evaluate the feasibility of the approach and to optimize the
conditions and yields. Transformation of tributylstannylmethanol
into the corresponding chloride worked cleanly with Ph3P/CCl4
in dry acetonitrile (Appel protocol), giving 2 and later on [D1]-
2 in 93% yield.20
To test the microscopic stability of chloromethyllithium, we
used an in situ quench method, which means that the stannane
was transmetalated with the electrophile already in the reaction
mixture (Scheme 2). We used benzaldehyde as the standard
electrophile, which facilitates comparison of results with the
oxymethyllithiums tested previously. This protocol ensures a
very short half-life for the chemically labile chloromethyllithium
because it is trapped as soon as it is formed. To optimize the
yield, several conditions for transmetalation of the easily
available unlabeled compound were tested first (Table 1).
Results and Discussion
Recently, we launched a project to study the configurational
stability of chiral methyllithiums with a variety of heteroatom
substituents. So far, we have unraveled the microscopic and
macroscopic configurational stability of oxygen-substituted
chiral methyllithiums.17,18 Now, as the first halomethyllithium,
we address the chlorine-substituted one, despite its chemical
instability observed by Ko¨brich and Fischer9a and the known
fact that 1-chloroalkylstannanes produce alkenes upon treatment
with n-BuLi.19 We were primarily interested in its preparation
(11) (a) Ko¨brich, G.; Flory, K.; Fischer, H. R. Chem. Ber. 1966, 99, 1782-
1792. (b) Miller, W. T., Jr.; Kim, C. S. Y. J. Am. Chem. Soc. 1959, 81,
5008-5009.
(12) (a) Barluenga, J.; Ferna´ndez-Simo´n, J. L.; Concello´n, J. M.; Yus, M. J.
Chem. Soc., Chem. Commun. 1987, 915-916. (b) Mori, M.; Okada, K.;
Shimazaki, K.; Chuman, T. Tetrahedron Lett. 1990, 31, 4037-4040. (c)
Kobayashi, T.; Pannell, K. H. Organometallics 1991, 10, 1960-1964. (d)
Brown, H. C.; Phadke, A. S.; Bhat, N. G. Tetrahedron Lett. 1993, 34, 7845-
7848. (e) Soundararajan, R.; Li, G.; Brown, H. C. Tetrahedron Lett. 1994,
35, 8957-8960. (f) Thadani, A. N.; Batey, R. A. Tetrahedron Lett. 2003,
44, 8051-8055. (g) Dixon, S.; Fillery, S. M.; Kasatkin, A.; Norton, D.;
Thomas, E.; Whitby, R. J. Tetrahedron 2004, 60, 1401-1416.
(13) Ko¨brich, G.; Goyert, W. Tetrahedron 1968, 24, 4327-4342.
(14) (a) Taylor, K. G.; Chaney, J. J. Am. Chem. Soc. 1976, 98, 4158-4163. (b)
Taylor, K. G.; Chaney, J.; Deck, J. C. J. Am. Chem. Soc. 1976, 98, 4163-
4167. (c) Schmidt, A.; Ko¨brich, G.; Hoffmann, R. W. Chem. Ber. 1991,
124, 1253-1258. (d) Topolski, M.; Duraisamy, M.; Rachon, J.; Gawronski,
J.; Gawronska, J.; Goedken, V.; Walborsky, H. M. J. Org. Chem. 1993,
58, 546-555.
(15) (a) Hoffmann, R. W.; Brumm, K.; Bewersdorf, M.; Mikolaiski, W.; Kusche,
A. Chem. Ber. 1992, 125, 2741-2747. (b) Hoffmann, R. W.; Bewersdorf,
M.; Kru¨ger, M.; Mikolaiski, W.; Stu¨rmer, R. Chem. Ber. 1991, 124, 1243-
1252.
(16) (a) Hoffmann, R. W.; Bewersdorf, M. Chem. Ber. 1991, 124, 1259-1264.
(b) Hoffmann, R. W.; Ruhland, T.; Bewersdorf, M. J. Chem. Soc., Chem.
Commun. 1991, 195-196.
(17) Kapeller, D.; Barth, R.; Mereiter, K.; Hammerschmidt, F. J. Am. Chem.
Soc. 2007, 129, 914-923.
(19) Torisawa, Y.; Shibasaki, M.; Ikegami, S. Tetrahedron Lett. 1981, 22, 2397-
2400.
(18) Kapeller, D. C.; Brecker, L.; Hammerschmidt, F. Chem.sEur. J. 2007,
13, 9582-9588.
(20) Appel, R. Angew. Chem. 1975, 87, 863-874; Ibid, Angew. Chem., Int.
Ed. Engl. 1975, 35, 1518-1520.
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2330 J. AM. CHEM. SOC. VOL. 130, NO. 7, 2008

Stability of Chiral Chloro-[D1]methyllithiums
A R T I C L E S
Table 1. Reaction Conditions and Yields of Chlorohydrine 4
Scheme 3. Preparation of (R)-Mosher Esters from (()-4 and
(()-[2-D1]4a
entry
base
solvent
temp (
°
C)
yielda (%)
1
2
3d
4
5
6
7
8
n-BuLi
n-BuLi
n-BuLi
n-BuLi
s-BuLi
MeLi
THF
THF
THF
Et2O/TMEDA
THF
THF
THF
THF
-78
-100
-100
-78
-78
-78
-95
0
16b
c
0
1
0
77
21
0
MeLi
MeLi
a Determined from 1H NMR spectrum of the crude product (losses upon
chromatography). b Recovered starting material: 23%. c Recovered starting
material: 53%. d Benzaldehyde was added 30 s after the addition of n-BuLi.
Using similar conditions as in previous experiments with
carbamoyloxy-substituted methyllithiums,17 we transmetalated
chloromethylstannane 2 with n-BuLi at -78 °C (entry 1 in Table
1). The yield of chlorohydrine 4 was only 16%. It seemed that
the addition of n-BuLi to benzaldehyde was faster than
transmetalation, as there was still starting material left after the
workup. This effect was even more pronounced when the
temperature was lowered to -100 °C (entry 2 in Table 1). The
yield decreased to zero, while the percentage of starting material
increased to over 50%. When benzaldehyde was not present
upon the addition of n-BuLi to stannane, but added 30 s later,
no product could be isolated (entry 3 in Table 1). This
experimental setup would address the macroscopic configura-
tional stability in the case of labeled methyllithium. The solvent
used in all cases was THF, which was reported to accelerate
metalation, especially at low temperatures.21 We can confirm
these findings by repeating the experiment in Et2O/TMEDA
(entry 4 in Table 1). Only traces of the product were found
under these conditions. As we did not obtain any chlorohydrine
4, we discontinued the approach with n-BuLi as the alkyllithium.
Replacing it with s-BuLi did not improve the yield either (entry
5 in Table 1).
a (a) (S)-MTPACl/pyridine (quantitative).
diastereomers could be separated by flash chromatography.
Anticipating later results, the less polar ester (Rf ) 0.38 in
hexanes/EtOAc ) 15:1) was derived from chlorohydrine (R)-
4, while the more polar one (Rf ) 0.34) was from (S)-4. But
actually, this was not necessary for ee determination at C-2 and
thus only was performed in rare cases. As expected, two sets
of ABX-systems with well-separated X-parts for the benzylic
1
hydrogens were found in the H NMR spectrum (Figure 1).
The two sets of the diastereotopic hydrogen atoms at C-2
resonated as AB-systems, which were sufficiently resolved to
allow for integration of the signals, when the spectrum was
recorded in toluene-d8. Figure 1A shows the section of the two
right parts of the AB-systems of 4‚MTPA-(R) that were used
for integration in the labeled series. The four resonances at the
lower field were assigned to the pro-S hydrogen atom of
unlabeled (S)-chlorohydrine and those at higher field to the
pro-R hydrogen of the (R)-enantiomer.
Before investing more time into optimizing the conditions
for transmetalation, we wanted to obtain a first result regarding
the microscopic configurational stability of [D1]3. If (R)-[D1]3
retained its configuration for the short lifetime between its
generation and its addition to benzaldehyde being present upon
transmetalation, two labeled stereoisomers, (1RS,2R)-[2-D1]4,
would result, as the enantioselectivity concerning the configu-
ration at C-1 is zero. If (R)-[D1]3 enantiomerizes, all four
possible chlorohydrines would be formed, their ratio depending
on the difference in the reaction rate between racemization and
trapping. The experiment described in Table 1, entry 1 (THF,
-78 °C) was repeated with chloromethylstannane (R)-[D1]2.
The crude product contained indeed chlorohydrine [2-D1]4 in
Now, the separation of the components of the crude product
containing the deuterated chlorohydrine was resumed. Lengthy
purification by HPLC was necessary to finally give [D1]4 in
10% yield, still containing 35% of another alcohol that was
identified as 1-phenyl-[2-D1]hexanol. This side product origi-
nated from n-BuLi attacking chloromethyllithium, a reaction
that had first been observed by Ko¨brich and Merkle and later
on by Huisgen and Burger (Scheme 4).10,22 The ee of the
resulting alcohols was then determined by transformation into
diastereomeric Mosher esters. [D1]6 was racemic; however, (S)-
[D1]4 was found to have an ee of 70% (1H NMR of Mosher
esters). For the sake of clarity, it is more convenient here to
give the enantiomeric excess for each chiral center individually
(ee). As the enantioselectivity of the chiral chloromethyllithium
is zero, (R)- and (S) configurations at C-1 were always formed
in equal amounts, resulting in a product with zero ee (i.e.,
racemic at C-1). However, the Mosher esters were not racemic
at C-2 (ee 70%). This result was quite encouraging, as it
indicated that the chiral chloromethyllithium was at least partly
microscopically configurationally stable.
1
about 25% yield (by H NMR). But, it was in an admixture
with several byproducts, among them tetrabutyltin and a large
excess of 1-phenylpentanol, the latter derived from the addition
of n-BuLi to benzaldehyde, preventing isolation of the desired
product by flash chromatography. Isolation was therefore
postponed until a suitable reagent to derivatize the chlorohy-
1
drines to determine their configuration at C-1 by H NMR
spectroscopy was found.
Thus, a sample of unlabeled (()-2-chloro-1-phenylethanol
was converted to the (R)-Mosher esters (Scheme 3). The two
(21) Ko¨brich, G.; Merkle, H. R.; Trapp, H. Tetrahedron Lett. 1965, 6, 969-
972.
(22) Huisgen, R.; Burger, U. Tetrahedron Lett. 1970, 11, 3053-3056.
9
J. AM. CHEM. SOC. VOL. 130, NO. 7, 2008 2331

A R T I C L E S
Kapeller and Hammerschmidt
1
Figure 1. Relevant sections of selected H NMR spectra of Mosher esters of unlabeled (A: 400 MHz, toluene-d8, right parts of AB-systems) and labeled
4 (B and C: 400 MHz and D: 600 MHz toluene-d8). (A) (()-4‚MTPA-(R) derived from (()-4; (B) (1S,2R)-[2-D1]4‚MTPA-(R) of 98% ee plus 3% (()-
4‚MTPA-(R); (C) (1S,2R)-[2-[D1]4‚MTPA-(R) of 70% ee {signal at 3.05 ppm of (1R,2S)-[2-[D1]4‚MTPA-(R)} plus 3% (()-4‚MTPA-(R); and (D) (1S,2R)-
[2-D1]4‚MTPA-(R) of 40% ee {signal at 3.06 ppm of (1R,2S)-[2-[D1]4‚MTPA-(R)} plus 3% (()-4‚MTPA-(R).
Scheme 4. Formation and Esterification of (2S)-[D1]4 and [D1]6
meric chlorohydrines [2-D1]4 as reference compounds and
converted them to (R)-Mosher esters (Scheme 5). Starting from
with (S)-Mosher Chloridea
diol (1R,2R)-[2-D1]7,17 the primary hydroxyl group was selec-
tively protected with TBDMSCl/Et3N.23 Then, the secondary
group was benzoylated using either benzoyl chloride/Et3N or
the Mitsunobu reaction [Ph3P/diisopropyl azodicarboxylate
(DIAD)/PhCO2H] to give benzoates (1R,2R)- and (1S,2R)-[2-
D1]9, respectively.24 The silyl groups were removed from the
protected diols 9,25 and the alcohols 10 were transformed into
the diastereomeric benzoates 10 under Appel conditions.20
Reductive removal of the benzoyl groups finally furnished the
diastereomeric deuterated chlorohydrines (1R,2S)- and (1S,2S)-
[2-D1]4, respectively, which were further transformed into the
Mosher esters. The yields for the individual steps of the sequence
ranged from 71 to 99%. The diagnostic CHD groups of these
(R)-Mosher esters resonated as deuterium induced broadened
doublets at different chemical shifts in the 1H NMR spectra (600
(23) Moreno-Dorado, F. J.; Guerra, F. M.; Ortega, M. J.; Zubia, E.; Massanet,
G. M. Tetrahedron: Asymmetry 2003, 14, 503-510.
(24) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Hughes, D. L. Org. React.
1992, 42, 335-656.
a (a) (S)-MTPACl, pyridine, CH2Cl2 (both 98%).
To prove the stereochemistry, overall retention, or inversion
of configuration, we independently synthesized two diastereo-
(25) Kumar, P.; Ohkura, K.; Beiki, D.; Wiebe, L. I.; Seki, K. Chem. Pharm.
Bull. 2003, 51, 300-403.
9
2332 J. AM. CHEM. SOC. VOL. 130, NO. 7, 2008

Stability of Chiral Chloro-[D1]methyllithiums
A R T I C L E S
Scheme 5. Synthesis of Reference Compounds of Deuterated Chlorohydrines [2-D1]4 and Their (R)-Mosher Estersa
a (a) TBDMSCl, Et3N, DMAP, CH2Cl2 (87%); (b) PhC(O)Cl, Et3N, CH2Cl2 (99%); (c) PhCO2H, Ph3P, DIAD, THF (97%); (d) KF, PhCO2H, CH3CN,
75 °C (78 and 87%); (e) Ph3P, CCl4, CH3CN (95% and 99%); (f) DIBAH, THF, -50 °C (71 and 76%); and (g) (S)-MTPACl, pyridine, CH2Cl2 (quantitative).
Table 2. Conditions and Results for Transmetalation/Addition
MHz, toluene-d8) [(1R,2S)-[2-D1]4‚MTPA-(R): δ ) 3.06 ppm,
Sequence of (S)-[D1]2 (Preparation via Appel Protocol) with MeLi
J ) 3.3 Hz and (1S,2S)-[2-D1]4‚MTPA-(R): δ ) 3.31 ppm, J
) 8.8 Hz]. Comparison with the spectrum of the (R)-Mosher
ester of the chlorohydrine derived from chiral chloromethyl-
stannane (R)-[D1]2 revealed that 85% of the molecules had an
(S) configuration at C-2, and 15% had an (R) configuration [i.e.,
ee 70%; spectral data deduced from transmetalation experiments
and the unlabeled compound: (1S,2R)-[2-D1]4‚MTPA-(R): δ
) 3.10 ppm, J ) 4.0 Hz]. Consequently, transmetalation and
trapping with benzaldehyde followed an overall retentive course,
implying for both steps a retention of configuration, as tin-
lithium exchange proceeded with retention.
entry
solvent
temp (
°
C)
yielda (%)
ee (%)
1
2
3
THF
Et2O/TMEDA
THF
-78
-78
-95
90
36
45
39
41
40
a Determined from H NMR spectra of the crude product (losses upon
chromatography).
1
2). The same was true for lowering the temperature to -95 °C
(entry 3 in Table 2). Despite these changes in the reaction
conditions, the ee stayed virtually the same, reproducibly around
40%, which made us suspicious of the ee of the starting
chloromethylstannane, which we had not assessed indepen-
dently. We reasoned that perhaps the chiral chloromethyllithiums
were configurationally stable but that the stannane precursor
partially racemized during preparation. Chloride ions could react
with part of the chiral chloromethylstannane, prone to SN2
reactions in acetonitrile, leading to inversion of configuration.
To prove this, we needed to find a way to determine the ee
of chloromethylstannane [D1]2. Therefore, we attempted to
replace the butyl group at tin by a substituent with stereogenic
centers. We hoped that the diastereotopicity induced at the
SnCH2Cl group would be enough to differentiate between the
Now, we returned to optimizing the transmetalation process
with the unlabeled chloromethylstannane (Scheme 2). Using
MeLi instead of n-BuLi finally led to success. Performing the
reaction at -78 °C furnished chlorohydrine 4 in 77% yield
(Table 1, entry 6), which again decreased when the temperature
was lowered to -95 °C (entry 7 in Table 1). The yields given
1
in Table 1 for entries 6-8 were calculated from the H NMR
spectra of the crude products, using the CH3Sn group as a
convenient internal standard. Another positive effect of this
switch in alkyllithium reagent was the easier isolation of
chlorohydrine 4, as 1-phenylethanol, formed by the addition of
excess MeLi to excess benzaldehyde, could be removed by flash
chromatography as compared to 1-phenylpentanol and 1-phe-
nylhexanol. Furthermore, in neither case were we able to detect
1-phenylpropanol, formed by homologation of MeLi analo-
gously to n-BuLi (see Scheme 4). Perhaps the lower basicity
of MeLi as compared to n-BuLi inhibited its attack on the
intermediate chloromethyllithium.5a
1
two hydrogen atoms by H NMR spectroscopy. Building on
chemistry previously performed in our laboratory, we exchanged
the tributylstannyl group for the menthyldimethylstannyl group
derived from (-)-menthol (Scheme 6).17 (-)-Menthyldimethyl-
stannylmethanol (12) and its deuterated analogue (1R)-[1-D1]-
12 were transformed under the same conditions as used for the
tributylstannyl series into the chlorides 13 and (1S)-[1-D1]13,
respectively. But despite screening several solvents (CDCl3,
toluene-d8, and DMSO-d6), the two diastereotopic hydrogen
atoms of the SnCH2Cl group of chloride 13 always resonated
as a singlet in the 1H NMR spectrum, making determination of
the diastereomeric ratio futile in the labeled series. Despite that
failure, we finally decided to transmetalate (1S)-[1-D1]13 and
to react the formed chiral chloromethyllithium with benzalde-
hyde as usual. As expected, chlorohydrine (1RS,2R)-[2-D1]4 was
obtained in 57% yield with an ee of 70% at C-2. This result
With this optimized procedure, we repeated the transmeta-
lation and quenching of the intermediate chloromethyllithium
(R)-[D1]3, generated from the (S)-chloro-[D1]methylstannane
(Table 2). The yield was excellent (90%) when the reaction was
performed at -78 °C, but the ee at C-2 of the isolated
chlorohydrine was surprisingly low (entry 1 in Table 2).
Changing THF for Et2O/TMEDA as the solvent only led to the
expected decrease in yield and no change in ee (entry 2 in Table
9
J. AM. CHEM. SOC. VOL. 130, NO. 7, 2008 2333

A R T I C L E S
Kapeller and Hammerschmidt
Scheme 6. Preparation of
Table 3. Transmetalation/Quench Sequence of (S)-[D1]2 on the
Macroscopic Time Scale
(-)-(Chloromethyl)menthyldimethylstannanes [13 and (S)-[D1]13]
and Conversion of (S)-[D1]13 to Chlorohydrine [2-D1]4a
entry
temp (
°
C)
time (s)
yield (%)
ee (%)
1
2
-95
-78
30
30
54a
traces
98
97
a
1H NMR spectroscopy of the crude product showed 29% starting
material.
by the Appel method was transformed into chiral sulfides [D1]-
17, displaying a strong singlet at δ 1.72 ppm [diastereomer with
an (S) configuration at CHD] and a weak one at δ 1.56 ppm
[diastereomer with an (R) configuration at CHD] with a small
deuterium induced shift to higher field as compared to the
unlabeled species. Integration revealed an ee of 69% for the
chloromethylstannane (R)-[D1]2. With this irrevocable proof for
partial racemization under Appel conditions, we had to search
for a method to obtain enantiopure [D1]2.
a (a) Ph3P, CCl4, CH3CN {yield for 13: 80%; yield for (1S)-[1-D1]13:
88%} and (b) PhCHO, MeLi {yield for (1RS,2S)-[2-D1]4: 54%}.
Scheme 7. Synthesis of Homochiral Thiol (R)-16 and Its
Alkylation with (R)-[D1]2a
Compelled by this finding, we switched to the system of
N-chlorosuccinimide/Ph3P in dry THF.29 Thus, stannylmethanol
(R)-[D1]1 furnished (S)-[D1]2 in 80% yield with an ee of >98%
as determined by 1H NMR spectroscopy after conversion to the
sulfide (R,R)-[D1]17. Repeating the experiment (Table 2, entry
1, -78 °C, THF) with this homochiral chloromethylstannane
yielded chlorohydrine (2R)-[2-D1]4 of 98% ee at C-2, confirm-
ing that the intermediate chiral chloromethyllithium 3 was
completely configurationally stable on the microscopic time
scale.
Macroscopic Configurational Stability
After our success on the microscopic time scale, we focused
on the macroscopic configurational stability of chloromethyl-
lithium as well. This could be achieved in a similar experimental
setup as before, except that benzaldehyde was now added after
a certain period of time (aging of chloromethyllithium) following
transmetalation with MeLi. A lengthy trial and error period with
the unlabeled compound was required to find the thin line
between transmetalation and decomposition. The reproducibility
of yields was quite low, which was attributed to the chemical
instability of chloromethyllithium [D1]3. The best results (50%)
were achieved at -95 °C in THF, adding benzaldehyde 30 s
after the addition of MeLi. This, when repeated with the labeled
compound, gave chlorohydrine (2R)-[D1]4 in 54% yield with
an ee of 98% at C-2 (Table 3, entry 1). We also performed the
transmetalation at -78 °C, a temperature where decomposition
prevailed. We did not try to isolate the traces of the resulting
chlorohydrine, whose resonances were hardly visible in the 1H
NMR spectrum of the crude product. Instead, we converted it
directly into the (R)-Mosher ester, at which stage purification
by flash chromatography was possible. Satisfyingly, the ee at
C-2 was 97%. This means that chloromethyllithium [D1]3 is
macroscopically configurationally stable, although its half-life
at -78 °C must be in the rage of seconds. It rather decomposes
than racemizes. Our findings demonstrate that (chiral) chlo-
romethyllithium is a thermally very labile but configurationally
stable heteroatom-substituted organolithium of unknown ag-
gregation state.30
a (a) Ph3P, DIAD, MeC(O)SH, THF, room temperature (46%); (b)
LiAlH4, Et2O, reflux (90%); (c) n-BuLi, THF, 0 °C to room temperature;
and (d) 2 or (S)-[D1]2 (99% in both cases).
substantiated our suspicions but left us without proof and made
the determination of the ee of the starting chloromethylstannane
mandatory.
Our next approach was based on an excellent homochiral
nucleophile, which would react with the chloride to form
diastereomers. Assuming that the chloride ions replaced by the
nucleophile did not compete with it, the diastereomeric ratio
would accurately reflect the ee of the chiral chloromethylstan-
nanes. The salt of an enantiomerically pure thiol, such as (R)-
16, should be the nucleophile of choice and should be alkylated
very rapidly with the chloromethylstannane at low temperature,
thus preventing an interfering SN2 reaction by the chloride ions
(Scheme 7). Thiol (R)-16, a known but inadequately character-
ized compound,26 was accessed from enantiopure naphthyletha-
nol (S)-14,27 which was transformed into thioacetate (R)-15 by
a Mitsunobu reaction in low yield (46%) and then reduced to
thiol (R)-16 with LiAlH4.28 Thiol (R)-16 was converted to the
thiolate with n-BuLi and alkylated with chlorostannane 2 to yield
1
sulfide 17. Its H NMR spectrum gave an AB-system (JAB
)
9.4 Hz with calculated shifts for the diastereotopic protons at δ
) 1.74 and 1.57 ppm) for the SnCH2S group, allowing ee
determination in the labeled series. Similarly, (R)-[D1]2 prepared
(26) Nishibayashi, Y.; Onodera, G.; Inada, Y.; Hidai, M.; Uemura, S. Orga-
nometallics 2003, 22, 873-876.
(27) Laumen, K.; Schneider, M. P. J. Chem. Soc., Chem. Commun. 1988, 598-
600.
(28) Stratmann, O.; Kaiser, B.; Fro¨hlich, F.; Meyer, O.; Hoppe, D. Chem.s
Eur. J. 2001, 7, 423-435.
(29) Bose, A. K.; Lal, B. Tetrahedron Lett. 1973, 14, 3937-3940.
(30) (a) Pratt, L. M.; Ramachandran, B.; Xidos, J. D.; Cramer, C. J.; Truhlar,
D. G. J. Org. Chem. 2002, 67, 7607-7612. (b) Pratt, L. M.; Le, L. T.;
Truong, T. N. J. Org. Chem. 2005, 70, 8298-8302.
9
2334 J. AM. CHEM. SOC. VOL. 130, NO. 7, 2008

Stability of Chiral Chloro-[D1]methyllithiums
A R T I C L E S
Conclusion
was due to the chemical instability of this particular organo-
lithium.
In summary, we found that homochiral chloromethyllithium
prepared by tin-lithium exchange from the corresponding
tributyl(chloro-[D1]methyl)stannane was completely micro-
scopically and macroscopically configurationally stable up to
the border of its chemical stability. Chloromethyllithium
adds to benzaldehyde under retention of configuration.
Microscopically, yields of up to 90% (at -78 °C) were achieved,
while macroscopically, the best yield was 56% (-95 °C, 30 s).
Generally, the transmetalation reactions were highly reproduc-
ible concerning the ee values, but the yields for the addition
of the intermediate chloromethyllithium varied, which
Acknowledgment. This work was supported by Grant
P19869-N19 from the FWF. We thank S. Felsinger for recording
the NMR spectra and Dr. L. Brecker for help with its
interpretation. D.C.K. is grateful to the Austrian Academy of
Sciences for a DOC-FFORTE scholarship.
Supporting Information Available: All experimental proce-
dures and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA0779708
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J. AM. CHEM. SOC. VOL. 130, NO. 7, 2008 2335