On the preparation and determination of configurational stability of chiral thio- and bromo[D1]methyllithiums

Article abstract of DOI:10.1021/jo301441g

Thio- and bromo[D₁]methyllithiums (ee 99%) were generated from the respective stannanes by tin-lithium exchange at temperatures ranging from 0 to -95 °C. Thio[D₁]methyllithiums 6 were found to be microscopically configurationally labile on the time scale of the thiophosphate-α-mercaptophosphonate rearrangement even at -95 °C. Thio[D₁]methyllithiums 13a and 13b underwent a thia-[2,3]-Wittig rearrangement down to -95 °C and 13b only down to -50 °C. The former were microscopically configurationally stable below -95 °C, and the latter racemized completely at -50 °C. Chiral bromo[D₁]methyllithiums are chemically unstable at -78 °C but microscopically configurationally stable at the time scale of their addition to benzaldehyde and acetophenone.

Full text of DOI:10.1021/jo301441g

Article
pubs.acs.org/joc
On the Preparation and Determination of Configurational Stability of
Chiral Thio- and Bromo[D1]methyllithiums
Anna Wieczorek and Friedrich Hammerschmidt*
Institute of Organic Chemistry, University of Vienna, Wahringerstrasse 38, A-1090 Vienna, Austria
̈
S
* Supporting Information
ABSTRACT: Thio- and bromo[D1]methyllithiums (ee 99%)
were generated from the respective stannanes by tin−lithium
exchange at temperatures ranging from 0 to −95 °C.
Thio[D1]methyllithiums 6 were found to be microscopically
configurationally labile on the time scale of the thiophosphate-
α-mercaptophosphonate rearrangement even at −95 °C.
Thio[D1]methyllithiums 13a and 13b underwent a thia-
[2,3]-Wittig rearrangement down to −95 °C and 13b only down to −50 °C. The former were microscopically configurationally
stable below −95 °C, and the latter racemized completely at −50 °C. Chiral bromo[D1]methyllithiums are chemically unstable at
−78 °C but microscopically configurationally stable at the time scale of their addition to benzaldehyde and acetophenone.
The Hoffmann test of α-(phenylthio)butyllithium and α-
bromopentyllithium7 and secondary α-thiobenzyllithium8
established configurational stability of the former at −120
and −110 °C, respectively but instability of the latter at −78 °C
on the time scale of their addition to (S)-N,N-dibenzylphenyl-
alaninal. Secondary durylthioalkyllithiums are configurationally
stable at −110 °C.9 The configurationally most stable α-
thioalkyllithiums are tertiary ones with a carbamoyl substituent
at the sulfur atom.10 Theoretical calculations for methyllithiums
substituted with a heteroatom being an element of the third or
a higher row show that they are configurationally less stable
than those of the second row because of the increasing ease of
planarization of the carbanionic center.11 Thus, sulfur- and
selenium-substituted alkyllithiums are configurationally less
stable than the oxygen-substituted ones.12 The same is true
for phosphorus versus nitrogen and silicon versus carbon-
substituted chiral methyllithiums.13 Investigations of the
structure of many α-heteroatom-substituted alkyllithiums14
and mechanistic15 studies on the enantiomerization of α-
thioalkyllithiums have been performed. α-Alkyllithiums are
highly important synthetic reagents.16a−c Reich has recently
published an excellent Perspective of his structural work on
organolithium reagents using low-temperature NMR spectro-
scopy.16d It addresses all questions of relevance to those
studying or applying organolithiums.
INTRODUCTION
■
In previous papers, we have shown that heteroatom-substituted
chiral [D1]methyllithiums, the smallest organometallic com-
pounds, can be prepared in homochiral form by tin−lithium
exchange from the respective tributylstannyl derivatives at low
temperatures. They differ in their chemical as well as in their
macro- and microscopic configurational stability, depending on
the heteroatom, the solvent, and the temperature used. The
oxygen-substituted chiral methyllithiums 1a1 and 1b1 are the
macroscopically configurationally most stable ones, followed by
1c2 and 1d3 (Figure 1). The other oxygen-substituted ones are
chemically unstable but microscopically configurationally stable
on the time scale of a rearrangement. The silyloxy- and
germyloxy-substituted ones 1e and 1f undergo retro-Brook
rearrangements (1,2-Wittig rearrangements) with retention of
configuration.4 The (allyloxy)methyllithiums 1g isomerize (2,3-
Wittig rearrangement) with inversion of configuration, and the
phosphate2 1h rearranges (phosphate−phosphonate rearrange-
ment) with retention of configuration. The chiral
(dibenzylamino)methyllithiums5 (1i) are the most stable of
all nitrogen-substituted ones but not completely even at −95
°C. At the same temperature, compound 1j is configurationally
less stable than 1i.5 Homochiral isocyanomethyllithium (1k)
racemizes completely at −95 °C when generated in the
presence of benzaldehyde as electrophile.5 The phosphoric acid
amide 1l undergoes a phosphoramidate−α-aminophosphonate
rearrangement with retention of configuration.5 Chloro[D1]-
methyllithium 1m decomposes quickly but is macroscopically
configurationally stable for its short lifetime.6
RESULTS AND DISCUSSION
■
Generation of Chiral Thiomethyllithiums and Deter-
mination of Their Microscopic Configurational Stability.
Anticipating that chiral thio[D1]methyllithiums would not be
macroscopically configurationally stable, but only microscopi-
cally at best, we decided to intercept them after generation at
This paper addresses the configurational stability of chiral
thio- and bromo[D1]methyllithiums as compared to oxy- and
chloromethyllithiums to study the influence of going from
heteroatoms of the second (oxygen) and third (chlorine) row
elements to ones of the third (sulfur) and fourth (bromine)
one, respectively.
Received: July 16, 2012
Published: October 30, 2012
© 2012 American Chemical Society
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Figure 1. Known chiral [D1]methyllithiums with a heteroatom as substituent.
a
low temperatures by intramolecular reactions. Two types were
used, the thiophosphate α-mercaptophosphonate17 and the
thia-[2,3]-Wittig rearrangement18 involving short-lived thio-
alkyllithiums. The former was found to follow a retentive
course with microscopically configurationally stable (from −78
to 0 °C) (dialkoxyphosphinyl)thioalkyllithiums as intermedi-
ates and the latter an invertive one at the carbanionic center. α-
Allylthioalkyllithiums as intermediates of the thia-[2,3]-Wittig
rearrangement were found to be configurationally stable, but α-
benzylthioalkyllithiums were found to be unstable and partially
enantiomerized prior to the rearrangement.19 Furthermore,
Ikemoto et al. studied the effect of solvents and additives on the
steric course of oxy-[2,3]-Wittig rearrangement of the chiral
1,3-diphenyl-1-propenyloxy-2-propen-1-yl carbanion. They
found that the marked differences on the enantiomeric ratios
obtained with different solvents can be ascribed to the extent of
ion separation, which depends on the nature of solvent/
additive. THF favors conversion of a contact ion pair to a
separated ion pair. This finding induced us to study Et2O beside
THF as solvent.20
Scheme 1. Preparation of Diisopropyl Thiophosphates 5 ,
Thiomethyllithiums 6, and Their Thiophosphate-α-
mercaptophosphonate Rearrangement
The substrates for testing the configurational stability of
chiral (diisopropoxyphosphinyl)thiomethyllithiums, the diiso-
propyl S-tributylstannylmethyl thiophosphates, were prepared
according to Scheme 1. Here and in all other cases, reactions
were first optimized in the unlabeled series and then applied to
the labeled ones. Tributylstannylmethanol (2) was converted
via its lithium alkoxide at −78 °C to mesylate 3,4 which was
used directly to alkylate the triethylammonium salt of
diisopropyl thiophosphate16 (4). The S-tributylstannylmethyl
thiophosphate 5 was obtained in 79% overall yield. Similarly,
the deuterated enantiomers (S)- and (R)-[D1]5 were prepared
from (R)- and (S)-tributylstannyl[D1]methanol2 of 99% ee,
respectively, obtained by an improved procedure (see the
Experimental Section). To generate the short-lived dipole-
stabilized18 (diisopropoxyphosphinyl)thiomethyllithium (6),
a
Ms = methanesulfonyl; LiTMP = 2,2,6,6-tetramethylpiperidinyl-
lithium.
thiophosphate 5 was transmetalated in THF at −78 °C with
MeLi added dropwise every 3 s. Normally, alkyllithiums were
added with a syringe equipped with a needle to vigorously
stirred reaction mixtures. In analogy to previous results, we
assume tin−lithium exchange whenever used here in this paper
to generate heteroatom-substituted methyllithiums to follow a
retentive course.16d,21 It was found by Reich and Phillips22 and
others23 that tin−ate complexes form in quantities detectable
by NMR spectroscopy under special conditions, e.g., the
presence of HMPA as additive in THF, increasing the number
of phenyl substituents at tin, and low temperature (−80 °C).
Furthermore, tributyltin compounds are not favorable for the
formation of ate complexes, which are substantially less
reactive21 than lithium reagents. These facts induce us to
think that tin−ate complexes play only a minor role here, if at
all, and that salt free species of heteroatom-substituted
methyllithiums are produced. The migration of the phosphinyl
group from the sulfur to the carbon atom, a thermodynamically
driven reaction, gives phosphonate 7. Addition of AcOH 2 min
later, workup, and chromatographic purification furnished
mercaptomethylphosphonate17 8 in 60% yield. As no starting
material could be detected, transmetalation and the ensuing
rearrangement must be rapid reactions. When the experiment
was performed at 0 °C, it furnished merely 33% of the desired
mercaptophosphonate, although no starting material was left.
To determine the ee in the labeled series, mercaptophospho-
nate24 8 was derivatized with (R)-1-(1-naphthyl)ethyl iso-
1
cyanate to give thiocarbamates 10 (Scheme 2). Its H NMR
spectrum displayed well-separated signals for the diastereotopic
hydrogens of the SCH2P group, allowing evaluation of the ee of
the deuterated mercaptomethylphosphonates. With this in-
formation in hands, thiophosphates (S)- and (R)-[D1]5 were
rearranged at temperatures ranging from −95 to 0 °C, plausibly
assuming a retentive course as in the case of a secondary
phosphinylthioalkyllithium.17 The yields and the enantiomeric
excesses of the mercaptomethylphosphonates [D1]8 are given
in Table 1. The ee increased with decreasing temperature. The
rearrangement in Et2O at 0 °C gave racemic [D1]8; however in
THF a product with 23% ee (entries 3 and 1). The reason for
the stronger influence of Et2O compared to THF on the ee is
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Scheme 2. Derivatization of α-Mercaptomethylphosphonates
8 with Chiral Isocyanate
Scheme 3. Preparation of Allyl-, Benzyl-, and (1-
Naphthylmethyl)thiomethyltributylstannanes 12
Scheme 4. Thia-[2,3]-Wittig Rearrangement of
Allylthiomethyllithiums 13a and Conversion of the 3-
Butenethiols (15) Formed to Thiocarbamates 16
Table 1. Yields and ee of Mercapto[D1]methylphosphonates
[D1]8 Obtained by Rearrangement of Thiophosphates [D1]5
temp
(°C)
time
(s)
yield
(%)
ee
(%)
entry solvent/RLi/conf of [D1]5
1
2
3
4
5
THF/MeLi/(S)
Et2O/MeLi/(S)
Et2O/MeLi/(S)
THF/MeLi/(R)
THF/n-BuLi/(R)
0
−95
0
15
60
41
22
56
25
68
23
77
0
15
−95
−95
180
180
61
51
not clear, but possibly attributable to the differing degree of
solvation of lithium.20 The best result in terms of a combination
of yield (68%) and ee (51%) was obtained in THF with n-BuLi
at −95 °C (entry 5). In summary, these results show that chiral
(phosphinylthio)methyllithiums [D1]6 are microscopically
configurationally labile down to −95 °C on the time scale of
the thiophosphate-α-mercaptophosphonate rearrangement.
Generation of Chiral Allylthio- and (Arylmethylthio)-
methyllithiums and Determination of Their Microscopic
Configurational Stability. Three systems with differing
lifetimes for the intermediate thiomethyllithiums amenable to
thia-[2,3]-Wittig rearrangement were investigated. The re-
quired stannanes 12a−c were accessed from thiols 11a−c, t-
BuONa, and tributylstannylmethyl mesylates4 3 in yields of
82% to 92% (Scheme 3). The unlabeled allylthiomethylstan-
nane 12a was rearranged first. Tin−lithium exchange in THF at
−95 °C with n-BuLi produced thiomethyllithium 13a (Scheme
4). The ensuing thia-[2,3]-Wittig rearrangement furnished
lithium thiolate 14a, which would give on acidic workup and
extraction 3-butenethiol. Its boiling point25 of 70−80 °C is too
low to allow direct isolation of small amounts (<1 mmol).
Therefore, a substoichiometric amount of CF3CO2H (0.33
equiv relative to n-BuLi) was added 10 min after the addition of
n-BuLi, followed by excess (R)-1-phenylethyl isocyanate, to
convert thiol 15 for determination of yield and evaluation of ee
in the labeled series to thiocarbamate 16 in 83% overall yield.
The two diastereotopic hydrogens at C-1 formed an AB system
in the 1H NMR spectrum (DMSO-d6, 600 MHz), which
collapsed to two broadened singlets at 2.79 and 2.82 ppm on
decoupling of protons at C-2. Similarly, deuterated stannanes
(R)- and (S)-[D1]12a were rearranged using either THF or
Et2O as solvent at temperatures ranging from −95 to 0 °C
(Table 2).
Table 2. Conditions, Yields, and ee of Thiocarbamates [D1]
16 Obtained by Rearrangement of [D1]12a and
Derivatization of 3-Butenethiols formed
solvent/config of [D1]
temp
(°C)
time
(min)
yield
(%)
ee
(%)
entry
12
1
2
3
4
5
6
THF/S
THF/S
THF/S
THF/S
Et2O/R
Et2O/R
−95
−78
−40
0
10
10
10
3
83
95
99
72
62
45
≥95
91
83
71
−78
0
10
3
50
20
The data show that the yields and the ee are significantly
better for THF than Et2O. In analogy to the results for
secondary allythioalkyllithiums obtained by Brickmann and
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Bruckner,18 we assume that the rearrangement proceeds with
The chemical stability of benzylthiomethyllithium toward
thia-[2,3]-Wittig rearrangement at −78 °C enabled us to
investigate its microscopic and macroscopic configurational
stability. First, MeLi was added to a solution of unlabeled
stannane 12b in THF, followed by benzaldehyde as our
standard electrophile for chiral [D1]methyllithiums 10 min
later. Workup after 5 min and flash chromatography furnished
( )-β-benzylthio alcohol 19 in 77% yield (Scheme 6). The
̈
inversion of configuration at the carbanionic center.7
Surprisingly, chiral thiomethylithiums [D1]13a are configura-
tionally stable on the time scale of thia-[2,3]-Wittig rearrange-
ment below −95 °C in THF and ee of thiol obtained at 0 °C
was still 71%. It decreased only from ≥95% to 71% by going
from −95 to 0 °C in THF as solvent.
Next, the microscopic configurational stability of benzylth-
iomethyllithiums (13b) on time scale of [2,3]-rearrangement
was addressed. Benzylthiomethylstannane 12b was trans-
metalated with n-BuLi in THF already at −30 °C, as a higher
activation energy was expected than for allyl analogue (Scheme
5). As before, the rearranged lithium thiolate was converted to
Scheme 6. Transmetalation of Thiomethylstannanes 12b and
Interception of Benzylthiomethyllithiums Formed as
Intermediates with Benzaldehyde
Scheme 5. Thia-[2,3]-Wittig Rearrangement of
Benzylthiomethylstannanes 12b and Conversion of
Phenylmethanethiols 17 to Thiocarbamates 18
(R)-Mosher ester derived from (S)-α-methoxy-α-(trifluoro-
methyl)phenylacetyl chloride [(S)-MTPACl, (S)-Mosher
chloride] was prepared and investigated by 1H NMR
spectroscopy. The SCH2 group of each diastereomer displayed
a well-separated AB part of an ABX system, enabling the
determination of ee with an estimated accuracy of 3% at best at
deuterium bearing carbon atom in the labeled series. To
address macroscopic configurational stability of benzylthio-
[D1]methyllithium [(S)-13b], this experiment was repeated
with (R)-[D1]12b and yielded an alcohol being racemic at C-1
and C-2 as deduced from the 1H NMR spectrum (400 MHz) of
the mixture of (R)-Mosher esters. Despite the short time of 1
min between addition of MeLi for tin−lithium exchange and
addition of benzaldehyde, the lifetime was long enough to allow
complete racemization at deuterium bearing carbon atom.
To evaluate the microscopic configurational stability of (S)-
13b, MeLi was added dropwise to a solution of stannane (R)-
[D1]12b and benzaldehyde in THF at −78 °C. The deuterated
alcohol (S)-[2-D1]19 isolated in 24% yield, was derivatized with
(S)-Mosher chloride and the mixture of esters was investigated
thiocarbamate 18 via thiol 17. When the same reaction was
performed with stannane (R)-[D1]12b at −50 °C (reaction
time: 20 min), the yield of thiocarbamates [D1]18 was 59%.
However, the underlying thiol was found to be racemic. When
thiomethyllithium (S)-[D1]13b was generated at −78 °C and
quenched with CF3CO2H after 10 min, only benzyl methyl
sulfide was detected besides tetrabutyltin by 1H NMR
spectroscopy (400 MHz) in the crude product. The following
conclusions can be drawn from these three experiments. First,
benzylthiomethyllithium (13b) undergoes thia-[2,3]-Wittig
rearrangement down to −50 °C. At lower temperatures, the
activation energy, at least that for dearomatization correspond-
ing to resonance energy of benzene of 36 kcal·mol−1, cannot be
overcome. Second, this high activation energy increased the
lifetime of intermediates 13b and their chances to enantio-
merize, compared to those for allylthiomethyllithium (13a).
Racemization seems to be much faster than [2,3]-rearrange-
ment. Third, chiral benzylthio[D1]methyllithium is microscopi-
cally configurationally unstable on the time scale of thia-[2,3]-
Wittig rearrangement.
1
by H NMR spectroscopy. The ee at the deuterium bearing
stereo center was only 16%, but significant. This time
thio[D1]methyllithium (S)-[D1]13b was immediately intercep-
ted by benzaldehyde as the electrophile. Despite the short time
between generation and addition to carbonyl group, partial
racemization of the (very) labile thio[D1]methyllithium
interfered. The yield dropped to 9%, but the ee increased to
26%, when the reaction was performed at −95 °C in the
presence of 2 equiv of 12-crown-4. It was hoped that this Li+
complexing agent might influence the C−Li bond length and
thus enantiomerization.14 When the reaction was performed at
−50 °C, no thiol []D1]17 formed by rearrangement could be
detected (1H NMR) in the crude product besides deuterated
alcohol 19 (25%, 8% ee). This experiment shows that addition
of benzyl[D1]thiomethyllithium to benzaldehyde is (much)
faster than [2,3]-rearrangement. In the former case, the lifetime
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of the chiral carbanion is shorter and the chance to retain the
configuration higher. Finally, the reaction was performed at 0
°C and furnished racemic [D1]19. The low yields were
attributed to addition of MeLi to benzaldehyde as competing
reaction to transmetalation, a general phenomenon in experi-
ments for the determination of the microscopic configurational
stability of chiral heteroatom-substituted [D1]methyllithiums.5
Only part of the starting material was consumed. In summary,
benzylthio[D1]methyllithium is microscopically very labile on
the time scale of the addition to benzaldehyde.
To lower the activation energy for the thia-[2,3]-Wittig
rearrangement involving an aromatic compound, the phenyl
ring was replaced by a naphthyl substituent. A preliminary
experiment was performed with stannane 12c, which was
transmetalated with n-BuLi at −78 °C in THF and quenched
after 10 min (Scheme 7). The rearranged product 20 could be
ring of naphthalene up to 13 kcal·mol−1 less, that is 23
kcal·mol−1 (resonance energy of naphthalene is 59 kcal·mol−1,
as one benzene ring is retained: 59−36 = 23).26 Consequently,
the rearrangement of the naphthyl derivative proceeded even at
−95 °C, while the phenyl derivative rearranged only at
temperatures above −50 °C. The reaction rate of the former
was (much) higher than of the latter, so that the lifetime of
carbanion 13c was (much) shorter than that of 13b. Therefore
at −50 °C only the benzyl-substituted thio[D1]methyllithium
[D1]13b had enough time to racemize completely, while in the
case of the naphthylmethyl-substituted one 80% of the
molecules did not enantiomerize, resulting in an ee of 60%.
Synthesis and Configurational Stability of Homochi-
ral Bromo[D1]methyllithium. α-Haloalkyllithiums, also
termed lithium carbenoids, have nucleophilic and electrophilic
properties, depending on the solvent and the reaction
temperature.27 They are usually prepared in LiX-complexed
form by halogen−lithium exchange in α,α-dihaloalkanes,28,29
α,α-dihalocyclopropanes,30 or preferably dihalomethanes,29,31
at low temperatures (−78 to −120 °C) and are reacted with a
variety of electrophiles, especially aldehydes and ketones to
obtain epoxides. As chloro- and bromomethyllithiums decom-
pose easily, they are trapped in situ. Chiral α-chloroalkyl-
lithiums and α-chloroalkylmagnesium halides have also been
prepared elegantly, the latter being the configurationally more
stable species (below −20 °C).32 The experimental results are
nicely supplemented with theoretical calculations.14 Hoffmann
et al. showed that α-bromoalkyllithiums are macroscopically
configurationally stable at −110 °C.7,28 Enantiopure chloro-
[D1]methyllithium was prepared in our group and found to be
micro- and macroscopically configurationally stable at −78 °C,
but chemically very labile.6 Fluoromethyllithium has to the best
of our knowledge not yet been prepared.14a,33
Scheme 7. Transmetalation of 12c and thia-[2,3]-Wittig
rearrangement of thiomethyllithiums 13c
Here we address the configurational stability of enantiopure
bromo[D1]methyllithiums similarly to the chloro analogues.
However, the preparation of starting bromo[D1]methyl-
stannanes of ee ≥99% and the high propensity of BrCHDLi
to decomposition were challenging obstacles on the way to
success. We reasoned that we could generate bromomethyl-
lithium from bromomethyltributylstannane by tin−lithium
exchange and trap it in situ with benzaldehyde, resulting in
the formation of the lithium salt of the corresponding
bromohydrin. To check whether it is chemically stable and
whether its (R)-Mosher ester is suitable for the determination
of the ee in the labeled series, some exploratory experiments
were performed (Scheme 8). Phenacyl bromide was reduced
with DIBALH to bromohydrin ( )-23. When it was converted
to the lithium alkoxide in THF with MeLi at −78 °C and then
quenched with CF3CO2H after 5 min, it was recovered
unchanged in 95% yield. No epoxide 24 could be detected in
isolated in 45% yield. No methyl 1-naphthylmethyl sulfide and
only a trace of starting material could be detected in the crude
1
product by H NMR spectroscopy. Thiol 20 was converted to
thiocarbamate 21 to test its suitability for the determination of
the ee in the labeled series. The SCH2 group displayed an AB
1
system in the H NMR spectrum (400 MHz). Analogously,
thiomethylstannane (S)-[D1]12c was transmetalated at −50
and −95 °C, using either MeLi (entry 1) or n-BuLi (entries 2)
for tin−lithium exchange (Table 3). Surprisingly, the ees were
similar for the rearrangements at −50 and −95 °C. These
findings demonstrate that the activation energy for isomer-
ization of naphthyl derivative 13c is significantly lower than that
for phenyl derivative 13b. Qualitatively, dearomatization of
benzene could require up to 36 kcal·mol−1, that of one benzene
1
the H NMR spectrum (400 MHz) of the crude product as
evidenced by spiking with an authentic sample. Samples of
( )-23 and (S)-23 obtained by enantioselective reduction of
phenacyl bromide with (+)-DIP-chloride34 were converted to
diastereomeric (R)-Mosher esters and investigated by 1H NMR
spectroscopy. The CH2Br groups resonated as overlapping AB
parts of two ABX systems. The ee of (S)-23 was found to be
94%.
Bromomethyltributylstannane was prepared from tributyl-
stannylmethanol (2) in yields of up to 91% using Ph3P/NBS35
(Scheme 9). When it was transmetalated at −78 °C in THF
and the reaction quenched with CF3CO2H 30 s after the
addition of 1 M MeLi, the crude product was methyltributyl-
Table 3. Yields and ee of Thiol (R)-[D1]20 Formed by Thia-
[2,3]-Wittig Rearrangement of (R)-[D1]13c in THF
entry
RLi
temp (°C)
yield (%)
ee (%)
1
2
MeLi
−50
−95
28
60
60
72
n-BuLi
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of bromomethyllithium, we decided to do two in situ trappings
using 4 equiv of benzaldehyde in admixture with bromomethyl-
stannane in dry THF at −78 °C in analogy to the experiments
with chloromethyllithium. Four equiv of MeLi (1 M in
cumene/THF/diethoxymethane) were added dropwise and
the reaction was quenched with CF3CO2H after 5 and 15 min,
respectively. In both cases, only 25% of the starting material
was transmetalated, of which 80% formed bromohydrin ( )-23
in 19% yield for both experiments as evidenced by1H NMR
spectroscopy of the crude product. MeLi underwent two
competing reactions, tin−lithium exchange and addition to
benzaldehyde, which was faster and resulted in ( )-1-
phenylethanol as major side product. To slow down addition
of MeLi to the electrophile relative to transmetalation,
acetophenone was tested as alternative electrophile. The
desired bromohydrin ( )-27 was obtained in 13% yield along
with the tertiary alcohol derived from addition of MeLi to
acetophenone, and recovered starting material. Bromohydrin
( )-27 although a tertiary alcohol could be converted to
diastereomeric (R)-Mosher esters under forcing conditions (50
Scheme 8. Exploratory Experiments for Determination of
Configurational Stability of BrCHDLi
1
°C, 1,4-dioxane, 8 h). The H NMR spectrum (400 MHz)
showed AB systems for the CH2Br groups, demonstrating the
feasibility to determine the ee in the deuterated series.
Scheme 9. Preparation of Bromomethyllithiums and in Situ
Trapping with Benzaldehyde and Acetophenone
Chiral bromo[D1]methylstannane (R)-[D1]25 was prepared
from (S)-[D1]2 at first by the procedure used for the
preparation of the unlabeled compound in 92% yield.
Transmetalation and in situ trapping (with retention of
configuration) of the intermediate bromo[D1]methyllithium
[(S)-[D1]26] with benzaldehyde at −78 °C furnished
bromohydrin (2S)-[2-D1]23 in 11% yield with an ee of 57%
at C-2, determined by 1H NMR spectroscopy of the
corresponding (R)-Mosher ester. Being unsure about the ee
of the starting bromide, we determined it in the same way as
that of the chloride, using a homochiral thiol as derivatizing
agent and 1H NMR spectroscopy and found it to be 57%.6 This
proved that the chiral bromo[D1]methylstannane was not
enantiomerically pure and that it seemingly produced micro-
scopically configurationally stable bromo[D1]methyllithium,
which we wanted to corroborate by more experiments.
Apparently, the starting bromo[D1]methylstannane racemized
partly under the reaction conditions for the substitution
reaction, under which the chloro compound was configura-
tionally stable. Bromide ions in the reaction mixture replaced
bromide of the substrate by a SN2 mechanism, resulting in
partial enantiomerization.36 Then we switched to a modified
Mitsunobu reaction37 with Ph3P/DIAD (diisopropyl azodicar-
boxylate)/Ph3PHBr in toluene, optimized it, and finally
obtained (R)-bromo[D1]methylstannane of ≥99% ee in 35%
yield.38 Chiral bromo[D1]methylstannanes with ee ranging
from 77 to ≥99% were transmetalated in the presence of
benzaldehyde or acetophenone at −78 or −95 °C. The
bromohydrins formed were derivatized and the ee were
determined. The results are compiled in Table 4 (see also
Figure 2). The data show that the ee of the bromohydrins
reflect the ee of the respective starting bromo[D1]-
methylstannanes being microscopically configurationally stable,
irrespective of whether benzaldehyde or acetophenone was
used for the in situ trapping (Table 4, entries 3−5). In the case
of entry 5, the 1H NMR spectrum of the crude product
revealed the following molar ratios: (S)-[D1]2/PhCHO/
bromohydrin (2R)-[2-D1]23/Bu3SnCH3/PhCH(OH)CH3
=
stannane containing no starting material. Tin−lithium exchange
was therefore a rapid process. Anticipating fast decomposition
2:1.62:0.1:0.35:4.18. The major portion [85%; 2/(2 + 0.35)
= 0.85] of the starting material was recovered and only about
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addition of MeLi to acetophenone was slowed down compared
to benzaldehyde. Surprisingly, again only about one-third of the
bromo[D1]methyllithium generated was intercepted by aceto-
phenone. However, two-thirds decomposed apparently. We
expected a higher percentage of decomposition because the
lifetime of BrCHDLi will be longer in the presence of
acetophenone than benzaldehyde as the addition to the
electrophile will be slower. We cannot exclude that some of
the bromomethyllithiums reacted with the starting bromome-
thylstannanes to give finally tributylmethylstannane and ethene
as found for α-haloalkylstannanes.39 The main product was
( )-1-phenylethanol formed by addition of MeLi to
benzaldehyde. These results demonstrate that chiral bromo-
[D1]methyllithiums are microscopically stable on the time
scales of the addition to benzaldehyde and acetophenone, but
extremely labile.
Table 4. Conditions, Yields, and ee of Bromohydrins [D1]23
and [D1]27 Obtained by in Situ Trapping of Chiral
Bromo[D1]methyllithiums
a
temp
(°C)
yield
(%)
ee
entry
substrate (% ee)/product
(%)
b
1
(R)-[D1]2 (77)/(2S)-[2-D1]23
(R)-[D1]2 (77)/(1S)-[1-D1]27
(S)-[D1]2 (94)/(2R)-[2-D1]23
(S)-[D1]2 (94)/(1R)-[1-D1]27
(S)-[D1]2 (99)/(2R)-[2-D1]23
−78
−78
−78
−95
−78
18
12
9
76
75
c
2
b
3
94
c
4
31
93
b
5
14
≥99
a
Determined by 1H NMR spectroscopy of (R)-Mosher esters.
Benzaldehyde was used as electrophile. Acetophenone was used as
b
c
electrophile.
CONCLUSIONS
■
Four chiral thio[D1]methyllithiums with different substituents
at sulfur were prepared by tin−lithium exchange and their
microscopic configurational stability was determined relative to
the thiophosphate-α-mercaptophosphonate and thia-[2,3]-
Wittig rearrangements, respectively (Figure 3). The configura-
Figure 3. Microscopic configurational stability of various thio[D1]-
methyllithiums on the time scale of rearrangements for 6 and 13a−c
and on the time scale of addition of 13b and bromo[D1]-
methyllithiums 26 to benzaldehyde.
tional stability of chiral thio[D1]methyllithiums is delicately
influenced by their lifetime depending on the substitutent at
sulfur. The chances for enantiomerization of a thiomethyl-
lithium will increase with its lifetime, which is inversely
proportional to the rate of the rearrangement. While 13a is
configurationally stable at −95 °C, 13b underwent the thia-
[2,3]-rearrangement only down to −50 °C and racemized
completely. In case of 13b, the microscopic configurational
stability was also evaluated on the time scale of its addition to
benzaldehyde. Unfortunately, the solution structures of the
respective methyllithiums and their mechanism of enantiome-
rization are unknown. Hoffmann et al.40 and Reich and
Dykstra41 found for α-selenium- and α-sulfur-substituted
alkyllithiums that rotation about the C−heteroatom bond is
1
Figure 2. Signals of CHDBr groups in the H NMR spectra (400
MHz, toluene-d8) of (R)-Mosher esters derived from (A) (2S)-[2-D1]
23 of 76% ee and (B) (2R)-[2-D1]23 of 99% ee (D ≥96%).
one-third (0.1:0.35 = 0.29) of the chiral bromomethyllithium as
deduced from the formed tributylmethylstannane gave
bromohydrin. Evidently, the other two-thirds decomposed
because of low chemical stability. When acetophenone was used
as electrophile, the ratios for entry 4 of Table 4 in the crude
product were for (S)-[D1]2/PhC(O)CH3/bromohydrin (1R)-
[1-D1]27/Bu3SnCH3/PhC(OH)(CH3)2 = 0.0:0.93:-
0.39:1.0:0.72. This time transmetalation was complete as
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added, the solution was stirred for another 20 min, and then freshly
prepared triethylammonium salt of O,O-diisopropyl thiophosphoric
acid (3.84 mmol, 10.68 mL of solution prepared from 10 mmol of
phosphite in 25 mL of i-PrOH)17 was added. Stirring was continued
for 18 h at rt. The mixture was concentrated under reduced pressure,
and water (26 mL) was added. The aq phase was extracted with
CH2Cl2 (2 × 30 mL). The combined organic phases were washed with
water (30 mL), dried (Na2SO4), concentrated under reduced pressure,
and purified by flash chromatography (hexane/EtOAc, 7:1, Rf 0.38) to
yield thiophosphate 5 as a colorless oil (1.014 g, 79% for two steps).
IR (Si): ν 2958, 2927, 1253, 979 cm−1. 1H NMR (400.27 MHz,
CDCl3): δ 4.72 (dsept, J = 8.9, 6.2 Hz, 2H), 2.04 (d, J = 9.0 Hz,
J(117/119Sn) = 35.4 Hz, 2H), 1.60−1.38 (m, 6H), 1.36 (d, J = 6.3 Hz,
6H), 1.33 (d, J = 6.3 Hz, 6H), 1.29 (sext, J = 7.3 Hz, 6H), 1.04−0.87
(m, J(117/119Sn) = 50.8 Hz, 6H), 0.87 (t, J = 7.3 Hz, 9H). 13C NMR
(100.61 MHz, CDCl3): δ 72.1 (d, J = 6.0 Hz, 2C), 28.9 (J(117/119Sn) =
21.8 Hz, 3C), 27.2 (J(117/119Sn) = 56.5 Hz, 3C), 23.9 (d, J = 4.2 Hz,
2C), 23.7 (d, J = 5.6 Hz, 2C), 13.6 (3C), 9.7 (J(117/119Sn) = 323.4 Hz,
3C), 4.5 (d, J = 4.9 Hz). 31P NMR (161.98 MHz, CDCl3): δ 29.5.
Anal. Calcd for C19H43O3PSSn: C, 45.52; H, 8.65; S, 6.40. Found: C,
45.93; H, 8.85; S, 6.10.
the rate-determining step of enantiomerization. Chiral bromo-
[D1]methyllithiums generated by tin−lithium exchange (salt
free?) proved to be chemically very labile but microscopically
configurationally stable on the time scale of the addition to
benzaldehyde and acetophenone at −78 °C. In summary, we
assume that the rearrangements of 6 and 13a,c follow a
retentive and invertive course, respectively, in analogy to chiral,
nonracemic organolithiums with the same heteroatom, but an
alkyl group instead of the deuterium atom. Analogously,
thiomethyllithium 13b and bromomethyllithium 26 add to
benzaldehyde with retention of configuration. Thiomethyl-
lithium 13b enantiomerizes down to −50 °C prior to [2,3]-
rearrangement.
EXPERIMENTAL SECTION
■
1H/13C (J modulated) NMR spectra were measured at 300 K at
400.13, 400.27, 600.13 MHz/100.61, 100.65, 150.92 MHz, respec-
tively. 31P NMR spectra were recorded at 161.98, 162.03, or 242.94
MHz. All chemical shifts (δ) are given in ppm. They were referenced
either to residual CHCl3 (δH 7.24)/toluene-d8 (CHD2: δH 2.09)/
CD3OD (CHD2: δH 3.31)/DMSO-d6 (CHD2: δH 2.50) or CDCl3 (δC
77.00)/toluene-d8 (CD3: δC 21.04)/CD3OD (CD3: δC 49.00)/
DMSO-d6 (CD3: δC 39.50). IR spectra of films on a silicon disk
were recorded on FT-IR spectrometers or by using ATR.42 Optical
rotations were measured at 20 °C with a polarimeter in a 1 dm cell.
Melting points are uncorrected.
Similarly, (S)-tributylstannyl[D1]methanol {(S)-[D1]2} (826 mg,
2.56 mmol) and (R)-[D1]2 (731 mg, 2.27 mmol) were converted to
thiophosphates (R)-[D1]5 (1.014 g, 79%) and (S)-[D1]5 (947 mg,
83%), respectively. Their 1H NMR spectra (400.27 MHz, CDCl3)
were identical to that for 5 except for δ 2.04 (br d, J = 9.0 Hz,
J(117/119Sn) = 35.4 Hz, 1H).
Diisopropyl Mercaptomethylphosphonate, (S)- and (R)-
Diisopropyl Mercapto[D1]methylphosphonate {8, (S)- and
(R)-[D1]8}. Experiment 1. MeLi (0.52 mL, 0.52 mmol, 1 M in
THF/cumene) was added to a solution of S-stannylmethyl
thiophosphate 5 (217 mg, 0.43 mmol) in dry THF (3 mL) under
argon at −78 °C dropwise every 3 s. After 2 min, AcOH (0.5 mL, 2 M,
in THF) was added, and the solution was warmed and concentrated
under reduced pressure. Water (4 mL) was added, and the aq phase
was extracted with EtOAc (3 × 10 mL). The combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography (hexane/EtOAc, 1:1, Rf
0.14) to yield mercaptophosphonate 8 as a colorless oil (55 mg, 60%).
The spectroscopic data are identical to those of the literature.17
Experiment 2. Similarly, thiophosphate 5 (202 mg, 0.40 mmol) was
converted to mercaptophosphonate 8 (28 mg, 33%) except that MeLi
was added dropwise every 1 s and that the reaction was quenched after
1 min with AcOH (0.48 mL, 2 M, in THF).
Flash (column) chromatography was performed with silica gel 60
(230−400 mesh) and monitored by TLC, carried out on 0.25 mm
thick plates, silica gel 60 F254. Spots were visualized by UV and/or
dipping the plate into a solution of (NH4)6Mo7O24·4H2O (23.0 g) and
Ce(SO4)2·4H2O (1.0 g) in 10% aq H2SO4 (500 mL), followed by
heating with a heat gun.
Improved Preparation of (S)- and (R)-Tributylstannyl[D1]-
methanol {(S)- and (R)-[D1]2}.2 The two diastereomeric boronates
31 and 32 were reduced with LiBEt3D to (1S)-[1-2H1]- and (1R)-
[1-2H1]34, respectively (compound numbers are taken from the
literature2). An aqueous solution of NaOH (2.27 mL, 7.82 mmol, 3.44
M) and a solution of H2O2 (1.0 mL, 10.33 mmol, 30%) were added at
0 °C to (1S)-[1-2H1]34 (1.689 g, 3.13 mmol) dissolved in dry THF
(15.7 mL). After the biphasic mixture was stirred vigorously for 1 h,
more NaOH (2.27 mL) and H2O2 (1.0 mL) were added. Stirring was
continued for another 1 h, and then water (18 mL) and pentaerythritol
(600 mg) were added. The reaction mixture was stirred for 30 min.
The organic phase was separated, and the aqueous phase was extracted
with EtOAc (3 × 30 mL). The combined organic layers were washed
with water (30 mL) and brine (30 mL), dried (MgSO4), and
concentrated under reduced pressure. The residue was purified by
flash chromatography (hexane/EtOAc, 10:1, Rf 0.48) to give (S)-[D1]
2 (826 mg, 82%, D 96−98%).
Experiment 3. Similarly to experiment 1, (S)-[D1]5 (280 mg, 0.56
mmol) was converted to (R)-[D1]8 (48 mg, 41%, ee 23%) except that
the reaction was performed at 0 °C and quenched with AcOH 15 s
after the addition of MeLi, added dropwise every 1 s. The
1
spectroscopic data were identical to that of 8 except as follows. H
NMR (400.27 MHz, CDCl3): δ 2.60 (tdd, J = 13.4, 8.2, 2.1 Hz, 1H),
1.79 (dd, J = 8.5, 8.2 Hz, 1H). 13C NMR (100.61 MHz, CDCl3): δ
18.3 (dt, J = 151.8, 21.2 Hz).
Experiment 4. Similarly to experiment 1, (S)-[D1]5 (229 mg, 0.46
mmol) was converted to (R)-[D1]8 (22 mg, 22%, ee 77%) except that
the reaction was performed in Et2O at −95 °C, using 1.05 equiv of
MeLi. The reaction was quenched after 1 min.
Experiment 5. Similarly to experiment 4, (S)-[D1]5 (218 mg, 0.43
mmol) was converted to (R)-[D1]8 (52 mg, 56%, racemic), except
that the reaction was performed in dry Et2O at 0 °C. The reaction was
quenched with AcOH after 15 s.
Experiment 6. Similarly to experiment 4, thiophosphate (R)-[D1]5
(286 mg, 0.57 mmol) was converted to deuterated (S)-mercapto-
phosphonate (S)-[D1]8 (31 mg, 25%, ee 61%) except that the reaction
was performed in dry THF and quenched with AcOH 3 min after the
addition of MeLi.
Similarly, (1R)-[1-2H1]34 (1.617 g, 2.99 mmol) was converted to
(R)-[D1]2 (731 mg, 76%, D 96−98%).
Preparation of (R)-Mosher Esters of Secondary Alcohols:
General Procedure A. A solution of alcohol (0.10 mmol), dry
pyridine (0.25 mL), and (S)-MTPACl (0.3 mL, 0.15 mmol, 0.5 M in
dry CH2Cl2) in dry CH2Cl2 (2 mL) was left at rt (for bromohydrins 4
h, for all other alcohols 4−18 h). Afterward, CH2Cl2 (10 mL) and HCl
(10 mL, 1 M) were added. The organic phase was separated, washed
with saturated aq NaHCO3, dried (MgSO4), and concentrated under
reduced pressure. The crude product was purified by flash
chromatography to furnish oily (R)-Mosher esters.
Diisopropyl S-Tributylstannylmethyl Thiophosphate, (R)-
and (S)-Diisopropyl S-Tributylstannyl[D1]methyl Thiophos-
phate {5, (R)- and (S)-[D1]5}. TMP (432 mg, 3.07 mmol) was
dissolved in dry THF (12.4 mL) under argon and the solution cooled
to −10 °C. n-BuLi (1.93 mL, 3.07 mmol, 1.6 M in hexane) was added.
After 15 min, the solution was cooled to −78 °C, tributylstannylme-
thanol (2) (826 mg, 2.56 mmol) in dry THF (4.2 mL) was added, and
the solution was stirred for 15 min. MsCl (258 μL, 3.33 mmol) was
Experiment 7. Similarly to experiment 6, (R)-[D1]5 (249 mg, 0.50
mmol) was converted to (S)-[D1]8 (73 mg, 68%, ee 52%) except that
MeLi was replaced by n-BuLi.
S-(Diisopropoxyphosphinyl)methyl (R)-1-(1-Naphthyl)-
ethylthiocarbamate, (R)- and (S)-S-(diisopropoxyphosphinyl)-
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[D1]methyl (R)-1-(1-naphthyl)ethylthiocarbamate {10b, (R)-
and (S)-[D1]10b}. A solution of mercaptomethylphoshonate24 8 (76
mg, 0.36 mmol) and (R)-(−)-1-(1-naphthyl)ethyl isocyanate (0.62
mL, 0.72 mmol, ee 95%) in dry THF (3 mL) under argon was stirred
for 5 h at rt. Afterward, water (0.25 mL) was added, and the mixture
was stirred for another 2.5 h and concentrated under reduced pressure.
The residue was purified by flash chromatography (hexane/EtOAc,
1:2, Rf 0.61) to yield thiocarbamate 10b (136 mg, 97%) as a colorless
oil. IR (Si): ν 3222, 2980, 2931, 1675, 1533, 1238, 1216, 994 cm−1. 1H
NMR (400.13 MHz, CDCl3): δ 8.04 (d, J = 8.3 Hz, 1H), 7.85−7.75
(m, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.55−7.35 (m, 4H), 6.59 (br s, 1H,
NH), 5.85 (br s, 1H), 4.61 (dsept, J = 7.7, 6.3 Hz, 2H), 3.18 (AB-syst,
JAB = 15.0 Hz, J = 12.9 Hz, 2H), 1.63 (d, J = 6.8 Hz, 3H), 1.27 (d, J =
6.0 Hz, 3H), 1.26 (d, J = 5.7 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.21
(d, J = 6.2 Hz, 3H). 13C NMR (100.61 MHz, CDCl3): δ 164.3 (br s),
137.9, 133.8, 130.7, 128.8, 128.8, 128.3, 126.4, 125.7, 125.2, 123.0,
122.6, 71.40 (d, J = 6.7 Hz), 71.38 (d, J = 6.7 Hz), 60.3, 24.0 (d, J =
153.2 Hz), 23.94 (d, J = 4.5 Hz), 23.91 (d, J = 4.4 Hz), 23.79 (d, J =
4.8 Hz), 23.77 (d, J = 5.2 Hz), 21.1 (br s). 31P NMR (161.98 MHz,
CDCl3): δ 22.5. Anal. Calcd for C20H28NO4PS: C, 58.66; H, 6.89; N,
3.42; S, 7.83. Found: C, 59.05; H, 7.14; N, 3.80; S, 8.41.
not detected, 129.0 (2C, Carom), 128.3 (2C, Carom), 126.6 (Carom), 42.5
(CH2S), 29.0 (J(117/119Sn) = 20.6 Hz, 3C, 3 × CH2(CH2)2Sn), 27.2
(J(117/119Sn) = 55.2 Hz, 3C, 3 × CH2-CH2Sn), 13.7 (3C, 3 ×
CH3(CH2)3), 9.5 (J(117/119Sn) = 334.4 Hz, 3C, 3 × SnCH2(CH2)2),
8.3 (t, J(117/119Sn) = 223.0 Hz, SCH2Sn). Anal. Calcd for C20H36SSn:
C, 56.22; H, 8.49; S, 7.50. Found: C, 56.48; H, 8.45; S, 7.26.
Similarly, mesylates (R)-[D1]3 (1.0 g, 2.49 mmol) and (S)-[D1]3
(1.690 g, 4.22 mmol) were converted to benzylthio-[D1]-
methylstannanes (S)-[D1]12b (870 mg, 82%) and (R)-[D1]12b
1
(1.535 g, 85%), respectively. Their H NMR spectra (400.27 MHz,
CDCl3) were identical to that of 12b except for δ 1.77 (s, J(117/119Sn)
= 41.6 Hz, 1H).
(1-Naphthylmethyl)thiomethyl- and (R)-(1-naphthylmethyl)-
thio[D1]methyltributylstannane {12c, (R)-[D1]12c}. 1-Naphthyl-
methanethiol43 (745 mg, 4.66 mmol) was alkylated with mesylate 3
(1.240 g, 3.11 mmol) by the procedure used for the preparation of
allylthiomethylstannane 12a. The combined organic layers were
washed with brine (25 mL) and 2 M NaOH (3 × 25 mL), dried
(MgSO4), and concentrated under reduced pressure. The crude
product was purified by flash chromatography (hexane/CH2Cl2, 30:1,
Rf 0.33) to yield (1-naphthylmethyl)thiomethylstannane 12c (1.219 g,
82%) as a colorless oil. IR (Si): ν 2954, 2922, 2851, 1510, 1462, 1376,
Similarly, (R)-[D1]8 (48 mg, 0.22 mmol) was converted to (R)-
1
1
[D1]10b (66 mg, 73%, ee 23%). The H NMR spectrum (400.27
1074, 1016 cm−1. H NMR (400.27 MHz, CDCl3): δ 8.19−8.11 (d, J
MHz, CDCl3) was identical to that of 10b except for δ 3.22 (d, J =
13.3 Hz, 0.38H), 3.17 (d, J = 13.2 Hz, 0.61H).
= 8.5 Hz, 1H), 7.85−7.68 (m, 2H), 7.55−7.42 (m, 2H), 7.41−7.33 (m,
2H), 4.12 (s, 2H), 1.83 (s, J(117/119Sn) = 40.1 Hz, 2H), 1.49−1.33 (m,
6H), 1.21 (sext, J = 7.3 Hz, 6H), 0.98−0.83 (m, 6H), 0.81 (t, J = 7.3
Hz, 9H). 13C NMR (100.61 MHz, CDCl3): δ 134.1, 133.7, 131.6,
128.6, 127.7, 127.2, 125.8, 125.6, 125.0, 124.3, 40.4, 28.9 (J(117/119Sn)
= 20.9 Hz, 3C), 27.2 (J(117/119Sn) = 55.1 Hz, 3C), 13.6 (3C), 9.5
(J(117/119Sn) = 319.6 Hz, 3C), 9.1 (J(117/119Sn) = 214.4 Hz). Anal.
Calcd for C24H38SSn: C, 60.39; H, 8.02. Found: C, 60.34; H, 7.76.
Similarly, mesylate (S)-[D1]3 (678 mg, 1.69 mmol) was converted
to thiomethylstannane (R)-[D1]12c (642 mg, 79%). The spectro-
Similarly, (S)-[D1]8 (31 mg, 0.14 mmol) was converted to (S)-[D1]
1
10b (50 mg, 86%, ee 51%). The H NMR spectrum (400.27 MHz,
CDCl3) was identical to that of (R)-[D1]10b except for the different
integration of the two doublets δ 3.22 (d, J = 13.3 Hz, 0.74H), 3.17 (d,
J = 13.2 Hz, 0.23H).
(Allylthiomethyl)tributylstannane, (S)- and (R)-(Allylthio[D1]-
methyl)tributylstannane {12a, (S)-and (R)-12a}. Allylmercaptan
(0.20 mL, 2.37 mmol) was added to a solution of t-BuONa (228 mg,
2.37 mmol) in dry THF (5.0 mL) and stirred under argon for 10 min.
The reaction mixture was cooled to −30 °C, and tributylstannylmethyl
mesylate (3) (632 mg, 1.58 mmol) in dry THF (3 mL) was added.
After the mixture was stirred for 15 min, 1 M HCl (8 mL) and hexane
(8 mL) were added. The organic phase was separated and washed with
brine (20 mL), dried (MgSO4), and concentrated under reduced
pressure. The residue was purified by flash chromatography (hexane/
CH2Cl2, 30:1, Rf 0.54) to yield tributylstannylmethyl sulfide (12a)
(500 mg, 84%) as a colorless oil. IR (Si): ν 2956, 2926, 2853, 1635,
1464, 1376, 911 cm−1. 1H NMR (400.27 MHz, CDCl3): δ 5.74 (tdd, J
= 17.2, 10.0, 7.3 Hz, 1H), 5.07 (tdd, J = 10.0, 1.7, 0.8 Hz, 1H), 5.03
(tdd, J = 17.2, 1.7, 1.2 Hz, 1H), 3.06 (ddd, J = 7.3, 1.2, 0.8 Hz, 2H),
1.80 (s, J(117/119Sn) = 41.3 Hz, 2H), 1.60−1.38 (m, 6H), 1.30 (sext, J =
7.3 Hz, 6H), 1.10−0.82 (m, J(117/119Sn) = 50.6 Hz, 6H), 0.87 (t, J =
7.3 Hz, 9H). 13C NMR (100.61 MHz, CDCl3): δ 133.9, 116.7, 41.0,
29.0 (J(117/119Sn) = 20.9 Hz, 3C), 27.3 (J(117/119Sn) = 55.2 Hz, 3C),
13.7 (3C), 9.5 (J(117/119Sn) = 334.7, 319.6 Hz, 3C), 7.5. Anal. Calcd
for C16H34SSn: C, 50.94; H, 9.08. Found: C, 51.16; H, 9.14.
1
scopic data were identical to that of 12c except for the following. H
NMR (400.27 MHz, CDCl3): δ 1.81 (s, J(117/119Sn) = 41.0 Hz, 1H,
CHDSn). 13C NMR (100.61 MHz, CDCl3): δ 8.8 (t, J = 21.0 Hz, 1C,
SCHDSn).
[2,3]-Rerrangement of (Allylthiomethyl)stannanes 12, (R)-
and (S)-[D1]12a, and Derivatization of 3-Butenethiols Formed
from Thiocarbamate 16. Experiment 1. n-BuLi (0.25 mL, 0.39
mmol) was added to the solution of sulfide 12a (131 mg, 0.33 mmol)
in dry THF (2.5 mL) at −95 °C under argon. After 10 min, 2 M
CF3CO2H (70 μL, 0.13 mmol) was added and the mixture was used
immediately for the derivatization as thiol 15 cannot be isolated
because of its low boiling point.25
(R)-(+)-1-Phenylethyl isocyanate (0,10 mL, 0.66 mmol, ee 99%)
was added at −95 °C. The cooling bath was removed and stirring was
continued at rt. After 45 min a saturated aqueous solution of NaHCO3
(10 mL) was added and the mixture was extracted with EtOAc (2 × 20
mL). The combined organic phases were dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
two flash chromatographies (first: hexane/EtOAc, 10:1, Rf 0.38, side
product derived from isocyanate 0.45; second: hexane/CH2Cl2, 1:1, Rf
0.29, side product derived from isocyanate 0.68) to yield
thiocarbamate 16 (64 mg, 83%) as colorless crystals. Mp: 46−47 °C
Similarly, mesylates4 (R)- and (S)-[D1]3 (690 mg, 1.72 mmol and
635 mg, 1.59 mmol) were converted to sulfides (S)-[D1]12a (537 mg,
1
83%) and (R)-[D1]12a (375 mg, 63%), respectively. The H NMR
spectra (400.27 MHz, CDCl3) were identical to that of 12 except for δ
(hexane). [α]20 = −97.78 (c 0.90, acetone). IR (Si): ν 3293, 2977,
1.78 (br s, J(117/119Sn) = 40.7 Hz, 1H).
D
1652, 1520, 1495, 1217, 699 cm−1. 1H NMR (400.27 MHz, CDCl3): δ
7.37−7.18 (m, 5H, Harom), 5.77 (tdd, J = 17.0, 10.2, 6.7 Hz, 1H, CH
CH2), 5.54 (br s, 1H, NH), 5.06 (qd, J = 17.0, 1.6 Hz, 1H, CH
CH2), 5.05 (br s, 1H, CHCH3), 5.01 (tdd, Jci = 10.2, 1.6, 1.2 Hz, 1H,
CHCH2), 2.95 (AB-sys, JAB = 13.4 Hz, J = 7.1 Hz, 2H, CH2S), 2.35
(tddd, J = 7.1, 6.7, 1.6, 1.2 Hz, 2H, CH2CH2S), 1.49 (d, J = 6.9 Hz, 3H,
CH3CH). 13C NMR (100.61 MHz, CDCl3): δ 142.8, 136.3, 128.7
(2C), 127.5 (2C), 126.0, 116.3, 51.1, 34.5, 29.2, 22.0. Anal. Calcd for
C13H17NOS: C, 66.34; H, 7.28; N, 5.95; S, 13.62. Found: C, 66.16; H,
7.25; N, 6.04; S, 13.40.
Benzylthiomethyl- and (R)- and (S)-Benzylthio[D1]-
methyltributylstannane {12b, (R)- and (S)-[D1]12b}. Benzylmer-
captan (0.35 mL, 3.0 mmol) was alkylated with mesylate 3 (798 mg,
2.0 mmol) by the procedure used for the preparation of
allylthiomethylstannane 12a. The crude product was first heated (45
°C, 0.5 mbar) to remove excess benzylmercaptan and then purified by
flash chromatography (hexane/CH2Cl2, 30:1, Rf 0.33) to yield
benzylthiomethylstannane 12b (786 mg, 92%) as a colorless oil. IR
1
(Si): ν 2955, 2923, 2851, 1493, 1453, 1376, 1071 cm−1. H NMR
(400.27 MHz, CDCl3): δ 7.35−7.15 (m, 5H, Harom), 3.64 (s, 2H,
CH2S), 1.77 (s, J(117/119Sn) = 41.6 Hz, 2H, CH2Sn), 1.57−1.33 (m,
6H, 3 × CH2CH2Sn), 1.30 (sext, J = 7.3 Hz, 6H, 3 × CH2(CH2)2Sn),
0.97−0.80 (m, J(117/119Sn) = 49.6 Hz, 6H, 3 × CH2Sn), 0.85 (t, J = 7.3
Hz, 9H, 3x CH3(CH2)3Sn). 13C NMR (100.61 MHz, CDCl3): δ Cq
1
The H NMR spectra (400.27 MHz, CDCl3) of (R)- and (S)-[D1]
16 were identical to that of 16, except for δ 2.95 (t, J = 7.2 Hz, 1H,
CHD), 2.34 (t, J = 6.9 Hz, CH2CHD). To determine the ee of
derivatives [D1]16 the 1H NMR experiments were performed in
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Article
DMSO-d6 (600.13 MHz) with irradiation at 2.24 ppm (decoupling of
SCHDCH2). Two broad singlets (δ 2.79 and 2.82) were observed for
the two diastereotopic protons of the SCHD group. (S)-[D1]12a gave
the carbamate with the broad singlet at δ 2.82.
Experiment 2. Allylthio[D1]methylstannane (S)-[D1]12a (174 mg,
0.46 mmol) was converted to thiocarbamate (S)-[D1]16 (90 mg, 83%,
ee ≥95%) by the procedure used for experiment 1.
Experiment 3. Stannane (S)-[D1]12a (161 mg, 0.43 mmol) was
converted to (S)-[D1]16 (95 mg, 95%, ee 91%) by the procedure used
for experiment 1 except that it was performed at −78 °C.
syst J = 9.2, 3.7 Hz, 1H), 3.71 (s, 2H), 2.78 (A-part of ABX-syst, JAB =
14.0 Hz, J = 3.7 Hz, 1H), 2.65 (B-part of ABX-syst, JAB = 14.0 Hz, J =
9.2 Hz, 1H), 2.47 (br s, 1H, OH).
Experiment 2. Similarly, stannane (R)-[D1]12b (233 mg, 0.54
mmol) was transformed into alcohol ( )-[2-D1]19 (95 mg, 72%) by
the procedure used for experiment 1 except that benzaldehyde (0.54
mL, 1.08 mmol, 2 M in dry THF), was added 1 min after the addition
of MeLi (0.27 mL, 0.82 mmol, 3 M in diethoxymethane).
The spectroscopic data of (2S)-[2-D1]19 were identical to that of
1
19 except for the following. H NMR (400.13 MHz, CDCl3): δ 4.59
Experiment 4. Stannane (S)-[D1]12a (172 mg, 0.45 mmol) was
converted to (S)-[D1]16 (104 mg, 99%, ee 83%) by the procedure
used for experiment 1 except that it was performed at −40 °C.
Experiment 5. Stannane (S)-[D1]12a (164 mg, 0.43 mmol) was
converted to (S)-[D1]16 (73 mg, 72%, ee 71%) by the procedure used
for experiment 1 except that it was performed at 0 °C and that the
reaction was quenched with CF3CO2H 3 min after the addition of n-
BuL.
(2 overlapping d, J = 9.2, 3.7 Hz, 1H), 2.82 (br s, 1H, OH), 2.68 (br s,
1H, SCHD), 2.58 (br d, J = 9.2 Hz, 1H, SCHD). 13C NMR (100.61
MHz, CDCl3): δ 40.4 (t, J = 21.5 Hz, 1C, SCHD).
Experiment 3. (R)-Benzylthio[D1]methylstannane [(R)-[D1]12b]
(213 mg, 0.50 mmol) was transformed into alcohol (S)-[D1]19 (30
mg, 24%, ee 16%) by the procedure used for the preparation of the
racemic alcohols except that the benzaldehyde (0.50 mL, 1.0 mmol, 2
M in dry THF) was present in the reaction mixture when MeLi was
added dropwise every 3 s.
Experiment 4. Similarly, (R)-[D1]12b (228 mg, 0.53 mmol) was
transformed into (2S)-[2-D1]19 (11 mg, 9%, ee 26%) by the
procedure used for experiment 3 except that it was performed at
−95 °C and that 2 equiv of 12-crown-4 were present in the reaction
mixture.
Experiment 5. Similarly, (R)-[D1]12b (237 mg, 0.55 mmol) was
transformed into (S)-[D1]19 (34 mg, 25%, ee 8%) by the procedure
used for experiment 3, except that the experiment was performed at
−50 °C. Part of starting stannane was recovered (50%).
Experiment 6. Similarly, (R)-[D1]12b (228 mg, 0.53 mmol) was
transformed into ( )-[D1]19 (26 mg, 21%) by the procedure used for
experiment 3, except that the experiment was performed at 0 °C.
(R)-Mosher Esters of Alcohols 19 and (2S)-[2-D1]19. Racemic
alcohol 19 (mg, mmol) was converted to a 1:1 mixture of
diastereomeric (R)-Mosher esters according to general procedure A.
The crude product was purified by flash chromatography (hexane/
EtOAc, 10:1, Rf 0.51) to yield esters 19·(R)-MTPA (28 mg, 94%) as a
colorless oil. 1H NMR (600.13 MHz, CDCl3): δ 7.48−7.07 (m, 30H),
5.97 (X-part of ABX-syst, J = 8.2, 5.7 Hz, 1H, diastereomer A), 5.86
(X-part of ABX-syst, J = 9.0, 4.8 Hz, 1H, diastereomer B), 3.66 (AB-
syst, JAB = 13.5 Hz, 2H), 3.60 (t, J = 1.2 Hz, 3H, 3.52 (s, 2H), 3.45 (t, J
= 1.2 Hz, 3H), 2.87 (A-part of ABX-syst, JAB = 14.4 Hz, J = 9.0 Hz, 1H,
B), 2.83 (A-part of ABX-syst, JAB = 14.4 Hz, J = 8.2 Hz, 1H, A), 2.70
(B-part of ABX-syst, JAB = 14.4 Hz, J = 4.8 Hz, 1H, B), 2.69 (B-part of
ABX-syst, JAB = 14.4 Hz, J = 5.7 Hz, 1H, A).
Experiment 6. Stannane (R)-[D1]12a (189 mg, 0.50 mmol) was
converted to (R)-[D1]16 (74 mg, 62%, ee 50%) by the procedure used
for experiment 3 except that it was performed in dry Et2O.
Experiment 7. Stannane (R)-[D1]12a (184 mg, 0.49 mmol) was
converted to (R)-[D1]16 (51 mg, 45%, ee 20%) by the procedure used
for experiment 5 except that it was performed in dry Et2O.
[2,3]-Rearrangement of Benzylthiomethylstannanes 12b
and (R)-[D1]12b, Derivatization of 2-Methylphenylmethane-
thiols Formed, and Determination of ee. n-BuLi (0.41 mL, 0.65
mmol) was added to a solution of 12b (231 mg, 0.54 mmol) in dry
THF (3.8 mL) at −30 °C under argon. After 30 min, 2 M CF3CO2H
(0.11 mL, 0.22 mmol) was added, and the mixture was used directly
for the derivatization. The 2-methylphenylmethanethiol 17 (detectable
by TLC: hexane/CH2Cl2, 10:1, Rf 0.54) was not isolated because of its
volatility (bp 97 °C/14 mm44). (R)-(+)-1-Phenylethyl isocyanate
(0.17 mL, 1.08 mmol) was added. After the mixture was stirred for 1.5
h at rt, water (1 mL) was added and the reaction mixture was
concentrated under reduced pressure. The residue was purified by
flash chromatography (hexane/CH2Cl2, 1:1, Rf 0.43) to yield
thiocarbamate 18 (66 mg, 43%) as colorless crystals; mp 92−93 °C
(i-Pr2O). IR (ATR): ν 3277, 2972, 2926, 1643, 1527, 1493, 1446, 1216
1
cm−1. H NMR (400.27 MHz, CDCl3): δ 7.41−7.20 (m, 6H, Harom),
7.19−7.05 (m, 3H, Harom), 5.52 (br s, 1H, CHCH3), 5.08 (br s, 1H,
NH), 4.16 (AB-sys, JAB = 13.7 Hz, 2H, CH2S), 2.33 (s, 3H, CH3Ph),
1.49 (d, J = 6.9 Hz, 3H, CH3CH). 13C NMR (100.61 MHz, CDCl3): δ
CO n. d., 142.7 (Cq arom), 136.6 (Cq arom), 136.1 (Cq arom), 130.4
(Carom), 129.9 (Carom), 128.7 (2C, Carom), 127.6 (2C, Carom), 127.5
(Carom), 126.2 (Carom), 126.0 (Carom), 51.2 (CHCH3), 32.4 (CH2S),
22.0 (br s, CH3CH), 19.4 (CH3Ph). Anal. Calcd for C17H19NOS: C,
71.54; H, 6.71; N, 4.91; S, 11.23. Found: C, 71.29; H, 6.77; N, 4.92; S,
11.06.
Similarly, alcohol (2S)-[2-D1]19 (11 mg, 0.045 mmol), obtained by
determination of microscopic configurational stability of chiral
benzylthiomethyllithium by experiment 5 was converted to (R)-
Mosher esters (S)-[D1]19·(R)-MTPA (18 mg, 87%).
The 1H NMR spectrum (600.13 MHz, CDCl3) was identical to that
of 19·(R)-MTPA except for δ 2.85 (d, J = 9.0 Hz, 0.42H, CHD), 2.81
(d, J = 8.2 Hz, 0.67H, CHD), 2.68 (2 overlapping d, 1H, CHD); ee of
underlying alcohol 26%.
Similarly, (S)-benzylthio[D1]methylstannane (S)-[D1]12b (232 mg,
0.54 mmol) was converted to thiocarbamate [D1]18 (92 mg, 59%)
except that the reaction temperature was −50 C and the reaction time
1
20 min. The H NMR spectrum (400.27 MHz, CDCl3) was identical
(1-Methylnaphth-2-yl)methanethiol and (1-Methylnaphth-
2-yl)[D1]methanethiol {20 and (S)-[D1]20}. n-BuLi (0.50 mL, 0.79
mmol) was added to the solution of (1-naphthylmethylthiomethyl)-
tributylstannane (12c) (314 mg, 0.66 mmol) in dry THF (4.6 mL) at
−78 °C under argon. After 10 min, CF3CO2H (0.43 mL, 0.87 mmol, 2
M in CH2Cl2) was added, and the mixture was extracted with EtOAc
(3 × 10 mL). The combined organic phases were dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
flash chromatography (hexane/CH2Cl2, 10:1, Rf 0.32) to yield thiol 20
(57 mg, 45%) as a colorless oil. IR (Si): ν 3050, 2924, 1597, 1510,
1382, 1264, 1248, 1210, 1060 cm−1. 1H NMR (400.27 MHz, CDCl3):
δ 8.04 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.4
Hz, 1H), 7.55−7.40 (m, 2H), 7.38−7.33 (m, 1H), 3.94 (d, J = 7.0 Hz,
2H), 2.69 (s, 3H), 1.71 (t, J = 7.0 Hz, 1H). 13C NMR (100.61 MHz,
CDCl3): δ 136.1, 133.1, 132.8, 131.1, 128.5, 127.3, 126.7, 126.1, 125.4,
124.1, 27.7, 14.2. Anal. Calcd for C12H12S: C, 76.55; H, 6.42; S, 17.03.
Found: C, 76.38; H, 6.39; S, 16.76.
to that of the unlabeled species 18 except for δ 4.17 (s, 1H, CHD),
4.13 (s, 1H, CHD) (thiol [D1]17 was racemic).
Experiments To Test Macroscopic and Microscopic Config-
urational Stability of (S)-Benzylthio[D1]methyllithium. Gener-
ation of Benzylthiomethyllithiums 13b and (S)-[D1]13b and
Their Addition to Benzaldehyde To Give 2-Benzylthio-1-
phenylethanol45 (19) and Benzylthio-1-phenyl[2-D1]ethanol
{(2S)-[2-D1]19}. Experiment 1. n-BuLi (0.17 mL, 0.26 mmol) was
added to a solution of benzylthiomethylstannane 12b (92 mg, 0.22
mmol) in dry THF (1.6 mL) at −78 °C under argon. After 10 min,
benzaldehyde (0.17 mL, 0.33 mmol, 2 M in dry THF) was added,
followed by saturated aq NaHCO3 (3 mL) 5 min later. The mixture
was extracted with EtOAc (3 × 15 mL). The combined organic phases
were dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by flash chromatography (hexane/EtOAc, 10:1, Rf
0.26) to yield alcohol43 19 (42 mg, 77%) as a colorless oil. H NMR
1
(400.27 MHz, CDCl3): δ 7.40−7.18 (m, 10H), 4.66 (X-part of ABX-
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Article
Similarly, (R)-[D1]12c (206 mg, 0.43 mmol) was rearranged to (R)-
[D1]20 (22 mg, 28%, ee 60%) except that transmetalation was
chromatography (hexane/EtOAc, 7:1) to yield (S)-(+)-2-bromo-1-
phenylethanol [(S)-(+)-23] as a colorless oil (193 mg, 26%), ee 94%
1
1
(by H NMR of (R)-Mosher ester), [α]20 +39.24 (c 1.975, CH2Cl2)
performed with MeLi (3 M, in diethoxymethane) at −50 °C. The H
D
[lit.46 [α]20 +40.10, (c 1.81, CHCl3), ee 92%]. The 1H NMR
NMR spectrum (400.27 MHz, CDCl3) was identical to that of 20
except for δ 3.92 (dt, J = 7.0, 1.8 Hz, 1H, CHDSH), 1.69 (d, J = 7.0
Hz, 1H, CHDSH).
D
spectrum was identical to that of the racemate.
(R)-Mosher Esters of ( )-23 and (S)-(+)-23. ( )-2-Bromo-1-
phenylethanol [( )-23] (20 mg, 0.10 mmol) was converted to (R)-
Mosher esters using general procedure A. The crude product was
purified by flash chromatography (hexane/EtOAc,10:1, Rf 0.66) to
yield a mixture of diastereomeric Mosher esters ( )-23·(R)-MTPA
Similarly, stannane (R)-[D1]12c (208 mg, 0.43 mmol) was
rearranged to thiol (R)-[D1]20 (49 mg, 60%, ee 72%) except that
transmetalation was performed with n-BuLi at −95 °C.
S-(1-Methylnaphth-2-yl)methyl (R)-N-(1-Phenylethyl)-
thiocarbamate and (R)-(1-Methylnaphth-2-yl)[D1]methyl (R)-
N-(1-Phenylethyl)thiocarbamate {21 and (R)-[D1]21}. A solution
of (R)-(+)-1-phenylethyl isocyanate (67 μL, 0.48 mmol) and thiol 20
(46 mg, 0.24 mmol) in dry THF (1.2 mL) was left for 1 h under argon
at rt. Water (1 mL) was added, and the mixture was extracted with
EtOAc (3 × 15 mL). The combined organic phases were dried
(MgSO4) and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/CH2Cl2, 1:1, Rf 0.37) to
yield thiocarbamate 21 (39 mg, 50%) as colorless crystals. Mp: 134−
135 °C (i-Pr2O). IR (ATR): ν 3284, 2975, 2925, 1640, 1509, 1446,
1204, 1179, 1101 cm−1. 1H NMR (400.27 MHz, CDCl3): δ 8.03 (d, J
= 8.5 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H),
7.53−7.39 (m, 3H), 7.38−7.19 (m, 5H), 5.46 (br s, 1H), 5.10 (br s,
1H), 4.38 (AB-sys, JAB = 13.2 Hz, 2H), 2.65 (s, 3H), 1.50 (d, J = 6.9
Hz, 3H). 13C NMR (100.61 MHz, CDCl3): δ CO (n. d.), 142.7,
133.0, 132.9, 132.4, 128.8, 128.5, 128.2, 127.6, 126.4, 126.0, 125.4,
124.1, 51.3, 33.3, 22.1 (br s), 14.5. Anal. Calcd for C21H21NOS: C,
75.19; H, 6.31; N, 4.18; S, 9.56: Found: C, 74.89; H, 6.22; N, 4.05; S,
9.56.
1
(39 mg, 94%). H NMR (400.13 MHz, toluene-d8): δ 7.59−7.55 [m,
2H, (R,S)-diastereomer], 7.51−7.47 [m, 2H, (R,R)], 7.08−6.91 [m,
14H, 8H of (R,S), 6H of (R,R)], 6.78−6.75 [m, 2H, (R,R)], 6.04 [X-
part of an ABX-syst, J = 8.8, 4.2 Hz, 1H, (R,S)], 5.90 [X-part of an
ABX-syst, J = 9.6, 3.3 Hz, 1H, (R,R)], 3.58 [q, J = 1.0 Hz, 3H, (R,R)],
3.32 [q, J = 1.0 Hz, 3H, (R,S)], 3.07 [AB-part of an ABX-syst, JAB
=
11.1 Hz, J = 8.8, 4.2 Hz, 2H, (R,S)], 3.01 [AB-part of an ABX-syst, JAB
= 11.4 Hz, J = 9.6, 3.3 Hz, 2H, (R,R)].
Similarly, (S)-(+)-23 [20 mg, 0.10 mmol, [α]20 +39.24, (c 1.98,
D
CH2Cl2)] was converted to (R)-Mosher esters (40 mg, 96%); ee of
1
alcohol: 94%. The H NMR spectrum was identical to that of the
racemic alcohol, except that the signals of the diastereomers differed in
intensity.
Test of Chemical Stability of Lithium Alkoxide Derived from
( )-2-Bromo-1-phenylethanol toward Formation of Phenyl-
oxirane at −78 °C. A solution of MeLi (0.60 mL, 0.60 mmol, 1 M in
cumene/THF) was added quickly at −78 °C to the ( )-bromohydrin
( )-23 (100 mg, 0.5 mmol) dissolved in dry THF (2.5 mL) under
argon atmosphere. After the mxiture was stirred for 5 min, CF3CO2H
(75 mg, 0.65 mL, 0.65 mmol, 1.3 equiv, 1 M in dry CH2Cl2) and water
(5 mL) 3 min later were added. The organic phase was separated and
the aqueous one was extracted with Et2O (3 × 15 mL). The combined
organic layers were dried (Na2SO4) and concentrated under reduced
pressure. The crude product did not contain phenyloxirane as
Similarly, thiol (R)-[D1]20 (49 mg, 0.26 mmol, obtained by
rearrangement at −95 °C with n-BuLi) was converted to
thiocarbamate (R)-[D1]21 (36 mg, 42%).
The spectroscopic data were identical to that of 21 except for the
following. 1H NMR (400.27 MHz, CDCl3): δ 4.38 (br s, 0.86H,
CHD), 4.35 (br s, 0.14H, CHD). 13C NMR (100.61 MHz, CDCl3): δ
33.1 (t, J = 21.9 Hz, 1C, CHDS).
( )- and (S)-(+)-2-Bromo-1-phenylethanol [( )-23 and (S)-
(+)-23]. ( )-23: A solution of DIBALH (3.98 mL, 5.97 mmol, 1.5 M
in toluene) was added dropwise to ω-bromoacetophenone (995 mg,
5.0 mmol) dissolved in dry Et2O (25 mL) at −78 °C under argon. The
reaction mixture was stirred for 2 h at −78 °C and then 1 h at −50 °C.
The reaction was quenched with MeOH (0.5 mL) and water (2.5 mL)
and stirred for another 30 min at rt. A solution of HCl (12 mL, 2 M)
was added at 0 °C. The organic phase was separated, and the aqueous
phase was extracted with Et2O (3 × 10 mL). The combined organic
layers were washed with water (15 mL) and satd aq NaHCO3 (15
mL), dried (MgSO4), and concentrated under reduced pressure. The
crude product was purified by flash chromatography (hexane/EtOAc,
7:1, Rf 0.43) to yield ( )-2-bromo-1-phenylethanol [( )-23] (591
mg, 59%) as a colorless oil. 1H NMR (400.13 MHz, CDCl3): δ 7.39−
7.29 (m, 5H), 4.92 (dd, X-part of an ABX-syst, J = 9.1, 3.5 Hz, 1H),
3.58 (AB-part of an ABX-syst, JAB = 10.4 Hz, J = 9.1, 3.5 Hz, 2H), 2.59
(br s, 1H).
1
determined by H NMR spectroscopy after spiking with an authentic
sample. The crude product was purified by flash chromatography
(hexane/EtOAc, 7:1, Rf 0.42) to recover bromohydrin ( )-23 (95 mg,
95%). Its Rf value and 1H NMR spectrum were identical to that of the
starting material.
Bromomethyl- and (R)- and (S)-(Bromo[D1]methyl)-
tributylstannane Tributylstannane {25, (R)- and (S)-[D1]25}
and Determination of ee by the Method6 Used for Chloro-
[D1]methylstannane except That Reaction Was Performed at
−50 °C Instead of 0 °C. Using NBS/Ph3P:6 A solution of Ph3P (772
mg, 2.94 mmol) in dry CH2Cl2 (3 mL) was added dropwise to NBS
(523 mg, 2.94 mmol) dissolved in dry CH2Cl2 (5 mL) under argon at
−78 °C. After 10 min tributylstannylmethanol (2) (787 mg, 2.45
mmol) dissolved in dry CH2Cl2 (4 mL) was added, and the reaction
mixture was stirred rt for 30 min. A few drops of MeOH were added,
and the mixture was concentrated under reduced pressure. The residue
was flash chromatographed (hexane/CH2Cl2, 1:1, Rf 0.98) to yield
bromomethylstannane47 25 (859 mg, 91%) as a colorless oil. 1H NMR
(400.13 MHz, CDCl3): δ 2.63 (s, J(117/119Sn) = 14.6 Hz, 2H), 1.55−
1.46 (m, 6H), 1.30 (sext, J = 7.3 Hz, 6H), 1.00−0.95 (m, J(117/119Sn) =
51.4 Hz, 6H), 0.88 (t, J = 7.3 Hz, 9H).
Similarly, (S)-[D1]2 (197 mg, 0.61 mmol, prepared by an improved
procedure, see below) was converted to (R)-[D1]25 (205 mg, 92%, ee
60%). The 1H NMR spectrum (400.13 MHz, CDCl3) was identical to
that of 25 except for δ 2.61 (t, J = 1.5 Hz, 1H, CHD).
When the reaction was performed in the same way as before, except
that two instead of 1.2 equiv of Ph3P/NBS were used, (R)-[D1]2 (251
mg, 0.78 mmol) were converted to (S)-[D1]25 (230 mg, 77%, ee
18%).
(S)-(+)-23: (+)-DIP-chloride34 (1.8 g, 5.61 mmol, dissolved in 5
mL of dry THF) was added to ω-bromoacetophenone (744 mg, 3.74
mmol, dissolved in 5 mL of dry THF) under argon at 0 °C. The
solution was stirred overnight at rt. At 0 °C water (1 mL),
pentaerythritol (916 mg, 6.73 mmol) and again water (15 mL) were
added and the mixture was stirred for another 30 min at rt. The
organic phase was separated and the aqueous one was extracted with
Et2O (3 × 15 mL). The combined organic layers were washed with
water (2 × 10 mL), dried (MgSO4), concentrated under reduced
pressure, and purified by flash chromatography (hexane/EtOAc, 10:1).
The still impure product was again dissolved in dry THF (10 mL) and
pentaerythritol (680 mg, 5 mmol, dissolved in 5 mL of water) was
added. The solution was stirred overnight at rt. The organic phase was
separated and the aqueous one was extracted with Et2O (3 × 15 mL).
The combined organic layers were washed with water (2 × 10 mL),
dried (MgSO4) and concentrated under reduced pressure. Ten drops
of dry pyridine were added and the crude product was purified by flash
Using Mitsunobu reaction with Ph3P·HBr: Ph3P (109 mg, 0.62
mmol), Ph3P·HBr (845 mg, 2.46 mmol), and stannylmethanol 2 (657
mg, 2.05 mmol) were dissolved in dry toluene (8.2 mL) under argon.
After stirring for 5 min at 0 °C DIAD (0.71 mL, 4.47 mmol) was
added and the reaction mixture was stirred for another 90 min. The
reaction was quenched with a few drops of MeOH. The mixture was
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The Journal of Organic Chemistry
Article
purified by flash chromatography (hexane/CH2Cl2, 1:1, Rf 0.98) to
give bromomethylstannane 25 (383 mg, 49%) as a colorless oil.
Similarly, (R)-[D1]2 (852 mg, 2.65 mmol, prepared by an improved
procedure, see below) was converted to (S)-D1]25 (491 mg, 48%, ee6
74%) except that the reaction time was 10 min. After the addition of
methanol, the reaction mixture was immediately applied to the silica
column for flash chromatography. The entire procedure (also flash
chromatography) was performed in the cold room (3 °C). No bath
was used during concentration of bromide-containing solutions under
reduced pressure.
Similarly, (R)-[D1]2 (958 mg, 2.98 mmol) was converted to (S)-
[D1]25 (521 mg, 45%, ee 94%) as before except that the reaction was
performed at −10 °C for 10 min.
Similarly, (R)-[D1]2 (417 mg, 1.30 mmol) was converted to (S)-
[D1]25 (179 mg, 35%, ee ≥99%) as before except that the reaction
was performed at −25 °C for 10 min.
electrophile. The bromhydrine was isolated by flash chromatography
(hexane/EtOAc, 15:1; TLC: hexane/EtOAc, 10:1, Rf 0.34).
Experiment 4. (S)-[D1]2 (218 mg, 0.57 mmol, ee 94%) was
converted to (2R)-[2-D1]23 (10 mg, 9%, ee 94%) by the procedure
used for experiment 2.
Experiment 5. (S)-[D1]2 (259 mg, 0.67 mmol, ee 94%) was
converted to (1R)-[1-D1]27 (45 mg, 31%, ee 93%) by the procedure
used for experiment 3 except that the reaction was performed at −95
°C.
Experiment 6. (S)-[D1]2 (179 mg, 0.46 mmol, ee ≥99%) was
converted to (2R)-[2-D1]23 (13 mg, 14%, ee ≥99%) by procedure
used for experiment 2.
Determination of Enantiomeric Excess at C-2 of Deuterated
Bromohydrins [2-D1]23, Using Their (R)-Mosher Esters [2-D1]
23 (R)-MTPA. They were prepared in quantitative yield from alcohols
[1-D1]23 according to general procedure A and they were purified by
flash chromatography (hexane/EtOAc, 10:1, Rf 0.78). The two
diastereomeric (R)-Mosher esters obtained in quantitative yield were
separated by preparative TLC chromatography (hexane/CH2Cl2, 3:1)
in one case. The less polar one (Rf 0.56) was derived from (1R,2S)-[2-
D1]23 (56% ee) and the more polar one (Rf 0.35) from (1S,2S)-[2-
D1]23 (57% ee) in quantitative yield.
Determination of Ease of Transmetalation of (Bromo-
methyl)tributylstannane. A solution of MeLi (0.51 mL, 0.51
mmol, 1 M in cumene/THF) was added quickly at −78 °C to the
(bromomethyl)tributylstannane 25 (163 mg, 0.42 mmol) dissolved in
dry THF (2 mL) under argon atmosphere. After 30 s, CF3CO2H (64
mg, 0.55 mL, 0.55 mmol, 1.3 equiv, 1 M in dry CH2Cl2) was added,
followed by water (5 mL) 1 min later. The organic phase was
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were washed with water (15 mL),
dried (Na2SO4), and concentrated under reduced pressure. The crude
product was virtually homogeneous tributylmethylstannane as
Significant resonances of (R)-Mosher ester derived from (1R,2S)-
1
[2-D1]23. H NMR (400.13 MHz, toluene-d8): δ 5.89 (br d, J = 2.5
Hz, 1H), 2.89 (d, J = 2.5 Hz, 1H, CHD). Significant resonances of
1
(R)-Mosher ester derived from (1S,2S)-[2-D1]23. H NMR (400.13
MHz, toluene-d8): δ 5.94 (d, J = 8.8 Hz, 1H), 3.05 (d, J = 8.8 Hz, 1H,
CHD).
1
determined by H NMR spectroscopy, which did not contain starting
Bromohydrins ( )-27 and [1-D1]27 and Their (R)-Mosher
Esters ( )-27·MTPA-(R) and [1-D1]27·MTPA-(R). ( )-27: 1H
NMR (400.27 MHz, CDCl3): δ 7.47−7.42 (m, 2H), 7.39−7.33 (m,
2H), 7.31−7.25 (m, 1H), 3.71 (AB-sys, JAB = 10.4 Hz, 2H), 2.52 (br s,
1H), 1.67 (s, 3H).
material.
Determination of Chemical Stability of Bromomethyllithium
under the Conditions of Evaluation of Its Microscopic
Configurtional Stability. ( )-2-Bromo-1-phenylethanol [( )-23].
A solution of MeLi (1.85 mL, 1.85 mmol, 1 M in cumene/THF) was
quickly added to a solution of bromomethylstannane 25 (178 mg, 0.46
mmol) and benzaldehyde (194 mg, 0.93 mL, 1.85 mmol, freshly
distilled, 2 M in THF) in dry THF (2 mL) under argon atmosphere at
−78 °C. After 5 min, CF3CO2H (232 mg, 2 mL, 2 mmol, 1 M in
CH2Cl2) and water (5 mL) were added. The organic phase was
separated, and the aqeous phase was extracted with CH2Cl2 (3 × 10
mL), dried (Na2SO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography (CH2Cl2, Rf 0.46) to give
bromohydrin ( )-23 as a colorless oil (17 mg, 19%). The
spectroscopic data were identical to those of the authentic sample.
Determination of Microscopic Configurational Stability of
Chiral Bromo[D1]methyllithiums: Preparation of 2-Bromo-1-
phenyl[2-D1]ethanols {(2S)- and (2R)-[2-D1]23} and 1-Bromo-2-
phenyl-2-[1-D1]propanols {(1S)- and (1R)-[1-D1]27}. Experiment
1. A solution of benzaldehyde (198 mg, 0.94 mL, 1.87 mmol, freshly
distilled, 2 M in dry THF) was added at −78 °C to the (R)-bromo[1-
D1]methylstannane (R)-[D1]2 (180 mg, 0.47 mmol, ee 50%) in dry
THF (2 mL) under argon atmosphere, followed dropwise by MeLi
(1.87 mL, 1.87 mmol, 1 M in cumene/THF). After 10 min, the
reaction was quenched with CF3CO2H (240 mg, 2.07 mL, 2.07 mmol,
1 M in THF). Water (5 mL) was added, and the organic phase was
separated and the aqueous one was extracted with CH2Cl2 (3 × 5
mL). The combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure. The residue was purified by
flash chromatography (CH2Cl2, Rf 0.43) to give bromohydrin (2S)-[2-
D1]23 (7 mg, 11%, ee 57%) as a colorless oil; impure fractions
(estimated product about 10 mg) were discarded.
[1-D1]27: The 1H NMR spectra (400.27 MHz, CDCl3) were
identical to that of ( )-27 except for δ 3.73 (br s, 0.5H, CHD), 3.68
(t, J = 1.4 Hz, 0.5H, CHD).
The (R)-Mosher esters of ( )-27 and [1-D1]27 were prepared by a
modified general procedure As exemplified for (1R)-[1-D1]27·MTPA-
(R): A solution of bromohydrin (1R)-[1-D1]27 (16 mg, 0.074 mmol),
(S)-Mosher chloride (0.15 mmol, 2 equiv, 0.29 mL of a 0.53 M
solution in dry 1,4-dioxane), and DMAP (37 mg, 0.30 mmol, 4 equiv)
in dry dioxane (1 mL) was heated at 50 °C for 8 h (no starting
material present). After the solution was cooled to rt, a few drops of
water were added and stirring was continued for 5 min. CH2Cl2 (3
mL) and HCl (3 mL, 1 M) were added. The mixture was extracted
with CH2Cl2 (2 × 15 mL). The combined organic layers were washed
with saturated aq NaHCO3, dried (Na2SO4), and concentrated under
reduced pressure. The residue was flash chromatographed (hexane/
EtOAc, 15:1, Rf 0.56) to yield (1R)-[1-D1]27·MTPA-(R) (20 mg,
62%).
1
( )-27·MTPA-(R): H NMR (400.27 MHz, CDCl3): δ 7.59−7.51
(m, 4H), 7.45−7.35 (m, 6H), 7.35−7.26 (m, 8H), 7.23−7.18 (m, 2H),
3.97 (AB-sys, JAB = 11.0 Hz, 2H), 3.77 (AB-sys, JAB = 11.0 Hz, 2H),
3.62 (q, J = 1.3 Hz, 3H), 3.57 (q, J = 1.2 Hz, 3H), 2.10 (s, 3H), 2.02
(s, 3H).
1
(1R)-[1-D1]27·MTPA-(R): The H NMR spectrum (400.27 MHz,
CDCl3) was identical to that of ( )-27·MTPA-(R) except for δ 3.91
(br s, 0.85H, CHD), 3.81 (br s, 0.85H, CHD) and 4.00 (br s, 0.02H),
3.71 (br s, 0.03H); 93% ee for bromohydrin at C-1.
ASSOCIATED CONTENT
* Supporting Information
Experiment 2. (R)-[D1]2 (157 mg, 0.41 mmol, ee 77%) was
converted to (2S)-[2-D1]23 (15 mg, 18%, ee 76%) by procedure used
for experiment 1 except using 2 equiv of benzaldehyde and MeLi (1 M
solution obtained by dilution of 3 M MeLi in diethoxymethane with
dry THF) which was added dropwise every 5 s. If 3 M MeLi in
diethoxymethane was used or it was added more rapidly, no product
or only product traces were obtained.
Experiment 3. (R)-[D1]2 (161 mg, 0.42 mmol, ee 77%) was
converted to (1S)-[1-D1]27 (11 mg, 12%, ee 75%) by the procedure
used for experiment 2 except that acetophenone was used as
■
S
NMR spectra or segments of NMR spectra of selected
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: friedrich.hammerschmidt@univie.ac.at.
■
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The Journal of Organic Chemistry
Article
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
114, 6577−6579. (d) Hammerschmidt, F.; Hanninger, A.; Vollenkle,
̈
The research was funded by the Austrian Science Fund (FWF):
P19869-N19. We thank S. Felsinger for recording NMR
spectra, L. Brecker for help with the interpretation of some
NMR spectra, and J. Theiner for performing combustion
analyses.
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