Configurational stability of oxymethyllithiums as intermediates in intramolecular rearrangements

Article abstract of DOI:10.1002/chem.200701054

Several homochiral oxymethyllithiums, chiral by virtue of the hydrogen isotopes protium and deuterium, were prepared. They were tested for their microscopic configurational stability in intramolecular isomerizations, such as the silyl- and germyl-[1, 2]-r

Full text of DOI:10.1002/chem.200701054

DOI: 10.1002/chem.200701054
Configurational Stability of OxymethyllithiumsasIntermediatesin
Intramolecular Rearrangements
Dagmar C. Kapeller, Lothar Brecker, and Friedrich Hammerschmidt*[a]
Abstract: Several homochiral oxyme-
thyllithiums, chiral by virtue of the hy-
drogen isotopes protium and deuteri-
um, were prepared. They were tested
for their microscopic configurational
stability in intramolecular isomeriza-
tions, such as the silyl- and germyl-
[1,2]-retro-Brook and the sigmatropic-
G
termediate carbanions was studied.
Furthermore, the stereochemical
course of these rearrangements was
elucidated, resulting in highly enan-
tioenriched alcohols (90–97% ee; ee=
enantiomeric excess) up to tempera-
tures of 08C.
Introduction
different time scales, not counting variable temperature
NMR for half-lives less than a second due to interconver-
sion of diastereotopic signals.[1a] There is microscopic config-
urational stability, which lies in the range of seconds. It
refers to the stability relative to a chemical reaction and re-
quires the rate for addition of a chiral organolithium to an
electrophile to be faster than enantiomerization. Then, a
species is macroscopically configurationally stable, if it re-
tains its configuration for at least a few seconds to a few mi-
nutes. An elegant method for evaluating the configurantion-
al stability of an alkyllithium is the Hoffmann test.[4]
Despite years of research and great effort dedicated to-
wards this problem relatively little is known about the
means of racemization. Mechanistic studies revealed three
pathways for inversion of configuration, which can only be
applied to a fraction of organolithium compounds. There is
the classic dissociative mechanism involving a solvent sepa-
rated ion pair,[5] a conducted tour mechanism with intramo-
lecular Lewis base coordination,[6] and one predestined for
sulfur and selenium compounds containing bond rotation.[7]
However, the investigation of a-oxygen, a-nitrogen, and to
a lesser extent a-sulfur, a-selenium, and a-halogen-substitut-
ed organolithiums gave us a good idea of their configura-
tional stability, qualitatively speaking.
The synthesis of chiral, nonracemic a-heteroatom-substitut-
ed organolithiums has inspired various chemists for the last
few decades.[1] Nowadays, these reagents have found their
way into many organic laboratories, being versatile tools in
asymmetric carbon–carbon or carbon–heteroatom bond for-
mation. They can be trapped with a wide variety of electro-
philes or act as intermediates in anionic rearrangements.[2]
Still and Sreekumar were the first to demonstrate that a
heteroatom at a carbanionic centre dramatically increased
its configurational stability, which is the prerequisite for
their application in enantioselective syntheses. They found
that a-alkoxyalkyllithiums are configurationally stable at
low temperature (À788C) and can be stereospecifically alky-
lated with retention of configuration.[3] This sparked a wide-
spread interest not only amongst preparative chemists but
also amongst mechanistically orientated chemists studying
the methods of enantiomerization of these species and theo-
retically inclined chemists performing predictive calcula-
tions.
Up to now, many organolithiums have been tested for
their configurational stability. This is usually done on two
[a] D. C. Kapeller, Dr. L. Brecker, Prof. Dr. F. Hammerschmidt
University of Vienna, Institute of Organic Chemistry
Währingerstr. 38, 1090 Vienna (Austria)
Fax : (+43)1-4277-9521
E-mail: friedrich.hammerschmidt@univie.ac.at
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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Experimental findings led to a sequence of eroding stabil-
ity: O>N>S/Se.[8] They are nicely supported by quantum
chemical calculations at different levels.[9]
which give a-silyl alcohols on workup. The rearrangement
usually proceeds under retention of configuration in the
case of aliphatic compounds[15] and under inversion with
benzylic ones.[16] The reverse and thermodynamically fa-
vored process is well documented and has found numerous
practical applications, such as the preparation of chiral
methanol.[17] Boche et al. have determined the crystal struc-
ture of diphenyl(trimethylsilyloxy)methyllithium·3THF and
found that the lithium is ligated to the oxygen atom and the
benzylic carbon resembles more closely an sp2- than sp3-hy-
bridized carbon atom.[9b]
Additionally, we wanted to take a look at the Wittig rear-
rangement. It is formally related to the Brook rearrange-
ment, despite the two proceeding through completely differ-
ent mechanisms. A direct conversion was ineligible for our
purposes, as the [1,2]-Wittig rearrangement involves the for-
mation of radicals and thus has inadequate stereocontrol.
Accordingly, we decided on the [2,3] variant, which is a su-
prafacial six-electron pericyclic process.[2a] This sigmatropic
rearrangement proceeds under inversion of configuration at
the carbanionic centre. Its high synthetic value is displayed
by numerous applications in natural product synthesis.[2d,18]
As such it is an interesting target for our investigations.
The most widely used heteroatom-substituted alkyllithi-
ums are the ones a to oxygen. Among those, the carbamoyl-
oxy group introduced by Hoppe et al. is prominent.[10] An
exception in the nitrogen series are a-aminoalkyllithiums
derived from Boc-protected cyclic amines, found by Beak
et al.[1c,11] In both cases, configurational stability of these
species ranges from À78 to about À408C. Their easy access
in a highly enantioenriched form by metalation with (À)-
sparteine/sBuLi makes them attractive reagents for organic
synthesis. Recently, relative thermodynamic stability scales
of such organolithiums were derived from measurements of
tin–lithium exchange equilibria.[12]
Previous studies revealed that alkyllithiums of type 1a dif-
fered in their macroscopic configurational stability, depend-
ing on the substitutent R and whether 1a was a metalated
ether, carbamate, or ester. For the sake of simplicity, calcu-
lations in the oxygen series concentrated on species with
R=H and a hydroxy- or formyloxy-substituent, consistently
neglecting alkyl and other oxygen-containing groups as sub-
stituents.[9] However, those with deuterium replacing the
alkyl substituent could not be accessed until recently. These
chiral methyllithiums are challenging targets of unknown
configurational stability, that will play an important role in
mechanistic studies in bioorganic chemistry. We have found
Results and Discussion
that enantiomerically pure methyllithiums
OC(O)NiPr2 resist racemization at low temperature and
that those with X=OP(O)(OiPr)2 undergo the phosphate–
3
with X=
G
AHCTREUNG
phosphonate rearrangement with retention of configuration
up to 08C (Scheme 1).[13]
Scheme 1. (S)- and (R)-tributylstannyl[D1]methanol as precursors for a-
heteroatom-substituted methyllithiums.
Herein, we expand our studies towards the microscopic
configurational stability of chiral oxymethyllithiums and de-
scribe their role in the preparation of primary, stereospecifi-
cally labeled alcohols of known configuration. They are gen-
erated by tin–lithium exchange and accessible from enantio-
pure tributylstannyl[D1]methanols ([D1]2) as common pre-
cursors easily prepared in five steps (Scheme 1).[13]
We examine chiral oxymethyllithiums as short-lived inter-
mediates in [1,2]-retro-Brook[14] and analogous rearrange-
ments. The former involves the intramolecular migration of
a silicon atom from an oxygen atom to a carbon atom.
Thereby, silyloxyalkyllithiums 3 (for X=OSiR3) rearrange
via pentacoordinated intermediates to lithium alkoxides,
Scheme 2. Preparation and retro-Brook rearrangement of dimethylphe-
nylsilyloxymethyllithium (6).
Hexabutyldistannane (4) was treated with nBuLi and para-
formaldehyde to give lithium tributylstannylmethoxide,
which was quenched with dimethylphenylsilyl chloride to
yield silyl ether 5. Further addition of nBuLi effected a
smooth transmetalation, followed immediately by a [1,2]-
retro-Brook rearrangement to give silylmethanol 8 after
acidic workup. The overall yields of 58% (30 min, À788C)
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F. Hammerschmidt et al.
and 49% (30 s, 08C) encouraged us to continue in the la-
beled series (Scheme 3).
[D1]5 was prepared similarly to its unlabeled analogue by
deprotonation of enantiopure [D1]2 with nBuLi and quench-
groups on silicon could impede the migration from the
oxygen to the carbon atom and thus increase the lifetime
and enantiomerization of the intermediate silyloxymethyl-
lithium. Applying the same sequence as before, this time
with triisopropylsilyl triflate, a much more powerful trapping
agent than the chloride, furnished silylmethanol 11 in quan-
titative yield (Scheme 4).[20] When using iPr3SiCl, virtually
Scheme 3. Preparation and retro-Brook rearrangement of [D1]6.
Scheme 4. Preparation and retro-Brook rearrangement of silyloxymethyl-
lithiums 10 and (S)-[D1]10.
ing with dimethylphenylsilyl chloride. This was followed by
transmetalation, rearrangement, and acidic workup under
various conditions (Table 1, entries 1–3).
no 11 was formed under comparable conditions, which is
due to its lower reactivity with the lithium stannylmethox-
ide. The yield was improved by performing the silylation at
room temperature for extended periods of time, but still re-
mained unsatisfactory.
When the experiment was repeated with (R)-[D1]2 at 08C,
the desired product (R)-[D1]11 of 95% ee was isolated
(Scheme 4; Table 1, entry 4). This result proves that the ste-
reochemical outcome of the [1,2]-retro-Brook rearrange-
ment is independent of the substituents on the silicon atom.
In all cases of silyl migration studied, no silyl ether was de-
tected in the crude product by TLC.
Table 1. Reaction conditions and results of rearrangements.
Entry Substrate/product
Solvent t [min][a] T [8C] Yield/ee [%]
1
2
3
4
5
6
7
8
(S)-[D1]5/(S)-[D1]8
(S)-[D1]5/(S)-[D1]8
(R)-[D1]5/(R)-[D1]8
(R)-[D1]9/(R)-[D1]11
(S)-[D1]12/(S)-[D1]14
(R)-[D1]12/(R)-[D1]14 THF
(S)-[D1]16/(S)-[1-D1]18 THF
(S)-[D1]16/(S)-[1-D1]18 THF
THF
THF
Et2O
THF
THF
30
0.5
0.5
0.5
30
0.25
5
À78
0
0
81/96
67/97
71/97
99/95
61/90
68/92
80/94
71/94
0
À78
0
À78
0
0.5
[a] Reaction time for transmetalation/rearrangement.
Silylmethanols [D1]8 were then transformed into the dia-
stereomeric Mosher esters to determine their ee values and
absolute configurations. Their 1H NMR spectra were in
complete agreement with those reported in the literature.[17]
Stannylmethanols (S)- and (R)-[D1]2 gave silylmethanols
(S)- and (R)-[D1]8, respectively. Consequently, the retro-
Brook rearrangement proceeds with retention of configura-
tion. Complete configurational stability of the intermediate
silyloxymethyllithiums [D1]6 in diethyl ether as well as THF
is observed from À78 to 08C. This result nicely interlocks
with the finding that the KOH-catalyzed Brook rearrange-
ment of scalemic [D1,T]6 in N,N,N’,N’-tetramethylurea (plus
5% of water) gives chiral methanols with retention of con-
figuration at room temperature, despite the experimental
setting being different.[17] In the former case, the silyl group
can, in principle, migrate between the carbon and oxygen
atoms, even though the equilibrium lies with the lithium sil-
ylmethoxide. In the latter case, the formal silyloxymethyl-
anion is intercepted rapidly and irreversibly by a proton.
To address the influence of substituents at the silicon
atom on the stereochemistry and rate of the rearrangement,
the dimethylphenylsilyl group was replaced by the bulkier
triisopropylsilyl one. We reasoned that the three isopropyl
C
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Intramolecular Rearrangements
FULL PAPER
Scheme 5. Preparation and rearrangement of germyloxymethyllithiums
13 and [D1]13.
ranged alcohol 14 in merely 36% yield, despite the fact that
it was a spot to spot transformation. This was probably due
to the high volatility of the product, which was also a prob-
1
lem with silyl alcohol 8. The H NMR spectrum of its (R)-
Mosher ester showed an AB system (J=12.6 Hz) for the
GeCH2 group, reminiscent of the SiCH2 group of the silyl-
methyl analogues.
Scheme 6. Preparation and [2,3]-Wittig rearrangement of stannylme-
thyllthiums 17 and (R)-[D1]17 (the configurations given with the numbers
refer to the stannylmethyl part of the labeled compounds); Ms=MeSO2,
Ts=4-MeC6H4SO2.
Similarly, labeled [D1]2 was converted to germylmethanol
[D1]14, performing the rearrangement at À78 and 08C. By
taking care to minimize losses during isolation and purifica-
tion (Scheme 5; Table 1, entries 5 and 6), the yields in-
creased to 61 and 68%, respectively. We propose retention
of configuration in analogy to the silyl series based on the
Mosher esters. The significantly lower ee for [D1]14 (90 and
92%) compared to those of the silyl series (95–97%) likely
reflects some enantiomerization (2–3%) for germyloxyme-
thyllithium [D1]13.
We also tried to convert tributylstannylmethanol to the
corresponding trimethylstannyl ether, by using trimethyltin
chloride for quenching. Again, the ether could not be de-
tected by TLC. But this time the metalation/rearrangement
sequence did not yield trimethylstannylmethanol. Probably,
nBuLi exclusively attacked the trimethylstannyl group on
the oxygen atom rather than the tributylstannyl one bound
to the carbon atom, if the ether was formed at all.
crown-6 (Scheme 6).[24] Ether (S)-[D1]16 was then subjected
to quantitative tin–lithium exchange. This led to the forma-
tion of intermediate oxymethyllithium (R)-[D1]17, which im-
mediately rearranged to give homoallylic alcohols (S)-[1-
D1]18, as an E/Z mixture in a ratio of 40:60. The yields of
the [2,3]-Wittig rearrangement performed in THF at À788C
(5 min) and 08C (30 s) were 80 and 71%, respectively
(Table 1, entries 7 and 8). Catalytic hydrogenation on Pd/C
furnished octanols (S)-[1-D1]19. Their ee, determined by
1H NMR spectroscopy of the (R)-Mosher esters, was 94%.
The S configuration of [1-D1]19 was inferred from the
1H NMR spectrum of its Mosher ester being identical with
the one from an authentic sample prepared by HLADH-cat-
alyzed (HLADH=horse liver alcohol dehydrogenase) re-
duction of [formyl-D1]octanal.[25] Clearly, the [2,3]-Wittig re-
arrangement proceeded with inversion of configuration up
to 08C. The very small percentage of racemization (at worst
3% of enantiomerization) might have occurred during
etherification or rearrangement.
[2,3]-Wittig rearrangement: Finally, the stereochemistry of
the sigmatropic [2,3]-Wittig rearrangement employing a
chiral oxymethyllithium as the intermediate was examined.
According to the work of Still and Mitra, who demonstrated
the feasibility of the rearrangement for such compounds,
stannane 16 was chosen as the substrate.[23] Furthermore, the
product could be converted easily to deuterated octanol of
known configuration. Optimization of all steps was done in
the unlabeled series to avoid unnecessary losses of the la-
beled compounds (Scheme 6).
Interestingly, the tosylate 15a of alcohol 2, which we
wanted to use initially, gave only low yields under several
standard conditions tried. It also turned out to be very
labile.
Conclusion
We have found that silyloxymethyllithiums are configura-
tionally stable at temperatures between À78 and 08C. They
easily undergo a retro-Brook rearrangement following a re-
tentive course independent of the substituents at silicon
(95–97% ee). If silicon is exchanged for germanium, a simi-
lar isomerization takes place, although the intermediate ger-
myloxymethyllithium [D1]13 is significantly less microscopi-
cally configurationally stable (90–92% ee). The temperature
influences neither stereochemistry nor ee. The [2,3]-Wittig
reaction proceeds with virtually complete inversion of con-
In the labeled series, mesylate (R)-[D1]15b prepared from
(R)-[D1]2 was used to alkylate the potassium salt of 1-
hepten-3-ol (two steps: 60% yield) in the presence of 18-
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F. Hammerschmidt et al.
nol 8 (for yields see Table 1) as a colorless oil. 1H NMR (400.13 MHz,
CDCl3): d=7.57–7.53 (m, 2Harom), 7.39–7.34 (m, 3Harom), 3.57 (s, 2H),
1.13 (brs, 1H), 0.34 ppm (s, 6H); 13C NMR (100.61 MHz, CDCl3): d=
136.8, 133.6 (2C), 129.4, 128.0 (2C), 55.5, À5.0 ppm (2C); IR (Si): n˜ =
figuration. The various oxymethyllithiums generated are un-
doubtedly short-lived. They are microscopically configura-
tionally stable and do not behave as carbenoids.[26]
3354, 3070, 2958, 2897, 1427, 1249, 1115 cmÀ1
.
Transformation of (tributylstannyl)methanol (2) and (R)-tributylstan-
nyl[D1]methanol ([D1]2) into (triisopropylsilyl)methanol (11) and (R)-
triisopropylsilyl[D1]methanol ([D1]11) asa one-pot reaction, retro-Brook
rearrangement: Tributylstannylmethanol (160 mg, 0.50 mmol) and
TMEDA (70 mg, 90 mL, 0.60 mmol) were dissolved in dry THF (3.5 mL)
under argon. nBuLi (375 mL, 0.60 mmol, 1.6m solution in hexane) was
added to the mixture at À788C. After stirring for 15 min, triisopropylsilyl
triflate (184 mg, 162 mL, 0.60 mmol) was added. Stirring was continued at
À78 and 08C for 15 min each before addition of a second portion of
nBuLi (438 mL, 0.70 mmol, 1.6m solution in hexane). 30 s later 1m acetic
acid (0.7 mL) and water (3 mL) were added. The organic phase was sepa-
rated and the aqueous one extracted three times with diethyl ether. The
combined organic layers were dried (MgSO4) and concentrated under re-
duced pressure. The crude product was purified by flash chromatography
(CH2Cl2, Rf =0.43) to quantitatively yield (triisopropylsilyl)methanol as a
colorless oil, probably containing some triisopropylsilanol.
Experimental Section
1H and 13C NMR spectra were measured in CDCl3 at 300 K on a Bruker
Avance DRX 250/DRX 400/DRX 600 at 250.13/400.13/600.13 and 100.61/
150.92 MHz, respectively. Chemical shifts were referenced to residual
CHCl3 (dH =7.24) and CDCl3 (dC =77.0). All chemical shifts (d) are
given in ppm. IR spectra were run on a silicon disc on a Perkin–Elmer
1600 FTIR spectrometer.[27] TLC was carried out on 0.25 mm thick
Merck plates, silica gel 60F254. Flash chromatography was performed with
Merck silica gel 60 (230–400 mesh). Spots were visualized by UV and/or
dipping the plate into a solution of (NH4)6Mo7O24·4H2O (23.0 g) and of
Ce(SO4)2·4H2O (1.0 g) in 10% aqueous H2SO4 (500 mL), followed by
heating with a heat gun.
G
TMEDA (N,N,N’,N’-tetramethylethylenediamine) and pyridine were re-
fluxed over powdered CaH2, distilled and stored over molecular sieves
4 Š. Et2O was refluxed over LiAlH4 and THF over potassium under
argon. Both were distilled prior to use. CH2Cl2 was dried by passing
through aluminum oxide 90 active neutral (0.063–0.200 mm, activity I)
and stored over molecular sieves 3 Š. TMP (2,2,6,6-tetramethylpiperi-
dine) was used as supplied.
(Triisopropylsilyl)methanol (11): 1H NMR (400.13 MHz, CDCl3): d=3.61
(s, 2H), 1.15–1.03 (m, 21H), 1.00 ppm (v. brs, 1H); 13C NMR
(100.61 MHz, CDCl3): d=51.5, 18.7 (6C), 10.1 ppm (3C); IR (Si): n˜ =
3380, 2942, 2892, 2867, 1465 cmÀ1
.
(R)-Triisopropylsilyl[D1]methanol ((R)-[D1]11): 1H NMR (400.13 MHz,
CDCl3): d=3.58 (t, J=1.9 Hz, 1H), 1.15–1.01 ppm (m, 22H); 13C NMR
(100.61 MHz, CDCl3): d=51.1 (t, J=20.3 Hz), 18.7 (6C), 10.1 ppm (3C);
Small quantities of reagents (mL) were measured with appropriate syring-
IR (Si): n˜ =3385, 2942, 2891, 2866, 1463, 1015 cmÀ1
.
es (Hamilton).
The deuterium content of all labeled compounds lay between 97–98%,
as determined by NMR spectroscopy.
Tributylstannylmethyl triisopropylsilyl ether (9) as reference material:
Tributylstannylmethanol (300 mg, 0.93 mmol), triisopropylsilyl chloride
(300 mL, 1.40 mmol), and imidazole (190 mg, 2.80 mmol) were dissolved
in DMF (2 mL) and stirred for 1 h at RT. After this time, water was
added (2 mL), the organic phase separated, and the aqueous one extract-
ed two times with hexane. The combined organic layers were dried
(MgSO4), concentrated, and purified by flash chromatography (hexane,
Rf =0.72) to yield the product as a colorless oil (204 mg, 46%). 1H NMR
(400.13 MHz, CDCl3): 3.98 (s, J(117/119Sn)=13.4 Hz, 2H), 1.55–1.45 (m,
6H), 1.28 (sext, J=7.3 Hz, 6H), 1.11–1.01 (m, 21H), 0.90–0.85 (m,
J(117/119Sn)=50.5, 48.5 Hz, 6H), 0.87 ppm (t, J=7.3 Hz, 9H); 13C NMR
(100.61 MHz, CDCl3): d=53.9 (1C, J(117/119Sn)=400.9, 391.6 Hz), 29.2
(3C, J(117/119Sn)=20.7 Hz), 27.4 (3C, J(117/119Sn)=52.0 Hz), 18.3 (6C), 13.7
(3C), 11.8 (3C), 8.9 ppm (3C, J(117/119Sn)=313.6, 299.8 Hz); IR (Si): n˜ =
2956, 2867, 1653, 1465, 1437, 1050 cmÀ1; elemental analysis calcd (%) for
C22H50OSiSn (477.43): C 55.35, H 10.56; found: C 55.65, H 10.31.
Dimethylphenylsilylmethanol (8), one-pot rearrangement in the unla-
beled series: Hexabutyldistannane (4) (580 mg, 1.0 mmol) and TMEDA
(139 mg, 0.18 mL, 1.2 mmol) were dissolved in dry THF (4 mL) under
argon. The flask was cooled to 08C and nBuLi (0.75 mL, 1.2 mmol, 1.6m
solution in hexane) was added, followed by paraformaldehyde (33 mg,
1.1 mmol) after 15 min. The mixture was stirred for 2 h at RT, then
cooled down to the respective temperature (À78/08C) and quenched
with dimethylphenylsilyl chloride (205 mg, 1.2 mmol) to yield intermedi-
ate tributylstannylmethyl dimethylphenylsilyl ether (5). Further addition
of nBuLi (0.88 mL, 1.4 mmol, 1.6m solution in hexane) 45 min later in-
duced tin–lithium exchange followed by [1,2]-retro-Brook rearrangement.
After the respective reaction time (30 min/30 s), acetic acid (210 mg,
0.20 mL, 3.5 mmol), water (10 mL), and CH2Cl2 (10 mL) were added.
The organic phase was separated and the aqueous one extracted with
CH2Cl2 (2”5 mL). The combined organic layers were washed with water
(2”5 mL), dried (MgSO4), and concentrated in vacuo. The crude product
was purified by flash chromatography (hexane/EtOAc 4:1, Rf =0.42) to
yield (dimethylphenylsilyl)methanol ([D1]8) (96 mg, 58%/82 mg, 49%) as
a colorless oil. 1H NMR (250.13 MHz, CDCl3): d=7.57–7.53 (m, 2Harom),
7.39–7.35 (m, 3Harom), 3.54 (t, J=1.9 Hz, 1H), 0.39 (s, 1H), 0.33 ppm (s,
6H).
Transformation of (tributylstannyl)methanol (2) and (S)- and (R)-tribu-
tylstannyl[D1]methanol ([D1]2) into (triethylgermyl)methanol (14) and
(R)- and (S)-(triethylgermyl)-[D1]methanol ([D1]14) asa one-pot reac-
tion: Tributylstannylmethanol (161 mg, 0.50 mmol) was dissolved in dry
solvent (3.5 mL) under argon. After addition of TMEDA (90 mL,
0.60 mmol), the flask was cooled to À788C and nBuLi (380 mL,
0.60 mmol, 1.6m solution in hexane) was added, followed by triethyl-
germyl chloride (117 mg, 0.60 mmol in 0.50 mL of solvent) 15 min later.
After stirring for 30 min at RT to form the intermediate tributylstannyl-
methyl triethylgermyl ether 12, the reaction mixture was cooled to the re-
spective temperature (see Table 1). nBuLi (440 mL, 0.70 mmol, 1.6m solu-
tion in hexane) was added, followed by 1m acetic acid (1.75 mL, 1m in
water), after the respective time span (see Table 1), and water (5 mL).
The organic phase was separated, and the aqueous one extracted with di-
ethyl ether (3”5 mL). The combined organic layers were washed with
water (2”5 mL), dried (MgSO4), and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography (CH2Cl2,
Rf =0.28) to yield (triethylgermyl)methanol (for yields see Table 1) as a
colorless oil.
Transformation of (R)- and (S)-tributylstannyl[D1]methanol ([D1]2) into
(R)- and (S)-dimethylphenylsilyl[D1]methanol ([D1]8) asa one-pot reac-
tion, retro-Brook rearrangement: Tributylstannyl[D1]lmethanol (80 mg,
0.25 mmol) and TMEDA (35 mg, 45 mL, 0.30 mmol) were dissolved in
dry solvent (2 mL, see Table 1) under argon. The flask was cooled to
À788C and nBuLi (188 mL, 0.30 mmol, 1.6m solution in hexane) was
added, followed 30 min later by dimethylphenylsilyl chloride (52 mg,
0.30 mmol) to yield silyl ether 5. After stirring for another 30 min, the
temperature of the cooling bath was adjusted (see Table 1), and nBuLi
(219 mL, 0.35 mmol, 1.6m solution in hexane) was added. At the end of
the respective reaction time, acetic acid (53 mg, 50 mL, 0.88 mmol), water
(3 mL), and CH2Cl2 (3 mL) were added. The organic phase was separated
and the aqueous one extracted with CH2Cl2 (2”3 mL). The combined or-
ganic layers were washed with water (2”3 mL), dried (MgSO4), and con-
centrated under reduced pressure. The crude product was purified by
flash chromatography (hexane/EtOAc 4:1, Rf =0.42) to yield silylmetha-
(Triethylgermyl)methanol (14): 1H NMR (400.13 MHz, CDCl3): d=3.73
(s, 2H), 1.04 (t, J=8.0 Hz, 9H), 0.88 (v. brs, 1H), 0.79 ppm (m, 6H);
13C NMR (100.61 MHz, CDCl3): d=53.9, 8.9 (3C), 2.9 (3C); IR (Si): n˜ =
9586
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Chem. Eur. J. 2007, 13, 9582 – 9588

Intramolecular Rearrangements
FULL PAPER
3327, 2949, 2907, 2872, 1464 cmÀ1; elemental analysis calcd (%) for
C7H18GeO (190.86): C 44.05, H 9.51; found: C 44.30, H 9.30.
(60 mg, 72%) as a colorless oil or [D1]16 (549 mg, 77%) starting from
[D1]15b (750 mg, 1.70 mmol).
3-(Tributylstannylmethoxy)hept-1-ene (16): 1H NMR (600.13 MHz,
CDCl3): d=5.66 (ddd, J=17.4, 10.6, 7.6 Hz, 1H), 5.13 (dd, J=10.6,
1.9 Hz, 1H), 5.12 (dd, J=17.4, 1.9 Hz, 1H), 3.76, 3.46 (d, J=10.2 Hz,
J(117/119Sn)=15 Hz, 2H), 3.35 (m, 1H), 1.56–1.36 (m, 8H), 1.33–1.21 (m,
4H), 1.28 (sext, J=7.6 Hz, 6H), 0.90–0.84 (m, 9H), 0.87 ppm (t, J=
7.0 Hz, 9H); 13C NMR (150.92 MHz, CDCl3): d=139.8, 116.3, 85.5, 58.9,
35.1, 29.2 (J(117/119Sn)=21 Hz, 3C), 27.6, 27.3 (J(117/119Sn)=51 Hz, 3C),
22.7, 14.1, 13.7 (3C), 9.0 ppm (J(117/119Sn)=319 Hz, 3C); IR (Si): n˜ =2957,
(S)- and (R)-(triethylgermyl)-[D1]methanol ([D1]14): (S)- and (R)-[D1]14
were spectroscopically identical. 1H NMR (400.13 MHz, CDCl3): d=3.70
(t, J=1.7 Hz, 1H), 1.04 (t, J=7.8 Hz, 9H), 0.88 (brs, 1H), 0.79 ppm (m,
6H); 13C NMR (161.98 MHz, CDCl3): d=53.5 (t, J=21.0 Hz), 8.9 (3C),
2.9 ppm (3C); IR (Si): n˜ =3339, 2954, 2930, 2873, 2349, 1463, 1008 cmÀ1
.
Tributylstannylmethyl methanesulfonate (15b) and tributylstan-
nyl[D1]methyl methanesulfonate ([D1]15b): 2,2,6,6-Tetramethylpiperi-
dine (52 mg, 0.37 mmol) was dissolved in dry THF (1.5 mL) under argon
and cooled to À108C. nBuLi (0.23 mL, 0.37 mmol, 1.6m solution in
hexane) was added and the solution stirred for 15 min, before it was
cooled to À788C for the addition of tributylstannylmethanol (100 mg,
0.31 mmol) in dry THF (0.5 mL). Methanesulfonyl chloride (31 mL,
0.40 mmol) was added after 20 min, followed by water (2 mL) and 2m
HCl (2 mL) after 20 min. The organic layer was separated and the aque-
ous one extracted with EtOAc (3”2 mL). The combined organic phases
were washed with a saturated solution of NaHCO3 and water, dried
(MgSO4), and concentrated under reduced pressure. The crude product
was purified by flash chromatography (hexane/EtOAc 7:1, Rf =0.43) to
give 15b (80 mg, 80%, reproducible in all cases) as a colorless oil, con-
taining 5% of tributylstannylmethanol.
2928, 2872, 1465, 1051 cmÀ1
(S)-(Tributylstannyl[D1]methoxy)hept-1-ene
.
((S)-[D1]16):
1H NMR
(400.13 MHz, CDCl3): d=5.61 (ddd, J=16.9, 10.9, 7.6 Hz 1H), 5.16–5.03
(m, 2H), 3.74, 3.44 (s, J=16.2 Hz, J(117/119Sn)=14.7 Hz, 1H), 3.35 (m,
1H), 1.53–1.38 (m, 8H), 1.33–1.22 (m, 4H), 1.28 (sext, J=7.3 Hz, 6H),
0.95–0.78 (m, 9H), 0.87 ppm (t, J=8.1 Hz, 9H); 13C NMR (100.61 MHz,
CDCl3): d=139.8, 116.3, 85.4, 58.5 (t, J=19.9 Hz), 35.1, 29.2 (J(117/119Sn) =
21 Hz, 3C), 27.6, 27.3 (J(117/119Sn)=52 Hz, 3C), 22.7, 14.1, 13.7 (3C),
8.99 ppm (J(117/119Sn)=319.7, 305.2 Hz, 3C); IR (Si): n˜ =2957, 2928, 2872,
2856, 1465, 1377, 1052 cmÀ1
.
Oct-3-en-1-ol (18) and [1-D1]oct-3-en-1-ol ([1-D1]18), [2,3]-Wittig rear-
rangement: nBuLi (0.49 mL, 0.78 mmol, 1.6m solution in hexane) was
added to a stirred solution of 3-tributylstannylmethoxy-1-heptene (16)
(271 mg, 0.65 mmol) in dry THF (4 mL) at the respective temperature
(see Table 1) under argon. The reaction was quenched with acetic acid
(2.5 mL, 1m in water) after the time given in Table 1. The organic layer
was separated and the aqueous one extracted three times with diethyl
ether. The combined organic layers were dried (MgSO4) and concentrat-
ed under reduced pressure. The residue was purified by flash chromatog-
raphy (CH2Cl2, Rf =0.29) to yield 3-octen-1-ol (for yields see Table 1,
E/Z 40:60) as a colorless liquid.
Tributylstannylmethyl methanesulfonate (15b): 1H NMR (400.13 MHz,
CDCl3): d=4.27 (s, J(117/119Sn)=14 Hz, 2H), 2.93 (s, 3H), 1.55–1.46 (m,
6H), 1.29 (sext, J=7.3 Hz, 6H), 1.02–0.95 (m, 6H), 0.88 ppm (t, J=
7.3 Hz, 9H); 13C NMR (100.61 MHz, CDCl3): d=59.6 (J(117/119Sn)=260.0,
248.6 Hz), 35.7, 28.8 (J(117/119Sn)=22 Hz, 3C), 27.2 (J(117/119Sn)=56 Hz,
3C), 13.6 (3C), 9.4 ppm (J(117/119Sn)=341.1, 326.6 Hz, 3C); IR (Si): n˜ =
2957, 2925, 2852, 1356, 1173 cmÀ1
.
(S)- and (R)-tributylstannyl[D1]methyl methanesulfonate ([D1]15b):
1H NMR (400.13 MHz, CDCl3): d=4.26 (t, Jꢀ1.0 Hz, J(117/119Sn)=14 Hz,
1H), 2.92 (s, 3H), 1.54–1.45 (m, 6H), 1.28 (sext, J=7.3 Hz, 6H), 1.02–
0.96 (m, 6H), 0.87 ppm (t, J=7.3 Hz, 9H); 13C NMR (100.61 MHz,
CDCl3): d=59.3 (t, J=22.2 Hz), 35.7, 28.8 (J(117/119Sn)=21 Hz, 3C), 27.2
(J(117/119Sn)=54 Hz, 3C), 13.6 (3C), 9.3 (J(117/119Sn)=341.1, 325.8 Hz,
Oct-3-en-1-ol (18):
Z
isomer (in mixture): 1H NMR (400.13 MHz,
CDCl3): d=5.58–5.48 (m, 1H), 5.40–5.29 (m, 1H), 3.61 (t, J=6.8 Hz,
2H), 2.31 (m, 2H), 2.06 (m, 2H), 1.46 (brs, 1H), 1.37–1.22 (m, 4H),
0.874 ppm (t, J=7.0 Hz, 3H); 13C NMR (100.61 MHz, CDCl3): d=133.5,
124.9, 62.3, 31.8, 30.8, 27.1, 22.3, 13.9 ppm;
E isomer (in mixture):
3C); IR (Si): n˜ =2957, 2926, 2872, 2853, 1357, 1176 cmÀ1
.
1H NMR (400.13 MHz, CDCl3): d=5.84–5.48 (m, 1H), 5.40–5.29 (m,
1H), 3.60 (t, J=6.6 Hz, 2H), 2.23 (m, 2H), 2.00 (m, 2H), 1.46 (brs, 1H),
1.37–1.22 (m, 4H), 0.86 ppm (t, J=7.1 Hz, 3H); 13C NMR (100.61 MHz,
CDCl3): d=134.3, 125.7, 62.0, 36.0, 32.3, 31.6, 22.2, 13.9 ppm; IR (Si): n˜ =
Tributylstannylmethyl 4-methylphenylsulfonate (15a): Tributylstannylme-
thanol (100 mg, 0.31 mmol) and DMAP (4 mg, 0.03 mmol) were dissolved
in dry CH2Cl2 (1.5 mL) and cooled to 08C. NEt3 (100 mL, 0.72 mmol) was
added and the solution stirred for 20 min. Tosyl chloride (92 mg,
0.48 mmol) in dry CH2Cl2 (0.5 mL) was added and stirring was continued
for 2 h. The reaction was quenched with water (2 mL), the organic layer
was separated, and the aqueous one extracted with CH2Cl2 (3”2 mL).
The combined organic phases were washed with a saturated solution of
NaHCO3 and water, before being dried over MgSO4 and concentrated
under reduced pressure. The crude product was purified by flash chroma-
tography (hexane/CH2Cl2 2:1, Rf =0.43) to produce the pure product in
67% yield. 1H NMR (400.13 MHz, CDCl3): 7.75 (d, J=8.1 Hz, 2Harom),
7.31 (d, J=8.1 Hz, 2Harom), 4.04 (s, J(117/119Sn)=14.2 Hz, 2H), 2.42 (s,
3H), 1.47–1.37 (m, 6H), 1.23 (sext., J=7.3 Hz, 6H), 0.94–0.88 ppm (m,
6H), 0.84 (t, J=7.3 Hz, 9H); 13C NMR (100.61 MHz, CDCl3): d=144.4,
132.5, 129.6 (2C), 128.2, 60.2 (J(117/119Sn)=265.4 Hz), 28.8 (J(117/119Sn)=
22.2 Hz, 3C), 27.2 (J(117/119Sn)=53.4 Hz, 3C), 21.6, 13.6 (3C), 9.3 ppm
(J(117/119Sn)=340.4, 325.1 Hz, 3C); IR (Si): n˜ =2957, 2926, 1363, 1187,
1175 cmÀ1; elemental analysis calcd (%) for C20H36O3SSn (475.27): C
50.54, H 7.63; found: C 50.83 C, H 7.63.
3335, 3009, 2957, 2928, 1466, 1049 cmÀ1
.
(S)-[1-D1]Oct-3-en-1-ol ((S)-[1-D1]18): Z isomer (in mixture): 1H NMR
(400.13 MHz, CDCl3): d=5.58–5.48 (m, 1H), 5.40–5.29 (m, 1H), 3.59 (td,
J=6.8 Hz, 1.0, 1H), 2.30 (m, 2H), 2.04 (m, 2H), 1.48 (brs, 1H), 1.37–1.25
(m, 4H), 0.91–0.83 ppm (m, 3H); 13C NMR (100.61 MHz, CDCl3): d=
133.4, 124.9, 62.0 (t, J=22.2 Hz), 31.8, 30.7, 27.1, 22.3, 13.9 ppm; E
isomer (in mixture): 1H NMR (400.13 MHz, CDCl3): d=5.84–5.48 (m,
1H), 5.40–5.29 (m, 1H), 3.57 (td, J=6.8, 1.0 Hz, 1H), 2.23 (m, 2H), 1.99
(m, 2H), 1.48 (brs, 1H), 1.37–1.25 (m, 4H), 0.91–0.83 ppm (m, 3H);
13C NMR (100.61 MHz, CDCl3): d=134.3, 125.7, 61.7 (t, J=22.2 Hz),
35.9, 32.3, 31.6, 22.2, 13.9 ppm; IR (Si): n˜ =3332, 2924, 2853, 2330, 1466,
1070 cmÀ1
.
AHCTREUNG
10%) was prehydrogenated in dry EtOAc (2 mL) before the addition of
[1-D1]18 (55 mg, 0.43 mmol) dissolved in EtOAc (0.5 mL). The mixture
was stirred for 1 h under hydrogen at 1 atm, before being directly puri-
fied by flash chromatography (CH2Cl2/diethyl ether 30:1; TLC: hexane/
EtOAc 3:1, Rf =0.29) to yield the alcohol [1-D1]19 (18 mg, 33%, low
3-(Tributylstannylmethoxy)hept-1-ene
(16)
and
3-(tributylstan-
yield due to loss at chromatography) as
a
colorless oil. 1H NMR
nyl[D1]methoxy)hept-1-ene ([D1]16): KOtBu (263 mg, 2.34 mmol), 18-
crown-6 (619 mg, 2.34 mmol), and hept-1-en-3-ol (343 mg, 3.0 mmol)
were dissolved in dry THF (1.5 mL) at 08C under argon. After stirring
for 1 h at RT, 15b (80 mg, 0.20 mmol, dissolved in 0.5 mL of dry THF)
was added and the mixture was stirred for a further 1 h at low tempera-
ture. The reaction was quenched with water (2 mL) and 2m HCl (1 mL).
The organic phase was separated and the aqueous one extracted with di-
ethyl ether (2”2 mL). The combined organic layers were dried (MgSO4)
and concentrated under reduced pressure. The residue was purified by
flash chromatography (hexane/CH2Cl2 15:1, Rf =0.49) to give ether 16
(400.13 MHz, CDCl3): d=3.59 (tt, J=6.8, 1.5 Hz, 1H), 1.53 (q, J=6.8 Hz,
2H), 1.51 (v. brs, 1H), 1.36–1.21 (m, 10H), 0.86 ppm (t, J=6.8 Hz, 3H);
13C NMR (100.61 MHz, CDCl3): d=62.7 (t, J=21.4 Hz), 32.7, 31.8, 29.4,
29.3, 25.7, 22.6, 14.1 ppm; IR (Si): n˜ =3338, 2956, 2927, 2856, 2145,
1467 cmÀ1
.
Esterification of alcohols with (S)-Mosher acid chloride ((S)-MTPACl):
A solution of the alcohol (0.06 mmol), dry pyridine (0.17 mL), and (S)-
MTPACl (0.18 mL, 0.09 mmol, 0.5m solution in dry CH2Cl2) in dry
CH2Cl2 (1.40 mL) was left overnight at RT. CH2Cl2 (10 mL) and 1m HCl
Chem. Eur. J. 2007, 13, 9582 – 9588
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9587

F. Hammerschmidt et al.
(3 mL) were added, the organic layer was separated and washed with a
saturated aqueous solution of NaHCO3 (5 mL). The organic phase was
dried (Na2SO4) and concentrated under reduced pressure. The crude
product was purified by flash chromatography to yield the (R)-Mosher
ester as a colorless oil in virtually quantitative yield.
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2000, 65, 6121–6131.
(R)-Mosher ester of (dimethylphenylsilyl)methanol (8·MTPA-(R)):
Chromatography: hexane/EtOAc 10:1, Rf =0.48; 1H NMR (400.13 MHz,
CDCl3): d=7.49–7.45 (m, 2Harom), 7.44–7.30 (m, 8Harom), 4.18 (AB
system, JAB =14.1 Hz, 2H); 3.44 (q, J=1.0 Hz, 3H); 0.34 ppm (s, 6H);
[3] W. C. Still, C. Sreekumar, J. Am. Chem. Soc. 1980, 102, 1201–1202.
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4715.
1
(S)-[D1]8·MTPA-(R): H NMR (400.13 MHz, CDCl3): spectrum was iden-
tical to that of 8·MTPA-(R) except for the signal at d=4.12 ppm (t, J=
1.3 Hz, 1H); (R)-[D1]8·MTPA-(R): 1H NMR (400.13 MHz, CDCl3): spec-
trum was identical to that of 8·MTPA-(R) except for the signal at d=
4.20 ppm (t, J=1.3 Hz, 1H).
[6] D. J. Cram, L. Gosser, J. Am. Chem. Soc. 1964, 86, 2950–2952.
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(R)-Mosher ester of (triisopropylsilyl)methanol (11·MTPA-(R)): Chro-
matography: hexane/CH2Cl2 3:1, Rf =0.29; 1H NMR (400.13 MHz,
CDCl3): d=7.50–7.44 (m, 2Harom), 7.38–7.32 (m, 3Harom), 4.09 (AB
system, JAB =14.7 Hz, 2H), 3.51 (q, J=1.0 Hz, 3H), 1.08–0.94 (m, 21H);
(R)-[D1]11·MTPA-(R): 1H NMR (400.13 MHz, CDCl3) spectrum was
identical to that of 11·MTPA-(R) except for the signal at d=4.14 (t, J
ꢀ1.0 Hz, 1H). Furthermore, a very weak signal was found at d=3.99 (t,
Jꢀ1.0 Hz), which we attributed to (S)-[D1]11·MTPA-(R).
(R)-Mosher ester of (triethylgermyl)methanol (14·MTPA-(R)): Chroma-
tography: hexane/CH2Cl2 4:1, Rf =0.28; 1H NMR (400.13 MHz, CDCl3):
d=7.51–7.46 (m, 2Harom), 7.39–7.35 (m, 3Harom), 4.26 (AB system, JAB
=
12.6 Hz, 2H), 3.51 (q, J=1.0 Hz, 3H), 0.98 (t, J=7.8 Hz, 9H), 0.77 ppm
(m, 6H); (S)-[D1]14·MTPA-(R): 1H NMR (400.13 MHz, CDCl3): spec-
trum was identical to that of 14·MTPA-(R) except for the signal at d=
4.18 ppm (t, J=1.4 Hz, 1H); (R)-[D1]14·MTPA-(R): 1H NMR
(400.13 MHz, CDCl3): spectrum was identical to that of 14·MTPA-(R)
except for the signal at d=4.31 ppm (t, J=1.3 Hz, 1H).
(R)-Mosher ester of 1-octanol (19·MTPA-(R)): Chromatography:
hexane/CH2Cl2 4:1, Rf =0.27. 1H NMR (400.13 MHz, CDCl3): d=7.53–
7.48 (m, 2Harom), 7.41–7.32 (m, 3Harom), 4.29 (t, AB system, JAB =10.9, J=
6.7 Hz, 2H), 3.54 (q, J=0.8 Hz, 3H), 1.67 (quin, J=6.9 Hz, 2H), 1.39–
1
1.18 (m, 10H), 0.86 (t, J=6.9 Hz, 3H); (S)-[1-D1]19·MTPA-(R): H NMR
(400.13 MHz, CDCl3): spectrum was identical to that of 19·MTPA-(R)
except for the signal at d=4.30 (brt, J=6.6 Hz, 1H); when irradiated at
1.67 ppm it collapsed to
(400.13 MHz, CDCl3) spectrum was identical to that of 19·MTPA-(R)
except for the signal at d=4.26 (brt, J=6.6 Hz, 1H); when irradiated at
1.67 ppm it collapsed to a brs.
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a
brs; (R)-[1-D1]19·MTPA-(R): 1H NMR
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Acknowledgements
This work was supported by grant no. P19869-N19 from the Fonds zur
Fçrderung der wissenschaftilichen Forschung. D.K. is grateful to the Aus-
trian Academy of Sciences for a DOC-FFORTE scholarship.
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[1] For reviews see: a) J. Clayden in Tetrahedron Organic Chemistry
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[2] a) K. Tomooka in The Chemistry of Organolithium Compounds,
Vol. 2 (Eds.: Z. Rappoport, I. Marek), Wiley-VCH, Weinheim, 2004,
Received: July 10, 2007
Published online: September 17, 2007
9588
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9582 – 9588