Preparation of enantiopure chiral amino- [D1]methyllithium compounds and determination of their micro- and macroscopic configurational stabilities

Article abstract of DOI:10.1002/chem.200802668

Chiral amino-[D1]methyllithiums have been tested with regard to their microscopic and macroscopic configurational stabilities. The N-Boc-N-diethoxyphosphinyl-sub-stituted analogue immediately rearranged, showing complete retention of configuration at up t

Full text of DOI:10.1002/chem.200802668

FULL PAPER
DOI: 10.1002/chem.200802668
Preparation of Enantiopure Chiral Amino-[D1]methyllithium Compounds
and Determination of Their Micro- and Macroscopic Configurational
Stabilities
Dagmar C. Kapeller and Friedrich Hammerschmidt*[a]
Abstract:
Chiral
amino-
merized at À788C, but displayed an ee
value of 65% at À958C under macro-
scopic conditions when quenched with
benzaldehyde seconds after its genera-
tion. Isocyanomethyllithium proved to
be configurationally labile at this tem-
perature and racemized completely,
even on the microscopic timescale.
Only the non-stabilized N,N-dibenzyl-
aminomethyllithium was found to be
virtually macroscopically configuration-
ally stable below À958C.
[D1]methyllithiums have been tested
with regard to their microscopic and
macroscopic configurational stabilities.
The N-Boc-N-diethoxyphosphinyl-sub-
stituted analogue immediately rear-
ranged, showing complete retention of
configuration at up to 08C. The N-Boc-
N-PMB-protected analogue enantio-
Keywords: chirality · configuration
analysis · tin–lithium exchange
Introduction
developed a method for the determination of the configura-
tional stability of alkyllithiums.[5] Structural studies[6] and
quantum chemical calculations[7] have underlined the impor-
tance of the heteroatom for the configurational stability of
these compounds. In summary, it has been found that stabili-
ty decreases in the following sequence: O > N > S.[8]
Many dipole-stabilized aminoorganolithiums can be pre-
pared directly by metalation with alkyllithiums and are syn-
thetically very useful reagents.[9–14] However, N,N-dialkyla-
minomethyllithiums can only be generated by tin–lithium
exchange (Figure 1, 1–5).[15–17] The enantioselective prepara-
Chirality is of pivotal importance in chemistry and biology.
The synthesis of enantiomerically pure compounds is still
one of the main topics in organic chemistry. Combinations
of the chiral methyl group (CHDT), chiral by virtue of the
three isotopes of hydrogen, and a substituent such as CO2H,
NH2, CN, or OH represent the smallest compounds that can
exist as enantiomers. The first synthesis of such a compound
in the form of chiral acetic acid by the groups of Cornforth
and Arigoni and its use in the elucidation of reaction mech-
anisms in chemistry and enzymology were milestone ach-
ievements.[1,2] Recent years have witnessed an increased in-
terest in chiral, nonracemic a-heteroatom-substituted alkyl-
metals, especially alkyllithiums, sparked by the research of
Still and Sreekumar.[3] They found that a-oxy-substituted de-
rivatives are configurationally stable up to À308C and react
stereospecifically with electrophiles. Hoppe et al. prepared
highly enantiomerically enriched a-oxyalkyllithiums by
enantioselective metalation of carbamates derived from pri-
mary alcohols using sBuLi/(À)-sparteine.[4] Hoffmann et al.
Figure 1. Survey of several aminomethyllithiums.
tion, configurational stability, and reactivity of secondary a-
aminoalkyllithiums have been extensively studied by the
groups of Beak, Gawley, and others.[10,12,17–21] The configura-
tionally most stable a-aminoorganolithiums are the 2-lithio-
N-methyl-pyrrolidines and -piperidines, which retain their
configurations at up to À408C.[18,22,23]
[a] Dr. D. C. Kapeller, Prof. Dr. F. Hammerschmidt
Department of Organic Chemistry, University of Vienna
Wꢀhringerstrasse 38, 1090 Vienna (Austria)
Fax : (+43)1-4277-9521
Until recently, no methyllithium of the general formula
XCHDLi (X=heteroatom or heteroatom-containing func-
tional group), which we refer to as chiral methyllithiums,
has been accessible. These species are the smallest possible
E-mail: friedrich.hammerschmidt@univie.ac.at
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802668.
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chiral organolithiums and represent the calculated species
better than those in which deuterium is replaced by an alkyl
group. We have found that carbamoyloxy-,[24a] (2,4,6-triiso-
propylbenzoyl)oxy-,[24b] and chloromethyllithium[25] are mac-
roscopically configurationally stable at low temperature.
Herein, we report our findings on the preparation and con-
figurational stability of four chiral aminomethyllithiums. Mi-
croscopic configurational stability[5] refers to the configura-
tional stability of a chiral, enantioenriched carbanion rela-
tive to the rate of an intramolecular reaction or its reaction
with an electrophile already present upon the generation of
the carbanion (in situ quenching). Macroscopic configura-
tional stability, on the other hand, refers to prior formation
of the enantioenriched carbanion, its aging for some time
(here from 30 seconds to minutes), and finally its reaction
with an added electrophile.
MeLi, respectively, and then quenched with AcOD after
15 min (entries 1 and 2 in Table 1). In the former case, over
100% deuterium incorporation was found by NMR spec-
troscopy, confirming that intermediate aminophosphonate
10 had been lithiated by excess nBuLi. With MeLi, the yield
of aminophosphonate 11 was higher and only partial deuter-
ation was observed (D1 =57%). Reducing the amount of
nBuLi from 2.5 to 1.1 equiv resulted in comparable yields at
À78 and 08C (entries 3 and 4). However, in both cases
about 20–30% of the starting material was recovered. In the
case of MeLi (1.25 equiv, 08C) no starting material was pres-
ent (entry 5).
Results and Discussion
Microscopic configurational stability: To study the micro-
scopic configurational stability of a dipole-stabilized amino-
methyllithium (relative to its reaction), the phosphorami-
date–aminophosphonate rearrangement was chosen.[26] It is
an intramolecular isomerization with a short-lived aminome-
thyllithium as intermediate and therefore allows comparison
with its oxygen analogue, the phosphate–hydroxyphospho-
nate rearrangement.[24a] We again chose the enantiopure
tributylstannyldeuteromethanols (ee 99%) as precursors,
which are easily prepared in five steps.[24a] However, before
performing the reactions in the labeled series, unlabeled 6
was first transformed into 8 in 93% yield by a Mitsunobu
reaction with phosphoramidate 7[27] to optimize the reaction
conditions (Scheme 1). The conversion was then repeated
with (R)- and (S)-[D1]-6 (SN2).
Scheme 2. Transmetalation and rearrangement of 8; tests relating to dili-
thiation.
Table 1. Transmetalation/rearrangement in the unlabeled series: condi-
tions and results.
Entry
RLi (equiv)
T [8C]
t [min]
Yield[a] [%]
1
2
3
4
5
nBuLi (2.5)
MeLi (2.5)
nBuLi (1.1)
nBuLi (1.1)
MeLi (1.25)
À78
À78
À78
0
15
15
30
0.5
1
57[b]
79[c]
56[d]
57[e]
69
0
[a] Determined by NMR spectroscopic analysis of the crude product.
[b] Quenching with AcOD led to 115% deuterium incorporation.
[c] Quenching with AcOD led to 57% deuterium incorporation. [d,
e] Starting material was present: 23% and 31%, respectively.
It was decided to determine the ee values of the deuterat-
ed aminomethylphosphonates by 1H NMR spectroscopic
analysis of the (R)-Mosher amides formed upon removal of
the Boc group (Scheme 3).
Scheme 1. Preparation of stannanes 8.
It was then possible to start testing the conditions for the
transmetalation/rearrangement sequence by treating unla-
beled 8 with an alkyllithium (Scheme 2, Table 1). We feared
that excess RLi might further metalate the intermediate
product 10 a to the phosphorus atom to give dilithiated 12,
reminiscent of a similar observation concerning the rear-
rangement of N-benzyl-N-Boc phosphoramidate.[26] This
would lead to a decrease in ee in the labeled series, assum-
ing 12 to be configurationally labile. To test this, stannane 8
was transmetalated at À788C with 2.5 equiv of nBuLi or
Scheme 3. Strategy for ee determination in the case of labeled 11.
Accordingly, N-Boc-aminophosphonate 11 was smoothly
deprotected with an ethereal solution of HCl to quantita-
tively afford 13·HCl, which was transformed into the (R)-
1
Mosher amide. Its H NMR spectrum showed a nicely sepa-
rated AB system (d=3.42 ppm, JAB =15.7 Hz) with addition-
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Chiral Amino-[D1]methyllithiums
FULL PAPER
interfered in the previous experiment. Similarly, phosphora-
midate (R)-[D1]-8 furnished (S)-[D1]-11 with an ee of 96%
(entry 3). When the rearrangement was performed at 08C,
still hardly any enantiomerization was detected, as evi-
denced by the high ee of 94% (entry 4). These results dem-
onstrate that the N-Boc-protected (diethoxyphosphinyl)ami-
nomethyllithium is microscopically configurationally stable
and rearranges stereospecifically from À788C up to 08C,
probably following a retentive course.
Figure 2. Relevant parts of 1H NMR spectra (400 MHz, [D8]toluene).
Top : 13·(R)-MTPA. Middle: (R)-[D1]-13·(R)-MTPA of 94% ee.
Bottom: A) (R)-[D1]-13·(R)-MTPA of 94% ee, 31P-decoupled; B) (S)-
[D1]-13·(R)-MTPA of 96% ee, 31P-decoupled.
Scheme 4. Transmetalation/rearrangement of [D1]-8.
al NH (J=6.2 Hz) and phosphorus (J=11.8 Hz) couplings
(Figure 2).
Macroscopic configurational stability of Boc- and PMB-pro-
tected aminomethyllithium: The above findings cleared the
way for further studying the configurational stability of an
aminomethyllithium on the macroscopic timescale, that is,
first its generation followed by its reaction with an electro-
phile after aging. We envisaged a dipole-stabilized system,
because the required precursor would transmetalate more
readily than any non-stabilized analogue, for which there is
literature precedence.[18] Boc and PMB were chosen as pro-
tecting groups as each of these can be removed selectively.
The required precursors, 16 and (S)-[D1]-16, were ac-
cessed from the respective stannylmethyl mesylates 14[28]
and (R)-[D1]-14 by treating them with the sodium salt of
amide 15 derived from p-methoxybenzylamine and Boc an-
hydride (Scheme 5). The unlabeled stannane 16 was then
Finally, the rearrangement was performed with the la-
beled phosphoramidates under optimized conditions
(Scheme 4). Initially, we used only a slight excess (1.3 equiv)
of MeLi, hoping that it would not effect dilithiation, while
still giving a good yield (85%) of the protected aminome-
thylphosphonate (R)-[D1]-11 (entry 1 in Table 2). The (R)-
Table 2. Transmetalation/rearrangement of [D1]-8: conditions and results.
Entry [D1]-8 MeLi (equiv) T [8C] t [min] Yield[a] [%] ee [%]
1
2
3
4
(S)
(S)
(R)
(S)
1.3
1.0
1.0
0.9
À78
À78
À78
0
10
5
5
85
89
89
99
96
94
90
1
74[b]
[a] Determined by NMR spectroscopic analysis of the crude product;
losses upon work-up. [b] Recovered starting material (25%).
configuration was deduced by assuming that the migration
followed a retentive course.[26] Unfortunately, the ee was
only 89%. The 1H NMR spectrum of the respective (R)-
Mosher amide now exhibited a doublet of doublets, which
collapsed to
a doublet upon phosphorus decoupling
(Figure 2). Evidently, excess MeLi preferentially removed
hydrogen over deuterium from a small amount of supposed-
ly enantiopure [D1]-10 to yield configurationally labile [D1]-
12. Aqueous work-up then furnished a small amount of rac-
emic [D1]-11, resulting in an erosion of the ee. Repeating
this experiment with a stoichiometric amount of MeLi and
quenching after 5 min to minimize dilithiation[26] delivered
[D1]-11 with 99% ee in excellent yield (entry 2). This result
unequivocally proved that aminomethyllithium [D1]-9 was
microscopically configurationally stable and that [D1]-12 had
Scheme 5. Preparation of stannane 16, its transmetalation, plus testing of
the macroscopic configurational stability of [D1]-17.
used to test the conditions of transmetalation/quenching
with benzaldehyde as the electrophile (Scheme 5, Table 3).
When the reaction was performed at À788C with addition
of the aldehyde 1 and 10 min after the addition of nBuLi,
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F. Hammerschmidt and D. C. Kapeller
Table 3. Transmetalation/trapping of 16 in the unlabeled series: condi-
tions and results.
Entry
T [8C]
t [min]
Yield [%]
1
2
3
À78
À78
À35
1
10
0.5
78
75
56
racemic amino alcohol 18 was isolated in yields of 78 and
75%, respectively (entries 1 and 2). Carrying out the trans-
metalation/quenching sequence at À358C furnished amino
alcohol 18 in 56% yield, demonstrating a higher chemical
stability of the a-aminomethyllithium 17 compared to that
of its oxygen analogue (entry 3).[24a]
1
Figure 3. Relevant parts of H NMR spectra (600 MHz, [D8]toluene) with
concentration/aggregation induced shifts. A) (1R)-[1-D1]-20·(R)-MTPA of
6% ee; B) (1R)-[1-D1]-20·(R)-MTPA of 65% ee.
Before repeating the sequence with the labeled com-
pound, a method for the determination of the ee value of
the amino alcohol [2-D1]-18 had to be elaborated
(Scheme 5). For the sake of clarity, it is more convenient
here to only give the enantiomeric excess of the deuterated
center (ee at C-2), as C-1 is always racemic, resulting in a
product with 0% de in the case of configurational stability.
In preliminary experiments, 18 was transformed into its
(R)-Mosher ester (Scheme 6). However, 1H NMR spectra
hyde 1 min after the addition of nBuLi used to effect tin–
lithium exchange (entry 1 in Table 4).
The resulting amino alcohol [2-D1]-18 was found to be
racemic at C-1, as expected, and almost racemic (6% ee) at
Table 4. Transmetalation/trapping of 16 in the labeled series: conditions
and results.
Entry
T [8C]
t [s]
Yield [%]
ee [%]
1
À78
À78
À95
À95
60
30
30
10
66
48
68
75
6
2[a]
3[a]
4[a]
17
65
64
[a] In the presence of a twofold excess of [12]crown-4.
the deuterated center C-2 (Figure 3A). Shortening the life-
time of (R)-[D1]-17 to 30 s did not greatly improve the
result, as the ee was still only 17% (entry 2). At À958C, the
yields were comparable to those obtained at higher temper-
atures, but the ee was improved to 65%, irrespective of
whether benzaldehyde was added after 10 or 30 s (entries 3
and 4, Figure 3B). In some cases (entries 2–4), [12]crown-4
was used, which we hoped would increase the stability of
the intermediate aminomethyllithium by complexing the
lithium cation, based on quantum chemical calculations[30]
with water as a ligand for lithium. TLC analysis of the crude
product from each of the experiments revealed the presence
of some starting material, implying that transmetalation had
yet to reach completion when the aldehyde was added.
Therefore, some aminomethyllithium (R)-[D1]-17 was still
formed after the addition of benzaldehyde, the amount de-
pending on the relative rates of transmetalation and the ad-
dition of nBuLi to benzaldehyde. This would suggest that
these experiments also involved partial microscopic stability.
Consequently, the ee values for the macroscopic configura-
tional stability would be slightly lower than those given in
Table 4, especially considering the very short reaction time.
To verify this, the experiment of entry 3 was repeated using
methanol for trapping. The amount of 16 present in the
Scheme 6. Efforts towards the ee determination of [D1]-18.
recorded in [D8]toluene, CDCl3, [D6]DMSO, CD3OD, and
[D6]acetone did not show adequate resolution of the ABX
system of the CHCH2N group. The same result was found
for [D1]-19·(R)-MTPA after cleavage of the PMB group
with CAN.[29] The second option, removal of the Boc group
from [D1]-18·(R)-MTPA, proceeded quantitatively on treat-
ment with TFA. The resulting salt 20·(R)-MTPA finally
showed resolved signals for the AB parts of the ABX sys-
tems [at d=3.10 and 3.07 ppm for the (S)- and (R)-config-
ured alcohol, respectively, with J=13.5, 8.7, and 3.8 Hz],
which allowed integration of the signals of the individual
diastereomers in the labeled series (Figure 3).
Having established a method for the determination of the
ee, we transmetalated chiral (S)-[D1]-16, which was expected
to afford aminomethyllithium (R)-[D1]-17 assuming a reten-
tive course for the tin–lithium exchange (Scheme 5). The
first experiment was performed at À788C, adding benzalde-
1
crude product was calculated to be 15% by H NMR spec-
troscopy, substantiating a small amount of interfering micro-
scopic stability. In summary, [D1]-17 was found to be quite
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Chiral Amino-[D1]methyllithiums
FULL PAPER
configurationally labile, at least above À958C. However,
comparably protected aminoalkyllithiums are configurative-
ly more stable.[20]
Configurational stability of isocyanomethyllithium: Isocya-
nomethyllithium, which was first prepared by Schoellkopf
and Gerhart,[31a] is a well-known reagent in organic chemis-
try.[9,10] It may be considered as a specially protected amino-
methyllithium, in which the carbanion is inductively stabi-
lized by the dipole of the isocyano group. In contrast to the
corresponding cyano analogue,[32] a-isocyano-2,2-diphenylcy-
clopropyllithium was found to be virtually macroscopically
configurationally stable up to À528C, which can be largely
attributed to the prevention of enantiomerization by the
ring strain. To test this smallest protected aminomethyllithi-
um, enantiomerically pure deuterated isocyanomethylstan-
nane was prepared (Scheme 7).
Scheme 8. Transmetalation/trapping of 24 and [D1]-24 and subsequent ee
determination.
Table 5. Transmetalation of 24: conditions and results.
Entry
T [8C]
t [s]
Yield[a] [%]
SM[b] [%]
1
2
3
À95
À95
À78
60
0
30
70
20
84
30
10
traces
[a] Deduced from the 1H NMR spectrum of the crude product; losses
upon work-up. [b] SM=starting material.
temperature was increased to À788C, only a trace of the
starting isonitrile remained after 30 s of tin–lithium ex-
change (entry 3). An experiment was also performed to
study the possible microscopic configurational stability (with
benzaldehyde being present upon tin–lithium exchange) of
isocyanomethyllithium, in case it proved macroscopically
configurationally labile. Unfortunately, the isolated yield of
26 was very low, as the addition of nBuLi to benzaldehyde
was evidently faster than the transmetalation (entry 2).
Esterification of isocyano alcohol 26 with (S)-MTPACl
furnished the (R)-Mosher ester, the 1H NMR spectrum of
which displayed two well-separated AB systems for the CH2
groups of the diastereomers, suitable for the determination
of the ee in the labeled series [d=2.78 ppm, J=15.3, 8.3,
4.0 Hz and d=2.71 ppm, J=15.5, 9.2, 3.4 Hz].
Scheme 7. Preparation of isocyanomethylstannanes 24.
Next, an exploratory experiment with labeled isocyano-
methylstannane (S)-[D1]-24 was performed (À958C/benzal-
dehyde added 90 s after the addition of nBuLi). The isocya-
no alcohol was obtained in 59% yield (along with 15% of
Thus, first unlabeled and then labeled tributylstannylme-
thanol were converted into phthalimides 21 by a Mitsunobu
reaction.[20] The unlabeled analogue was deprotected[33] to
give the labile amine 22, which was immediately converted
to formamide 23, employing 2,2,2-trifluoroethyl formate[34,35]
as the reagent of choice. Dehydration under Appel condi-
tions (Ph3P/CCl4)[36] finally delivered isonitrile 24 in an over-
all yield of 54% based on tributylstannylmethanol.
Next, the feasibility of the transmetalation of isonitrile 24,
followed by reaction of the intermediate isocyanomethyl-
lithium with benzaldehyde (macroscopic configurational sta-
bility), and determination of the ee were studied in the unla-
beled series (Scheme 8). In all cases, THF was used as the
solvent and nBuLi was used for transmetalation. Acidic
work-up was necessary, as otherwise cyclization to 5-phenyl-
2-oxazoline would have occurred.[31b,37] The first experiment
was performed at À958C and involved the addition of benz-
aldehyde 1 min after initiating transmetalation with nBuLi
(Table 5, entry 1). Isocyano alcohol 26 was isolated in 70%
yield and a 1H NMR spectrum of the crude product revealed
that it contained 30% unreacted staring material. When the
1
the starting material) and H NMR spectroscopic analysis of
the corresponding (R)-Mosher ester showed it to be racemic
at both chiral centers. To ascertain whether isocyanomethyl-
lithium might be at least microscopically configurationally
stable, transmetalation was performed in the presence of
benzaldehyde at À958C. The labeled isocyano alcohol [2-
D1]-26, isolated in 25% yield, was found to be racemic. Con-
sequently, isocyanomethyllithium is neither macroscopically
nor microscopically configurationally stable.
Macroscopic configurational stability of N,N-dibenzylamino-
methyllithium: Having proven the (relative) configurational
lability of dipole-stabilized aminomethyllithiums, we decided
to test a non-stabilized one. Utilizing the experience of Pear-
son and Stevens, N,N-dibenzyl-tributylstannylmethyl-
amine[38,39] was chosen as the precursor. It was prepared by
SN2 reaction of the mesylate 14[28] with excess dibenzylamine
in 90% average yield (Scheme 9).
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5733

F. Hammerschmidt and D. C. Kapeller
yields and concomitant increases in the amounts of recov-
ered starting material (entries 2 and 3).
For the later determination of ee at the deuterated center,
N,N-dibenzylamino alcohol 28 was converted to the (R)-
1
Mosher ester. The H NMR spectrum of this derivative fea-
tured a well-separated ABX system, suitable for the deter-
mination of ee in the labeled series [AB parts of ABX sys-
tems for (1S)-28·(R)-MTPA: d=2.90 ppm, J=13.9, 8.1,
4.8 Hz and (1R)-28·(R)-MTPA: d=2.86 ppm, J=13.9, 7.8,
5.3 Hz; Figure 4, top].
Scheme 9. Preparation of [D1]-27, its transmetalation, and testing of the
macroscopic configurational stability of [D1]-5.
To ensure that no racemization occurred under these
conditions, the 1H NMR spectrum of 27 in an admixture
with
the
chiral
shift
reagent
(R)-(+)-tert-butyl-
ACHTUNGTRENNUNG
displayed an AB system for the diastereotopic protons (d=
2.35 ppm, JAB =13.4 Hz). Its resonances collapsed to broad-
ened singlets following deuterium labeling [(S)-[D1]-27: d=
2.36 ppm and (R)-[D1]-27: d=2.27 ppm] and showed that
both enantiomers of [D1]-27 were enantiomerically pure.
Having established this, we could then try subjecting the un-
labeled stannane to transmetalation/quenching with benzal-
dehyde to optimize the reaction conditions for labeled [D1]-
27 in order to probe the configurational stability of the in-
Figure 4. Relevant parts of 1H NMR spectra (400 MHz, CDCl3).
Top : 28·(R)-MTPA. Bottom: A) racemic [2-D1]-28·(R)-MTPA; B) (2R)-
[2-D1]-28·(R)-MTPA of 30% ee; C) (2S)-[2-D1]-28·(R)-MTPA of 70% ee;
D) (2R)-[2-D1]-28·(R)-MTPA of 90% ee.
termediate
N,N-dibenzylaminomethyllithium
[D1]-5
(Scheme 9). All experiments were performed at À458C with
15 min between the addition of nBuLi and trapping with
benzaldehyde. Initially, 2 equiv of nBuLi was used for tin–
lithium exchange (entry 1 in Table 6). The yield of the N,N-
Repeating the transmetalation/quenching sequence with
labeled [D1]-27 under our optimized conditions (nBuLi,
THF, À458C, addition of benzaldehyde 15 min after addi-
tion of the alkyllithium) yielded a completely racemic prod-
uct (entry 1 in Table 7). Reasoning that only a significant de-
crease of temperature could slow down enantiomerization,
the reaction was performed at À788C and the time before
quenching was doubled to compensate for the expected de-
crease in reaction rate (entry 2). Satisfyingly, the yield of al-
cohol [D1]-28 and its ee increased to 47% and 30%, respec-
Table 6. Transmetalation/trapping of 27 in the unlabeled series: condi-
tions and results.
Entry[a]
Solvent
RLi
Yield[b] [%]
SM[c] [%]
1
2
3
THF
THF
Et2O/TMEDA
nBuLi
MeLi
nBuLi
70
20
44
30
60
50
[a] Reaction temperature: À458C; reaction time for transmetalation:
15 min. [b] Deduced from the 1H NMR spectrum of the crude product;
losses upon work-up. [c] SM=starting material.
Table 7. Transmetalation/trapping of [D1]-27: conditions and results.
Entry
[D1]-27
T [8C]
t [min]
Yield[a] [%]
ee [%]
dibenzylamino alcohol 28 was 70%, but tin–lithium ex-
change was incomplete, as evidenced by 30% recovery of
the starting material being detected in the 1H NMR spec-
trum of the crude product. Replacing nBuLi by MeLi or
THF by Et2O/TMEDA led to significant erosion of the
1
2
3
4
(R)
(R)
(S)
(S)
À45
À78
À78
À95
15
30
15
15
38
47
33
10
0
30
69
90
[a] Isolated yield of [2-D1]-28.
5734
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 5729 – 5739

Chiral Amino-[D1]methyllithiums
FULL PAPER
ene over sodium/benzophenone, then distilled and stored over 4 ꢂ mo-
lecular sieves. CH2Cl2 was dried by passing it through aluminum oxide 90
active neutral (0.063–0.200 mm, activity grade I) and stored over 3 ꢂ mo-
lecular sieves. Et2O was refluxed over LiAlH4, Et3N over powdered
CaH2, and THF over potassium and each was distilled prior to use. All
glassware for moisture-sensitive reactions was dried for several hours at
1008C. Reactions at À788C were performed in an acetone/dry-ice bath,
those at À958C with additional liquid nitrogen. Small quantities of re-
agents (mL) were measured with appropriate syringes (Hamilton).
tively. When the time allowed for the transmetalation was
reduced from 30 to 15 min, the ee increased to 69%, but the
yield decreased to 33% (entry 3). Finally, the reaction tem-
perature was lowered to À958C, which resulted in a further
decrease in yield to 10% and a concomitant increase in ee
to 90% (entry 4). Strictly speaking, the experiments sum-
marized in Table 7 may not simply reflect the macroscopic
configurational stability of chiral [D1]-5, but a combination
with the microscopic stability. As the starting material and
nBuLi were present in the reaction mixture when benzalde-
hyde was added, tin–lithium exchange was still in progress
during the addition of N,N-dibenzylamino-[D1]methyllithium
to the aldehyde. However, as tin–lithium exchange was obvi-
ously quite slow and addition of nBuLi to benzaldehyde
usually proceeds very rapidly, the amount of product reflect-
ing microscopic configurational stability is negligible. These
data show that the temperature is of decisive importance for
the enantiomerization of [D1]-5. Below À958C it is fairly
slow, while at À458C complete racemization is observed.
The experimental procedures, when identical for the non-deuterated and
deuterated compounds, are generally given for the former. The deuteri-
um content of all compounds, unless otherwise specified, lay between 97
and 98%.
General procedure for the preparation of (R)-Mosher esters/amides: A
solution of alcohol/amine (0.10 mmol), dry pyridine (0.25 mL), and (S)-
MTPACl (300 mL, 0.5m solution in dry CH2Cl2, 0.15 mmol) in dry CH2Cl2
(2 mL) was stirred for 18 h at RT. Further CH2Cl2 (10 mL) and 1m HCl
(10 mL) were then added, and the organic layer was separated, washed
with saturated aqueous NaHCO3 solution, and dried (MgSO4). The sol-
vent was removed under reduced pressure. The residue was purified by
flash column chromatography.
Diethyl
N-tributylstannylmethyl-N-(tert-butoxycarbonyl)phosphorami-
date {8, (R)- and (S)-[D1]-8}: A solution of 6 (570 mg, 1.48 mmol), diethyl
N-(tert-butoxycarbonyl)phosphoramidate[27] (7, 454 mg, 1.80 mmol), and
Ph3P (370 mg, 1.80 mmol) in dry THF (7 mL) was cooled to 08C. After
the addition of DEAD (314 mg, 290 mL, 1.80 mmol), the mixture was
stirred for 30 min at the bath temperature and for 2 h at RT. Water
(3 drops) was then added, the solvent was removed using a rotary evapo-
rator, and the residue was purified by flash chromatography (hexane/
EtOAc 5:1; Rf =0.22) to yield 8 as a colorless oil (762 mg, 93%).
Conclusion
We have found that N-Boc-N-diethoxyphosphinyl-protected
enantiopure amino-[D1]methyllithium [D1]-9 rearranges to
aminophosphonate [D1]-11 under complete stereocontrol up
to 08C, proving the microscopic configurational stability of
the former. The N-Boc-N-PMB-protected, dipole-stabilized
aminomethyllithium [D1]-17 was found to be configuration-
ally labile at À788C, but gave an amino alcohol of 65% ee
at the deuterium-bearing center when the reaction tempera-
ture was lowered to À958C (30 s). Isocyano-substituted
methyllithium [D1]-25 was found to be completely configu-
rationally labile, racemizing at À958C, even under micro-
scopic conditions. Enantiopure N,N-dibenzylaminomethyl-
lithium [D1]-5 was by far the most configurationally stable
of all of the studied aza-substituted methyllithiums, reacting
with benzaldehyde after 15 min at À958C to afford a prod-
uct of 90% ee.
Compound 8: 1H NMR (400.13 MHz, CDCl3): d=4.16–4.00 (m, 4H),
ACTHNUTRGNEUNG
3.18 (d, J(117/119Sn)=23.7 Hz, J(31P)=8.3 Hz, 2H), 1.51–1.41 (m, 6H), 1.45
(s, 9H), 1.31 (td, J
6H), 0.89–0.83 (m, 6H), 0.86 ppm (t, J=7.3 Hz, 9H); 13C NMR
(31P)=1.0 Hz, J=7.1 Hz, 6H), 1.27 (sext, J=7.3 Hz,
ACHTUNGTRENNUNG
(100.61 MHz, CDCl3): d=154.4 (d, JACTHNUTRGENNUG ACHTUNGTRENNUNG
(31P)=6.1 Hz), 81.7, 63.1 (d, J(31P)=
5.4 Hz, 2C), 32.2 (J(117/119Sn)=322.8, 308.2 Hz), 29.0 (J(117/119Sn)=
19.1 Hz, 3C), 28.1 (3C), 27.4 (J(117/119Sn)=58.1, 55.1 Hz, 3C), 16.1 (d, J-
AHCTUNGTRENNUNG
(31P)=6.9 Hz, 2C), 13.7 (3C), 10.2 ppm (J(117/119Sn)=330.4, 315.9 Hz,
3C); 31P NMR (161.97 MHz, CDCl3): d=4.18 ppm (J(117/119Sn)=25.8 Hz);
IR (Si): n˜ =2957, 2927, 1707, 1326, 1263, 1164, 1030 cmÀ1; elemental anal-
ysis calcd (%) for C22H48NO5PSn (556.3): C 47.50, H 8.70, N 2.52; found:
C 47.71, H 8.56, N 2.58.
(R)- and (S)-[D1]-8: The spectroscopic data were identical to those of 8,
except for the following signals: 1H NMR (400.13 MHz, CDCl3): d=
ACTHNUTRGNEUNG
3.16 ppm (brd, J(117/119Sn)=23.2 Hz, J(31P)=8.1 Hz, 1H) and 13C NMR
(100.61 MHz, CDCl3): d=32.0 ppm (t, J=21.4 Hz).
Diethyl N-(tert-butoxycarbonyl)aminomethylphosphonate {11, (S)- and
(R)-[D1]-11}: The alkyllithium reagent was added to a solution of 8
(215 mg, 0.40 mmol) and TMEDA (51 mg, 66 mL, 0.44 mmol) in dry Et2O
(2.5 mL) under argon at the requisite temperature. After stirring for the
requisite time, the reaction was quenched with AcOH (AcOD) (0.56 mL,
1.4m solution in THF, 0.78 mmol) and then water (3 mL) was added. The
organic phase was separated, the aqueous phase was extracted with Et2O,
and the combined organic layers were dried over MgSO4. The solvent
was removed under reduced pressure and the crude product was purified
by flash chromatography (EtOAc; Rf =0.29) to give 11[42] as a colorless
oil (for details, see Table 1).
Experimental Section
General methods and materials: 1H/13C (J-modulated) NMR spectra
were measured, unless otherwise specified, at 300 K on a Bruker Avance
DPX 250, DRX 400, or DRX 600 spectrometer at 250.13/62.90 MHz,
400.13/100.61 MHz, or 600.13/150.92 MHz, respectively. 2D spectra were
recorded on the DRX 400. All chemical shifts (d) are given in ppm. They
were referenced either to residual CHCl3 (dH =7.24)/toluene (dH =2.09)
or CDCl3 (dC =77.00)/[D8]toluene (CHD2: dC =21.40). 31P NMR spectra
were measured on the Bruker Avance DRX 400 at 161.97 MHz. IR spec-
tra were acquired on a silicon disc[41] on a Perkin-Elmer 1600 FT-IR spec-
trometer. Optical rotations were measured at 208C on a Perkin-Elmer
351 polarimeter in a 1 dm cell. Flash column chromatography was per-
formed on Merck silica gel 60 (230–400 mesh) and monitored by TLC,
which was carried out on Merck plates coated with 0.25 mm thick silica
gel 60 F254. Spots were visualized by UV and/or by dipping the plate into
Methyllithium (1.6m solution in Et2O) was added to a solution of [D1]-8
(221 mg, 0.40 mmol) and TMEDA (51 mg, 66 mL, 0.44 mmol) in dry Et2O
(2.5 mL) under argon at the desired temperature. After stirring for the
requisite time, the reaction was quenched with 1m aqueous acetic acid
(1.0 mL, 1.0 mmol) and then water (3 mL) was added. The work-up was
identical to that of the unlabeled compound (for details, see Table 2).
Compound 11: 1H NMR (400.13 MHz, CDCl3): d=4.78 (brs, 1H), 4.18–
4.06 (m, 4H), 3.53 (dd, J
1.30 ppm (t, J=7.1 Hz, 6H); 13C NMR (100.61 MHz, CDCl3): d=80.1,
62.5 (d,
(31P)=6.1 Hz, 2C), 36.1 (d, (31P)=136.7 Hz), 28.3 (3C),
(31P)=11.3 Hz, J=6.0 Hz, 2H), 1.42 (s, 9H),
ACHTUNGTRENNUNG
a solution of (NH4)6Mo7O24·4H2O (23.0 g) and CeACHTUNGTRNEUG(N SO4)2·4H2O (1.0 g) in
10% aqueous H2SO4 (500 mL), followed by heating with a heat gun.
TMEDA, DMF, and pyridine were refluxed over powdered CaH2, tolu-
J
N
JACHTUNGTRENNUNG
Chem. Eur. J. 2009, 15, 5729 – 5739
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5735

F. Hammerschmidt and D. C. Kapeller
16.4 ppm (d,
(161.97 MHz, CDCl3): d=24.38 ppm; IR (Si): n˜ =3272, 2981, 2930, 1714,
1527, 1367, 1255, 1173, 1028 cmÀ1
J
G
hexane/EtOAc 10:1; Rf =0.75) to yield 16 (199 mg, 86%) as a colorless
oil.
Compound 16: 1H NMR (400.13 MHz, 808C, [D8]toluene): d=7.14–7.09
(m, 2Harom), 6.77–6.72 (m, 2Harom), 4.33 (s, 2H), 3.40 (s, 3H), 2.81 (brs,
J(117/119Sn)=26.8 Hz, 2H), 1.65–1.56 (m, 6H), 1.43 (s, 9H), 1.37 (sext, J=
7.3 Hz, 6H), 1.00–0.94 (m, J(117/119Sn)=50.8 Hz, 6H), 0.93 ppm (t, J=
7.3 Hz, 9H); 13C NMR (100.61 MHz, 808C, [D8]toluene): d=161.0 (from
HMBC), 132.3, 130.3 (2C), 115.7 (2C), 80.5, 56.0, 34.9, 30.8 (J(117/119Sn)=
20.6 Hz, 3C), 29.8, 28.9 (J(117/119Sn)=55.1 Hz, 3C), 14.9 (3C), 12.7 ppm;
2C not detected; IR (Si): n˜ =2956, 2923, 1679, 1514, 1250, 1164 cmÀ1; ele-
mental analysis calcd (%) for C26H47NO3Sn (540.4): C 57.79, H 8.77, N,
2.59; found: C 57.86, H 8.77, N 2.66.
(S)- and (R)-[D1]-11: The spectroscopic data were identical to those of
11, except for the following signals: 1H NMR (400.13 MHz, CDCl3): d=
3.52 ppm (brdd,
(100.61 MHz, CDCl3): d=155.4 (d, J
156.8 Hz, J=20.7 Hz).
JACHTUNGTRENNUNG
(31P)=11.3 Hz, J=6.0 Hz, 1H) and 13C NMR
(31P)=6.1 Hz), 35.8 ppm (dt, J(31P)=
ACHUTGTNRENNUG CAHTUNGTRENNUGN
Diethoxyphosphinylmethylammonium chloride {13·HCl, (R)- and (S)-
[D1]-13·HCl}: A solution of 11 (76 mg, 0.28 mmol) in ethanol (1 mL) was
cooled to 08C. HCl (1 mL, 5m solution in Et2O) was then added and the
resulting mixture was stirred for 3 h at RT. Thereafter, the solvent was re-
moved using a rotary evaporator and the residue was dried under high
vacuum to give the salt 13·HCl as colorless crystals (57 mg, 100%).
(S)-[D1]-16: The spectroscopic data were identical to those of 16, except
for the following signals: 1H NMR (400.13 MHz, 808C, [D8]toluene): d=
2.78 ppm (vbrs, 1H) and 13C NMR (100.61 MHz, 808C, [D8]toluene): d=
34.5 ppm (t, J=21.8 Hz).
Compound 13·HCl: 1H NMR (250.13 MHz, CDCl3): d=8.60 (brs, 3H),
4.30–4.12 (m, 4H), 3.50 (d, JACHTNUGRTNEUNG
(31P)=12.8 Hz, 2H), 1.32 ppm (t, J=7.0 Hz,
2-(N-tert-Butoxycarbonyl-N-p-methoxybenzylamino)-1-phenylethanol {18
and (2R)-[2-D1]-18}: The stannane 16 (190 mg, 0.35 mmol) was dissolved
in dry THF (3.5 mL) under argon and the solution was cooled to the re-
quired temperature. nBuLi (275 mL, 1.6m solution in hexane, 0.44 mmol)
was added (yellow color) and the reaction was later quenched with ben-
zaldehyde (0.70 mL, 1m solution in dry THF, 0.70 mmol). After 15 min,
water (3 mL) was added. The organic phase was separated and the aque-
ous phase was extracted with Et2O (3ꢃ3 mL). The combined organic
layers were washed with brine, dried (MgSO4), and concentrated under
reduced pressure, and the residue was purified by flash chromatography
(hexane/EtOAc 3:1; Rf =0.30) to yield 18 as a colorless oil (for details,
see Tables 3 and 4).
Compound 18: 1H NMR (400.13 MHz, 808C, [D8]toluene): d=7.28–7.23
(m, 2Harom), 7.15–7.09 (m, 2Harom), 7.08–6.95 (m, 3Harom), 6.71–6.67 (m,
2Harom), 4.81 (X part of ABX system, J=7.6, 3.8 Hz, 1H), 4.27 (AB
system, J=15.2 Hz, 2H), 3.37 (s, 3H), 3.37 (AB part of ABX system, J=
14.7, 7.6, 3.8 Hz, 2H), 1.40 ppm (s, 9H); 13C NMR (100.61 MHz, 808C,
[D8]toluene): d=160.9, 144.9, 132.2, 130.3, 129.6 (2C), 128.6 (2C), 127.4
(2C), 115.7 (2C), 81.2, 75.3, 56.9, 56.0, 53.1, 29.6 ppm (3C); 1C not de-
tected; IR (Si): n˜ =3437, 2975, 2930, 1692, 1464, 1412, 1367, 1248,
1165 cmÀ1; elemental analysis calcd (%) for C21H27NO4 (357.4): C 70.56,
H 7.61, N 3.92; found: C 71.22, H 7.65, N 3.91.
6H).
(R)- and (S)-[D1]-13·HCl: 1H NMR (400.13 MHz, CDCl3): d=8.61 (brs,
3H), 4.28–4.14 (m, 4H), 3.49 (brd, J
(31P)=13.1 Hz, 1H), 1.32 ppm (t, J=
7.1 Hz, 6H); 13C NMR (100.61 MHz, CDCl3): d=63.7 (d, J(31P)=6.1 Hz,
2C), 33.8 (td, J
(31P)=154.5, J=19.9 Hz), 16.3 ppm (d, J(31P)=6.1 Hz,
2C); 31P NMR (161.97 MHz, CDCl3): d=20.24 ppm; IR (Si): n˜ =3402,
2920, 2850, 1626, 1587, 1371, 1229, 1163, 1017 cmÀ1
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
G
ACHTUNGTRENNUNG
.
(R)-Mosher amides of 13, (S)-, and (R)-[D1]-13: These were prepared in
84% yield starting from the hydrochloride according to the general pro-
cedure for Mosher esters/amides and were purified by flash chromatogra-
phy (EtOAc, Rf =0.51). Chemical shifts and coupling constants varied
slightly due to differences in concentration/aggregation.
Compound 13·(R)-MTPA: 1H NMR (400.13 MHz, [D8]toluene): d=7.65
(brd, J=7.6 Hz, 2Harom), 7.12–7.00 (m, 3Harom), 6.75 (brs, 1H), 3.88–3.76
(m, 4H), 3.42 (ddAB system, JAB ꢀ16 Hz, J
ACHTUNGTRENNUNG
3.22 (q, J=1.5 Hz, 3H), 1.00 (t, J=7.1 Hz, 3H), 0.97 ppm (t, J=7.1 Hz,
3H); 31P NMR (161.97 MHz, [D8]toluene): d=22.77 ppm.
(R)-[D1]-13·(R)-MTPA: The spectroscopic data were identical to those
of 13·(R)-MTPA, except for the following signal: 1H NMR (400.13 MHz,
[D8]toluene): d=3.31 ppm (brdd, JACTHUNGTRENNNUG
collapsed to a brd after 31P decoupling.
(2R)-[2-D1]-18: The spectroscopic data were identical to those of 18,
except for the following signals: 1H NMR (400.13 MHz, 808C,
[D8]toluene): d=4.80 (brd, J=6.8 Hz, 1H), 3.40–3.31 ppm (m, 1H) and
13C NMR (100.61 MHz, 808C, [D8]toluene): d=75.3 and 75.2 (two diaste-
reomers), 56.6 ppm (t, J=19.1 Hz).
(S)-[D1]-13·(R)-MTPA: The spectroscopic data were identical to those of
13·(R)-MTPA, except for the following signal: 1H NMR (400.13 MHz,
[D8]toluene): d=3.55 ppm (brdd, JACTHUNGTRENNNUG
collapsed to a brd after 31P decoupling.
tert-Butyl N-p-methoxybenzylcarbamate (15): p-Methoxybenzylamine
(686 mg, 0.65 mL, 5.00 mmol) was added to a solution of Boc2O (1.11 g,
5.10 mmol) and Et3N (758 mg, 1.04 mL, 7.50 mmol) in dry CH2Cl2
(15 mL) at 08C. The solution was stirred for 2.5 h at RT and then 0.5m
HCl (10 mL) was added. The organic phase was separated and the aque-
ous phase was extracted with EtOAc (3ꢃ10 mL). The combined organic
layers were washed with water, dried (MgSO4), and concentrated under
reduced pressure. The crude product was purified by flash chromatogra-
phy (hexane/EtOAc 5:1; Rf =0.37) to yield 15[43] (1.19 g) as colorless crys-
tals in quantitative yield. 1H NMR (250.13 MHz, CDCl3): d=7.28 (d, J=
8.5 Hz, 2Harom), 6.84 (d, J=8.5 Hz, 2Harom), 4.73 (brs, 1H), 4.22 (d, J=
5.8 Hz, 2H), 3.77 (s, 3H), 1.44 ppm (s, 9H); 13C NMR (62.90 MHz,
CDCl3): d=158.9, 155.8, 131.0, 128.8 (2C), 114.0 (2C), 55.3, 44.2,
28.4 ppm (3C); 1C not detected.
(R)-Mosher esters of 18 and (2R)-[2-D1]-18: These were prepared in
80% yield according to the general procedure for Mosher esters/amides
and were purified by flash chromatography (hexane/EtOAc 5:1; TLC:
hexane/EtOAc 3:1; Rf =0.53).
Compound 18·(R)-MTPA: 1H NMR (400.13 MHz, 808C, [D8]toluene):
d=7.58–7.50 (m, 2Harom), 7.29–7.25 (m, 1Harom), 7.19–7.16 (m, 1Harom),
7.14–6.96 (m, 8Harom), 6.69–6.65 (m, 2Harom), 6.46 (X part of ABX
system, J=7.4, 5.7 Hz, 1H) and 6.36 (X part of ABX system, J=8.6,
5.1 Hz, 1H), 4.36 and 4.17 (AB system, JAB =15.4 Hz, 2H), 3.61–3.44 (m,
2H), 3.43 and 3.38 (q, J=1.0 Hz, 3H), 3.369 and 3.366 (s, 3H), 1.42 and
1.41 ppm (s, 9H); two diastereomers.
(2R)-[2-D1]-18·(R)-MTPA: The spectroscopic data were identical to
those of 18·(R)-MTPA, except for the following signals: 1H NMR
(400.13 MHz, 808C, [D8]toluene): d=6.45 (d, J=7.6 Hz, 1H) and 6.36 (d,
J=8.3 Hz, 1H), 3.58–3.41 ppm (m, 1H). Resolution of the relevant sig-
nals was not adequate, even when other solvents (CDCl3, [D6]DMSO,
CD3OD, [D6]acetone) were used.
tert-Butyl N-p-methoxybenzyl-N-tributylstannylmethylcarbamate {16 and
(S)-[D1]-16}: NaH (34 mg, 0.64 mmol, 60% in mineral oil) was washed
three times with hexane and then suspended in dry DMF (1.5 mL) under
argon at 08C. A solution of carbamate 15 (151 mg, 0.64 mmol) in dry
DMF (0.5 mL) was added and the mixture stirred for 30 min, and then a
solution of mesylate 14 (170 mg, 0.43 mmol) in dry DMF (0.5 mL) was
added. After 1 h, the reaction was quenched with water (3 mL). The or-
ganic phase was separated and the aqueous phase was extracted with
Et2O (3ꢃ3 mL). The combined organic layers were washed with brine,
dried (MgSO4), and concentrated under reduced pressure, and the resi-
due was purified by flash chromatography (hexane/EtOAc 40:1; TLC:
(R)-Mosher ester of (2R)-2-(N-tert-butoxycarbonylamino)-1-phenyl-[2-
D1]ethanol {(2R)-[2-D1]-19·(R)-MTPA} (PMB cleavage): A solution of
the (R)-Mosher ester of [2-D1]-18 (11 mg, 0.02 mmol) and CAN (28 mg,
0.08 mmol) in MeCN (0.4 mL)/water (0.1 mL) was stirred for 1.5 h at
08C. Water (2 mL) and EtOAc (2 mL) were then added, the organic
phase was separated, and the aqueous phase was extracted with EtOAc.
The combined organic layers were dried (MgSO4) and concentrated
5736
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ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 5729 – 5739

Chiral Amino-[D1]methyllithiums
FULL PAPER
under reduced pressure. The residue was purified by flash chromatogra-
phy (hexane/EtOAc 10:1; Rf =0.15) to give (2R)-[2-D1]-19·(R)-MTPA in
quantitative yield (9 mg). 1H NMR (400.13 MHz, 808C, [D8]toluene): d=
7.56–7.48 (m, 2Harom), 7.17–6.94 (m, 8Harom), 6.09 (d, J=4.3 Hz, 1H), 6.08
(d, J=8.3 Hz, 1H), 5.98 (d, J=8.1 Hz, 1H), 5.98 (d, J=4.7 Hz, 1H),
4.21–4.08 (brm, 1H), 3.41 and 3.34 (q, J=1.1 Hz, 3H), 3.42–3.29 (m,
1H), 3.23–3.16 (m, 0.5H), 3.12–3.06 (m, 0.5H), 1.38 and 1.37 ppm (s,
9H).
(100.61 MHz, CDCl3): d=29.2 (J(117/119Sn)=19.1 Hz, 3C), 27.4
(J(117/119Sn)=52.8 Hz, 3C), 25.3 (t, J=20.7 Hz), 13.7 (3C), 8.5 ppm
(J(117/119Sn)=317.4, 303.6 Hz, 3C); IR (Si): n˜ =2956, 2923, 2871, 1569,
1464 cmÀ1
.
1
Compound 23: H NMR (400.13 MHz, [D8]toluene): d=7.56 (s, 1H), 4.47
(brs, 1H), 2.332 and 2.330 (d, J=4.3 Hz, J(117/119Sn)=31.6 Hz, 2H), 1.65–
1.56 (m, 6H), 1.38 (sext, J=7.3 Hz, 6H), 1.02–0.97 (m, 6H), 0.97 ppm (t,
J=7.3 Hz, 9H); 13C NMR (100.61 MHz, [D8]toluene): d=161.7, 30.6
(J(117/119Sn)=20.7 Hz, 3C), 28.9 (J(117/119Sn)=54.3 Hz, 3C), 23.3, 15.0
(3C), 12.2 ppm (J(117/119Sn)=336.5, 321.1 Hz, 3C); IR (Si): n˜ =3255, 3044,
2956, 2922, 2853, 1651, 1376 cmÀ1; elemental analysis calcd (%) for
C14H31NOSn (348.1): C 48.30, H 8.98, N 4.02; found: C 49.15, H 9.00, N
4.07.
(R)-Mosher esters of N-(2-hydroxy-2-phenylethyl)-N-4-methoxybenzyl-
ammonium trifluoroacetate {20·(R)-MTPA and (1R)-[1-D1]-20·(R)-
MTPA} (Boc cleavage): A solution of 18·(R)-MTPA (30 mg, 0.052 mmol)
in TFA (1 mL) was stirred for 1.5 h at 08C. The solvent was then re-
moved in vacuo to give 20·(R)-MTPA as a colorless oil in quantitative
yield. Chemical shifts and coupling constants varied slightly due to differ-
ences in concentration/aggregation.
Compound 20·(R)-MTPA: 1H NMR (600.13 MHz, [D8]toluene): d=9.26
(vbrs, 2H), 7.49 (d, J=7.7 Hz, 1Harom), 7.41–7.37 (m, 1Harom), 7.21 (d,
J=6.8 Hz, 1Harom), 7.12–6.96 (m, 9Harom), 6.65 (dd, J=8.7, 2.9 Hz,
2Harom), 6.36 (X part of ABX system, J=8.7, 3.8 Hz, 1H) and 6.31 (X
part of ABX system, J=8.7, 3.8 Hz, 1H), 3.71 and 3.57 (AB system,
(S)-[D1]-23: The spectroscopic data were identical to those of 23, except
for the following signals: 1H NMR (400.13 MHz, [D8]toluene): d=
2.31 ppm
(t,
J=1.9 Hz,
J(117/119Sn)=31.1 Hz,
1H);
13C NMR
(100.61 MHz, [D8]toluene): d=23.02 ppm (t, J=21.0 Hz, 1C).
Tributyl(isocyanomethyl)stannane {24 and (S)-[D1]-24}: Et3N (101 mg,
138 mL, 1.0 mmol) was added to a solution of 23 (290 mg, 0.83 mmol) and
Ph3P (262 mg, 1.0 mmol) in dry MeCN (1.3 mL) and CCl4 (0.5 mL) under
argon at 58C. The mixture was stirred for 2.5 h, during which it was al-
lowed to warm to RT. A few drops of water were added and the solution
was directly subjected to flash chromatography (hexane/EtOAc 40:1;
Rf =0.28) to furnish 226 mg (82%) of 24 as a colorless oil. The slightly re-
duced yield is due to the instability of the isonitrile and its decomposition
on silica gel (probably through conversion to the formamide).
Compound 24: 1H NMR (400.13 MHz, CDCl3): d=2.96 (s, J(117/119Sn)=
28.6 Hz, 2H), 1.57–1.47 (m, 6H), 1.31 (sext, J=7.3 Hz, 6H), 1.08–1.02
(m, 6H), 0.89 ppm (t, J=7.3 Hz, 9H); 13C NMR (100.61 MHz, CDCl3):
d=28.7 (J(117/119Sn)=22.2 Hz, 3C), 27.2 (J(117/119Sn)=57.4 Hz, 3C), 21.5,
13.6 (3C), 9.8 ppm (J(117/119Sn)=338.0, 323.5 Hz, 3C); 1C not detected;
IR (Si): n˜ =2958, 2929, 2872, 2131, 1464 cmÀ1; elemental analysis calcd
(%) for C14H29NSn (330.1): C 50.94, H 8.86, N 4.24; found: C 51.79, H
9.17, N 4.16; HRMS: m/z: calcd for C14H29NSn+H+: 331.1324 [M+H+];
found: 331.1332.
JAB =13.1 Hz, 2H), 3.43 and 3.30 (s, 3H), 3.20 (s, 3H), 3.15 (dd [AB part
of ABX system], J=13.5, 8.7 Hz, 1H), 3.11 (dd [AB part of ABX
system], J=13.5, 8.7 Hz, 1H), 3.05 (dd [AB part of ABX system], J=
13.5, 3.8 Hz, 1H), 3.02 ppm (dd [AB part of ABX system], J=13.5,
3.8 Hz, 1H); two diastereomers.
(1R)-[1-D1]-20·(R)-MTPA: The spectroscopic data were identical to
those of 20·(R)-MTPA, except for the following signals: 1H NMR
(600.13 MHz, [D8]toluene): d=6.23 (d, J=4.0 Hz, 1H) and 6.15 (d, J=
8.4 Hz, 1H), 3.02 (d, J=8.4 Hz, 1H) and 2.95 ppm (d, J=4.0 Hz, 1H).
(1S)-[1-D1]-20·(R)-MTPA: The spectroscopic data were identical to
those of 20·(R)-MTPA, except for the following signals: 1H NMR
(600.13 MHz, [D8]toluene): d=6.23 (d, J=7.5 Hz, 1H) and 6.14 (d, J=
4.4 Hz, 1H), 3.04 (d, J=7.5 Hz, 1H) and 2.93 ppm (d, J=4.4 Hz, 1H).
N-Tributylstannylmethylphthalimide {21 and (S)-[D1]-21}: Tributylstan-
nylmethanol 6 (1.44 g, 4.50 mmol), Ph3P (1.42 g, 5.4 mmol), and phthali-
mide (792 mg, 5.40 mmol) were dissolved in dry THF (22.5 mL) under
argon. DEAD (940 mg, 850 mL, 5.40 mmol) was added at 08C, and then
the mixture was stirred at ambient temperature for 1 h. The reaction was
quenched by adding a few drops of water, the solvent was removed
under reduced pressure, and the residue was purified by flash chromatog-
raphy (hexane/EtOAc 15:1; Rf =0.33) to give 1.85 g (91%) of 21 as a
yellow oil. The spectroscopic data of the unlabeled compound were iden-
tical to those reported in the literature.[44]
(S)-[D1]-24: The spectroscopic data were identical to those of 24, except
for the following signals: 1H NMR (400.13 MHz, CDCl3): d=2.94 ppm
(brs, J(117/119Sn)=28.3 Hz, 1H) and 13C NMR (100.61 MHz, CDCl3): d=
21.2 ppm (t, J=22.2 Hz).
2-Isocyano-1-phenylethanol {26 and [2-D1]-26}: Macroscopic: nBuLi
(225 mL, 1.6m solution in hexane, 0.36 mmol) was added to a solution of
24 (99 mg, 0.30 mmol) in dry THF (3 mL) under argon at the requisite
temperature. The intermediate organolithium was trapped with benzalde-
hyde (390 mL, 1m solution in dry THF, 0.39 mmol) after the required
time. After a further 3 min, acetic acid (330 mL, 1m solution in dry THF,
0.33 mmol) was added, followed by a saturated aqueous solution of
NaHCO3 (5 mL). The organic phase was separated, the aqueous phase
was extracted with Et2O (3ꢃ5 mL), and the combined organic layers
were dried over MgSO4. The solvent was removed under reduced pres-
sure and the residue was purified by flash chromatography (hexane/
EtOAc 3:1; Rf =0.23) to give isocyano alcohol 26 as a colorless oil (for
details, see Table 5).[31b,37]
(S)-[D1]-21: 1H NMR (400.13 MHz, CDCl3): d=7.80–7.75 (m, 2Harom),
7.67–7.62 (m, 2Harom), 3.20 (brs, J(117/119Sn)=26.0 Hz, 1H), 1.52–1.43 (m,
6H), 1.25 (sext, J=7.3 Hz, 6H), 0.95–0.89 (m, 6H), 0.83 ppm (t, J=
7.3 Hz, 9H); 13C NMR (100.61 MHz, CDCl3): d=168.8 (2C), 133.6 (2C),
132.4 (2C), 122.8 (2C), 28.9 (J(117/119Sn)=20.7 Hz, 3C), 27.3 (J(117/119Sn)=
55.8 Hz, 3C), 21.0 (t, J=21.4 Hz), 13.6 (3C), 10.4 ppm (J(117/119Sn)=
335.0, 319.2 Hz, 3C); IR (Si): n˜ =2955, 2922, 2870, 2853, 1768, 1708, 1465,
1396 cmÀ1
.
N-(Tributylstannylmethyl)formamide {23 and (S)-[D1]-23}: N2H4·H2O
(6.0 mL) was added dropwise to a refluxing solution of 21 (1.35 g,
3.0 mmol) in ethanol (9 mL). The mixture was stirred for 1 h, cooled, and
diluted with freshly distilled Et2O (20 mL). The organic phase was sepa-
rated, washed with water (4ꢃ10 mL) and brine (2ꢃ10 mL), and concen-
trated under reduced pressure. The crude product (860 mg, 2.68 mmol)
was dissolved in tert-butyl methyl ether (6 mL), treated with 2,2,2-tri-
fluoroethyl formate (687 mg, 5.37 mmol, redistilled from P2O5),[33,34] and
the resulting mixture was stirred for 1.5 h. The solvent was then removed
under reduced pressure and the residue was purified by flash chromatog-
raphy (hexane/EtOAc 3:1; Rf =0.26) to give formamide 22 (760 mg,
73%) as a colorless oil. The spectroscopic data of 22 were identical to
those reported in the literature.[44]
Microscopic: nBuLi (0.75 mL, 1.6m solution in hexane, 1.2 mmol) was
slowly added to a solution of 24 (99 mg, 0.30 mmol) and benzaldehyde
(1.2 mL, 1m solution in dry THF, 1.2 mmol) in dry THF (2 mL) under
argon at À958C. After 3 min, acetic acid (1.32 mL, 1m solution in THF,
1.32 mmol) was added. The subsequent work-up was the same as de-
scribed for the macroscopic conditions. Compound 26 proved to be quite
unstable; if not stored as a dilute solution in toluene at À208C, it rapidly
cyclized to 5-phenyl-2-oxazoline.
1
Compound 26: H NMR (400.13 MHz, CDCl3): d=7.41–7.31 (m, 5Harom),
4.95 (t, J=5.9 Hz, 1H), 3.61 (d, J=5.9 Hz, 2H), 2.56 ppm (s, 1H);
13C NMR (100.61 MHz, CDCl3): d=157.9, 139.3, 128.9 (2C), 128.8, 125.9
(2C), 72.0, 49.2 ppm (t, J=6.9 Hz); IR (Si): n˜ =3392, 3033, 2919, 2850,
2153, 1454, 1065 cmÀ1; HRMS: m/z: calcd for C9H9NO: 147.0684; found:
147.0686 (also 147.1172).
(S)-[D1]-22: 1H NMR (400.13 MHz, CDCl3): d=2.60 (brs, J(117/119Sn)=
29.3 Hz, 1H), 2.09 (vbrs, 2H), 1.53–1.48 (m, 6H), 1.29 (sext, J=7.3 Hz,
6H), 0.93–0.86 (m, 6H), 0.88 ppm (t, J=7.3 Hz, 9H); 13C NMR
Chem. Eur. J. 2009, 15, 5729 – 5739
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5737

F. Hammerschmidt and D. C. Kapeller
A
Compound 28: 1H NMR (400.13 MHz, CDCl3): d=7.36–7.19 (m,
15Harom), 4.69 (t, J=6.8 Hz, 1H), 3.69 (AB system, JAB =13.4 Hz), 2.63
(d, J=6.8 Hz, 2H), 1.59 ppm (brs, 1H); 13C NMR (100.61 MHz, CDCl3):
d=142.1, 138.3 (2C), 129.1 (4C), 128.5 (4C), 128.3 (2C), 127.4, 127.4
(2C), 125.9 (2C), 69.6, 61.9, 58.4 ppm (2C); IR (Si): n˜ =3452, 3028, 2924,
for the following signals: 1H NMR (400.13 MHz, CDCl3): d=4.95 (d, J=
5.3 Hz, 1H), 3.60 ppm (brs, 1H) and 13C NMR (100.61 MHz, CDCl3): d=
48.95 ppm (tt, J=22.3, 6.9 Hz).
(R)-Mosher esters of 26 and [2-D1]-26: These were prepared according
to the general procedure for Mosher esters/amides, except that 2 equiv of
(S)-MTPACl was used and the reaction was terminated after 3 h, as oth-
erwise the formation of an unidentified side product predominated. The
crude product was purified by flash chromatography (hexane/EtOAc 7:1;
Rf =0.24) to give the esters in an average yield of 50%.
1602, 1494, 1453 cmÀ1
.
(2R)-[2-D1]-28: 1H NMR (400.13 MHz, CDCl3): d=7.37–7.20 (m,
15Harom), 4.69 (d, J=10.4 Hz, 1H) and 4.69 (d, J=3.3 Hz, 1H), 3.71 and
3.70 (AB system,
J
AB =13.4 Hz), 2.66–2.60 ppm (m, 1H); 13C NMR
(100.61 MHz, CDCl3): d=142.13 and 142.10 (2C), 138.29 and 138.28,
129.1 (4C), 128.5 (4C), 128.2 (2C), 127.39 (1C), 127.35 (2C), 125.9 (2C),
69.53 and 69.48, 61.51 and 61.47 (t, J=21.0 Hz), 58.34 and 58.32 ppm
(2C); two diastereomers.
Compound 26·(R)-MTPA: H NMR (400.13 MHz, [D8]toluene): d=7.58–
7.53 (m, 1Harom), 7.49–7.42 (m, 1Harom), 7.11–6.88 (m, 7Harom), 6.74–6.68
(m, 1Harom), 5.78 (X part of ABX system, J=8.3, 4.0 Hz, 1H) and 5.61
(X part of ABX system, J=9.2, 3.4 Hz, 1H), 3.56 (q, J=1.5 Hz, 3H) and
3.30 (q, J=1.0 Hz, 3H), 2.78 (AB part of ABX system, J=15.3, 8.3,
4.0 Hz, 2H) and 2.71 ppm (AB part of ABX system, J=15.5, 9.2, 3.4 Hz,
2H); two diastereomers.
(R)-Mosher esters of 28, (2S)-, and (2R)-[2-D1]-28: These were prepared
in 45% yield according to the general procedure for Mosher esters/
amides, except that instead of 1m HCl only water was added. The prod-
ucts were purified by flash column chromatography (hexane/CH2Cl2 1:1;
Rf =0.57).
Compound 28·(R)-MTPA: 1H NMR (400.13 MHz, CDCl3): d=7.48–7.05
(m, 20Harom), 6.08 (X part of ABX system, J=7.8, 5.3 Hz, 1H) and 6.03
(X part of ABX system, J=8.1, 4.8 Hz, 1H), 3.66 and 3.56 (AB system,
ACHTUNGTRENNUNG[2-D1]-26·(R)-MTPA: The spectroscopic data were identical to those of
26·(R)-MTPA, except for the following signals: 1H NMR (400.13 MHz,
[D8]toluene): d=5.79 (d, J=8.3 Hz, 1H) and 5.79 (d, J=4.0 Hz, 1H),
5.62 (d, J=9.2 Hz, 1H) and 5.62 (d, J=3.4 Hz, 1H), 2.87 (brd, J=8.3 Hz,
1H) and 2.82 (brd, J=9.2 Hz, 1H), 2.71–2.68 (m, 1H) and 2.63–2.59 ppm
(m, 1H); four diastereomers in equal amounts.
JAB =13.6 Hz, 4H), 3.48 and 3.40 (q, J=1.0 Hz, 3H), 3.06 (dd [AB part
of ABX system], J=13.9, 8.1 Hz, 1H) and 2.99 (dd [AB part of ABX
system], J=13.9, 7.8 Hz, 1H), 2.74 ppm (dd [AB part of ABX system],
J=13.9, 4.8 Hz, 1H) and 2.73 (dd [AB part of ABX system], J=13.9,
5.3 Hz, 1H); two diastereomers.
N,N-Dibenzyl(tributylstannylmethyl)amine {27, (R)- and (S)-[D1]-27}: A
solution of tributylstannylmethyl mesylate (14, 883 mg, 2.20 mmol) and
Bn2NH (1.74 g, 1.69 mL, 8.80 mmol) in MeCN (15 mL) was stirred for
1 day at 508C. Water (10 mL) was then added, the aqueous layer was ex-
tracted with EtOAc (3ꢃ10 mL), and the combined organic layers washed
with brine and dried (MgSO4). After removal of the solvent under re-
duced pressure, the residue was purified by flash chromatography
(hexane/EtOAc 40:1; Rf =0.43) to yield tertiary amine 27 as a colorless
oil (992 mg, 90%). The spectroscopic data of 27 were identical to those
reported in the literature.[38]
(2R)-[2-D1]-28·(R)-MTPA: The spectroscopic data were identical to
those of 28·(R)-MTPA, except for the following signals: 1H NMR
(400.13 MHz, CDCl3): d=6.092 (d, J=5.1 Hz, 1H) and 6.033 (d, J=
8.1 Hz, 1H), 3.04 (d, J=8.1 Hz, 1H) and 2.71 ppm (d, J=5.1 Hz, 1H).
(2S)-[2-D1]-28·(R)-MTPA: The spectroscopic data were identical to
those of 28·(R)-MTPA, except for the following signals: 1H NMR
(400.13 MHz, CDCl3): d=6.088 (d, J=7.8 Hz, 1H) and 6.038 (d, J=
4.6 Hz, 1H), 2.98 (d, J=7.8 Hz, 1H) and 2.73 ppm (d, J=4.6 Hz, 1H).
(R)- and (S)-[D1]-27: 1H NMR (400.13 MHz, CDCl3): d=7.36–7.18 (m,
10Harom), 3.44 (AB system,
20.0 Hz, 1H), 1.48–1.39 (m, 6H), 1.26 (sext, J=7.3 Hz, 6H), 0.90–0.84
(m, 6H), 0.85 ppm (t, J=7.3 Hz, 9H); 13C NMR (100.61 MHz, CDCl3):
d=140.0 (2C), 128.7 (4C), 128.2 (4C), 126.8 (2C), 62.5 (J(117/119Sn)=
28.3 Hz, 2C), 42.5 (t, J=19.9 Hz), 29.2 (J(117/119Sn)=19.9 Hz, 3C), 27.4
(J(117/119Sn)=54.3 Hz, 3C), 13.7 (3C), 10.0 ppm (J(117/119Sn)=299.8,
Acknowledgements
This work was supported by Grant No. P19869-N19 from the FWF.
D.C.K. is grateful to the Austrian Academy of Sciences for a DOC-
FFORTE scholarship.
286.8 Hz, 3C); IR (Si): n˜ =2956, 2924, 2854, 1496, 1454 cmÀ1
To determine the ee of [D1]-27, it was treated with 2 equiv of (R)-(+)-
.
tert-butylACHTUNGTRENNUNG
(phenyl)monothiophosphinic acid and a 1H NMR spectrum was
immediately recorded.[40]
Salt of 27: 1H NMR (400.13 MHz, [D8]toluene): d=8.18–8.09 (m,
3Harom), 7.42–7.35 (m, 2Harom), 7.16–6.95 (m, 10Harom), 4.31 (AB system,
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AB =13.9 Hz, 4H), 2.35 (AB system, JAB =13.4 Hz, 2H), 1.45–1.20 (m,
12H), 1.25 (d, J=16.4 Hz, 9H), 1.05–0.97 (m, 6H), 0.88 ppm (t, J=
7.3 Hz, 9H).
Salt of (S)-[D1]-27: The spectroscopic data were identical to those of the
unlabeled compound, except for the following signal: 1H NMR
(400.13 MHz, [D8]toluene): d=2.36 ppm (s, J(117/119Sn)=30.8 Hz, 1H).
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2-(N,N-Dibenzylamino)-1-phenyl-1-ethanol {28, (2S)- and (2R)-[2-D1]-
28}: A solution of 27 (160 mg, 0.32 mmol) in dry THF (3 mL) was treated
with nBuLi (400 mL, 1.6m solution in hexane, 0.64 mmol) under argon at
the requisite temperature. After the required time, the reaction was
quenched with benzaldehyde (0.39 mL, 2m in dry THF, 0.78 mmol), and
then hexane (3 mL) and 10% H2SO4 (4 mL) were added. The organic
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bined aqueous phases were neutralized with solid NaOH and then ex-
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Received: December 18, 2008
Published online: April 28, 2009
Chem. Eur. J. 2009, 15, 5729 – 5739
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5739