Enantioselective Alkynylation of Aldehydes by Mixed Aggregates of 3-Aminopyrrolidine Lithium Amides and Lithium Acetylides

Article abstract of DOI:10.1021/acs.organomet.5b00647

Lithium acetylides form, with 3-aminopyrrolidine lithium amides, noncovalent 1/1 mixed aggregates that have been characterized by 1D and 2D multinuclear NMR spectroscopy and DFT computations. The results show that the complex adopts a structure organized around a N-Li-C-Li core and that the acetylide appendage lies within the plane of this quadrilateral, midway between the two lithium cations. These complexes have been employed for the enantioselective alkynylation of a series of aromatic aldehydes and provided the expected propargylic alcohols in ee values up to 85% in THF at -78 °C.

Full text of DOI:10.1021/acs.organomet.5b00647

Article
pubs.acs.org/Organometallics
Enantioselective Alkynylation of Aldehydes by Mixed Aggregates of
3‑Aminopyrrolidine Lithium Amides and Lithium Acetylides
Gabriella Barozzino-Consiglio, Yi Yuan, Catherine Fressigne,
and Jacques Maddaluno*
́
Anne Harrison-Marchand,* Hassan Oulyadi,
Normandie Universite,
Mont-Saint-Aignan Cedex, France
́ ́
Laboratoire COBRA, UMR 6014 & FR 3038 CNRS, Universite de Rouen, INSA de Rouen, 76821
*
S Supporting Information
ABSTRACT: Lithium acetylides form, with 3-aminopyrroli-
dine lithium amides, noncovalent 1/1 mixed aggregates that
have been characterized by 1D and 2D multinuclear NMR
spectroscopy and DFT computations. The results show that
the complex adopts a structure organized around a N−Li−C−
Li core and that the acetylide appendage lies within the plane
of this quadrilateral, midway between the two lithium cations. These complexes have been employed for the enantioselective
alkynylation of a series of aromatic aldehydes and provided the expected propargylic alcohols in ee values up to 85% in THF at
−
78 °C.
INTRODUCTION
(3APLi) as chiral inductors. With the aim of extending our
procedure to the sp nucleophiles, we present in this paper
results describing the enantioselective alkynylation of several
aromatic aldehydes by 3APLi/RCCLi mixed aggregates.
Additionally, a detailed multinuclear NMR analysis and a DFT
theoretical study are presented that shine more light on the
structure of the aggregates that could be at the origin of the
asymmetric induction.
■
Propargylic alcohols are important building blocks for the
synthesis of pharmaceuticals and agrochemicals as well as
natural products, because they are direct precursors of useful
derivatives going from the allylic or benzylic alcohols to allenes
and many others. Accessing such compounds enantioselectively
1
is therefore a persistent subject of interest. Two major
methods are known to give enantioenriched propargylic
alcohols: reduction of propargylic ketones or alkynylation of
carbonyl compounds. The latter is more general, since the
reduction requires the preliminary synthesis of sensitive ynones
and does not give access to tertiary alcohols.
The enantioselective alkynylation route demands a nucleo-
philic acetylide RCCM, generally obtained by deprotonation
of the corresponding terminal alkyne. In combination with the
appropriate chiral catalysts, diverse metals have been used. Zinc
RESULTS AND DISCUSSION
■
Enantioselective Alkynylation of Aromatic Aldehydes.
The alkynylations have been carried out with lithium acetylides
1
-Li−4-Li (Scheme 1). The aggregation states of the lithium
acetylides 1-Li−3-Li have been well described in THF at low
temperature (−90 to −115 °C) and correspond to a dimer for
1
15,16
15,17
-Li,
a tetramer for 2-Li,
and a dimer + tetramer
2
3
4
acetylides, such as those developed by Pu, Chan, Carreira,
7b,15
5
mixture depending on the concentration for 3-Li.
The
and others have led to extremely efficient systems.
6
7
8
9
structure of lithium acetylide 4-Li has been elucidated in a 1/3
Mukaiyama, Grabowski, Schaf
̈
er, Jiang, and more recently
18
1
0
THF/Me O mixture at −123 °C and corresponds to a dimer.
2
Nakajima have shown that lithium acetylides can also add
enantioselectively. The work by Grabowski and Collum is
worth underlining, since their results have been applied to the
industrial synthesis of Efavirenz, an HIV-1 reverse transcriptase
inhibitor, and have been the object of a remarkable structure−
On the other hand, three 3APLi compounds (5a-Li−5c-Li,
Scheme 1) have been selected among those that have given the
12−14
best results in previous cases.
Each 3APLi/Li-acetylide
aggregate was prepared in situ at −20 °C by simultaneous
deprotonation of the terminal acetylenic substrate and the
amine. They were then reacted at −78 °C with o-tolualdehyde
7
,11
reactivity study. The conclusion of that study was that well-
organized [Li,Li] mixed aggregates between the lithium
acetylides and the chiral lithium alkoxides employed as chiral
inductors in this process are forming at low temperature in
THF.
(
2-methylbenzaldehyde) 6 in a 1.5/1.5/1 3APLi/Li-acetylide/
aldehyde ratio in classical solvents (THF, diethyl ether, and
12−14
toluene, Table 1).
Note that the amide, acetylide, and
aldehyde ratio was based on previous results optimized for
alkylation and arylation reactions.
Our own interest in the chemistry of these bimetallic entities
led us previously to describe the enantioselective addition of
3
12
13
2
13b,14
alkyl (sp ), alkenyl, and aryl (sp )
organolithium
derivatives to aldehydes. The system we use consists of 1/1
mixed aggregates of 3-aminopyrrolidine lithium amides
Received: February 26, 2015
©
XXXX American Chemical Society
A
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Article
Scheme 1. Alkynylation of o-Tolualdehyde 6 by Lithium Acetylides 1-Li−4-Li in the Presence of 3APLi Compounds 5a-Li−5c-Li
Table 1. Enantioselective Alkynylation of o-Tolualdehyde 6
by 1-4-Li in the Presence of 3APLi Compounds 5a-Li−5c-Li
The next stage of this work consisted of applying the above
optimized conditions to various aromatic aldehydes. The 1/1
mixed complex 3APLi/Li-acetylide 5b-Li/1-Li (1 equiv) was
thus reacted with aldehydes 11−23 (0.67 equiv, Scheme 2,
a
b
yield, %
ee, %
d
entry RCCLi 3APLi
solvent
THF
(alcohol)
(confign)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1-Li
5a-Li
5a-Li
5a-Li
5b-Li
5b-Li
5b-Li
5c-Li
5c-Li
5c-Li
5a-Li
5b-Li
5c-Li
5a-Li
5b-Li
5c-Li
5a-Li
5b-Li
5c-Li
51 (7)
31 (R)
21 (R)
<5 (e)
70 (R)
37 (R)
<5 (e)
59 (S)
13 (S)
<5 (e)
c
Scheme 2. Alkynylation of Aldehydes 11−23 in the Presence
of Mixed Complex 5b-Li/1-Li in THF at −78 °C
Et O
2
71 (7)
c
toluene
THF
10 (7)
71 (7)
c
Et O
2
60 (7)
c
toluene
THF
45 (7)
81 (7)
c
Et O
2
45 (7)
c
toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF
42 (7)
f
0
1
2
3
4
5
6
7
8
2-Li
3-Li
4-Li
59 (8)
69 (8)
67 (8)
42 (9)
58 (9)
46 (9)
56 (10)
67 (10)
12 (−)
35 (−)
38 (+)
f
f
f
11 (−)
20 (−)
18 (+)
f
f
Table 2) at −78 °C in THF. The results indicate that the
alkynylation applies to a large range of aromatic aldehydes,
affording the expected propargylic alcohols in medium to good
yield. Table 2 also gives some indication of the influence of the
susbtituents on the ees. A comparison of entries 1, 4, and 12
f
47 (+)
f
59 (+)
f
80 (10)
b
53 (−)
a
Determined after flash chromatography. Determined on a chiral
c
HPLC column (see the Experimental Section). The formation of 2-
methylbenzyl alcohol was observed in 12−42% yield in Et O and
2
d
Table 2. Enantioselective Alkynylation of Aldehydes 6 and
11−23 in the Presence of the Mixed Complex 5b-Li/1-Li
toluene. The absolute configuration was assigned by comparison with
e
f
the literature. Undetermined. The absolute configuration not being
accessible for alcohols 8−10, the sense of induction is given on the
basis of optical rotatory data.
a
b
c
entry
aldehyde
yield, % (alcohol) ee, % (confign)
1
2
3
4
5
6
7
8
9
PhCHO (11)
47 (24)
71 (7)
78 (R)
70 (R)
65 (R)
72 (R)
o-MeC H CHO (6)
6
4
m-MeC H CHO (12)
49 (25)
68 (26)
90 (27)
42 (28)
50 (29)
Overall, the chemical yields are medium to good, despite the
relative instability of these benzylic/propargylic alcohols on
silica gel. The results obtained with Li-acetylide 1-Li (PhC
CLi, entries 1−9) show that measurable enantiomeric excesses
6
4
p-MeC H CHO (13)
6
4
d
2,6-Me -C H CHO (14)
85 (−)
38 (R)
73 (R)
2
6
3
o-MeOC H CHO (15)
6
4
m-MeOC H CHO (16)
(
ees) are obtained only in ethereal solvents, racemic mixtures
6
4
e
p-MeOC H CHO (17)
10 (30)
6
4
being isolated in toluene (entries 3, 6, and 9). Note that in this
latter solvent, 2-methylbenzyl alcohol up to 42% was recovered
additionally to alcohol 7. This secondary product also formed
o-ClC H CHO (18)
76 (31)
44 (32)
51 (33)
37 (34)
76 (35)
42 (36)
72 (R)
32 (R)
51 (R)
38 (R)
73 (R)
55 (R)
6
4
10
11
12
13
14
m-ClC H CHO (19)
6 4
p-ClC H CHO (20)
6
4
in Et O, but in a lesser proportion (<20%). The best yields
2
p-CF C H CHO (21)
3
6
4
(with the exclusive formation of alcohol 7) and stereochemical
α-naphthylCHO (22)
β-naphthylCHO (23)
inductions were obtained in THF (entries 1, 4, and 7). Thus,
the alkynylations involving Li-acetylides 2-Li−4-Li were run
only in THF (entries 10−18). With regard to the inductions,
the 3APLi compounds 5b-Li and 5c-Li lead to better ees than
a
b
Determined after flash column chromatography. Determined on a
c
chiral HPLC column (see the Experimental Section). The absolute
5
a-Li, independent of the lithium acetylide. The phenomenon,
configuration is based on measurements of the optical rotation and
already noticed in previous work, of an inversion of the
d
comparison with the literature values. The absolute configuration has
absolute configuration of the resulting alcohols depending on
not been assigned, and the sense of induction is given on the basis of
12
e
the use of 5b-Li or 5c-Li is observed. Li-acetylides 1-Li and 4-
Li were the best nucleophiles, allowing ees higher than 50%.
optical rotatory value. More than 50% starting aldehyde 17 was
recovered.
B
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suggests that the electron-rich substituents have little, if any,
influence on the induction process, while electron-deficient
groups tend to play a detrimental effect. The dual influence of
the p-chloro substituent translates into a medium ee of 51%.
The steric influence is harder to understand, even if hindering
the ortho positions seems rather favorable, 2,6-dimethylben-
zaldehyde (14) giving the best result (85% ee). The low yield
obtained from the electron-rich p-MeOC H -CHO (17, entry
6
4
8
) is worth noting in relation to a comparable result obtained
13a
during the vinylation of this same aldehyde.
This result
suggests that an intermediate α-amino alkoxide, resulting from
the 1,2-addition of the nucleophilic lithium amide (instead of
the acetylide), forms in the medium. The nucleophilic character
of a comparable lithium amide with respect to benzaldehyde
19
was observed before by NMR. Upon hydrolysis, these
unstable products would decompose to 17 and the starting
amine 5b.
6
Figure 1. Li NMR spectra of (a) 5b-Li, (b) acetylide 1-Li, and (c) 1/
5b-Li/1-Li mixed aggregate in THF-d at 195 K (−78 °C).
1
8
Overall, the lithium acetylides lead to enantioselectivities in
the same range as for the alkyl- and alkenyllithium
1
2,13
derivatives.
Thus, the addition of mixed aggregates
2
3
involving sp, sp , and sp organolithium compounds to
aldehydes all seem to involve similar mixed aggregate
intermediates. To check this hypothesis, we determined the
structure of 5b-Li/1-Li in THF.
NMR Study of the Aggregate 5b-Li/1-Li in THF. The
NMR study has been run on the mixture amide 5b-Li + lithium
acetylide 1-Li because it affords higher ees (up to 85%) in
THF, likely to be related to the presence of one major mixed
6
complex. The better sensitivity and resolution provided by Li
6
NMR spectroscopy led us to select Li-labeled derivatives to
12
pursue this study. Note that the preparation of the NMR
samples could not rely on the same protocol employed for the
above alkynylation experiments, since we needed to check and
Figure 2. (left) 13C NMR spectrum of 1/1 5b-Li/1-Li mixed
aggregate in THF-d at 195 K (−78 °C): signal of the acetylide carbon
8
sp
(CLi = C ) at 141.3 ppm. (right) Representation of the N−Li−C−
characterize 5b-Li and 1-Li separately before the formation of
Li quadrilateral core of the complex.
6
any aggregate. Thus, 1 equiv of n-Bu Li in THF-d (1 M) was
8
added to a solution of 5b in THF-d at −20 °C. Next, 1 equiv
8
of 1-Li in the same solvent, prepared from acetylene 1 and n-
suggesting that this carbon seats next to two lithium cations.
From these data, and on the basis of our previous experiences
with comparable systems, we assumed that a 1/1 mixed dimer
organized around a N−Li−C−Li quadrilateral (Figure 2, right)
was the most plausible structure. The magnetic difference
between the two lithium atoms, denoted Li1 and Li , is
supported by a supplementary coordination imposed to one Li
6
Bu Li at −20 °C, was introduced. To keep a good signal/noise
ratio, we worked with concentrations higher (c ≈ 0.2 M) than
those retained for the alkynylation experiments (c = 0.05 M).
We checked that following this protocol instead of that
described in the Experimental Section did not change the
2
20
chemical yield nor the ees.
1
We have adopted the same analytical procedure that we had
set up before for other types of mixed aggregates. First of all,
by the pyrrolidinic nitrogen (Li ).
1
1
The two-dimensional H, H NOESY (Figure 3, left) and
Li, H HOESY (Figure 3, right) spectra have next been
1
6
13
6
1
the H, Li, and C spectra of the labeled n-BuLi, of lithium
amide 5b-Li, and of the acetylide 1-Li were recorded separately
at 195 K (−78 °C). Then, the same experiments were repeated
8
4
registered. The NOESY experiment shows that H is near H ,
4
5
H ′, and H ′, as expected after puckering of the pyrrolidine
1
13
6
1
on the 1/1 mixture. The H and C spectra are gathered in the
core. The arrangement was further detailed, thanks to a Li, H
HOESY experiment (Figure 3, right), which exhibits
6
Figures S1 and S2 in the Supporting Information, and the Li
2
2
spectra are displayed in Figure 1.
correlations between Li and both bridgehead H protons.
These data suggest that the acetylide lies along the convex face
of the aza-norbornyl-like structure adopted by the amide.
6
The Li data show that the amide and acetylide signals
(
characterized by one singlet at δ 1.63 and 0.44 ppm,
1
respectively) vanish and are replaced by two signals of similar
Finally, a series of H DOSY experiments (see Figures S4−
6
intensities at 1.19 and 0.83 ppm. A monodimensional Li
S7 and Tables S1 and S2 in the Supporting Information) were
run to verify the aggregation state and evaluate the solvation of
these species. This spectroscopy, carried out with five internal
references (squalene, 1,3,5-triphenylbenzene, cyclododecene,
INADEQUATE spectrum (Figure S3 in the Supporting
Information) shows that these two signals are coupled.
Therefore, 5b-Li and 1-Li lead to a product that includes
two distinct lithium atoms (Li1 and Li ) in the same
proportions.
2
THF-d , and butane), was first applied to the lithium acetylide
7
alone (1-Li), for which solvation in THF was unknown. The
DOSY leads to MW 369, confirming a dimeric structure (MW
13
The C spectrum of the 5b-Li/1-Li mixture exhibits a signal
15,16
at 141.3 ppm, characteristic of the lithiated acetylide carbon. It
214),
associated with 1.9 THF. With regard to the complex,
1
appears as a quintet (Figure 2, left) with J
= 8.7 Hz,
the DOSY led to MW 378, a result in accordance with a 1/1
C−Li
C
DOI: 10.1021/acs.organomet.5b00647
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1
1
6
1
Figure 3. 2D NMR spectra of 1/1 5b-Li/1-Li mixed aggregate in THF-d at 195 K (−78 °C): H, H NOESY (left) and Li, H HOESY (right).
8
5
b-Li/1-Li mixed aggregate (MW 315) solvated by 0.9
which fully matches the above NMR data, is not unexpected,
since comparable arrangements have been proposed before
molecule of THF.
22
12,13b,23
DFT Calculations on the Aggregate 5b-Li/1-Li in THF.
DFT calculations were complementarily undertaken to better
understand the organization of the complex and in particular
the orientation of the acetylide that can hardly be deduced from
the NMR technique (see the Theoretical Details). On the basis
from experimental or theoretical
descriptions. It is
worth noting that the solvent exerts an important effect on the
geometry of the acetylide orientation, since previous calcu-
lations run on unsolvated oligomeric propynyllithium evi-
21c
denced the CC−Li bond alignment. We also tried to take
21
of the above NMR data and extensive DFT studies run before
into account the bulk solvent by testing the additional influence
24
3
2
on mixed aggregates between 3APLi and sp , sp , and sp
organolithium entities, we performed our optimizations from
starting points built around a folded lithium amide leading to a
N−Li−C−Li quadrilateral arrangement (Figure 2, right). We
then explored a conformational space involving systematic
rotations (θ = 0, 120, 240°) around the lateral α-
methylbenzylamino chain, combined with the two possible
initial orientations of the acetylide group (Li −CC or Li −
CC = 180°). The results below correspond to the optimal
situations.
Although the DOSY experiment clearly suggested mono-
solvation, this observation could also result from the average
between the contributions of nonsolvated and poorly solvated
entities. Therefore, we considered all the complexes [5b-Li/1-
Li]·nTHF (with n = 0−3) in our computational studies. Upon
optimization, all of these mixed aggregates led to a
conformation in which the lateral chiral appendage is oriented
in a fashion such that the phenyl ring lies on the outside of the
of an implicit PCM. No significant alteration of the structures
or of the energies of the series of complexes was observed,
while the computations were significantly slowed down by this
extra solvation step. With regard to the relative stabilities
between the above stabilized solvated complexes, the solvation
sol
free energies corresponding to ΔG have been calculated at
1
95 K (−78 °C). Overall, the results are in agreement with the
1
2
DOSY experiments, since the sole monosolvation by THF is
significantly exergonic. Note that recent mass spectrometry
results on a comparable aggregate also suggest that a
2
5
monosolvated complex prevails in the gas phase.
CONCLUSION
■
The results presented here show that 3-aminopyrrolidine
lithium amides can be employed as chiral auxiliaries for the
enantioselective alkynylation of aromatic aldehydes, providing
propargylic alcohols in ees up to 85% in THF at −78 °C.
Considering the simplicity of the experimental conditions, this
system represents one of the most efficient involving lithium
acetylides. The formation of a 1/1 noncovalent mixed
aggregate, mainly solvated by one THF, could be proposed
on the basis of a series of NMR experiments. This result is
12,13b
complex, as noted before for other aggregates.
With regard
to the acetylide orientation, the results indicate that, whatever
the solvation state, the triple bond lies midway between the two
lithium cations (Li−CC ≈ 120°, Figure 4). This geometry,
D
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distilled over sodium and benzophenone. Toluene was distilled from
sodium. pentane was purified by distillation over calcium hydride. All
aldehydes were purified as follows: after dilution in CH Cl and
2
2
washings with saturated aqueous NaHCO and H O, the solutions
3
2
were dried (MgSO ), concentrated (rotavap), and distilled under
4
vacuum in the presence of a small amount of powdered K CO . Then,
2
3
the purified aldehydes were stored in glass ampules under argon in the
6
dark. Li (95% purchased from Sigma-Aldrich) was washed in freshly
distilled pentane prior to use. 1,3,5-Triphenylbenzene (TPB),
cyclododecene (CDD), and squalene (SQA) were used as internal
references for DOSY experiments without purification. Reactions were
monitored by thin-layer chromatography (TLC) carried out on Merck
0
.25 mm silica gel coated aluminum plates using UV light at 254 nm as
the visualizing agent and aqueous KMnO4 solution followed by
heating as a developing agent. E. Merck silica gel (60, particle size
0
.040−0.063 mm) was used for flash column chromatography.
1 13 19
Routine H, C, and F NMR spectra were recorded at room
temperature on a Bruker Avance DMX-300 spectrometer at 300 MHz,
7
1
13
5, and 282 MHz, respectively. Calibrations of H and C NMR
spectra were obtained with the use of an internal reference derived by
residual undeuterated solvent: the solvent was always deuteriochloro-
1
form (CDCl ) with a calibration at 7.26 ppm for H spectra and 77.16
3
ppm for 13C spectra. Chemical shifts (δ) are given in parts per million
(ppm) and the coupling constants (J) in hertz (Hz). The following
abbreviations were used to designate the multiplicities: s = singlet, d =
doublet, t = triplet, m = multiplet, and br = broad. The specific NMR
experiments of the lithiated intermediates were acquired at 195 K
(
−78 °C) on a Bruker AVIII 500 spectrometer operating at 500.13
1 13 6
MHz for H, 125.13 MHz for C, and 73.60 MHz for Li.
Experiments were run under TopSpin (version 3.2, Bruker Biospin,
Karlsruhe, Germany) with a BBFO{ H,X} probe and a z-gradient coil
giving a maximum gradient of 50 G cm . H and C chemical shifts
were referenced to the residual solvent signals of THF-d (δ 1.73 ( H)
1
−1
1
13
1
Figure 4. Optimized structures of the [5b-Li/1-Li]·nTHF complexes
8
sol
13
(
n = 0−3). The solvation free energies are taken as ΔG = G[cpx-
and 25.31 ppm ( C)). Lithium spectra were referenced to external 0.3
M LiCl solution in THF-d (δ 0.0). IR spectra were recorded by
6
THF ] − G[cpx-THF ] − G[THF], where cpx stands for the [5b-
8
n
n−1
Li/1-Li] aggregate.
transmission on a PerkinElmer 16PC IRTF spectrometer with
diamond ATR accessory. High-resolution MS data (EI ionization
mode) were obtained using a JEOL AccuTOF 4G mass spectrometer.
Melting points were measured with a Stuart SMP30 apparatus. Optical
rotations were recorded on a PerkinElmer 341 polarimeter using the
sodium D line (589 nm). Chiral HPLC separations were performed on
a Thermo Scientific SpectraSYSTEM UV100 instrument. The columns
and the conditions are specified case by case. The commercially
available n-BuLi solution (1,6 M in hexanes) and the synthesized
perfectly in line with several studies we have performed
12,13
previously on similar systems.
DFT computations confirm
that (i) such a complex corresponds to a local energy
minimum, (ii) the acetylide group lies midway between the
two lithium cations, and (iii) one molecule of THF binds
exothermically to one of the lithiums. Studying the reactivity of
this aggregate toward aldehydes by NMR is expected to be
lithium-6 n-BuLi solutions (in pentane and in THF-d
) were titrated
8
26
27
using a procedure reported by Duhamel. The 3-aminopyrrolidines
tedious, because monitoring a fast reaction is very difficult.
1
2
5
a−c were synthesized as reported in the literature.
Procedures for the Alkynylation Reactions and Data
However, within the limits of the Curtin−Hammett principle,
which implies that the enantioselectivity is determined by the
relative energies of the transition states, one can assume that
this entity is involved in the kinetically determining step of the
Characterizing the Final Propargylic Alcohols. Typical Proce-
dure for the Alkynylation of o-Tolualdehyde in the Presence of 5a-
Li−5c-Li/1-Li−4-Li Mixed Aggregates. 3APLi 5a-Li (3S), 5b-Li
(3S,8R), and 5c-Li (3S,8S) as well as lithium acetylides 1-Li−4-Li
were simultaneously prepared by addition of a solution of n-BuLi (1.6
M in hexanes; 1.0 mL, 1.50 mmol) to a mixture of the amines 5a−c
12
reaction, as proposed in earlier papers. The whole work
demonstrates that, whatever the hybridization of the lithiated
3
2
carbon (sp , sp , sp), the structure and the level of
enantioselectivity are comparable (see previous results on
(0.75 mmol) and the corresponding acetylenes (phenylacetylene 1,
12
13
14
tert-butylacetylene 2, cyclopropylacetylene 3, and trimethylsilylacety-
aggregates of 5-Li and n-BuLi, Vinyl-Li, or PhLi ). The 3-
aminopyrrolidine lithium amides can thus be considered as
universal auxiliaries for the enantioselective 1,2-addition of
organolithium reagents on aromatic aldehydes.
lene 4; 0.75 mmol) in anhydrous solvents (THF, toluene, or Et O 15
2
mL) at −20 °C under an argon atmosphere. The reaction mixture was
stirred at this temperature for the first 30 min and at −78 °C for the
following 30 min. Then, a solution of o-tolualdehyde 6 (0.5 mmol) in
the same solvent (THF, toluene, and Et O, respectively; 2 mL) was
2
EXPERIMENTAL SECTION
added for a 5 min period, and after 3 h, the reaction was quenched
with 3 N aqueous HCl (10 mL). The medium was warmed to room
temperature, and the resulting acidic aqueous layer was extracted with
■
General Considerations. All synthetic and spectroscopic
manipulations were carried out under an atmosphere of anhydrous
and deoxygenated argon in flame- or oven-dried glassware. Argon was
dried and deoxygenated by bubbling through a commercial solution of
n-BuLi in hexanes. All solvents and reagents were purchased from
commercial sources at the highest commercial quality and used
without further purification, unless otherwise stated. Tetrahydrofuran
Et
O (3 × 15 mL). The organic layers were combined, washed with
2
aqueous saturated NaHCO
(2 × 10 mL) and then brine (1 × 10 mL),
3
dried (MgSO ), filtered, and concentrated. The resulting alcohols (7−
4
10) were purified by flash column chromatography. The 3-amino-
pyrrolidines 5a−c, instead, were recovered, after reaction, with a
treatment of the acidic aqueous phases with 4 M NaOH until pH >10
(
THF), diethyl ether (Et O), and tetrahydrofuran-d (THF-d ) were
2
8
8
E
DOI: 10.1021/acs.organomet.5b00647
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
and a following extraction with CH Cl (3 × 10 mL). The combined
saturated NaHCO (2 × 10 mL) and then brine (1 × 10 mL), dried
2
2
3
organic layers were then washed with brine and dried over MgSO4,
and the solvent was removed under vacuum, giving the recovered 5a−
c as pale yellow oils in good yields.
(MgSO ), filtered, and concentrated. The resulting alcohols (24−36)
4
were purified by flash column chromatography. The 3-amino-
pyrrolidine 5b, instead, was recovered, after reaction, by means of a
treatment of the acidic aqueous phases with 4 M NaOH until pH >10
and a following extraction with CH Cl (3 × 10 mL). The combined
2
a,5e,n,28
3
-Phenyl-1-o-tolylprop-2-yn-1-ol (7).
Purification of crude
7
by column chromatography (pentane/Et O 10/1) gave the pure
2
2
2
product as a white solid; mp 45−47 °C. The yield and ee are gathered
organic layers were washed with brine and dried over MgSO , and the
4
in Table 1. The ee values were determined by HPLC analyses
solvent was removed under vacuum to give the recovered 5b as a pale
−
1
(
Chiracel OD-H 250 × 4.6 mm 5 μL column, flow 1 mL min ,
yellow oil in good yield.
1,3-Diphenylpro-2-yn-1-ol (24).
2a,5e,n,31−34
mobile phase n-heptane/2-propanol 95/5, 254 nm). Retention times:
0.00 min (R enantiomer) and 24.00 min (S enantiomer). H NMR
Purification of crude
1
1
24 by column chromatography (pentane/Et O 10/1) gave the pure
2
(
7
3
300 MHz, CDCl , 298 K (=25 °C)): δ 7.75−7.72 (m, 1H), 7.49−
product as a colorless oil. The yield and ee are gathered in Table 2.
3
.46 (m, 2H), 7.35−7.20 (m, 6H), 5.85 (d, J = 5.4 Hz, 1H), 2.51 (s,
The ee value was determined by HPLC analysis (Chiracel OD-H 250
H), 2.20 (br d, J = 5.4 Hz, 1H). 13C NMR (75 MHz, CDCl , 298 K
× 4.6 mm 5 μL column, flow 1 mL min , mobile phase n-heptane/2-
−1
3
(
(
2
=25 °C)): δ 138.5, 136.2, 131.9 (2C), 131.0, 128.7, 128.6, 128.4
propanol 90/10, 254 nm). Retention times: 11.77 min (R enantiomer)
and 17.35 min (S enantiomer). [α]D20 = +1.78° (c = 1.11, CHCl ). H
1
2C), 126.7, 126.4, 122.7, 88.7, 86.7, 63.2, 19.2. IR (neat): 3320, 2977,
3
−1
190, 1600, 1488, 1460, 1014, 764, 734 cm . HRMS-EI (m/z): calcd
NMR (300 MHz, CDCl , 298 K (=25 °C)): δ 7.65−7.62 (m, 2H),
3
13
for C H O 222.1045, found 222.1034.
7.51−7.31 (m, 8H), 5.71 (s, 1H), 2.49 (br s, 1H). C NMR (75 MHz,
1
6
14
2
9
4
,4-Dimethyl-1-o-tolylpent-2-yn-1-ol (8). Purification of crude 8
CDCl , 298 K (=25 °C)): δ 140.8, 131.9 (2C), 128.8 (2C), 128.7,
3
by column chromatography (pentane/Et O 10/1) gave the pure
product as a white solid; mp 37−38 °C. The yield and ee are gathered
in Table 1. The ee values were determined by HPLC analyses
128.6, 128.4 (2C), 126.9 (2C), 122.5, 88.8, 86.8, 65.2. IR (neat): 3327,
2
−1
3060, 3020, 2193, 1600, 1489, 1443, 1030, 960, 754, 689 cm .
HRMS-EI (m/z): calcd for C H O 208.0888, found 208.0880.
1
5
12
−1
28b−f,h,34
(
Chiralpak AD-H 250 × 4.6 mm 5 μL column, flow 1 mL min ,
3-Phenyl-1-m-tolylpro-2-yn-1-ol (25).
Purification of
mobile phase n-heptane/2-propanol 95/5, 220 nm). Retention times:
4
crude 25 by column chromatography (pentane/Et O 10/1) gave the
2
1
.85 and 5.59 min. H NMR (300 MHz, CDCl , 298 K (=25 °C)): δ
pure product as a colorless oil. The yield and ee are gathered in Table
3
7
(
.66−7.63 (m, 1H), 7.24−7.16 (m, 3H), 5.59 (d, J = 5.7 Hz, 1H), 2.45
2. The ee value was determined by HPLC analysis (Chiracel OD-H
s, 3H), 1.96 (br d, J = 5.4 Hz, 1H), 1.26 (s, 9H). 13C NMR (75 MHz,
250 × 4.6 mm 5 μL column, flow 1 mL min , mobile phase n-
−1
CDCl , 298 K (=25 °C)): δ 139.1, 136.3, 130.8, 128.3, 126.6, 126.2,
9
1
heptane/2-propanol 90/10, 254 nm). Retention times: 9.06 min (R
3
20
5.8, 78.3, 62.8, 31.1 (3C), 27.7, 19.1. IR (neat): 3313, 2968, 2240,
enantiomer) and 17.65 min (S enantiomer). [α]D = +2.81° (c = 1.21,
−1
1
600, 1461, 1362, 1262, 1063, 1005, 746, 727 cm . HRMS-EI (m/z):
CHCl ). H NMR (300 MHz, CDCl , 298 K (=25 °C)): δ 7.53−7.46
3
3
calcd for C H O 202.1358, found 202.1352.
(m, 4H), 7.34−7.31 (m, 4H), 7.23−7.21 (m, 1H), 5.67 (d, J = 6.0 Hz,
14
18
3
-Cyclopropyl-1-o-tolylprop-2-yn-1-ol (9). Purification of crude 9
1H), 2.38 (s, 3H) 2.26 (d, J = 6.0 Hz, 1H). 13C NMR (75 MHz,
by column chromatography (pentane/Et O 10/1) gave the pure
product as a colorless oil. The yield and ee are gathered in Table 1.
CDCl , 298 K (=25 °C)): δ 140.7, 138.4, 131.8 (2C), 129.1, 128.6,
2
3
128.5, 128.3 (2C), 127.5, 123.9, 122.6, 89.0, 86.5, 65.1, 21.5. IR (neat):
−1
The ee values were determined by HPLC analyses (Chiralpak AD-H
3319, 3054, 2225, 1607, 1489, 1442, 1030, 754, 689 cm . HRMS-EI
−
1
2
50 × 4.6 mm 5 μL column, flow 1 mL min , mobile phase n-
(m/z): calcd for C H O: 222.1045, found 222.1035.
3-Phenyl-1-p-tolylpro-2-yn-1-ol (26).
16
14
2
a,5n,28b−i,32,34
heptane/2-propanol 95/5, 220 nm). Retention times: 9.23 and 13.63
Purification of
1
min. H NMR (300 MHz, CDCl , 298 K (=25 °C)): δ 7.69−7.66 (m,
crude 26 by column chromatography (pentane/Et O 10/1) gave the
3
2
1
(
H), 7.31−7.20 (m, 3H), 5.61 (d, J = 5.1 Hz, 1H), 2.48 (s, 3H), 2.14
pure product as a white solid; mp 46−48 °C. Yield and ee are gathered
13
br d, J = 5.1 Hz, 1H), 1.41−1.31 (m, 1H), 0.88−0.74 (m, 4H).
C
in Table 2. The ee value was determined by HPLC analysis (Chiracel
−1
NMR (75 MHz, CDCl , 298 K (=25 °C)): δ 139.1, 136.0, 130.8,
OD-H 250 × 4.6 mm 5 μL column, flow 1 mL min , mobile phase n-
3
1
3
28.3, 126.5, 126.4, 90.5, 75.0, 62.7, 19.1, 8.4 (2C), − 0.31. IR (neat):
heptane/2-propanol 80:20, 254 nm). Retention times: 5.79 min (R
20
333, 3013, 2233, 1600, 1487, 1461, 1044, 980, 764, 890, 753, 734
enantiomer) and 8.85 min (S enantiomer). [α]D = +2.33° (c = 1.03,
−1
1
cm . HRMS-EI (m/z): calcd for C H O 186.1045, found 186.1050.
CHCl ). H NMR (300 MHz, CDCl , 298 K (=25 °C)): δ 7.53−7.46
13
14
3
3
3
0
3
-Trimethylsilyl-1-o-tolylprop-2-yn-1-ol (10). Purification of
(m, 4H), 7.34−7.31 (m, 3H) 7.23−7.21 (m, 2H), 5.66 (d, J = 6.0 Hz,
crude 10 by column chromatography (pentane/Et O 20/1) gave the
1H) 2.38 (s, 3H), 2.26 (d, J = 6.0 Hz, 1H). 13C NMR (75 MHz,
2
pure product as a colorless oil. The yield and ee are gathered in Table
CDCl , 298 K (=25 °C)): δ 138.2, 137.9, 131.8 (2C), 129.3 (2C),
3
1
. The ee values were determined by HPLC analyses (Chiracel OD-H
128.5, 128.3 (2C), 126.8 (2C), 122.6, 89.1, 86.4, 64.9, 21.2. IR (neat):
−1
−1
2
50 × 4.6 mm 5 μL column, flow 1 mL min , mobile phase n-
3320, 3054, 2865, 2228, 1597, 1489, 1030, 818, 754, 690 cm .
heptane/2-propanol 98/2, 254 nm). Retention times: 9.90 and 11.45
HRMS-EI (m/z): calcd for C H O 222.1045, found 222.1040.
1
6
14
1
35
min. H NMR (300 MHz, CDCl , 298 K (=25 °C)): δ 7.67−7.64 (m,
1-(2,6-Dimethylphenyl)-3-phenylprop-2-yn-1-ol (27). Purifica-
3
1
(
H), 7.25−7.17 (m, 3H), 5.60 (d, J = 6.0 Hz, 1H), 2.45 (s, 3H), 2.15
tion of crude 27 by column chromatography (pentane/Et O 10/1)
2
d, J = 6.0 Hz, 1H), 0.20 (s, 9H). 13C NMR (75 MHz, CDCl , 298 K
gave the pure product as a white solid; mp 76−78 °C. The yield and ee
3
(
=25 °C)): δ 138.2, 136.3, 130.9, 128.6, 126.7, 126.3, 104.9, 91.6, 63.1,
are gathered in Table 2. The ee value was determined by HPLC
−1
1
8
2
9.1, 0.0 (3C). IR (neat): 3327, 2959, 2173, 1600, 1462, 1249, 1038,
analysis (Chiralpak IC 250 × 4.6 mm 5 μL column, flow 1 mL min ,
mobile phase n-heptane/2-propanol 99/1, 254 nm). Retention times:
20.53 min (major enantiomer) and 24.67 min (minor enantiomer).
[α]D20 = −10.20° (c = 0.98, CHCl ). H NMR (300 MHz, CDCl , 298
−1
38, 749 cm . HRMS-EI (m/z): calcd for C H OSi 218.1127, found
13
18
18.1124.
Typical Procedure for the Alkynylation of Aldehydes 11−23 in
1
3
3
the Presence of the 5b-Li/1-Li Mixed Aggregate. 3APLi 5b-Li and
lithium acetylide 1-Li were simultaneously prepared by addition of a
solution of n-BuLi (1.6 M in hexanes; 1.0 mL, 1.50 mmol) to a mixture
of the amine 5b (153 mg, 0.75 mmol) and phenylacetylene 1 (76.6
mg, 0.75 mmol) in anhydrous THF at −20 °C under an argon
atmosphere. The reaction mixture was stirred at this temperature for
the first 30 min and at −78 °C for the following 30 min. Then, a
solutions of aldehydes 11−23 (0.5 mmol) in dry THF (2 mL) were
added for a 5 min period and, after 3 h, the reaction was quenched
with 3 N aqueous HCl (10 mL). The medium was warmed to room
K (=25 °C)): δ 7.45−7.42 (m, 2H), 7.32−7.28 (m, 3H), 7.16−7.11
(m, 1H), 7.07−7.05 (m, 2H), 6.16 (d, J = 3.9 Hz, 1H), 2.61 (s, 6H),
2.15 (d, J = 3.9 Hz, 1H). 13C NMR (75 MHz, CDCl , 298 K (=25
3
°C)): δ 136.8 (2C), 136.5, 131.8 (2C), 129.4 (2C), 128.5, 128.4 (2C),
128.3, 122.8, 88.7, 86.0, 61.1, 20.6 (2C). IR (neat): 3200, 3070, 2140,
−1
1587, 1488, 1306, 1175, 1044, 754, 687 cm . HRMS-EI (m/z): calcd
for C H O 221.0966, found 221.0964.
16
13
1 - ( 2 - M e t h o x y p h e n y l ) - 3 - p h e n y l p r o p - 2 - y n - 1 - o l
2
a,5e,n,28a,d,e,h,i,32−34
(28).
Purification of crude 28 by column
chromatography (pentane/Et O 5/1) gave the pure product as a
2
temperature, and the resulting aqueous layer was extracted with Et O
white solid; mp 48−50 °C. The yield and ee are gathered in Table 2.
The ee value was determined by HPLC analysis (Chiracel OD-H 250
2
(
3 × 15 mL). The organic layers were combined, washed with aqueous
F
DOI: 10.1021/acs.organomet.5b00647
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
−
1
−1
×
4.6 mm 5 μL column, flow 1 mL min , mobile phase n-heptane/2-
min , mobile phase n-heptane/2-propanol 90:10, 254 nm). Retention
2
0
propanol 90/10, 254 nm). Retention times: 13.32 min (R enantiomer)
times: 7.78 min (R enantiomer) and 20.28 min (S enantiomer). [α]D
= +4.59° (c = 1.11, CHCl ). H NMR (300 MHz, CDCl , 298 K (=25
and 16.10 min (S enantiomer). [α]D20 = −9.19° (c = 1.23, CHCl ). H
1
1
3
3
3
NMR (300 MHz, CDCl , 298 K (=25 °C)): δ 7.66 (dd, J = 9.0 and 3.0
°C)): δ 7.56−7.52 (m, 2H) 7.49−7.46 (m, 2H), 7.38−7.31 (m, 5H),
3
Hz, 1H), 7.51−7.48 (m, 2H) 7.37−7.30 (m, 4H), 7.02 (td, J = 9.0, 3.0
5.66 (d, J = 6.0 Hz, 1H), 2.65 (d, J = 6.0 Hz, 1H). 13C NMR (75 MHz,
Hz, 1H), 6.94 (dd, J = 9.0 and 3.0 Hz, 1H), 5.96 (d, J = 6.0 Hz, 1H),
CDCl , 298 K (=25 °C)): δ 139.2, 134.3, 131.9 (2C), 128.9 (3C),
128.5 (2C), 128.2 (2C), 122.2, 88.4, 87.1, 64.5. IR (neat): 3300, 3056,
2228, 1597, 1489, 1089, 1014, 753, 689 cm . HRMS-EI (m/z): calcd
3
1
3
3
2
(
3
.92 (s, 3H), 3.15 (d, J = 6.0 Hz, 1H). C NMR (75 MHz, CDCl3,
98 K (=25 °C)): δ 157.0, 131.9 (2C), 129.8, 128.9, 128.5, 128.3
−1
35
2C), 128.1, 122.9, 121.0, 111.0, 88.5, 86.2, 61.7, 55.7. IR (neat): 3380,
054, 2938, 2229, 1600, 1489, 1240, 1027, 705, 690 cm . HRMS-EI
for C H ClO 242.0498, found 242.0505.
15 11
−1
28f
1-(4-(Trifluoromethyl)phenyl)-3-phenylprop-2-yn-1-ol (34). Pu-
(
m/z): calcd for C H O 238.0994, found 238.0994.
rification of crude 34 by column chromatography (pentane/Et O 10/
16
14
2
2
2
a,28b,d,e,h,32−34
1
-(3-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (29).
1) gave the pure product as a white solid; mp 33−35 °C. The yield
and ee are gathered in Table 2. The ee value was determined by HPLC
analysis (Chiracel OD-H 250 × 4.6 mm 5 μL column, flow 1 mL
Purification of crude 29 by column chromatography (pentane/Et O 5/
2
1
) gave the pure product as a white solid; mp 40−42 °C. The yield
−1
and ee are gathered in Table 2. The ee value was determined by HPLC
min , mobile phase n-heptane/2-propanol 90:10, 254 nm). Retention
−1
20
analysis (Chiralpak IC 250 × 4.6 mm 5 μL column, flow 1 mL min ,
mobile phase n-heptane/2-propanol 95/5, 254 nm). Retention times:
1
times: 7.14 min (R enantiomer) and 28.14 min (S enantiomer). [α]D
1
= +2.70° (c = 1.11, CHCl ). H NMR (300 MHz, CDCl , 298 K (=25
3
3
20
D
0.49 min (R enantiomer) and 12.30 min (S enantiomer). [α]
=
°C)): δ 7.75−7.72 (m, 2H) 7.68−7.65 (m, 2H) 7.49−7.46 (m, 2H),
1
+
8.30° (c = 1.12, CHCl ). H NMR (300 MHz, CDCl , 298 K (=25
7.35−7.33 (m, 3H), 5.75 (d, J = 6.0 Hz, 1H), 2.63 (d, J = 6.0 Hz, 1H).
3
3
1
3
°C)): δ 7.50−7.46 (m, 2H), 7.35−7.30 (m, 4H), 7.22−7.19 (m, 2H),
C NMR (75 MHz, CDCl , 298 K (=25 °C)): δ 144.6, 132.0 (2C),
3
2
1
6
6
1
8
1
2
.92−6.88 (m, 1H), 5.67 (d, J = 6.0 Hz, 1H), 3.84 (s, 3H), 2.37 (d, J =
1
30.7 (q, J
= 32.5 Hz), 129.7 (q, J
= 270.5 Hz), 129.1, 128.6
C−F
C−F
.0 Hz, 1H). 13C NMR (75 MHz, CDCl , 298 K (=25 °C)): δ 159.9,
3
3
(2C), 127.2 (2C), 125.8 (q, J
6
(
= 3.8 Hz, 2C), 122.2, 88.2, 87.5,
C−F
4.6. 19F NMR (282 MHz, CDCl , 298 K) δ: −62.54 (s, 3F). IR
−1
42.4, 131.9 (2C), 129.8, 128.7, 128.4 (2C), 122.5, 119.1, 114.2, 112.3,
8.8, 86.6, 65.1, 55.4. IR (neat): 3368, 3055, 2939, 2227, 1599, 1489,
3
neat): 3373, 2935, 2199, 1645, 1620, 1322, 1065, 756, 688 cm .
−1
255, 1031, 754, 689 cm . HRMS-EI (m/z): calcd for C H O
16
14
2
HRMS-EI (m/z): calcd for C H F O 276.0762, found 276.0751.
1
6
11 3
2
a,5n,28a,d,e,g,h,34
38.0994, found 238.0982.
-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (30).
Purification of crude 30 by column chromatography (pentane/Et O 5/
1
-(Naphthalen-5-yl)-3-phenylprop-2-ny-1-ol (35).
5
n,28a−f,h,i,32−34
1
Purification of crude 35 by column chromatography (pentane/Et O
2
2
10/1) gave the pure product as a yellow solid; mp 72−74 °C. The
yield and ee are gathered in Table 2. The ee value was determined by
HPLC analysis (Chiracel OD-H 250 × 4.6 mm 5 μL column, flow 1
1
) gave the pure product as a white solid; mp 70−71 °C. The yield is
1
indicated in Table 2. H NMR (300 MHz, CDCl , 298 K (=25 °C)): δ
7
6
3
−1
.56−7.54 (m, 2H) 7.49−7.47 (m, 2H), 7.34−7.31 (m, 3H), 6.95−
mL min , mobile phase n-heptane/2-propanol 80:20, 254 nm).
Retention times: 8.70 min (R enantiomer) and 13.75 min (S
.92 (m, 2H), 5.64 (d, J = 6.3 Hz, 1H), 3.82 (s, 3H), 2.39 (d, J = 6.3
13
3
enantiomer). [α]D20 = −27.43° (c = 1.05, CHCl ). H NMR (300
1
Hz, 1H). C NMR (75 MHz, CDCl , 298 K (=25 °C)): δ 159.8,
3
1
8
1
33.1, 131.9 (2C), 128.7, 128.4 (2C), 128.3 (2C), 122.6, 114.1 (2C),
9.1, 86.6, 64.8, 55.5. IR (neat): 3360, 3070, 2957, 2843, 2243, 1607,
MHz, CDCl , 298 K (=25 °C)): δ 8.40 (d, J = 9.0 Hz, 1H), 7.95−7.86
3
(
(
m, 3H), 7.62−7.48 (m, 5H), 7.36−7.31 (m, 3H), 6.36 (s, 1H), 2.62
−1
br s, 1H). 13C NMR (75 MHz, CDCl , 298 K (=25 °C)): δ 135.8,
515, 1255, 1026, 753, 688 cm . HRMS-EI (m/z): calcd for
3
C H O 238.0994, found 238.0986.
1
6
1
14
2
134.2, 131.9 (2C), 130.7, 129.5, 128.9, 128.7, 128.4 (2C), 126.6, 126.0,
25.4, 124.8, 124.1, 122.6, 88.7, 87.4, 63.5. IR (neat): 3320, 3046,
5
e,n,28b−h,34
-(2-Chlorophenyl)-3-phenylprop-2-yn-1-ol (31).
Puri-
1
fication of crude 31 by column chromatography (pentane/Et O 10/1)
gave the pure product as a colorless oil. The yield and ee are gathered
in Table 2. The ee value was determined by HPLC analysis (Chiracel
OD-H 250 × 4.6 mm 5 μL column, flow 1 mL min , mobile phase n-
heptane/2-propanol 90:10, 254 nm). Retention times: 14.19 min (R
−1
2
2193, 1600, 1489, 1007, 778, 754, 689 cm . HRMS-EI (m/z): calcd
for C H O 258.1045, found 258.1033.
19
14
1
(36).
- ( N a p h t h a l e n - 6 - y l ) - 3 - p h e n y l p r o p - 2 - n y - 1 - o l
−1
2a,28b,d,e,g,h,32−34
Purification of crude 36 by column chromatog-
raphy (pentane/Et O 10/1) gave the pure product as a pale yellow
2
20
enantiomer) and 20.98 min (S enantiomer). [α]D = −7.76° (c =
solid; mp 80−81 °C. The yield and ee are gathered in Table 2. The ee
1
1
7
5
.25, CHCl ). H NMR (300 MHz, CDCl , 298 K (=25 °C)): δ 7.86−
value was determined by HPLC analysis (Chiracel OD-H 250 × 4.6
3
3
−1
.83 (m, 1H), 7.50−7.46 (m, 2H), 7.46−7.39 (m, 1H), 7.35−7.27 (m,
mm 5 μL column, flow 1 mL min , mobile phase n-heptane/2-
propanol 80/20, 254 nm). Retention times: 8.55 min (R enantiomer)
H), 6.05 (d, J = 6.0 Hz, 1H), 2.57 (d, J = 6.0 Hz, 1H). 13C NMR (75
and 18.93 min (S enantiomer). [α]D20 = −5.09° (c = 1.14, CHCl ). H
1
MHz, CDCl , 298 K (=25 °C)): δ 138.1, 133.0, 131.9 (2C), 130.0,
1
(
3
3
29.9, 128.8, 128.6, 128.4 (2C), 127.4, 122.4, 87.7, 86.8, 62.3. IR
NMR (300 MHz, CDCl , 298 K (=25 °C)): δ 8.06 (s, 1H), 7.91−7.85
3
−1
neat): 3320, 3063, 2229, 1600, 1489, 1441, 1030, 744, 689 cm .
(m, 3H), 7.75−7.72 (dd, J = 8.5 and 1.7 Hz, 1H), 7.52−7.49 (m, 4H),
7.49−7.33 (m, 3H), 5.87 (d, J = 6.0 Hz, 1H), 2.36 (d, J = 6.0 Hz, 1H).
35
11
HRMS-EI (m/z): calcd for C H ClO 242.0498, found 242.0490.
15
2
a,28b−f,h,34
13
1
-(3-Chlorophenyl)-3-phenylprop-2-yn-1-ol (32).
Puri-
C NMR (75 MHz, CDCl , 298 K (=25 °C)): δ 138.1, 133.5, 133.4,
3
fication of crude 32 by column chromatography (pentane/Et O 10/1)
2
131.9 (2C), 128.8, 128.7, 128.5 (2C), 128.4, 127.9, 126.5 (2C), 125.7,
gave the pure product as a white solid; mp 34−36 °C. The yield and ee
are gathered in Table 2. The ee value was determined by HPLC
analysis (Chiracel OD-H 250 × 4.6 mm 5 μL column, flow 1 mL
min , mobile phase n-heptane/2-propanol 90/10, 254 nm). Retention
times: 7.93 min (R enantiomer) and 22.92 min (S enantiomer). [α]D
1
9
2
24.8, 122.6, 88.8, 87.1, 65.5. IR (neat): 3267, 3060, 2200, 1600, 1489,
−1
95, 863, 825, 750 cm . HRMS-EI (m/z): calcd for C H O
1
9
14
58.1045, found 258.1036.
−1
Procedures To Obtain the Lithiated Compounds and
20
Description of the NMR Experiments Used To Characterize
1
6
=
+5.84° (c = 1.13, CHCl ). H NMR (300 MHz, CDCl , 298 K (=25
These Intermediates. [ Li] n-Butyllithium “Salt-Free Solution” in
3
3
12,13b,36,37
°C)): δ 7.63−7.62 (m, 1H) 7.50−7.47 (m, 3H) 7.35−7.32 (m, 5H),
pentane.
Finely cut lithium-6 metal ribbon (0.6 g, 100
5
.67 (br. s, 1H), 2.49 (br. s, 1H). 13C NMR (75 MHz, CDCl , 298 K
=25 °C)): δ 142.7, 134.6, 131.9 (2C), 130.0, 128.9, 128.6, 128.5
mmol), 0.5% (weight) of sodium (ca. 3,0 mg, 0,12 mmol), and some
small pieces of broken glass were introduced into a two-necked pear-
shaped flask (100 mL) equipped with a glass stopper and a condenser
fitted with a balloon of dry argon. The metallic cuttings were covered
with octadecane (10 g), and the solution was heated (reflux of
octadecane 317 °C) with a hot air gun with vigorous stirring. When a
maximum amount of the lithium was melted, the flask was placed in a
cold bath (−40 °C), allowing the lithium to precipitate as a fine shiny
shot. The octadecane was pumped off with a syringe, and the residue
was washed with freshly distilled pentane (15 mL). After intense
3
(
(
2
2C), 127.0, 125.0, 122.2, 88.2, 87.2, 64.5. IR (neat): 3307, 3059,
−1
228, 1597, 1490, 1426, 1187, 1015, 754, 688 cm . HRMS-EI (m/z):
35
calcd for C H ClO 242.0498, found 242.0493.
15
11
2
a,5n,28a,c−h,32−34
1
-(4-Chlorophenyl)-3-phenylprop-2-yn-1-ol (33).
Purification of crude 33 by column chromatography (pentane/Et O
1
and ee are gathered in Table 2. The ee value was determined by HPLC
analysis (Chiracel OD-H 250 × 4.6 mm 5 μL column, flow 1 mL
2
0/1) gave the pure product as a white solid; mp 51−52 °C. The yield
G
DOI: 10.1021/acs.organomet.5b00647
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
stirring, the pentane was removed and the metal was washed twice
with this same solvent. The condenser was quickly replaced by a
septum, and a new 10 mL amount of pentane was introduced. Then, a
solution of freshly distilled n-bromobutane (4.3 mL, 40 mmol) in
pentane (12 mL) was syringed at room temperature over a 30 min
period. The resulting reaction mixture was stirred for 20 h at room
temperature under dry argon. The hydrocarbon solution was then
pumped out of the flask with a syringe and directly inserted into
centrifugation tubes placed under dry argon. The LiBr salt was
centrifuged, and the clear final solution was collected in a dry flask
flushed under dry argon and then titrated (1.0 to 1.5 M) and kept until
further use.
gradient pulse. Data were accumulated by linearly varying the diffusion
encoding gradients over a range from 2 to 95% for 16 gradient
increment values.
DOSY Processing. Processing of NMR data was performed using
Topspin, the constructor’s program (Bruker), and the diffusion
coefficient was measured with a T1/T2 relaxation module.
Theoretical Details. DFT computations were run with the B3P86
functional using the 6-31++G** basis set and Jaguar 7.6 software, in
1
3b
line with the procedure in our previous papers.
The computed
energies were corrected by the zero-point energy (ZPE) from
frequency calculations computed at the same theoretical level. The
implicit solvation model retained was the PCM Poisson−Boltzmann
6
12,13b,36,37
24
[
Li] n-Butyllithium “Salt-Free Solution” in THF-d .
A
continuum implemented in Jaguar 7.6. Thermodynamic properties
8
6
solution of [ Li] n-butyllithium in pentane prepared above (2.5 mL)
was syringed into a tube fitted with a septum and flushed under dry
argon. The tube was then placed under vacuum (20 mmHg) for 1 h to
evaporate the pentane. The resulting dense yellowish oil was then
were calculated with the assumption that the gas is ideal. The solvation
free energies were computed at the hypothetical standard states at 195
sol
K as ΔG = G[cpx-THF ] − G[cpx-THFn−1] − G[THF], cpx
n
denoting the [5b-Li/1-Li] aggregate.
dissolved in freshly distilled THF-d and concentrated under vacuum
8
for another 1 h to evaporate the last traces of pentane. A new volume
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.5b00647.
■
of THF-d8 (3.0−3.5 mL) was finally added at −78 °C, and the
*
S
2
8
resulting solution was titrated (∼1.0 M).
6
[
Li]-Lithium Phenylacelide 1-Li “Salt-Free Solution” in THF-d . A
8
solution of phenylacetylene 1 (57.0 mg, 0.5 mmol) in freshly distilled
THF-d (0.5 mL) was placed in a dry 5 mm NMR tube fitted with a
8
6
septum and flushed under argon. A 1.0 M [ Li] n-BuLi solution (1
NMR spectra of lithium amide, lithium acetylide and
complex 5b-Li/1-Li (PDF)
All xyz coordinates for the 5b-Li/1-Li·nTHF (n = 0−3)
complexes (XYZ)
equiv) in THF-d was added dropwise at −20 °C with a syringe to the
8
above solution (c = 0.7 M). The tube was vigorously shaken and
dropped in the precooled (−78 °C) NMR probe.
6
[
Li]-Lithium 3AP 5b-Li in THF-d Solution. A solution of 3AP 5b
8
(
20.7 mg, 0.1 mmol) in freshly distilled THF-d (0.5 mL) was placed
8
in a dry 5 mm NMR tube fitted with a septum and flushed under
AUTHOR INFORMATION
Corresponding Authors
E-mail for A.H.-M.: anne.harrison@univ-rouen.fr.
E-mail for J.M.: jmaddalu@crihan.fr.
Notes
6
■
argon. A 1.0 M [ Li] n-BuLi solution (1 equiv) in THF-d was added
8
dropwise at −20 °C with a syringe to the above solution. The tube was
vigorously shaken and, after 10 min, it was dropped in the precooled
*
*
(
−78 °C) NMR probe.
6
[
Li]-Lithium 5b-Li/1-Li Mixed Aggregate in THF-d Solution. A 1
8
equiv amount of lithium-6 labeled 1-Li (0.7 M THF-d solution)
8
The authors declare no competing financial interest.
prepared above was placed at −20 °C in a dry 5 mm NMR tube
6
containing a solution of [ Li]-3AP 5b-Li in THF-d . The tube was
8
ACKNOWLEDGMENTS
■
vigorously shaken and, after 10 min, it was dropped in the precooled
GB acknowledges the CNRS for a stipend. The LabEx SynOrg
(ANR-11-LABX-0029) partly supported this work. All
computations have been run on the supercomputers of
CRIHAN (St-Etienne-du-Rouvray). We are also very thankful
for the Region Haute-Normandie for a constant and generous
́
help to these researches through the CRUNCh interregional
network.
(
−78 °C) NMR probe.
1
D NMR Measurements. The proton and lithium one-dimensional
experiments were recorded with standard parameters. In order to
remove 13C− H coupling, the one-dimensional C spectra were
1
13
recorded with broad-band proton decoupling.
6
38
Li INADEQUATE. This method was used to detect scalar coupling
between nonequivalent lithium nuclea in the 5b-Li/1-Li mixed
aggregate. A standard sequence was used with Δ = 0.5 s.
6
1
39
Li/ H HOESY. The following parameters were used for acquiring
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