Steric course of the electrophilic substitution of a lithiocarbanion generated from (S,E)-1-phenylbut-2-en-1-yl diisopropylcarbamate and solvent effects

Article abstract of DOI:10.1002/ejoc.201100970

The effects of electrophiles and solvents on the stereochemistry of electrophilic substitution of a lithiocarbanion generated from (S,E)-1-phenylbut-2-en-1-yl diisopropylcarbamate were examined using various acids and carbon electrophiles. The stereochemical outcomes were influenced by the relative ability of the electrophiles and solvents to coordinate to lithium. The effects of electrophiles and solvents on the stereochemistry of electrophilic substitution of lithiocarbanion generated from (S,E)-1-phenylbut-2-en-1-yl diisopropylcarbamate were examined using various acids and carbon electrophiles. The stereochemical outcomes were influenced by the relative coordination ability of the electrophiles and solvents to a lithium atom. Copyright

Full text of DOI:10.1002/ejoc.201100970

FULL PAPER
DOI: 10.1002/ejoc.201100970
Steric Course of the Electrophilic Substitution of a Lithiocarbanion Generated
from (S,E)-1-Phenylbut-2-en-1-yl Diisopropylcarbamate and Solvent Effects
Hidaka Ikemoto,[a] Michiko Sasaki,[a] Masatoshi Kawahata,[b] Kentaro Yamaguchi,[b] and
Kei Takeda*[a]
Keywords: Reaction mechanisms / Reactive intermediates / Electrophilic substitution / Solvent effects / Carbanions
The effects of electrophiles and solvents on the stereochemis-
try of electrophilic substitution of a lithiocarbanion generated
from (S,E)-1-phenylbut-2-en-1-yl diisopropylcarbamate were
examined using various acids and carbon electrophiles. The
stereochemical outcomes were influenced by the relative
ability of the electrophiles and solvents to coordinate to lith-
ium.
To gain further insight into the generality of the solvent
effects, we became interested in defining the stereochemical
pathway (retention or inversion) of the intermolecular reac-
tion of chiral organolithiums with an electrophile in various
solvents. Regarding the stereochemistry of electrophilic
substitution with relatively configurationally stable benz-
yllithium compounds, considerable stereochemical diver-
gence has been observed that apparently depends on the
electrophile used (Scheme 2).[3] Whereas reactions of a li-
thio-derivative of 3, generated by sBuLi in the presence of
N,N,NЈ,NЈ-tetramethylethylenediamine (TMEDA) with
protic acids, aldehydes, ketones, and esters, occurred with
retention to give 5, reactions with alkyl, silyl, and stannyl
halides occurred with inversion to give ent-5. To rationalize
these results, the authors hypothesized that electrophiles
that are pre-complexed with a lithium cation, such as carb-
onyl compounds, prefer attack from the same side as the
lithium (retention), whereas electrophiles with less ability to
coordinate and with low-lying LUMO, such as alkyl hal-
ides, preferentially attack from the opposite side, which has
increased electron density because of the partially flattened
nature of the carbanion 4.
Introduction
We have recently shown that the configurational stability
of chiral carbanions[1] is greatly affected by the choice of
solvent and additive. This was demonstrated by taking ad-
vantage of the [2,3]-Wittig rearrangement of the 1,3-di-
phenyl-1-propenyloxy-2-propen-1-yl carbanion and its de-
rivatives 1, in which the stability of the intermediate was
estimated on the basis of the extent of chirality transfer to
the products 2 (Scheme 1).[2] It is noteworthy that reactions
performed in tetrahydrofuran (THF), one of the most com-
mon solvents for carbanion reactions, resulted in complete
racemization under all conditions; this is in sharp contrast
to the results obtained in other ethereal and hydrocarbon
solvents, where 67:33 to 93:7 enantiomeric ratios were ob-
served. We also proposed that the dependence of the config-
urational stability of chiral carbanions on the solvent re-
flects the ratio of contact ion pair (CIP) and solvent sepa-
rated ion pair (SIP) that is associated with their solvated
structures.
Scheme 1. Trapping of a chiral carbanion by [2,3]-Wittig rearrange-
ment.
[a] Graduate School of Medical Sciences, Hiroshima University,
1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8553, Japan
Fax: +81-82-257-5184
Scheme 2. Intermolecular reaction of chiral organolithiums with an
electrophile.
E-mail: takedak@hiroshima-u.ac.jp
[b] Tokushima Bunri University,
1314-1 Shido, Sanuki, Kagawa, 769-2193, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100970.
Strohmann and co-workers also showed that the coordi-
nating ability of a solvent to a lithium center plays a signifi-
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K. Takeda et al.
FULL PAPER
cant role in determining the stereochemical course of an tigate the stereochemical course of the reaction and the ef-
electrophilic substitution reaction of a diastereomerically fects of solvent upon it.
enriched benzyllithium compound.[4] Recently, Aggarwal
and co-workers reported that lithiated carbamates under-
went electrophilic substitution with boranes in the opposite
Results
sense of the stereochemical preferences; the reaction de-
pended on the steric bulk of diamine additives such as
TMEDA and sparteine, which were complexed to lithiated
carbamates.[5]
We first conducted the reaction of (S)-6, prepared from
1-phenyl-2-butenol by using Sharpless’ kinetic resolution,
with a carbon electrophile. When (S)-6 was treated with
nBuLi (2 equiv.) in THF at –50 °C for 5 min followed by
addition of benzyl bromide (BnBr; 5 equiv.) and the reac-
tion was stirred at the same temperature for 10 min, benzyl-
ated product 7a was obtained in 72% yield with inversion
of configuration (ret./inv. = 10:90) together with anti-SEЈ-
type product 8 in 21% yield in a 30:70 ratio of (S)-8 to
(R)-8[7] (Table 1, entry 1). In the other four solvent systems
(Table 1, entries 4, 7, 10, and 13), almost the same stereo-
chemical outcomes were observed. Addition of 2 equiv. of
TMEDA proved to have little effect on the stereochemical
outcome of the reaction (Table 1, entries 2, 5, 8, 11, and
14). Although the reactions with ethyl cyanoformate also
proceeded with marked preference for stereoinversion, the
ratio of the retention product increased in solvents other
than THF and N-methylmorpholine (NMM) in compari-
son with those for BnBr (Table 1, entries 9, 12, and 15), and
the corresponding SEЈ-type product was not detected. The
greater configurational stability of the lithiocarbanion of
(S)-6 than expected on the basis of results reported by
Hoppe, and the intrinsically higher kinetic acidity of (S)-
6,[8] makes the system shown in Scheme 3 an appropriate
probe with which to examine the effects of electrophiles and
On the basis of these studies, we decided to examine the
stereochemical course of the reaction of (S)-6 (Scheme 3)
with a variety of electrophiles, and to study the influence of
solvent upon it. In the reaction, an enantiopure carbanion
can be generated under conditions in which it is free of a
diamine ligand owing to its enhanced kinetic acidity, and
the reaction with an electrophile can be conducted without
introducing a possible diastereofacial bias. On the basis of
our previous experience,[6] we felt that even if a double bond
is introduced at the α-position of the carbanion in 3, which
can cause more planarization, the enantiomeric purity
would not be lost before trapping by an electrophile. Conse-
quently, it would provide a better probe with which to inves-
Scheme 3. Reaction of lithiocarbanion (S)-6 with an electrophile.
Table 1. Reaction of lithiocarbanion (S)-6 with a carbon electrophile (El).
Entry
Solvent[a]
El
TMEDA
equiv.
(S)- and (R)-7[b]
(S)- and (R)-8[b]
Yield [%]
ret./inv.
Yield [%]
S/R
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
THF
THF
THF
NMM
NMM
NMM
Et2O
BnBr
BnBr
NCCO2Et
BnBr
BnBr
NCCO2Et
BnBr
BnBr
NCCO2Et
BnBr
BnBr
NCCO2Et
BnBr
–
2
–
–
2
–
–
2
–
–
2
–
–
2
–
72
77
72
64
59
57
56
59
21
45
51
55
54
62
76
10:90
7:93
3:97
0:100
0:100
0:100
1:99
1:99
12:88
4:96
1:99
13:87
4:96
21
15
0
23
32
0
31
30
0
45
39
0
30:70
25:75
–
16:84
6:94
–
9:91
7:93
–
8:92
5:95
–
Et2O
Et2O
CPME
CPME
CPME
MTBE
MTBE
MTBE
33
37
0
8:92
5:95
–
BnBr
NCCO2Et
0:100
15:85
[a] N-methylmorpholine (NMM), CPME (cyclopentyl methyl ether), MTBE (methyl tert-butyl ether). [b] 7a: El = Bn, 7b: El = CO2Et,
8: El = Bn.
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Steric Course of the Electrophilic Substitution of a Lithiocarbanion
solvents on the stereochemical course of the electrophilic Table 3. Reaction of lithiocarbanion (S)-6 with a protonating
agent.
substitution.
In the reaction with acetone, the organolithium showed
distinctly different behavior toward the trapping agent, de-
pending on the solvent used (Table 2). Whereas the reac-
tions in THF and NMM afforded syn-SEЈ-type product 9[9]
exclusively, in other solvents, particularly diethyl ether,
compound (S)-6 protonated with retention of configura-
tion, and was obtained in marked preference to (R)-6. Ace-
tone was indicated as the proton source because no benzyl-
ated products were detected upon the addition of BnBr af-
ter treatment with acetone.
Entry Solvent
Proton source
Time
(S)- and (R)-6
10
[min] Yield [%] ret./inv. Yield [%]
1
2
THF
THF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
5
15
30
60
5[a]
5[a]
5[a]
5[a]
5
5
5
5
5
5
5
5
5
5
5
5
5
43
47
45
38
45
81
77
48
51
57
86
93
90
0
86:14
75:25
60:40
52:48
100:0
99:1
100:0
99:1
90:10
85:15
94:6
96:4
94:6
–
39
39
35
25
36
12
15
40
36
28
–
3
THF
4
THF
5
6
NMM
Et2O
Table 2. Reaction of lithiocarbanion (S)-6 with acetone.
7
8
9
CPME
MTBE
THF
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
diethyl malonate
10
11
12
13
14
15
16
17
18
19
20
21
22
23
NMM
Et2O
CPME
MTBE
THF
NMM diethyl malonate
Et2O diethyl malonate
CPME diethyl malonate
MTBE diethyl malonate
THF
NMM cyclopentadiene
Et2O cyclopentadiene
CPME cyclopentadiene
MTBE cyclopentadiene
–
3
Entry
Solvent
(S)- and (R)-6
Yield [%] ret./inv.
(R)- and (S)-9
75
75
26
34
33
41
32
28
32
36
Yield [%]
R/S
0
–
1
2
3
4
6
THF
NMM
Et2O
CPME
MTBE
0
0
74
58
32
–
–
96:4
95:5
92:8
80
82
21
36
60
87:13
97:3
89:11
71:29
94:6
65
42
47
54
47
53
37
41
98:2
97:3
98:2
38:62
65:35
71:29
53:47
46:54
cyclopentadiene
5
5
Because the results described above indicate that the use
of 2 equiv. of nBuLi at –50 °C for 5 min is sufficient to al-
low complete deprotonation[10] and that racemization aris-
ing from planarization prior to the addition of an electro-
phile occurs only to a negligible extent under the reaction
conditions, we then examined the deprotonation/proton-
ation reactions of (S)-6 using two classes of protonating
agent: oxygen acids (MeOH and CF3COOH) and carbon
acids [diethyl malonate (pKa 13) and cyclopentadiene
(pKa 16)]. The results are shown in Table 3. With pro-
longation of the reaction time prior to the addition of an
electrophile, a noticeable increase in the extent of racemiza-
tion was not observed any of the cases, except for the reac-
tions in THF, in which a gradual loss of the enantiomeric
purity occurred in time, and almost complete loss was ob-
served after 60 min (Table 3, entries 1–4).
[a] Upon addition of MeOH after 15 min, the ratio remained un-
changed.
Determination of Absolute Configuration
Benzylated compound 7a was converted into known diol
11[12] through a three-step sequence involving dihydrox-
ylation, oxidative cleavage of the diol by Pb(OAc)4 followed
by reductive workup, and removal of the carbamoyl group
by treatment with LiAlH4 (Scheme 4); the product showed
In contrast to the results obtained with carbon electro-
philes, protonation with oxygen acids proceeded with essen-
tially complete retention of configuration.[11] In solvents
other than THF, slight increases in the ratio of inversion
were observed by changing the electrophile from MeOH to
CF3COOH, which has less effective coordination to the
lithium cation (Table 3, entries 5–8 and 10–13). In the case
of carbon acids, the two agents gave contrasting results. The
reactions with diethyl malonate, which is capable of preco-
ordinating to the lithium cation, in acyclic ether solvents,
afforded 6 with almost complete retention of configuration
(Table 3, entries 16–18). In contrast, the reaction with cy-
clopentadiene, which does not have a coordinating atom,
led to a striking increase in the amount of stereoinversion
product (R)-6 (Table 3, entries 19–23).
Scheme 4. Determination of absolute configurations of 7.
Eur. J. Org. Chem. 2011, 6553–6557
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K. Takeda et al.
FULL PAPER
S absolute configuration. The absolute configuration of 7b
(El = CO2Et) was determined by X-ray crystallographic
analysis after derivatization into 12.
Discussion
A basic premise applied throughout this study is that the
organolithium derived from (S)-6 is configurationally more
stable than expected, in other words, little or no racemiza-
tion occurs under the reaction conditions (–50 °C, 5 min).
This premise is based on results obtained from the reactions
with carbon electrophiles (Table 1, entries 3, 4, 7, 10, and
13). Therefore, enantiomeric ratios obtained in the proton-
ation reactions should directly show that the electrophilic
substitution in the organolithiums occurs with either reten-
tion or inversion of configuration.
As a general trend, reactions with a proton source and a
carbon electrophile occur with retention and inversion of
configuration, respectively. This can be understood by in-
voking the precoordination of the proton sources to the
lithium atom, as suggested by Hoppe.[3] Moreover, attack
by carbon electrophiles can occur from the less-hindered
and uncoordinated backside of the molecule, in which the
electron density increases because of the partially flattened
nature of the carbanion. To explain the change in enantio-
meric ratio observed when the solvent and electrophile were
changed, we propose a stereochemical pathway that in-
volves equilibrium between a solvent-separated ion pair 13a
and contact ion pairs 13b–d (Scheme 5).
Scheme 5. Stereochemical process of the reaction of (S)-6 with an
electrophile.
The contact ion pairs differ in the number of solvent mo-
lecules coordinated to the lithium atom, which should be
determined by the balance of the coordinating ability of a
solvent and an electrophile to a lithium atom. Thus, the product formed is decreased by changing from MeOH to
lithium atom in 13, generated by deprotonation of (S)-6, CF3COOH, and (3) the relative amount of inversion prod-
has two vacant coordination sites that can be occupied by uct formed increases markedly in the reaction with cyclo-
a solvent and/or an electrophile molecule in a ratio that pentadiene, which lacks the ability to coordinate to a lith-
depends on their coordinating ability. In a strong electron- ium atom.
donating solvent such as THF, however, a solvent separated
The results obtained with diethyl malonate and acetone,
ion pair 13a might exist in some ratio even in the presence which are both able to coordinate strongly to lithium atoms,
of a strong coordinating carbamoyloxy group. We pre- deserve brief comment because they show contrasting be-
viously reported that the order of the coordinating ability havior depending on the solvent used. The fact that they
of solvents to a lithium atom in organolithium derivatives function as electrophiles in an SEЈ fashion in THF and
lacking a strong coordinating carbamoyloxy group is NMM can be understood by assuming that a solvent-de-
THFϾNMMϾEt2OϾCPMEϾMTBE, and that THF pendent equilibrium exists between 14a and 14b and be-
can drive the conversion of a contact ion pair into a sepa- tween 15a and 15b. Thus, in 14a and 15a, mainly in THF
rated ion pair.[2] This result can explain the racemization and NMM, the electrophiles coordinate to the lithium cat-
through planarization that occurs during the course of the ion as a monodentate ligand due to the strong coordinating
reaction in THF (Table 3, entries 2–4), which was not ob- ability of the solvents. On the other hand, in the case of a
served in other solvents. In the reaction with electrophiles less-coordinating solvent such as Et2O or a bulky ether sol-
that are able to precoordinate to the lithium atom, as either vent such as cPentOMe (CPME) or tBuOMe (MTBE), di-
the ability of the substrate to coordinate increases or the ethyl malonate can act as a bidentate ligand as shown in
ability of the solvent decreases, the equilibrium among 13a– 14b to give an SE protonation product in a retentive man-
d shifts to favor 13d. This speculative hypothesis can explain ner. In those solvents, acetone also becomes competitive
the following observations: (1) the reaction with ethyl cya- with the solvents at the second vacant coordinating site ow-
noformate, which is capable of precoordination to a lithium ing to its strong coordinating ability and, as a consequence,
atom, gives an increased ratio of the retentive product rela- can serve as a proton source as well as a carbon electro-
tive to that of BnBr; (2) the relative amount of retention phile, as shown in 15b.
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Steric Course of the Electrophilic Substitution of a Lithiocarbanion
sis (Ed.: D. M. Hodgson), Springer, New York, 2003, pp. 217–
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Conclusions
We have demonstrated that a lithiocarbanion generated
by deprotonation between phenyl and alkenyl groups has a
configurational stability that is sufficiently strong to be
trapped without racemization by a proton source or a car-
bon electrophile at –50 °C with the aid of a carbamoyloxy
group and that the stereochemical outcomes are affected
by changing the electrophile and solvent. The result can
be understood in terms of the existence of an equilibrium
involving a solvent-separated ion pair and three different
kinds of contact ion pairs in which the ligand coordinated
to the lithium atom differs.
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4663–4666.
[7] The absolute configuration of 8 was determined by conversion
into a known compound (see the Supporting Information for
details).
Experimental Section
General Procedure for Electrophilic Substitution. Reaction of (S)-6
with BnBr in N-Methylmorpholine: To a cooled (–50 °C) solution
of (S)-6 (99:1 er, 50.7 mg, 0.184 mmol) in N-methylmorpholine
(1.84 mL), was added a solution of nBuLi (2.32 m in hexane,
159 μL, 0.368 mmol). The reaction mixture was stirred at the same
temperature for 5 min, then a solution of benzyl bromide in N-
methylmorpholine (2.0 m, 460 μL, 0.920 mmol) was added drop-
wise. After stirring for 10 min, the reaction mixture was quenched
with saturated aqueous NH4Cl (2 mL). The resulting mixture was
extracted with Et2O (2ϫ 5 mL), and the combined organic phases
were washed with saturated brine (3 mL), dried, and concentrated.
The residual oil was subjected to column chromatography (silica
gel 10 g; hexane/AcOEt = 9:1) to give a mixture of 7 and 8 in a
ratio of 1:0.36 (59.1 mg, 87%).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, spectroscopic data, and copies of 1H
and 13C NMR spectra for all new compounds.
[8] The benzylation reactions of the corresponding O-methyl de-
rivative resulted in much lower conversion (10–37%) and al-
most complete racemization in all solvents.
[9] M. Seppi, R. Kalkofen, J. Reupohl, R. Fröhlich, D. Hoppe,
Angew. Chem. 2004, 116, 1447–1451; Angew. Chem. Int. Ed.
2004, 43, 1423–1424.
[10] Addition of nBuLi to a solution of (S)-6a and BnBr (5 equiv.)
at –50 °C resulted in complete recovery of (S)-6a, suggesting
that the rate of reaction of nBuLi with BnBr is much faster
than that of deprotonation of (S)-6a under the conditions.
Consequently, the possibility that deprotonation still occurs af-
ter addition of BnBr can be ruled out by the fact that (S)-6a
is not recovered from the reaction.
Acknowledgments
This research was partially supported by the Ministry of Educa-
tion, Culture, Sports, Science and Technology (MEXT) through a
Grant-in-Aid for Scientific Research (B) 22390001 (K. T.), a Grant-
in-Aid for Young Scientists (B) 22790011 (M. S.), and Grant-in-
Aid for Young Scientists (start-up) 21890151 (to H. I.). We thank
the Natural Science Center for Basic Research and Development
(N-BARD), Hiroshima University for the permission to use the
facilities.
[1] a) D. Hoppe, The Chemistry of Organolithium Compounds, vol.
1 (Eds.: Z. Rappoport, I. Marek), Wiley, Chichester, 2004, pp.
1055–1164; b) D. Hoppe, F. Marr, M. Brüggemann, Organo-
lithiums in Enantioselective Synthesis (Ed.: D. M. Hodgson),
Springer, New York, 2003, pp. 61–137; c) D. M. Hodgson, K.
Tomooka, E. Gras, Organolithiums in Enantioselective Synthe-
[11] Quenching with CH3CO2D afforded the corresponding deuter-
ated product in ca. 90% D/H ratio.
[12] R. Hof, R. M. Kellogg, J. Chem. Soc. Perkin Trans. 1 1996,
2051–2060.
Received: July 4, 2011
Published Online: September 19, 2011
Eur. J. Org. Chem. 2011, 6553–6557
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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