Enantioselective carbolithiation of S-alkenyl-N-aryl thiocarbamates: Kinetic and thermodynamic control

Article abstract of DOI:10.1039/c4ob02329c

The addition of n-butyllithium to alkenylthiocarbamates in the presence of (-)-sparteine or the (+)-sparteine surrogate leads to asymmetric carbolithiation, and returns enantiomerically enriched thiocarbamate derivatives of secondary thiols. In THF, with the (+)-sparteine surrogate, in situ aryl migration leads to an enantiomerically enriched tertiary thiol derivative. Remarkably, the two pseudoenantiomeric chiral ligands do not always give enantiomeric products, probably as a result of a complex interplay of kinetic and thermodynamic control. In situ IR and NMR studies of a stable, hindered lithiated thiocarbamate demonstrated its chemical and configurational stability over a period of hours at 0 °C. This journal is

Full text of DOI:10.1039/c4ob02329c

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Enantioselective carbolithiation of S-alkenyl-
N-aryl thiocarbamates: kinetic and
thermodynamic control†
Cite this: Org. Biomol. Chem., 2015,
13, 2330
Daniele Castagnolo,‡a Leonardo Degennaro,b Renzo Luisib and Jonathan Clayden*a
The addition of n-butyllithium to alkenylthiocarbamates in the presence of (−)-sparteine or the
(+)-sparteine surrogate leads to asymmetric carbolithiation, and returns enantiomerically enriched thio-
carbamate derivatives of secondary thiols. In THF, with the (+)-sparteine surrogate, in situ aryl migration
leads to an enantiomerically enriched tertiary thiol derivative. Remarkably, the two pseudoenantiomeric
chiral ligands do not always give enantiomeric products, probably as a result of a complex interplay of
kinetic and thermodynamic control. In situ IR and NMR studies of a stable, hindered lithiated thiocarb-
amate demonstrated its chemical and configurational stability over a period of hours at 0 °C.
Received 3rd November 2014,
Accepted 16th December 2014
DOI: 10.1039/c4ob02329c
www.rsc.org/obc
Introduction
The enantioselective synthesis of stereogenic centres carrying
sulfur represents challenge in synthetic chemistry.
a
Approaches used for the synthesis of enantiopure alcohols and
amines typically employ asymmetric reactions of CvO or CvN
bonds with nucleophiles,1–5 but corresponding strategies for
the synthesis of sulfur compounds using CvS bonds represent
a challenge.6 As a result, some relatively simple families of
sulfur-containing compounds are of limited synthetic accessi-
bility.7 The asymmetric synthesis of secondary thiols and their
simple derivatives is generally achieved by stereospecific sub-
stitution of chiral electrophilic precursors.6 For tertiary thiols,7
Hoppe’s thiocarbamate chemistry,8–14 despite its attendant
limitations of electrophiles, and the enantioselective palla-
dium-catalyzed sigmatropic rearrangement of O-allyl thio-
carbamates developed by Overman, are effective.15 We recently
reported some effective methods for the enantioselective syn-
thesis of tertiary thiols based on lithiation/aryl migration
sequences of S-benzyl-16 and S-allyl17,18 N-arylthiocarbamates
(Scheme 1). The methods involve the generation of enantio-
merically enriched configurationally stable organolithiums
by deprotonation of chiral non racemic S-benzyl or S-allyl
Scheme 1 Stereoselective strategies for the synthesis of enantiomeri-
cally enriched tertiary thiols.
N-arylthiocarbamates: the organolithiums undergo stereo-
specific aryl migration19 from the thiocarbamate N atom to
the C atom α to S. In parallel, in the racemic series, we
showed that the Li-coordinating abilities of the thiocarbamate
group8,11 could be exploited for a connective stereoselective
synthesis of thiols by a diastereoselective carbolithiation of
S-alkenyl groups followed by intramolecular N to C migration
of an aryl moiety.20 Carbolithiation of S-alkenyl N-arylthio-
aSchool of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL,
UK. E-mail: clayden@man.ac.uk
bDepartment of Pharmacy – Drug Sciences University of Bari “A. Moro”, Via
E. Orabona 4, 70125 Bari, Italy
†Electronic supplementary information (ESI) available: Details of NMR and IR
experiments. Full characterisation data for new compounds. Details of stereoche-
mical assignments. See DOI: 10.1039/c4ob02329c
carbamates with
leading to thiocarbamates and sulfur containing quaternary
a
variety of organolithium reagents,
‡Current address: Department of Applied Sciences, Northumbria University
Newcastle, Ellison Building, Ellison Place, Newcastle upon Tyne NE1 8ST, UK.
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and tertiary stereocentres, occurred stereoselectively in several
cases.
Table 1 Asymmetric carbolithiations of 5
The development of an equivalent asymmetric carbolithia-
tion21,22 of S-alkenyl N-arylthiocarbamates could expand the
portfolio of connective synthetic strategies leading to enantio-
enriched tertiary thiols (Scheme 1). Building on the relatively
limited number of previous reports of enantioselective
carbolithiations,23–30 we report the first asymmetric carbo-
lithiations of alkenyl thiocarbamates. Using the chiral diamine
ligands, such as (−)-sparteine and O’Brien’s (+)-sparteine
surrogate,31–33 we demonstrate the formation of enantio-
enriched thiocarbamates from achiral substrates. In addition,
we show the remarkable effect of the additive LiCl34 on the
stereochemical course of these reactions.
Results and discussion
We started our investigation by evaluating the carbolithiation
of S-alkenyl N-arylthiocarbamate
5 in the presence of
chiral lithium-coordinating ligands 1–4, and the results are
collected in Table 1. Compound 5, prepared according to
a reported procedure,20 was selected as a reference substrate
due to the known facility of N to C aryl migrations of the
4-chlorophenyl group in lithiated thiocarbamates16 and their
congeners.19,35,36
6 Yielda/ erb (R)-
Entry T/°C
Time Solvent
Ligand
%
6 : (S)-6
1
2
3
4
5
6
7
8
−78
−60
1 h
1 h
Et2O
Et2O
Et2O
3
3
3
3
3
3
1
1
2
4
33
35
24
36
36
18
35
37
32
31
67 : 33
47 : 53
48 : 52
66 : 34
67 : 33
50 : 50
60 : 40
51 : 49
50 : 50
84 : 16e
17 : 83e
−78 to −30 16 h
−78
−78
−78
−78
−30
−78
−78
−78
1 h
Cumene
(−)-Sparteine 3, the first ligand of choice for asymmetric
organolithium chemistry,37 was explored first (entries 1–3).
A freshly prepared mixture of the complex of 3 with n-BuLi was
treated with 5, under several different reaction conditions, to
give (after protonation) carbolithiated product 6 and variable
amounts of N-methyl-4-chloroaniline as side product. When
5 min Cumene
2 hc
3 h
3 h
1 h
1 h
4 h
tol, DMPU
Et2O
Et2O
Et2O
Et2O
9
10
11
Et2O
3/LiCld 49
the reaction was carried out in Et2O or cumene at −78 °C a Yields of isolated product 6. b Established by HPLC analysis on chiral
stationary phase. c 0.1 mmol of 5 in 0.4 mL of toluene were treated
product (R)-6 was obtained in 67 : 33 er (entries 1, 4–5), while
with BuLi-3 complex and stirred for 1 h at −78 °C. DMPU (0.1 mL) was
added and the resulting mixture was stirred at −78 °C for 1 h. d 10
at higher temperature 6 was formed as an essentially racemic
mixture (entries 2–3). Longer or shorter reaction times led to equiv. of LiCl were used. e Absolute configuration determined by
no improvement of the enantiomeric ratio. Treatment of 5
with the complex 3-n-BuLi in toluene for 1 h, followed by the
comparison of CD spectrum and [α]D values with those of related
compounds.
addition of DMPU (which usually promotes aryl migration, as
well as racemization19,35,36) still led to 6 (entry 6), again in
racemic form. Treatment of 5 with the complex of bis-oxazo-
added36 to the asymmetric carbolithiation induced by (−)-spar-
teine 3 (entry 11): carbolithiation of 5 in the presence of LiCl
and (−)-sparteine 3 at −78 °C led to compound (S)-6 in 83 : 17
er (entry 11). Nevertheless, compound 6 was obtained through-
out in low yields mainly due to the formation of the side reac-
tion product N-methyl-p-Cl-aniline as consequence of the
attack of BuLi on the carbonyl group.
Absolute configuration was assigned by comparison of the
CD spectrum and [α]D values of the material produced from
entries 10 and 11 with those of thiocarbamates of known con-
figuration (see ESI†). Nonetheless, this assignment does imply
that thiocarbamates undergo carbolithiation in the presence
of 4 with the opposite sense of asymmetric induction when
compared with ureas.23 The sense of (−)-sparteine-directed
enantioselective carbolithiation of carbamates depends on the
organolithium.26
line 1 and n-BuLi at −78 °C afforded 6 in 60 : 40 er, or 51 : 49 er
at −30 °C (entries 7–8). Using 2 as a ligand gave only racemic
material (entry 9).
Better enantioselectivity was obtained when 5 was treated
with the complex of (+)-sparteine surrogate 431–33 and n-BuLi
complex (entry 10). The carbolithiated product (R)-6 was
obtained in 84 : 16 er, remarkably with the same sense of
enantioselectivity as when (−)-sparteine was used. The higher
enantioselectivity observed with 4 may be a result of the ability
of 4 to give tighter complexes with organolithiums than 3, but
as far as we are aware the observation of the same sense of
enantioselectivity from (−)-sparteine and the (+)-sparteine
surrogate is unprecedented. Almost as surprisingly, enantio-
selectivity was also reversed when, in an attempt to promote
rearrangement of the intermediate organolithium, LiCl was
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Table 2 Carbolithiation reactions of 11 in the presence of chiral lithium
coordinating ligands
Scheme 2 Enantioselective carbolithiation-rearrangement in THF.
12 Yielda/ erb (R)-
Entry T/°C
Time Additive Ligand
%
12 : (S)-12
1
2
3
4
5
6
7
−78
−50
−50
1 h
1 h
3 h
—
—
LiCl
LiCl
—
3
3
3
3
4
4
2
0
—
74
61
23
28c
62
72
60 : 40
47 : 53
38 : 62
70 : 30
69 : 31
56 : 44
−78 to 0 4 h
−78
−50
−50
1 h
1 h
1 h
—
—
a Yields of isolated product 12. b Established by HPLC analysis on
chiral stationary phase. Configuration assigned by analogy with 6.
c Starting material 11 was recovered (55%).
Scheme 3 Synthesis of a more hindered thiocarbamate.
0 °C before quenching after 4 h, (S)-12 was formed in 38 : 62 er
(entry 4). Despite the low yield (23%) of product 12 (due to
decomposition of the lithiated intermediate at higher tempera-
ture) this result is remarkable because it demonstrates again
the ability of LiCl to invert the configuration of the carbolithia-
tion product formed using 3. Comparing entries 2–4 in Table 2
indicates that this inversion must arise after carbolithiation
has taken place, suggesting that the effect is a result of LiCl
promoting epimerization from a first-formed complex in
which (R)-12Li predominates to a thermodynamically more
stable complex in which (S)-12Li predominates.
When (+)-sparteine surrogate 4 was used as ligand, (R)-12
was obtained in 70 : 30 er, both at −78 °C (where yield
was compromised by the presence of 55% remaining
starting material) and at −50 °C (entries 5 and 6). Ligand 2
was once more found to be ineffective, giving 12 in 56 : 44 er
(entry 7).
Tables 1 and 2 both display some remarkable results with
common features. Firstly, they show that 3 and 4, despite
being pseudoenantiomeric, may give products with the same
absolute stereochemistry. Secondly, they show that the ‘enantio-
meric’ functions of 3 and 4 may be restored by adding LiCl
to carbolithiation reactions induced by 3: thus 3 + LiCl, but
not 3 alone, behaves like the enantiomer of 4. Consideration of
the two possible mechanisms by which enantioselectivity may
be induced in these processes allows us to propose two reac-
tion pathways, illustrated in Scheme 4. In the first pathway,
kinetic control induces facial selectivity in the addition step to
give a configurationally stable organolithium 6Li·L* or 12Li·L*,
whose stereospecific protonation yields enantiomerically
enriched compounds. In the second pathway, the addition
step may or may not be enantioselective, but thermodynamic
control over the equilibration of the resulting diastereo-
isomeric complexed organolithiums 6Li·L* or 12Li·L* gives
Unusually among lithium-complexing ligands, the
(+)-sparteine surrogate is competitive with THF as a ligand for
Li+, and can induce enantioselectivity even in reactions carried
out in THF solution.38 When 5 was treated with the complex of
4 and n-BuLi in THF, aryl migration followed directly from the
carbolithiation step and thiocarbamate 7 was isolated in 41%
yield and in 63 : 37 er (Scheme 2).39 As noted before,23 THF
promotes the aryl migration, possibly by assisting decomplex-
ation of Li+ from either or both of the thiocarbamate CvO or
the anionic C atom, leading to a solvent-separated ion
pair.40,41 However, as previously observed with DMPU,36 this
effect of THF also seems to lead to partial epimerization of
the lithiated intermediate, lowering the er of the rearranged
products.
Aiming to improve the yield and enantioselectivity of the
carbolithiation reaction, and to explore on a simpler and
better behaved system the erratic enantioselectivities obtained
in these reactions, we decided to replace the N-methyl group of
5 with the more sterically hindered N-isopropyl group, reason-
ing that this would obstruct attack of n-BuLi on the thiocarb-
amate carbonyl group. The N-isopropyl thiocarbamate 1120
was prepared by the synthetic route shown in Scheme 3. Thio-
carbamate 8, made by the method of Hoppe,8 was reduced to
the thiol with LiAlH4 and acylated with N-isopropyl-N-phenyl-
carbamoyl chloride42 to give compound 9. Mesylation to give
10 and NaH-promoted elimination afforded the S-alkenyl
N-isopropylthiocarbamate 11.
The thiocarbamate 11 was carbolithiated with n-BuLi in the
presence of ligands L* 2–4 (Table 2). No carbolithiation was
observed in the presence of (−)-sparteine at −78 °C (entry 1)
but at −50 °C (R)-12 was obtained after quenching, in 60 : 40 er
and high yield (entry 2). Adding LiCl to this reaction led to the
formation of 12 as a more or less racemic mixture after 3 h at
−50 °C (entry 3). However, on increasing the temperature to
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Table 3 Equilibration of the complex of 6Li and 3 in the presence of
LiCl
Entry
T/°C
Time
6 Yielda/%
erb (R)-6 : (S)-6
1
2
3
4
5
−78
−78
−78
−78
−40
30 min
1 h
2 h
4 h
1 h
27
22
30
49
30
57 : 43
50 : 50
33 : 67
17 : 83
41 : 59
Scheme 4 Pathway for reaction via diastereoisomeric organolithium
complexes.
a Yields of isolated product 6. b Established by HPLC analysis on chiral
stationary phase.
formation of a solvent-separated ion pair B would allow equili-
bration, perhaps via a conducted tour mechanism, to C and
hence to the more stable diastereomeric complex D. The con-
trasting behaviour of 4, which gives the opposite enantiomer
to 3 + LiCl in every case, could be explained by assuming that
the tighter coordination between the organolithium 6Li or
12Li and 4 leads directly to the product of thermodynamic
control without the need for an additive. Equilibration
between the diastereoisomeric complexes 6Li·4 or 12Li·4 is
faster than addition, and only the product ratio arising from
thermodynamic control is observed.
A series of experiments was designed to test this hypothesis
(Table 3). Thiocarbamate 5 was carbolithiated at −78 °C using
a freshly prepared complex of (−)-sparteine 3 and n-BuLi in the
presence of an excess (4 equiv.) of LiCl. Reactions were
stopped by quenching with MeOH at different times, in order
to follow the progress of any thermodynamic equilibration.
After 30 min. (R)-6 was obtained in 57 : 43 er (Table 3, entry 1);
after 1 h a racemic mixture was detected (Table 3, entry 2).
After 2 h the enantiomer (S)-6 was in excess (33 : 67, entry 3)
and after 4 h the final er of 17 : 83 in favour of (S)-6 was
reached (Table 3, entry 4). Carrying out the reaction for longer
time led to no further increase in er. Increasing the temp-
erature increased the apparent rate of epimerization, so
that even after 1 h at −40 °C, (S)-6 was the major enantiomer
(entry 5).
Further insight into the reaction pathway would be avail-
able from spectroscopic studies (in situ FT-IR, NMR) of the
organolithium intermediates. However, yields in all of the reac-
tions of 5 were compromised by competing formation of
N-methyl-4-chloroaniline as a side product, probably from a
combination of competing attack at the carbonyl group by
n-BuLi and decomposition of the intermediate organolithium.
Likewise, because 11 was carbolithiated only at high tempera-
tures, competitive aryl migration also led to mixtures of pro-
ducts. We thus sought a cleanly reacting substrate suitable for
spectroscopic studies. The reactivity of thiocarbamate 14,
designed as a hybrid of 5 and 11 and bearing a bulky N-aryl
Fig. 1 Pathway for equilibration between diastereoisomeric organo-
lithium complexes.
enantiomerically enriched products, again by stereospecific
protonation.
Based on these considerations, we propose that the enantio-
selectivity observed in the carbolithiation of thiocarbamates 5
and 11 with 3 alone can be explained by assuming that the
addition step occurs with some degree of face selectivity, and
that the resulting α-thiobenzyllithiums are configurationally
stable.8,16,20 On protonation, (R)-6 and (R)-12 are obtained as
the major enantiomers. The enantioselectivity switch, in the
presence of 3 and LiCl, may be rationalized by assuming that
LiCl weakens the interaction between the lithium cation and
either or both of the carbonyl O and the anionic C atoms – an
effect seen with THF or DMPU – and thus induces thermo-
dynamically-controlled equilibration of the lithiated adducts, as
illustrated in Fig. 1. The diastereoisomeric lithiated intermedi-
ates A and D represent respectively the kinetic and thermo-
dynamic favored complexes. In the presence of LiCl (L in Fig. 1),
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after longer reaction times or with a warm-cool protocol
(entries 7, 8).
On the other hand, when (+)-sparteine surrogate 4 was used
as ligand in Et2O or toluene an appreciable degree of stereo-
selectivity was observed (entries 9, 10). A lower, but still mea-
surable, degree of stereoselectivity was also observed using 4
in THF (entry 8). In both cases the (R)-17 enantiomer was
obtained as the major product, as it was (marginally) when
(−)-sparteine was used. For sake of comparison, and based on
a protocol developed by Hoppe and coworkers for the dynamic
thermodynamic resolution of lithiated S-benzyl thiocarb-
amates,8 the carbolithiation of 14 was performed in the pres-
ence of bis-oxazoline ligand 1. Only racemic adduct was
recovered (Table 4, entry 12).
The progress of the carbolithiation of 14 was investigated
by in situ FT-IR experiments carried out using a diamond ATR
probe and monitoring the CvO stretching of thiocarbamate
14. A 0.1 M toluene solution of 14 and ligand 4 (1.5 equiv.)
showed the stretching band of the CvO bond at 1680 cm−1 at
−78 °C (Fig. 2). Upon addition of n-BuLi a new signal, which
we ascribe to the lithiated intermediates (+)-4·(R)-17Li and
(+)-4·(S)-17Li, was observed at lower wavenumber (1590 cm−1),
probably as a result of coordination between Li and the CvO
group.41,44–47 Quenching with deuterated methanol restored
the signal for the CvO (1670 cm−1) of the thiocarbamate 17-D
(Fig. 2). Similar behaviour was noticed in the experiment
carried out in the presence of (−)-sparteine 3. The IR analysis
revealed that the addition of n-BuLi occurs very quickly with
both ligands 3 and 4. Nevertheless, a careful analysis of the
reaction profiles showed that the carbolithiation is slightly
faster in the presence of 3 with respect to 4: 80% of 14 was
consumed in 30 s in the presence of 3 and in 1 min in the
presence of 4 (see ESI†).
Scheme 5 Synthesis of thiocarbamate 14.
group, was therefore explored. This system could allow the
optimization of the carbolithiation reaction without a competi-
tive aryl migration, or the poor yields and poor reactivity seen
at −78 °C. Compound 14 was initially prepared from carb-
amoyl chloride 15 following the synthetic approach used for
11 (Scheme 5, route a), and then also by a shorter and more
efficient approach starting from 15 and benzyl thiol. Lithiation
of 16 with s-BuLi and reaction with chloroiodomethane furn-
ished thiocarbamate 14 in a high yielding single step methyle-
nation (Scheme 5, route b).43
The results of asymmetric carbolithiation of 14 in the pres-
ence of (−)-sparteine 3 and (+)-sparteine surrogate 4 are sum-
marized in Table 4. As expected the carbolithiation reaction
proceeded in very good yields even at low temperature and no
trace of migration product or aniline derivative was detected.
However, carbolithiation in the presence of (−)-sparteine 3
gave almost racemic samples of 17 under several reaction con-
ditions (entries 1–3). Neither solvent nor temperature affected
the stereoselectivity, which remained constant with reaction
time (entries 4–5). Likewise there was no change in enantio-
selectivity in the presence of LiCl as an additive (entry 6), even
Table 4 Carbolithiation of 14 in the presence of 3 or 4
Entry
Solvent
T/°C
Time (h)
Additive
L*
17 Yielda/%
erb (R)-17 : (S)-17
1
2
3
4
5
6
7
8
Et2O
−78
1
1
1
0.15
1–18
1
4
4
1
1
1
18
—
—
—
—
3
3
3
3
3
3
3
3
4
4
4
1
88
87
82
88
85
87
84
78
80
80
78
88
57 : 43
57 : 43
51 : 49
51 : 49
53 : 47
52 : 48
50 : 50
51 : 49
70 : 30
70 : 30
63 : 36
52 : 48
Toluene
Cumene
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Toluene
THF
−78
−78
−98
−78 – −45 – −78c
−78
LiCld
LiCld
LiCld
—
—
—
−78
−78 – 0 – −78c
9
−78
10
11
12
−78
−78
Et2O
−78 – −45 – −78c
—
a Yields of isolated product. b Established by HPLC analysis on chiral stationary phase. c A warm/cooling protocol was applied. Conditions:
BuLi-L* complex was added at −78 °C and after 1 h the reaction mixture was warmed to −45 °C and left overnight. The reaction was cooled to
−78 °C before quenching. d 10 equiv. LiCl added.
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Fig. 2 FT-IR monitoring of the enantioselective carbolithiation of 14 in the presence of ligands 3 and 4.
The IR spectra give no evidence with regard to stereo- give the corresponding deuterated product (>95% D) 17D with
selectivity or the existence of diastereoisomeric complexes, so an er of 75 : 25 (HPLC). This evidence lends support to the
the carbolithiation of 14 was also performed in an NMR tube, hypothesis that the signals observed by NMR belong to the two
1
acquiring H- and 13C-NMR spectra. Running the carbolithia- diastereomeric lithiated intermediates (+)-4·(R)-17Li and
tion reaction in the NMR tube at 200 K in d8-toluene and in (+)-4·(S)-17Li. In addition, the shielding observed for both
the presence of (+)-sparteine surrogate 4, two diastereomeric protons Hp and carbon Cp and the deshielding for the carbon
1
species were detected by H NMR. The reaction reached com- Ci, is in agreement with an increased charge density in the aro-
pletion as soon as 14 was added to a pre-cooled (−78 °C) matic ring directly bonded to the lithiated carbon. Further
0.05 M solution of 4-BuLi complex (1.5 equiv.) in agreement NMR evidence for the structure of the organolithium gener-
with the results of the IR experiments. In particular, the ated by carbolithiation was the deshielding of the carbonyl
aromatic region of the 1H NMR spectra revealed two sets of group (NCvO, ca. 184 ppm) that probably arises from intramo-
signals belonging to diastereomeric complexes (+)-4·(R)-17Li lecular coordination of the lithium cation. This conclusion is
and (+)-4·(S)-17Li in a 70 : 30 ratio (Fig. 3). Such signals also supported by the FT-IR experiments.
appeared separately in the range 6.50–6.70 ppm and were
The same experiment was performed using (−)-sparteine 3
unambiguously assigned, by HSQC-DEPT hetero-correlation as the chiral ligand. In this case, two lithiated intermediates
experiments, to the para protons of the phenyl ring linked to (−)-3·(R)-17Li and (−)-3·(S)-17Li were observed in an almost
the lithiated carbon. Fig. 3 also shows the aromatic region equimolar quantity (dr: 55 : 45) and the same chemical shift
(110–190 ppm) of the 13C NMR spectrum observed for the correlations were verified (Fig. 3). The aromatic region of the
diastereomeric mixture of (+)-4·(R)-17Li and (+)-4·(S)-17Li. 1H- and 13C-NMR spectra revealed a double set of signals, one
However, probably as a result of the low sample concentra- for each diastereomeric complex (−)-3·(R)-17Li and (−)-3·(S)-
tion, only the signals of the major lithiated intermediate are 17Li (Fig. 3). Trapping the lithiated intermediates with deuter-
detectable. In particular, by comparison of the 13C NMR ium source furnished 17-D as a racemic mixture.
chemical shifts of (+)-4·(R)-17Li and (+)-4·(S)-17Li with
those reported for
The identification by NMR of two diastereomeric organo-
a
similar lithiated benzylic thiocar- lithium complexes confirm that stereoselectivity in the carbo-
bamate by Hoppe,8 we can confidently assign the NCvO (ca. lithiation reaction of 14 originates from the diastereoisomeric
184 ppm), the Ci (ca. 153 ppm) and the Cp (ca. 110 ppm) ratio of organolithiums. In these reactions, it is evident
signals (Fig. 3).
that (+)-sparteine surrogate 4 provides better enantio-
The lithiated intermediates (+)-4·(R)-17Li and (+)-4·(S)-17Li selectivity than (−)-sparteine 3. However, these NMR results do
generated in the NMR tube were deuterated with CD3OD to not distinguish face selectivity in the addition step from
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Fig. 3 600 MHz HSQC-DEPT and 13C NMR spectra in toluene-d8 at 200 K for diastereomeric lithiated carbamates (+)-4·(S)-17Li and (+)-4·(R)-17Li
(upper part) (−)-3·(S)-17Li and (−)-3·(R)-17Li (lower part). The 13C NMR spectrum of neutral 14 is included as reference.
intermediates, so attempts were made to equilibrate the mix-
tures of (+)-4·(R)-17Li/(+)-4·(S)-17Li and (−)-3·(R)-17Li/(−)-3·(S)-
17Li with a warm-cool protocol. If the epimerization occurs, a
change of the signal intensities would be expected: such a
change was not evident. Warming the 70 : 30 diastereomeric
mixture of (+)-4·(R)-17Li and (+)-4·(S)-17Li in the range
200 K→253 K gave only line broadening without changing of
the initial diastereomeric ratio. The mixture was kept at 253 K
for 3 h before re-cooling the sample. Temperatures above
253 K resulted in decomposition. Similar results were obtained
from warm-cool procedures with the 55 : 45 diastereomeric
mixtures of (−)-3·(R)-17Li/(−)-3·(S)-17Li. Only line broadening
and a temperature dependent drift were noticed: the signal
ratio remained unchanged. The lithiated intermediates were
found to be chemically stable for 2 hours at 273 K but
decomposition occurred at 298 K (Fig. 4).
We thus propose that the lithiated thiocarbamate 17Li is
configurationally stable and that in this case it is likely the
stereoselectivity is determined by kinetic control in the
addition step with 3, with 3 and LiCl, or with 4. Other
examples of lithiated α-thio carbanions that are configuration-
ally stable on time scales of minutes to hours have been
reported8 and it seems that the configurational stability in
Scheme 6 Configurational stability in 17-Li.
thermodynamically-controlled resolution of the lithiated
intermediate.
A simple experiment (Scheme 6) demonstrated that the
complex of 17-Li and 4 is macroscopically configurationally
stable at −78 °C. A nearly racemic mixture of 17 was deproto-
nated using the complex of 4 and n-BuLi, to give a mixture
of (+)-4·(R)-17-Li and (+)-4·(S)-17-Li, and allowed to equi-
librate for an hour. Configurational instability would lead to
the same ratio of products as carbolithiation of 14. However,
deuteration of this mixture after 1 h at −78 °C returned 17-D
in the same enantiomeric ratio as the starting 17 (Scheme 6)
instead of the 70 : 30 obtained by carbolithiation of 14
(Table 4, entry 9).
Changes in product ratio with time show that our earlier
results with 6 and 12 clearly involve configurationally unstable
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Fig. 4 600 MHz 1H NMR spectra in toluene-d8 of diastereomeric mixtures of (+)-4·(R)-17-Li and (+)-4·(S)-17-Li (left) and (−)-3·(R)-17-Li and
(−)-3·(S)-17-Li (right). Attempts to demonstrate dynamic thermodynamic resolution.
17Li arises from presence of bulky substituents at the chiral rearrangement, generating the thiocarbamate derivative of a
centre, leading to an enhanced barrier to epimerization tertiary thiol in 63 : 37 er.
relative to 6Li and 12Li.
Experimental section
General methods
Conclusions
Carbolithiation of alkenylthiocarbamates in the presence of Nuclear Magnetic Resonance (NMR) spectra were recorded on
chiral diamine ligands followed by protonation gives enantio- a Bruker Ultrashield 300, 400, 500 or 600 MHz spectrometer.
merically enriched products. In some cases, the same enantio- 1H and 13C spectra were referenced relative to the solvent
mer of the product is obtained whether (−)-sparteine or residual peaks and chemical shifts (δ) reported in ppm down-
(+)-surrogate is used, though enantiomeric outcomes in those field of trimethylsilane (CDCl3 δ H: 7.26 ppm, δ C: 77.0 ppm;
cases are generally restored by adding LiCl to the reactions of CD3OD δ H: 3.31 ppm, δ C 49.05 ppm). Coupling constants (J)
(−)-sparteine. Time-course experiments suggest that the mod- are reported in Hertz and rounded to 0.5 Hz. Splitting patterns
erate enantioselectivity with (−)-sparteine results from kineti- are abbreviated as follows: singlet (s), doublet (d), triplet (t),
cally controlled carbolithiation to give organolithiums that are quartet (q), multiplet (m), broad (br) or some combination of
configurationally stable. NMR experiments confirmed that the these. Low and high resolution mass spectra were recorded by
enantiomeric ratio in the product reliably corresponds to the staff at the University of Manchester. Electrospray (ES) spectra
observable ratio of diastereoisomeric organolithium complexes were recorded on a Waters Platform II and high resolution
in solution, proving that protonation is stereospecific. For mass spectra (HRMS) were recorded on a Thermo Finnigan
some, but not all, lithiated thiocarbamates, the use of (+)-4 in MAT95XP and are accurate to 0.001 Da. Infrared spectra were
place of (−)-3, or adding LiCl to (−)-3, promotes equilibration recorded on an Ati Mason Genesis Series FTIR spectrometer as
to give a new, thermodynamically-controlled ratio of products. thin films on a sodium chloride plate. Thin layer chromato-
An N-aryl carbamate 5, on carbolithiation in THF in the pres- graphy (TLC) was performed using commercially available pre-
ence of (+)-4, led to a tandem enantioselective carbolithiation- coated plates (Macherey-Nagel alugram. Sil G/UV254) and visu-
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alized with UV light at 254 nm; K2MnO4 or phosphomolybdic S-(2-Trifluoromethanesulphonyloxy-1-phenylethyl)-
acid dips were used to reveal the products. Flash column N-isopropyl-N-phenyl thiocarbamate 10
chromatography was carried out using Fluorochem Davisil
40–63u 60 Å. All reactions were conducted under a nitrogen
atmosphere in oven-dried glassware unless stated otherwise.
The alcohol 9 (0.37 mmol) was dissolved in dry DCM (10 mL).
The solution was cooled at 0 °C and Et3N (2 mmol), MsCl
(0.48 mmol) and DMAP (0.037 mmol) were then added. The
Tetrahydrofuran was distilled under nitrogen from sodium
resulting mixture was stirred at room temperature overnight.
using a benzophenone indicator. Dichloromethane, toluene
The reaction was diluted with DCM and water (40 mL) was
and diethyl ether were obtained by distillation over calcium
then added. The organic layer was then separated and the
hydride under a nitrogen atmosphere. Anhydrous dimethyl-
aqueous layer was extracted with DCM (2 × 20 mL). The com-
formamide were purchased from Sigma-Aldrich. Acetonitrile
bined organic extracts were washed with brine (10 mL) dried
was further dried over 4 Å oven-activated molecular sieves for
over MgSO4, filtered and concentrated under reduced pressure
1 h prior to use. Triethylamine was distilled over calcium
to yield a crude product that was purified by column chromato-
hydride under nitrogen atmosphere. Petrol refers to the
graphy using Petroleum ether–AcOEt 3 : 1 as eluent. The
fraction of light petroleum ether boiling between 40 and 65 °C.
All other solvents and commercially available reagents were
used as received.
title compound 10 was obtained in quantitative yield. 1H NMR
(300 MHz CDCl3) δ 7.35 (m, 3H), 7.19 (m, 7H), 4.88–4.84 (m,
1H), 4.81–4.76 (m, 1H), 4.59–4.54 (m, 1H), 4.48–4.41 (m, 1H),
Thiocarbamates 5 and 14 were synthesised as previously
2.74 (s, 3H), 1.05 (dd, 6H, J = 6.4 Hz) ppm. 13C NMR (75 MHz
described.20 Carbamoyl chlorides were prepared as previously
CDCl3) δ 166.0, 136.8, 135.8, 131.6, 129.4, 129.1, 128.7, 128.3,
reported.42
128.0, 71.6, 49.0, 47.8, 37.2, 21.0 ppm. LRMS m/z (ESI) m/z: 394
[M + H]+.
S-(2-Hydroxy-1-phenylethyl)-N-isopropyl-N-phenyl
thiocarbamate 9
S-(1-Phenylethenyl)-N-isopropyl-N-phenyl thiocarbamate 11
Thiocarbamate 8, made by the method of Hoppe,8
Mesylate 10 (0.37 mmol) was dissolved in dry DMF (5 mL) and
the solution was cooled at 0 °C. NaH (0.55 mmol) was added
(1.52 mmol) was dissolved in dry THF (20 mL) and added with
and the resulting mixture was stirred at room temperature for
LiAlH4 (7.6 mmol, 1 M solution in Et2O). The resulting mixture
1 h. The reaction was diluted with AcOEt and quenched with
was refluxed overnight, cooled at 0 °C, diluted with AcOEt and
water. The organic layer was then separated and the aqueous
quenched by slow addition of HCl 1 N. The organic layer was
layer was extracted with AcOEt (2 × 20 mL). The combined
then separated and the aqueous layer was extracted with AcOEt
organic extracts were washed with brine (10 mL), dried over
(2 × 20 mL). The combined organic extracts were washed with
MgSO4, filtered and concentrated under reduced pressure to
brine (10 mL), dried over MgSO4, filtered and concentrated
yield a crude product that was purified by column chromato-
under reduced pressure to yield a crude hydroxythiol that was
graphy using Petroleum ether–AcOEt 4 : 1 as eluent. 1H NMR
purified by column chromatography using Petroleum ether–
(300 MHz CDCl3) δ 7.65–7.63 (m, 2H), 7.46 (m, 3H), 7.37–7.27
AcOEt 4 : 1 as eluent. Yield 75%. 1H NMR (300 MHz CDCl3)
(m, 5H), 5.98 (s, 1H), 5.72 (s, 1H), 4.82 (sept, 1H, J = 6.7 Hz),
δ 7.23–7.12 (m, 5H), 3.93 (dd, 1H, J = 13.9, 6.4 Hz), 3.77–3.71
1.08 (d, 6H, J = 6.7 Hz) ppm. 13C NMR (75 MHz CDCl3) δ 166.1,
(m, 1H), 3.65–3.59 (m, 1H), 2.68 (br s, 1H), 1.89 (d, 1H, 6.6 Hz)
140.2, 139.7, 136.7, 131.6, 129.3, 129.2, 128.2, 128.1, 126.6,
ppm. 13C NMR (75 MHz CDCl3) δ 140.6, 128.8, 127.8, 127.5,
125.1, 48.7, 21.1 ppm. IR νmax (film)/cm−1 2974, 1665,
68.2, 46.2 ppm. LRMS m/z (ES+) m/z: 177 [M + Na]+.
1492, 1238, 1221, 1114. LRMS m/z (ES+) m/z: 298 [M + H]+, 320
A solution of this material (1 mmol) in anhydrous THF
(8.0 mL) was added dropwise to an ice-cooled suspension of
[M + Na]+.
sodium hydride (1.2 mmol, 60% in mineral oil) in THF
General procedures for the asymmetric carbolithiation of
alkenyl thiocarbamates
(30 mL). After 30 min. a solution of N-isopropyl-N-phenylcarb-
amoyl chloride42 in 2 mL of THF was added and the resulting
mixture was stirred for 3 h at room temperature. The reaction
Method A. asymmetric carbolithiation. (−)-Sparteine or the
mixture was poured into a mixture of Et2O and 2 M aqueous (+)-sparteine surrogate33 (0.14 mmol) was dissolved in dry
HCl (30 mL). The organic layer was separated and the aqueous Et2O (0.4 mL) and cooled to −78 °C. BuLi (0.11 mmol, 1.6 M
solution was extracted with Et2O (30 mL). The combined solution in hexanes) was added and the resulting mixture was
extracts were stirred over solid Na2SO4/NaHCO3. The crude stirred for 20 minutes at 0 °C. In parallel, a solution of the
product was purified by flash chromatography on silica gel thiocarbamate 5, 11 or 14 (0.056 mmol) in Et2O (0.2 mL) was
(Et2O–hexanes, 1 : 4) to give the product 9 (280 mg, 89%) as an prepared and cooled at −78 °C (if required LiCl (0.5 mmol)
oil. 1H NMR (300 MHz DMSO-d6) δ 7.44 (m, 3H), 7.28–7.19 (m, was added). The complex sparteine/BuLi was then added at
7H), 4.71 (sept, 1H, J = 6.7 Hz), 4.46 (t, 1H, J = 7.7 Hz), this second solution at −78 °C and the resulting mixture was
3.72–3.60 (m, 2H), 1.03 (d, 3H, J = 6.7 Hz), 0.98 (d, 3H, J = stirred at the same temparture for the required time. The reac-
6.7 Hz) ppm. 13C NMR (75 MHz DMSO-d6) δ 166.0, 140.3, tion was then quenched with MeOH and diluted with AcOEt
136.0, 131.5, 129.0, 128.2, 128.1, 126.8, 64.3, 51.0, 48.1, 20.8, and water. The organic layer was then separated and the
20.7 ppm. LRMS m/z (ESI) m/z: 316 [M + H]+.
aqueous layer was extracted with AcOEt (2 × 2 mL). The com-
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bined organic extracts were washed with brine (2 mL), dried CDCl3) δ: 13.0, 16.5, 16.6, 21.4, 26.2, 28.5, 30.4, 34.1, 35.6,
over MgSO4, filtered and concentrated under reduced pressure 48.5, 125.7, 126.8, 127.2, 127.7, 127.7, 127.8, 136.2, 141.8,
to yield a crude product that was purified by column chromato- 167.4. IR νmax (film)/cm−1 2925, 1655, 1647, 1376, 1275, 1084,
graphy using hexanes–AcOEt 4 : 1 as eluent.
867, 696. LRMS m/z (ES+) m/z: 356 [M + H]+, HRMS (ESI): calcd
Method B. asymmetric carbolithiation–aryl migration. (+)- for C22H30ONS [M + H] 356.2048, found 356.2043. A sample of
Sparteine surrogate (0.13 mmol) was dissolved in dry THF 70 : 30 er R : S had [α]D +20 (c = 1, CHCl3).
(0.4 mL) and cooled to −78 °C. BuLi (0.12 mmol, 1.6 M solu-
tion in hexanes) was added and the resulting mixture was
stirred for 20 minutes at −78 °C. In parallel, a solution of the
appropriate thiocarbamate (0.06 mmol) in THF (0.2 mL) was
prepared and cooled at −78 °C. The sparteine surrogate–BuLi
complex was then added to this second solution at −78 °C and
the resulting mixture was stirred at the same temparture for
1.5 h. The reaction was quenched with EtCOOH (0.36 mmol)
and diluted with AcOEt and water. The organic layer was
then separated and the aqueous layer was extracted with AcOEt
(2 × 2 mL). The combined organic extracts were washed with
brine (2 mL), dried over MgSO4, filtered and concentrated
under reduced pressure to yield a crude product that was puri-
fied by column chromatography using hexanes–AcOEt 4 : 1 as
eluent.
S-Benzyl-N-methyl-N-2,6-dimethylphenyl thiocarbamate 16
A solution of benzyl thiol (1 mmol) in anhydrous THF (8.0 mL)
was added dropwise to an ice-cooled suspension of sodium
hydride (1.2 mmol, 60% in mineral oil) in THF (30 mL). After
30 min. a solution of N-methyl-N-2,6-dimethylphenylcarba-
moyl chloride42 in 2 mL of THF was added and the resulting
mixture was stirred for 3 h at room temperature. The reac-
tion mixture was poured into a mixture of Et2O and 2 M
aqueous HCl (30 mL). The organic layer was separated and
the aqueous solution was extracted with Et2O (30 mL). The
combined extracts were stirred over solid Na2SO4/NaHCO3.
The crude product was purified by flash chromatography on
silica gel (Et2O–hexanes, 1 : 4). 1H NMR (300 MHz, CDCl3) δ:
2.11 (s, 6 H), 3.12 (s, 3 H), 3.99 (s, 2 H), 6.98–7.20 (m, 8 H).
13C NMR (75 MHz, CDCl3) δ: 17.7, 35.1, 35.4, 127.0, 128.4,
128.9, 129.0, 137.4, 138.5, 138.7, 168.6. LRMS m/z (ES+) m/z:
286 [M + H]+.
S-(1-Phenylhexyl)-N-methyl-N-4-chlorophenyl thiocarbamate 6
By method A, using the conditions shown in Table 1, thiocarb-
1
amate 5 gave the title compound as an oil H NMR (300 MHz
CDCl3) δ 7.29–7.08 (m, 9H), 4.42 (dd, 1H, J = 8.9, 6.7 Hz), 3.19
(s, 3H), 1.84–1.76 (m, 2H), 1.21–1.16 (m, 6H), 0.84 (t, 3H, J =
6.4, 3H) ppm. 13C NMR (75 MHz CDCl3) δ 168.2, 142.7, 142.3,
129.3, 128.3, 128.0, 127.0, 126.5, 38.7, 38.4, 33.9, 29.2, 22.6,
17.3, 14.1 ppm. MS (ESI) m/z: 362 [M + H]+. IR νmax (film)/cm−1
2954, 2929, 2857, 1657, 1489. LRMS m/z (ES+) m/z: 384
[M + Na]+, HRMS (ESI): calcd for C20H24NOSClNa (M + Na+)
384.1160, found 384.1163.
Preparation of alkenyl thiocarbamate 14 using ClCH2I
A solution of sec-BuLi (6 mmol of a 1.4 M solution in hexane)
was added dropwise to a solution of thiocarbamate 16
(3 mmol) in 25 mL of dry THF −98 °C. The yellowish solution
was stirred for 1 h at a temperature between −98–−78 °C. The
solution was cooled to −98 °C and a solution of ClCH2I
(6 mmol in 1 mL of dry THF) was added. The resulting mixture
was stirred overnight and gradually warmed to room tempera-
ture. The reaction was quenched with water and extracted with
AcOEt. The organic extracts were dried over MgSO4, filtered,
and the solvent removed under reduced pressure. The crude
product was purified by flash chromatography on silica gel
using hexanes–AcOEt (85 : 15) as eluent to yield the title com-
S-(1-Phenylhexyl)-N-isopropyl-N-4-chlorophenyl
thiocarbamate 12
By method A, using the conditions shown in Table 2, thiocarb-
1
amate 5 gave the title compound as an oil H NMR (300 MHz
1
CDCl3) δ 7.31–7.07 (m, 10H), 4.80 (sept, 1H, J = 6.7 Hz), 4.4
(dd, 1H, J = 9.2, 6.4 Hz), 1.84–1.68 (m, 2H), 1.18–1.14 (m, 5H),
1.02 (d, 3H, J = 6.7 Hz), 0.96 (d, 3H, J = 6.7 Hz), 0.74 (m, 4H)
ppm. 13C NMR (75 MHz CDCl3) δ 168.0, 142.7, 136.6, 131.7,
128.9, 128.3, 127.8, 126.7, 125.2, 49.8, 48.4, 37.0, 31.4, 27.3,
22.4, 21.1, 14.0 ppm. IR νmax (film)/cm−1 2931, 1649, 1493,
1450, 1279, 1240, 1115, 755. LRMS m/z (ES+) m/z: 378
[M + Na]+, HRMS (ESI): calcd for C22H29NOSNa (M + Na+)
378.1863, found 378.1865.
pound 14 (775 mg, 87%) as an oil. H NMR (300 MHz, CDCl3)
δ: 2.35 (s, 6 H), 3.16 (s, 3 H), 5.74 (s, 1 H), 6.00 (s, 1 H),
7.20–7.40 (m, 6 H), 7.60–7.70 (m, 2 H). 13C NMR (75 MHz,
CDCl3) δ: 17.7, 35.4, 125.5, 126.8, 128.1, 128.2, 129.0, 129.2,
137.5, 138.9, 139.0, 140.5, 166.9. IR νmax (film)/cm−1 2922,
1670, 1489, 1336, 1084, 862, 769. LRMS m/z (ES+) m/z: 298
[M + H]+, HRMS (ESI): calcd for C18H20ONS [M + H] 298.1266,
found 298.1268.
S-(1-Phenylhexyl)-N-methyl-N-2,6-dimethylphenyl
thiocarbamate 17
Acknowledgements
By method A, using the conditions shown in Table 4, thiocarb- This work was funded in the UK by the EPSRC and in Italy by
amate 14 gave the title compound as an oil. 1H NMR National Project “FIRB – Futuro in Ricerca” code: CINECA
(300 MHz, CDCl3) δ: 0.75 (br. t., 3 H), 1.10–1.20 (m, 4 H), RBFR083M5N; “Laboratorio SISTEMA” code: PONa300369
1.60–1.80 (m, 2 H), 1.97 (s, 3 H), 2.19 (s, 3 H), 3.07 (s, 3 H), financed by the Italian MIUR; Regional project “Reti di Labora-
4.41 (t, J = 6.5 Hz, 1 H), 7.05–7.20 (m, 8 H). 13C NMR (75 MHz, tori Pubblici di Ricerca” Project Code 20.
This journal is © The Royal Society of Chemistry 2015
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