Carbolithiation of S-alkenyl-N-aryl thiocarbamates: Carbanion arylation in a connective route to tertiary thiols

Article abstract of DOI:10.1021/ol400570r

S-Alkenyl-N-arylthiocarbamates are formed from allylic alcohols by sigmatropic rearrangement and isomerization or C=C bond cleavage. They undergo carbolithiation with a range of organolithium reagents, generating benzyllithium intermediates in a stereospecific manner which may undergo N to C aryl migration to yield thiocarbamates with tertiary substituents. A simple base-promoted alcoholysis reveals a series of hindered tertiary thiols with branched carbon skeletons.

Full text of DOI:10.1021/ol400570r

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2116–2119
Carbolithiation of S‑Alkenyl‑N‑aryl
Thiocarbamates: Carbanion Arylation
in a Connective Route to Tertiary Thiols
Daniele Castagnolo,† Daniel J. Foley,† Hatice Berber,†,‡ Renzo Luisi,†,§ and
Jonathan Clayden*,†
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL,
ꢀ
ꢀ
U.K., Institut de Chimie Moleculaire de Reims, CNRS UMR 7312, Universite de Reims
Champagne-Ardenne, Faculte de Pharmacie, 51 rue Cognacq-Jay, F-51096 Reims
ꢀ
Cedex, France, and Department of Pharmacy, University of Bari “A. Moro”,
Via E. Orabona, 4. I-70125 Bari, Italy
clayden@man.ac.uk
Received March 4, 2013
ABSTRACT
S-Alkenyl-N-arylthiocarbamates are formed from allylic alcohols by sigmatropic rearrangement and isomerization or CdC bond cleavage. They
undergo carbolithiation with a range of organolithium reagents, generating benzyllithium intermediates in a stereospecific manner which may
undergo N to C aryl migration to yield thiocarbamates with tertiary substituents. A simple base-promoted alcoholysis reveals a series of hindered
tertiary thiols with branched carbon skeletons.
Sulfur plays an essential role in many classes of func-
tional molecules,1 and 7 of the top 10 best selling drugs in
2011 contain sulfur.2 Despite this, methods for the synthe-
sis of sulfur-containing compounds are much less well
developed than those leading to their O or N counterparts.
Sulfur functions are often considered more as useful tools
for the synthesis of nonsulfur containing targets than for
the synthesis of targets that retain the sulfur atom.3 Func-
tional groups containing S(II) in particular are generally
introduced late in a synthetic sequence, using substitution
chemistry, and even quite simple classes of compounds
(chiral tertiary thiols for example) remain relatively un-
explored as synthetic targets.4
Here we show that the thiocarbamate group, by virtue of
its Li-coordinating abilities,5 provides a useful tool for the
connective synthesis of thiols by promoting the carbo-
lithiation of S-alkenyl groups. Coupling the carbolithia-
tion with intramolecular delivery of an aryl group from
N to C allows the synthesis of tertiary thiols with, in many
cases, diastereoselective control.
We previously showed that the deprotonation of
S-benzyl-N-aryl thiocarbamates leads to configurationally
stable organolithiums that undergo aryl migration
reactions typical of related functional groups to form,
† University of Manchester.
‡
ꢀ
Universite de Reims Champagne-Ardenne.
§ University of Bari “A. Moro”.
(4) Clayden, J.; MacLellan, P. Beilstein J. Org. Chem. 2011, 7, 582.
(5) (a) Kaiser, B.; Hoppe, D. Angew. Chem., Int. Ed. 1995, 34, 323. (b)
Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. 1997, 36, 2282. (c) Hoppe,
(1) (a) Mellah, M.; Voituriez, A.; Schulz, E. Chem. Rev. 2007, 107,
5133. (b) Roland, A.; Schneider, R.; Razungles, A.; Cavelier, F. Chem.
Rev. 2011, 111, 7355.
€
D.; Kaiser, K.; Stratmann, O.; Frohlich, R.; Meyer, O.; Hoppe, D.
(2) Njararson research group. http://cbc.arizona.edu/njardarson/
group/top-pharmaceuticals-poster (accessed April 8, 2013).
(3) Organosulfur Chemistry in Asymmetric Synthesis; Toru, T., Bolm,
C., Eds.; Wiley-VCH: Weinheim, 2008.
Angew. Chem., Int. Ed. 1997, 36, 2784. (d) Stratmann, O.; Kaiser, B.;
Frohlich, R.; Meyer, O.; Hoppe, D. Chem.;Eur. J. 2001, 7, 423. (e)
Frohlich, R.; Kehr, S.; Nakamura, S.; Shibata, N.; Toru, T.; Hoppe, D.
€
Chem.;Asian J. 2008, 3, 88.
r
10.1021/ol400570r
Published on Web 04/15/2013
2013 American Chemical Society

stereospecifically, a new quaternary center adjacent to
the sulfur atom.6 Carbolithiation provides a connective
alternative to deprotonation for the formation of
organolithiums,7 and with the aim of investigating the
hitherto unexplored carbolithiation of unsaturated thio-
carbamates,8 two series of alkenes were made by the
methods illustrated in Scheme 1. Adapting approaches to
N-alkenylureas9 or O-alkenylcarbamates10 requiring a
CdX-containing precursor was not an option, given the
offensiveness of thioketones,11 so an alternative route was
developed. Cinnamyl alcohols 1 were treated with thiocar-
bonyldiimidazole (TCDI, 2) to form an adduct which
underwent immediate [3,3]-sigmatropic rearrangement to
3. Methylation of the remaining imidazole and substitu-
tion by an N-methylaniline gave the thiocarbamates 4.12
These were converted into the two classes of S-alkenyl
thiocarbamates either by base-promoted isomerization to
the trisubstituted alkenes 513 or by oxidative cleavage and
reduction to give 6 followed by elimination to the disub-
stituted alkenes 7.14 The trisubstituted alkenes 5 were
formed as an inseparable mixture of E/Z isomers, in which
the Z isomer predominated (as shown by NOE).
The reactivity of S-alkenyl thiocarbamates was explored
initially with thiocarbamates 7. A series of compounds
7aÀd was first treated at À78 °C in THF with a range of
organolithiums (Scheme 2). The results are reported in
Table 1. Treatment of thiocarbamate 7aÀc with n-BuLi,
s-BuLi, PhLi, and MeLi led to the formation of the
corresponding rearranged products 9 (entries 1, 3, 4, 6,
8À12). The reaction in these cases presumably proceeds by
initial attack of the alkyllithium on the β-position of the
Scheme 1. Synthesis of S-Alkenyl-N-aryl Thiocarbamates
vinylthiocarbamate, resulting in the formation of an
intermediate organolithium 8Li by carbolithiation. The
known6 N to C aryl migration ensues, giving the rear-
ranged thiocarbamate anion 9Li and hence, after low
temperature protonation,15 the tertiary thiocarbamate 9.
Rearrangement wasnot seenwith7ausing i-PrLi orwith
t-BuLi as nucleophiles. In the first case the carbolithiation
took place to give 8b in low yield and was accompanied by
amide byproducts arising from attack of i-PrLi on the
carbonyl group of the thiocarbamate. With t-BuLi, the
carbolithiation was high yielding, and on quenching the
unrearranged addition product 8e was obtained, presum-
ably because steric hindrance at the C R to S is too great to
allow intramolecular attackon the aromatic ring16 (though
rearrangement does take place with 7b). Yields from 7c
were low, probably because of the poor reactivity of the
electron-rich tolyl ring toward attack by the benzyllithium.
With the 2,6-dimethylated ring of 7d, unsurprisingly,
carbolithiation (giving 8l) but not rearrangement was
observed, even with n-BuLi (entry 13).17
(6) Clayden, J.; MacLellan, P. Chem. Commun. 2011, 3395.
(7) (a) Klein, S.; Marek, I.; Poisson, J.-F.; Normant, J.-F. J. Am.
Chem. Soc. 1995, 117, 8853. (b) Norsikian, S.; Marek, I.; Poisson, J.-F.;
Normant, J.-F. J. Org. Chem. 1997, 62, 4898. (c) Wei, X.; Taylor, R. J. K.
Tetrahedron: Asymmetry 1997, 8, 665. (d) Norsikian, S.; Marek, I.;
Normant, J. F. Tetrahedron Lett. 1997, 38, 7523. (e) Norsikian, S.;
Marek, I.; Klein, S.; Poisson, J.-F.; Normant, J.-F. Chem.;Eur. J. 1999,
5, 2055. (f) Norsikian, S.; Baudry, M.; Normant, J.-F. Tetrahedron Lett.
2000, 41, 6575. (g) Hogan, A.-M. L.; O’Shea, D. F. J. Org. Chem. 2008,
73, 2503.
Rearrangements of the carbolithiation products of 5
were slower than those from 7 (Scheme 3). In an initial
study (Table 2, entry 1), 5a was treated with n-BuLi
at À78 °C for 2 h. The carbolithiation product 10a was
formed in high yield, but no traces of rearranged 11a were
detected (entry 1). Although the starting material 5a was a
mixture of 7:1 Z/E isomers, the product 10a was formed as
a 4:1 mixture of diastereoisomers 10a and epi-10a suggest-
ing that the intermediate organolithium 10Li may undergo
(8) Related unsaturated ureas and carbamates undergo carbo-
lithiation: N-vinyl carbamates: (a) Gericke, R.; Harting, J.; Lues,
I.; Schittenhelm, C. J. Med. Chem. 1991, 34, 3074. (b) Lepifre, F.;
Cottineau, B.; Mousset, D.; Bouyssou, P.; Coudert, G. Tetrahedron
Lett. 2004, 45, 483. (c) Cottineau, B.; Gillaizeau, I.; Farard, J.;
Auclair, M. L.; Coudert, G. Synlett 2007, 1925. O-Vinyl carbamates:
€
(d) Peters, J. G.; Seppi, M.; Frohlich, R.; Wibbeling, B.; Hoppe, D.
Synthesis 2002, 3, 381. (e) Superchi, S.; Sotomayor, N.; Miao, G.;
Joseph, B.; Campbell, M. G.; Snieckus, V. Tetrahedron Lett. 1996, 37,
6061. (f) Fournier, A. M.; Clayden, J. Org. Lett. 2012, 14, 142. N-Vinyl
ureas: (g) Clayden, J.; Donnard, M.; Lefranc, J.; Minassi, A.; Tetlow,
D. J. J. Am. Chem. Soc. 2010, 132, 6624. (h) Tait, M.; Donnard, M.;
Minassi, A.; Lefranc, J.; Bechi, B.; Carbone, G.; O’Brien, P.; Clayden, J.
Org. Lett. 2013, 15, 34. (i) Lefranc, J.; Minassi, A.; Clayden, J. Beilstein
J. Org. Chem. 2013, 6, 628.
(15) Propionic acid remains liquid even at low temperature, avoiding
lack of reproducibility associated with the warming caused by freezing of
for example acetic acid. Warming the reaction mixture before this
acidifation leads to hydrolysis of the thiocarbamate: see later.
(16) The related vinylurea behaves similarly with t-BuLi: see ref 8a
(17) 2,6-Dimethylphenyl rings do however rearrange in lithiated
ureas: Clayden, J.; Dufour, J.; Grainger, D.; Helliwell, M. J. Am. Chem.
Soc. 2007, 129, 7488.
(18) Although we could not unequivocally assign the relative config-
uration of 10 or 11, we assume, in line with precedent (ref 6, 8g) that the
carbolithiation proceeds with syn stereospecificity, that the resulting
organolithiums are (in general) configurationally stable on the time scale
of the reactions, and that both protonation and aryl migration are
retentive.
ꢀ
(9) Lefranc, J.; Tetlow, D. J.; Donnard, M.; Minassi, A.; Galvez, E.;
Clayden, J. Org. Lett. 2011, 13, 296.
(10) Fournier, A. M.; Nichols, C. J.; Vincent, M. A.; Hillier, I. H.;
Clayden, J. Chem.;Eur. J. 2012, 18, 16478.
(11) Voss, J. J. Sulfur Chem. 2009, 30, 167.
(12) For a more general method developed recently, see: Mingat, G.;
Clayden, J. Synthesis 2012, 2723.
(13) An attempted isomerization using a ruthenium hydride catalyst
(see ref 9) failed.
(14) We have since developed a more efficient route to thiocarba-
mates 7: Castagnolo, D.; Luisi, R.; Clayden, J. Manuscript in
preparation.
Org. Lett., Vol. 15, No. 9, 2013
2117

substituents was explored. Thiocarbamates 5b and 5c with
a p-chlorophenyl and 1-naphthyl migrating ring respec-
tively were treated with MeLi, n-BuLi, i-PrLi, PhLi, or
t-BuLi (entries 7À13). Even in the absence of DMPU, all
reactions gave generally moderate to good yields of carbo-
lithiationÀrearrangement products 11cÀi. However, as
had been noted with 7a, the t-BuLi adduct of 5b was
reluctant to rearrange and the major product obtained
was the addition product 10f (entry 10). The increased rate
of the rearrangement relative to any epimerization of the
reaction intermediate is evident in the stereospecificity of
these reactions. The diastereoisomeric ratios of the rear-
rangement products 11 were uniformly 6.5:1 from 5b and
30:1 from 5c, both the same as the ratios of geometrical
isomers of the starting thiocarbamates. Presumably, in
these cases, rearrangement is faster than epimerization of
the organolithium intermediate 10Li.
Scheme 2. CarbolithiationÀRearrangement of Thiocarbamates 7
Two thiocarbamates 5d and 5e bearing an electron-
donating group on the N-phenyl ring (p-Me and p-OMe
respectively) were carbolithiated with n-BuLi in the pre-
sence of DMPU (entries 14, 15). Carbolithiation of 5d did
not initiate rearrangement, and 10j was isolated as the only
product. Interestingly, the methoxy-substituted thiocarba-
mate 5e underwent stereospecific rearrangement to give a
8:1 mixture of the diastereoisomers of 11k.
Finally, carbolithiation of thiocarbamates substituted
on the ring R to the S atom were explored. Treatment of 5f
with n-BuLi at À78 °C led to the carbolithiation product
10l in high yield (entry 16), indicating that the p-chloro-
phenyl ring is compatible with the carbolithiation step.
However no traces of rearranged 11l were observed.
Increasing the temperature to À60 °C promoted some
rearrangement, with a small amount of 11l formed after
16 h (entry 17). A further increase of the temperature
to À40 °C afforded 11l in 28% yield together with a
considerable amount of 10l (entry 18). However, when
the carbolithiation was carried out atÀ60 °C for 16 h in the
presence of LiCl,20 rearranged product 11l was obtained
almost exclusively in good yield, but as a 4:1 mixture of
diastereoisomers (entry 19), probably due to epimerization
during the prolonged reaction time.
Similarly, carbolithiation of 5f with PhLi under the same
reaction conditions led to rearranged 11m as a 2:1 mixture
of diastereoisomers (entry 20). The p-fluoro group of 5g
appears to be too anion stabilizing to permit rearrangement,
and the carbolithiated product 10n was isolated in good
yield (entry 21).
Rearranged products 9 and 11 were isolated as thiocarba-
mates by quenching with acid15 at temperatures <À40 °C.
Nevertheless, the carbolithiationÀrearrangement se-
quence provides an effective method to make functio-
nalized thiols stereospecifically, since ‘deprotection’ of
N-methyl thiocarabamates is straightforward. Treatment
of 9 or 11 with NaOEt in EtOH reveals thiols 13 (from 9)
and 12 (from 11) in good yield (Scheme 4).
Table 1. CarbolithiationÀRearrangement of 7
entry
R2
thiocarbamate
R
product
yield/%
1
2
3
4
5
6
8
9
10
11
12
13
H
H
H
H
H
4-Cl
4-Cl
4-Cl
4-Cl
7a
7a
7a
7a
7a
7b
7b
7b
7b
7c
7c
7d
n-Bu
i-Pr
Ph
s-Bu
t-Bu
n-Bu
Ph
t-Bu
Me
n-Bu
Ph
9a
8b
9c
9d
8e
9f
9g
9h
9i
60
10
84
54
46
66
60
38
44
31
24
80
4-Me
4-Me
2,6-diMe
9j
9k
8l
n-Bu
partial epimerization (as indicated in Scheme 3) to epi-10Li
on the time scale of the reaction.18
Next, thiocarbamate 5a was treated with n-BuLi for 1 h
at À78 °C and the reaction mixture was then allowed to
warm slowly to room temperature over 1 h (entry 2).
Rearrangement was complete under these conditions: no
traces of carbolithiation product 10a were detected, and
instead the rearranged thiol 12a was isolated in 52% yield.
Rearrangement to thiocarbamate 11Li, followed by elim-
ination of lithium thiolate 12Li from the lithiothiocarba-
mate, probably occurs at >À40 °C.
Reaction of 5a with i-PrLi at À78 °C also led to the
formation of the carbolithiated thiocarbamate 10b as the
only reaction product in good yield (entry 3). In an attempt
toacceleratethereaction withoutpromotingepimerization
or elimination, DMPU was added to this reaction, resulting
in a 1:2 mixture of 10b and 11b (entry 4).19 Carbolithiation
of 5a with PhLi and t-BuLi led however to the formation of
the carbolithiated adducts 10c and 10d as the only products
even in the presence of DMPU (entries 5, 6).
Since the electronic properties of the migrating ring may
influence the rate of the rearrangement, the carbolithia-
tion of thiocarbamates 5bÀe bearing a range of N-aryl
(20) LiCl, like DMPU, accelerates the rate of related rearrangements,
but without causing rapid epimerization at the lithium-bearing centre:
see Fournier, A. M.; Brown, R. A.; Farnaby, W.; Miyatake-Ondozabal,
H.; Clayden, J. Org. Lett. 2010, 12, 2222.
(19) DMPU, like other lithium coordinating cosolvents, typically
accelerates aryl migrations in organolithiums. See ref 17.
2118
Org. Lett., Vol. 15, No. 9, 2013

Scheme 3. Stereospecificity in the CarbolithiationÀRearrangement of Thiocarbamates 5
a 5c has an N-ethyl rather than an N-methyl substituent.
Table 2. CarbolithiationÀRearrangement of 5
Scheme 4. Tertiary Thiols from Tertiary Thiocarbamates
Z/E
entry R1
R2
SM ratio R = product yield/% dr
1
2
3
4
H
H
H
H
H
H
H
H
5a 7:1 n-Bu
5a 7:1 n-Bua
5a 7:1 i-Pr
5a 7:1 i-Prb
10a
12a
10b
10b
11b
10c
10d
11c
11d
11e
10f
11f
11g
11h
11i
10j
11k
10l
10l
11l
78
52
63
39
18
33
36
66
81
58
37
13
65
41
61
55
35
81
49
8
4:1
À
2:1
3.5:1
c
5
6
7
8
H
H
H
H
H
H
H
H
4-Cl
4-Cl
4-Cl
4-Cl
5a 7:1 Ph
5a 7:1 t-Bu
5b 6.5:1 Me
5b 6.5:1 n-Bu
5b 6.5:1 Ph
5b 6.5:1 t-Bu
À
1.6:1
c
À
6.5:1
6.5:1
5.6:1
9
10
11
12
13
14
15
H
H
H
H
H
2,3-benzod 5ce 30:1 n-Bu
2,3-benzod 5ce 30:1 i-Pr
2,3-benzod 5ce 30:1 Ph
4-Me
4-OMe
30:1
30:1
30:1
1:1
5d 6:1 n-Bub
5e 8:1 n-Bub
5f 5:1 n-Bu
5f 5:1 n-Buf
8:1
16 4-Cl H
17 4-Cl H
2.3:1
1.5:1
>4:1
1:1
18 4-Cl H
5f 5:1 n-Bug
10l
11l
57
28
55
65
76
5:1
4:1
2:1
2.3:1
19 4-Cl H
20 4-Cl H
21 4-F
5f 5:1 n-Buf,h 11l
5f 5:1 Phf,h
5g 8:1 n-Bu
11m
10n
H
a Allowed to warm to rt. b DMPU added (10:1 THF/DMPU by
vol. = ca. 6 equiv). c Not determined. d 1-Naphthyl. e 5c has an N-Et
rather than an N-Me substituent. f At À60 °C. g At À40 °C. h LiCl
(4 equiv) added.
Ricerca” (code: RBFR083M5N). We thank Ms. Marju
Laars (Tallinn University of Technology) for preliminary
studies.
In summary, carbolithiation of vinyl thiocarbamates gen-
erates benzylic organolithiums that may undergo intramole-
cular arylation to provide tertiary thiocarbamates, which are
themselves precursors to new families of tertiary thiols.
Supporting Information Available. Characterization
and experimental details for new compounds. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. This work was supported by the
EPSRC and by National Project “FIRB - Futuro in
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
2119