Enantioselective synthesis of tertiary thiols by intramolecular arylation of lithiated thiocarbamates

Article abstract of DOI:10.1039/c0cc04912c

Lithiation of N-aryl S-α-alkylbenzyl thiocarbamates leads to rearrangement with migration of the N-aryl ring to the anionic centre α to S, a process which generally proceeds with ca. 98% retention of stereochemistry and returns chiral benzylic tertiary thiols in high enantiomeric ratios.

Full text of DOI:10.1039/c0cc04912c

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COMMUNICATION
Enantioselective synthesis of tertiary thiols by intramolecular arylation of
lithiated thiocarbamatesw
Paul MacLellan and Jonathan Clayden*
Received 11th November 2010, Accepted 2nd February 2011
DOI: 10.1039/c0cc04912c
Lithiation of N-aryl S-a-alkylbenzyl thiocarbamates leads to
rearrangement with migration of the N-aryl ring to the anionic
centre a to S, a process which generally proceeds with ca. 98%
retention of stereochemistry and returns chiral benzylic tertiary
thiols in high enantiomeric ratios.
rearrangement to occur, but it substantially improved the yield
of 6a and of 6b.7 The longer reaction time required with 5d led
to cleavage of the thiocarbamate product to secondary thiol
7d. In the other cases deprotection of the product with sodium
ethoxide in ethanol returned the thiols 7, with or without
purification of the rearranged thiocarbamates. Thiocarbamate
cleavage was also generally observed when work-ups were
performed under basic conditions.
The asymmetric synthesis of simple tertiary alcohols 2 is
generally achieved by controlling enantiofacial selectivity in
a
prochiral ketone.1 Comparable
Hoppe had shown that a-methylbenzylthiocarbamate deriv-
atives of hindered amines may be deprotonated with alkyl-
lithiums to give configurationally stable benzyllithiums which
react stereospecifically (and usually invertively) with electro-
philes.8 We hoped to combine the reactivity revealed in
Scheme 1 with the deprotonation of an enantiopure substituted
benzylthiocarbamate as a means of achieving the otherwise
challenging asymmetric synthesis of chiral tertiary thiols.
Enantiomerically enriched (98 : 2 e.r.) thiocarbamate (S)-8a
was treated with LDA under the same conditions as 5
(Scheme 3). An excellent yield of the rearranged thiocarbamate
(S)-9a was obtained, but in essentially racemic form. DMPU
has been noted to promote racemisation of benzylic organo-
lithiums,6 and by carrying out the rearrangement in THF
alone higher enantiomeric ratios were obtained, both at
À78 1C and À60 1C. No reaction occurred in toluene, and in
Et2O rearrangement was slow. Nonetheless, a small but
significant loss of e.r. was consistently observed with LDA or
sec-BuLi in THF. A change of the base to LiTMP led to slower,
but almost completely stereospecific9 rearrangement: (S)-9a was
formed in 83% yield and 96 : 4 e.r. after 15 h at À78 1C.
The absolute stereochemistry of (S)-9a was determined by
cleavage of the thiocarbamate function with sodium ethoxide
to yield thiol (S)-10a, from which crystalline p-nitrothiobenzoate
derivative (S)-11 was formed (Scheme 3). Single crystal X-ray
analysis (Fig. 1) revealed that the rearrangement proceeded
with overall retention of configuration.10
nucleophilic attack on
approaches to tertiary thiols 1 are not practical, because of
the instability of thioketones, their tendency to undergo nucleo-
philic attack at sulfur rather than carbon, and their intolerable
stench.2 Alternative methods involving inversion at tertiary
centres,3 alkylation of S-substituted enolates,4 or conjugate
addition of sulfur nucleophiles5 are limited to structures
containing a- or b-carbonyl substituents. As a result, enantio-
merically pure tertiary thiols are, despite the simplicity of their
structure, a remarkably difficult class of compounds to make.
In this paper we report a solution to this problem. Treatment
of thiocarbamates 3 with base leads to intramolecular, stereo-
specific arylation to yield 4, and mild deprotection of 4 allows
the practical synthesis of enantiomerically enriched chiral
tertiary thiols 1 (Scheme 1).
Recent work on the lithiation of N-aryl carbamates6 had
indicated that such structures are unstable towards migration
of the N-aryl group to an anionic carbon atom, and we
suspected similar properties might be evident in the thio-
carbamate series. For a preliminary study to establish the
stability and reactivity of lithiated N-aryl thiocarbamates, a
group of simple N-aryl thiocarbamates 5a–d were made in one
step from commercially available benzylthiols. Thiocarba-
mates 5a–d were treated at À78 1C with 2 equiv LDA in a
4 : 1 mixture of THF and DMPU, conditions developed during
related work on the rearrangement of carbamates. After 2 h,
the reactions were quenched with propionic acid, and high
yields of products 6a–c were isolated in which, remarkably, the
N-aryl ring had migrated to the position a to the sulfur
(Scheme 2). DMPU was not always necessary for the
School of Chemistry, University of Manchester, Oxford Road,
Manchester M13 9PL, UK. E-mail: clayden@man.ac.uk
w Electronic supplementary information (ESI) available. CCDC
781954. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c0cc04912c
Scheme 1 Tertiary thiols and alcohols by aryl migration.
Chem. Commun., 2011, 47, 3395–3397 3395
c
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alcohols (R)-12. We found that the most effective way to carry
out this transformation was by invertive substitution of the
N,N-dimethylaminoformamidate derivative with thioacetic
acid,11 lithium aluminium hydride reduction, and coupling
with appropriate N-methylaniline via its carbonylimidazolium
adduct 1312 (Scheme 4). The thiocarbamates 8 were treated
with LiTMP in THF at À78 1C to yield rearranged products 9
with the yields and enantioselectivities shown in the Table 1.
Electron deficient (8d–f) and moderately electron rich (8a,c)
aryl rings migrate with good to excellent yield and selectivity,
as do moderately hindered aryl rings (8c,h). In most cases, the
products were formed highly stereospecifically with an e.r. no
more than 2% lower than the starting material. While the
more electron rich ring of 8b failed to migrate under these
conditions, we found that adding DMPU promoted rearrange-
ment in good yield but without enantioselectivity. High yields
but some loss of enantiomeric purity was also observed in 8k
(with an electron-deficient anion-stabilising ring) and cyclic 8m.
Stirring the thiocarbamates 9 with sodium ethoxide in
ethanol at ambient temperature led to rapid formation of
the thiols 10 in generally excellent yield (Scheme 4). These
chiral tertiary thiols showed no tendency to oxidise to disulfides,
and had an inoffensive odour reminiscent of grapefruit.
a
Scheme 2 Arylation of benzylthiocarbamates. 0% without DMPU;
b64% without DMPU; cYield from 5 without isolation of 6; dRequires
15 h at À60 1C; product isolated as thiol.
When the rearrangement was carried out using a mixture of
8f and 8k, mass spectrometry of the crude reaction mixture
showed only the products of intramolecular rearrangement.
We assume this rearrangement proceeds (Scheme 5) by initial
deprotonation at the benzylic site of 8 to yield a dipole-
stabilised carbanion,13 the benzyllithium represented as 14.
S-Benzylic thiocarbamates have been reported to be highly
configurationally stable, even at 0 1C.8 Retentive attack of the
Scheme 3 Stereospecificity in the aryl migration.
Fig. 1 X-ray crystal structure and absolute stereochemistry of (S)-11.
A series of chiral benzylic thiocarbamates 8a–m were made
in enantiomerically enriched form (generally 98 : 2 e.r., as
indicated in the Table 1) from the corresponding benzyl
Table 1 Scope of the rearrangement
SM, e.r.
Ar1
Ar2
R
9 yield (%) 9 e.r.
(S)-8a 98 : 2
(S)-8b 98 : 2
(S)-8c 97 : 3
(S)-8d 98 : 2
(S)-8e 98 : 2
(S)-8f 98 : 2
(S)-8g 98 : 2
(S)-8h 99 : 1
(S)-8i 98 : 2
(R)-8j 99 : 1
(R)-8k 96 : 4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-OMeC6H4
2-OMeC6H4
4-ClC6H4
3-ClC6H4
4-CNC6H4
Me 83
Me 94a
Me 89
Me 94
Me 69
Me 78
96 : 4
50 : 50
91 : 9
96 : 4
96 : 4
97 : 3
—
96 : 4
—
98 : 2
67 : 33
50 : 50
2,4,6-triMeC6H2 Me
0
1-Naphthyl
3-FC6H4
4-MeC6H4
Me 98
Me
0
n-Pr 74
Me 85
Me 86
3-CF3 Ph
(Æ)-8l 50 : 50 4-OMe 4-MeC6H4
(R)-8m 79 : 21
87
74 : 26
a
With DMPU (no reaction in absence of DMPU).
Scheme 4 Enantioselective synthesis of tertiary thiols 10.
c
3396 Chem. Commun., 2011, 47, 3395–3397
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Lett., 1976, 4295. A synthesis of thioacetone in Freiburg in 1889 was
abandoned after widespread public protests and the evacuation of
whole sectors of the city: see J. Voss, J. Sulfur Chem., 2009, 30, 167;
J. Clayden, et al., Organic Chemistry, OUP, Oxford, 2001, p. 4;
G. W. Kutney and K. Turnbull, J. Chem. Educ., 1984, 61, 372.
3 Y. Mukaiyama, K. Ikegai and W. Pluempanupat, Chem. Lett.,
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Bull. Chem. Soc. Jpn., 2006, 79, 780.
4 M. Kellogg and B. Strijtveen, Tetrahedron, 1987, 43, 5039;
J. M. McFadden, G. L. Frehywot and C. A. Townsend, Org.
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5 C. Palomo, M. Oiarbide, F. Dias, R. Lopez and A. Linden, Angew.
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R. T. Lopez, P. B. Gonzalez, E. Gomez-Bengoa, J. M. Saa and
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6 (a) J. Clayden, W. Farnaby, D. M. Grainger, U. Hennecke,
M. Mancinelli, D. J. Tetlow, I. H. Hillier and M. A. Vincent,
J. Am. Chem. Soc., 2009, 131, 3410; (b) A. M. Fournier,
R. A. Brown, W. Farnaby, H. Miyatake-Ondozabal and
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7 DMPU tends to increase substantially the nucleophilicity of organo-
lithiums: see ref. 14a and J. Clayden, F. E. Knowles and C. J. Menet,
Tetrahedron Lett., 2003, 44, 3397; J. Clayden, S. Parris, N. Cabedo
and A. H. Payne, Angew. Chem., Int. Ed., 2008, 47, 5060.
Scheme 5 Mechanistic overview.
carbanion centre of 1414 on the migrating aryl ring would yield
a transient dearomatised spirocycle 15 which may or may
not15 be a true intermediate. Ring opening of 15 generates
lithiocarbamate 16 and hence 9 in a reaction related to the
Truce-Smiles rearrangement.16,17
The slight loss of e.r. evident in all the rearrangements, but
particularly that of 8c, 8k, 8m and those involving LDA, was
ascribed to partial racemisation of 14 on the timescale of the
migration (rather than incompletely retentive attack on the
benzyllithium) because the e.r. of the product was found to be
time-dependent. When the rearrangement of 8k with LiTMP
was quenched after only 2 min, 14% 9k was obtained in 87 : 13
e.r., in contrast with an 85% yield and 68 : 32 e.r. after 15 h.
Likewise, treating 8a with LDA over various reaction times
(see supporting information) and quenching with CD3OD
showed that the product 9a was formed in low yield but higher
enantiomeric purity after short reaction times (18% and 94 : 6
e.r. after 10 min) than after longer ones (76% and 88 : 12 e.r.
after 40 min). Remaining starting material recovered from
these reactions was deuterated to the extent of 11% after 2 min
and 40% after 10 min, but was also found to be partially
racemised to an extent corresponding to the degree of deuteration,
suggesting that 14 racemises slowly and rearranges with high
retentive stereospecificity but deuterates essentially stereo-
randomly. The longer reaction times required and higher
e.r.s obtained with LiTMP are presumably a consequence of
slower lithiation coupled with higher configurational stability
resulting from increased steric bulk.18
8 O. Stratmann, B. Kaiser, R. Frohlich, O. Meyer and D. Hoppe,
¨
Chem.–Eur. J., 2001, 7, 423; F. Marr and D. Hoppe, Org. Lett.,
2002, 4, 4217; F. Marr, R. Frohlich and D. Hoppe, Org. Lett.,
¨
1999, 1, 2081. After deprotection of the bulky thiocarbamates,
these methods also allow the synthesis of tertiary thiols by intro-
duction of an alkyl group, rather than the arylation described here.
9 We use ‘‘stereospecific’’ in the sense of Zimmerman
(H. E. Zimmerman, L. Singer and B. S. Thyagarajan, J. Am.
Chem. Soc., 1959, 81, 108) as recommended by Eliel (E. L. Eliel
and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley,
New York, 1994) to mean a reaction whose stereochemical out-
come is dependent on the stereochemistry of the starting material.
10 X-ray data for (S)-11 has been deposited with the Cambridge
Crystallographic Data Cantre, deposition number 781954.
C22H19NO3S, Mr 377.44, monoclinic, P21, a 7.686(4), b 6.722(3),
c 18.277(0) A, b 93.998(8)1, 2701 reflections of which 2701 unique,
absolute structure parameter 0.09(15).
11 Y. Kawano, N. Kaneko and T. Mukaiyama, Chem. Lett., 2005, 34,
1612. The invertive substitution was generally reliable except with
electron rich benzylic alcohols, which gave rise to racemic
products, presumably due to intervention of an SN1 pathway.
12 R. A. Batey, C. Yoshina-Ishii, S. D. Taylor and V. Santhakumar,
Tetrahedron Lett., 1999, 40, 2669; J. A. Grzyb, M. Shen,
C. Yoshina-Ishii, W. Chi, R. S. Brown and R. A. Batey, Tetra-
hedron, 2005, 61, 7153.
The rearrangement of thiocarbamates offers chemists the
ability, for the first time, to synthesise a class of chiral tertiary
thiols in an asymmetric manner and to exploit their chemistry.
With many of the most widely used drugs containing sulfur
atoms, we expect this new method for the synthesis of a
previously unavailable compound type of such simplicity to
have an impact of the availability of new targets, both in
medicinal chemistry and also more widely in the design of
ligands for synthetic chemistry.
13 M. C. Whisler, M. MacNeil, V. Snieckus and P. Beak, Angew.
Chem., Int. Ed., 2004, 43, 2207.
14 Benzyllithiums may react with either retention or inversion,
depending on the electrophile: J. Clayden, Organolithiums selectivity
for synthesis, Pergamon, Oxford, 2003, pp. 249–256. Aryl migration
in lithiated carbamates is invertive (ref. 6) while aryl migration in
lithiated ureas (ref. 16) is retentive (ref. 16a,b). All reactions of
lithiated benzylthiocarbamates with electrophiles, bar protonation,
are reported to be invertive (ref. 8).
15 A dearomatised intermediate formed during naphthyl migration in
a lithiated urea has been trapped by oxidation (ref. 16a). Calcula-
tions on lithiated carbamates indicate however that in general
cyclic structures such as 15 are not minima on the reaction pathway
(see ref. 6a), and the detailed mechanism of this and related aryl
migrations is still unestablished.
16 For related reactions of ureas, see (a) J. Clayden, J. Dufour,
D. Grainger and M. Helliwell, J. Am. Chem. Soc., 2007, 129,
7488; (b) J. Clayden, M. Donnard, J. Lefranc, A. Minassi and
D. J. Tetlow, J. Am. Chem. Soc., 2010, 132, 6624; (c) J. Clayden
and U. Hennecke, Org. Lett., 2008, 10, 3567; (d) R. Bach,
J. Clayden and U. Hennecke, Synlett, 2009, 421.
We are grateful to the Royal Society of Chemistry for
funding this work through the Briggs scholarship (to PM)
and Hickinbottom award (to JC), and to Dr Madeleine
Helliwell for determining the X-ray crystal structure of (S)-11.
Notes and references
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c
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Chem. Commun., 2011, 47, 3395–3397 3397