Tertiary thiols from allylic thiocarbamates by tandem enantioselective [3,3]-sigmatropic rearrangement and stereospecific arylation

Article abstract of DOI:10.1021/ol5002522

The synthesis of tertiary thiols in enantiomerically enriched form is accomplished by lithiation of enantiomerically enriched N-aryl allylic thiocarbamates. Formation of an allyllithium derivative promotes intramolecular N to C aryl migration to the posit

Full text of DOI:10.1021/ol5002522

Letter
pubs.acs.org/OrgLett
Tertiary Thiols from Allylic Thiocarbamates by Tandem
Enantioselective [3,3]-Sigmatropic Rearrangement and
Stereospecific Arylation
Gaelle Mingat, Paul MacLellan, Marju Laars, and Jonathan Clayden*
̈
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
S
* Supporting Information
ABSTRACT: The synthesis of tertiary thiols in enantiomerically enriched form is accomplished by lithiation of enantiomerically
enriched N-aryl allylic thiocarbamates. Formation of an allyllithium derivative promotes intramolecular N to C aryl migration to
the position α to sulfur, generally with good stereospecificity. The substrates may themselves be obtained by Pd-catalyzed
enantioselective [3,3]-sigmatropic rearrangement of N-aryl O-allyl thiocarbamates. Solvolysis of the product thiocarbamates
yields tertiary thiols, which may be converted to sulfide derivatives.
f simple functional groups based on commonly occurring
elements, thiols must be among the most neglected.
is present in (S)-3-thio-3-methylhexan-1-ol 2, a component of
the smell of sweat, while (R)-thioterpineol 3 and 4-thio-4-
methylpentan-2-one 4 give the characteristic odors to grapefruit
and passion fruit.4
O
Thiols have little associated synthetic chemistry beyond trivial
substitution, addition, and redox reactions, and the synthesis of
thiols is invariably accomplished by late-stage introduction of
sulfur.1 Because of the impracticality of using thiocarbonyl
compounds as precursors,2 the asymmetric synthesis of thiols
and their simple derivatives is, with a handful of exceptions,
achieved by stereospecific substitution of chiral electrophilic
precursors.1 For substitution patterns compatible with SN2
reactions, this strategy has general application, but it means that
the general asymmetric synthesis of simple tertiary thiols
remains, remarkably, essentially an incompletely solved
problem.3
In this paper, we show that the rich chemistry of allylic
thiocarbamates5 provides a solution to the challenge of
synthesizing a range of tertiary thiols in enantiomerically pure
form. We show that enantiomerically pure allylic N-aryl
thiocarbamates may be synthesized by enantioselective [3,3]-
sigmatropic rearrangement and that lithiation of these
compounds promotes aryl migration from N to C, leading to
enantiospecific construction of quaternary stereogenic centers
bearing sulfur. From these products a range of tertiary thiols
and their derivatives may be made by simple thiocarbamate
hydrolysis.
Thiols are nonetheless widespread in nature (Figure 1).
Though a rare residue in proteins, Cys is present in the key
metabolic antioxidant glutathione 1. Tertiary thiol functionality
In the past few years, it has become clear that deprotonation
of N-aryl derivatives of the class of functional groups
ArNRCOX (X = NR′2: ureas;6 OR′: carbamates;7 SR′:
thiocarbamates8) typically leads to migration of the aryl
substituent from N to C, generally9 stereospecifically. Such
reactions create a new quaternary stereogenic carbon atom,10
and therefore with X = SR provide a plausible strategy for the
synthesis of tertiary thiols.3
Previous explorations in the area8 had employed only
benzylic thiocarbamates. Generalization of the reaction to a
fuller range of tertiary thiol targets is made possible by
Received: January 23, 2014
Published: February 6, 2014
Figure 1. Naturally occurring thiols.
© 2014 American Chemical Society
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Organic Letters
Letter
rearrangement. Rearrangement was invariably regiospecific,
with the substitution pattern of the starting material conserved
in the product. Warming the reaction mixture above −40 °C
prior to acidification led to partial or complete collapse of the
product thiocarbamate to the free thiol (see, for example, the
reaction of 6l).
Scheme 1. N to C Aryl Migration in an N-Aryl Allylic
Thiocarbamate
Enantiomerically enriched S-allyl thiocarbamates may be
readily generated by enantioselective palladium-catalyzed
sigmatropic rearrangement of O-allyl thiocarbamates 5 in the
presence of either the [(R,Sp)-(−)-COP-Cl]2 complex ((R)-
COP-Cl) 815 or with the bisphosphine [(R,R)-DACH-phenyl]
916 as a chiral ligand. These two catalytic methods were
compared in the rearrangement of 5b to 6b, as shown in
Scheme 2 and Table 2, with method A employing catalyst 8
promoting the generation of (R)-6b in 92% yield and 91:9 er.17
Method B gave lower enantioselectivity (ca. 80:20 er) and was
not explored further.
Using method A of Scheme 2, with 8 as a catalyst, we
prepared a series of enantioenriched S-allyl thiocarbamates 6 in
excellent yields, with enantiomeric ratios from 80:20 to 95:5.
Resubjection of rearranged S-allyl thiocarbamate 6g (3-F) (with
82:18 er) to the standard reaction conditions for a period of
15−40 h led to no racemization, indicating that the
rearrangement is irreversible. Reaction at a lower temperature
(0 °C) gave a better er of 94:6, but the reaction reached only
half-completion.
exploiting the chemistry of allylic thiocarbamates.11 Thiocarba-
mate 6a was made straightforwardly from crotyl alcohol via
[3,3]-sigmatropic rearrangement of 5a12 and treated with LDA
in THF for 2 h at −78 °C (Scheme 1). After acidic quench, the
rearranged tertiary thiocarbamate 7a was recovered in 78%
yield. Presumably, α-deprotonation of 6a generates an
allyllithium intermediate 6aLi whose nucleophilic α-carbon
attacks the N-aryl ring in an intramolecular aromatic
substitution reaction13 to yield the anion of 7a, which is
protonated on workup.
The successful arylation of 6a led us to explore a range of
allyl thiocarbamate structures and a range of migrating aromatic
rings. The results of these rearrangements are shown in Table
1. Rearrangements took place between −78 and −45 °C, and in
some cases lithium chloride was added14 to improve yields.
Migration was successful with a range of electron-deficient and
electron-rich rings substituted in the o, m, or p positions,
despite the nucleophilic aromatic substitution step of the
Scheme 2. Palladium-Catalyzed [3,3]-Sigmatropic
Rearrangements for the Enantioselective Synthesis of 6
Table 1. Aryl Migration in Racemic S-Allylic Thiocarbamates
Table 2. Enantioselective Synthesis of Thiocarbamates 6 by
Pd-Catalyzed Asymmetric Sigmatropic Rearrangement
(Scheme 2, Method A)
starting material
R1
R2
R3
product yield (%)
6b
6c
6d
6e
6f
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
Me
Me
H
7b
7c
7d
7e
7f
68
56
97
86
73
68
68
54
62
42
56
33
44
78
78
R2
R3
product yield (%)
er
a
a
a
starting material
4-Me
4-F
5a
5b
5c
5d
5e
5f
Me
Me
Me
Me
Me
Me
Me
Me
Me
n-Pr
n-Pr
n-Pr
4-Cl
H
(R)-6a
(R)-6b
(R)-6c
(R)-6d
(R)-6e
(R)-6f
(R)-6g
(R)-6g
(R)-6h
(R)-6j
(R)-6k
(R)-6l
95
92
99
94
95
98
89:11
91:9
3-OMe
3-Cl
4-Me
4-F
89:11
90:10
83:17
80:20
82:18
6g
6h
6i
3-F
7g
7h
7i
b
2,3-benzo
2-pyridyl
4-Cl
3-OMe
3-Cl
a
a
a
a
a
a
a
a
6j
7j
5g
5g
5h
5j
3-F
97
a
a
6k
6l
4-F
7k
10l
7l
3-F
<50
94:6
,
c
b
3-Cl
2,3-benzo
4-Cl
95
84:16
94:6
91:9
95:5
c
6l
3-Cl
91
d
d
6m
6n
6o
4-Me
4-Me
4-F
7m
7n
7o
5k
5l
4-F
92
93
3-Cl
a
1
Reaction run at 0 °C, 48 h. 50% conversion was determined by H
a
b
c
b
c
d
LiCl (5 equiv) was added. 1-Naphthyl. Reaction warmed to −45 to
−40 °C: the isolated product is the free thiol.
NMR . 1-Naphthyl. Rearranged at 14 °C for 48 h. Rearranged at 21
°C for 4−5 days.
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Letter
In general, para-substituted N-aryl rings gave the best er
values (89:11 to 94:6), while ortho- or meta-substituted rings
showed decreased enantioselectivity. Notably, the propyl-
bearing allylic thiocarbamates all rearranged with excellent
enantioselectivities, whatever the substitution pattern of the
aromatic ring.
Scheme 3. Solvolysis and Alkylation
The enantiomerically enriched thiocarbamates (R)-6 were
lithiated with LDA in THF and gave thiocarbamates (R)-7 in
enantiomerically enriched form (Table 3). The R configuration
Table 4. Formation of Thiols 10 and Sulfides 11/12
Table 3. Stereospecificity in the N to C Aryl Migration
yield
yield
starting
material
10
11/12
R2
R3
product
(%)
R4
(%)
a
(R)-7a
7d
Me
Me
Me
Me
Me
Me
n-Pr
n-Pr
4-Cl
4-F
(R)-10a
10d
26
a
20
7e
3-OMe
3-Cl
10e
90
87
59
92
67
80
Me
11e, 89
(R)-7f
(R)-7g
(R)-7h
7j
(R)-10f
(R)-10g
(R)-10h
10j
starting
material
yield
(%)
3-F
allyl
(R)-12g, 95
R2
R3
product
er of 6 er of 7
b
2,3-benzo
4-Cl
(R)-6a
(R)-6b
(R)-6c
(R)-6d
(R)-6e
(R)-6f
(R)-6g
(R)-6h
(R)-6j
(R)-6k
(R)-6l
Me
Me
Me
Me
Me
Me
Me
Me
4-Cl
H
(R)-7a
(R)-7b
7c
98
63
91:9
91:9
91:9
85:15
57:43
70:30
82:18
80:20
82:18
80:20
96:4
(R)-7l
3-Cl
(R)-10l
a
a
b
4-Me
4-F
11
89:11
89:11
83:17
80:20
82:18
84:16
96:4
Volatile product. 1-Naphthyl.
a
(R)-7d
(R)-7e
(R)-7f
(R)-7g
(R)-7h
(R)-7j
(R)-7k
(R)-7l
40
a
3-OMe
3-Cl
89
94
BuLi and electrophilic quench with methyl iodide or allyl
bromide to yield sulfides 11 and 12.
a
3-F
100
b
2,3-benzo
100
In summary, we show that the challenge of making
enantiomerically enriched tertiary thiols may be met through
an enantioselective [3,3]-sigmatropic rearrangement, leading to
enantioenriched allylic thiocarbamates. These may be rear-
ranged stereospecifically to give thiocarbamate derivatives of
allylic tertiary thiols. The thiols may be revealed by solvolysis
and converted by standard chemistry to a range of sulfide
derivatives.
a
n-Pr 4-Cl
n-Pr 4-F
n-Pr 3-Cl
81
a
52
91:9
72:28
94:6
a,c
48
95:5
a
b
c
LiCl (5 equiv) was added. 1-Naphthyl. Reaction warmed to −50
°C.
was assigned to starting materials 6 on the basis of the known
enantioselectivity of sigmatropic rearrangement induced by
(R,Sp)-COP-Cl15 and to products 7 on the basis of circular
dichroism studies of the products arising from further
transformations of the products 7 and their analogues.17 In
many cases, the aryl migration proceeded with complete
enantiospecificity, in other words, without loss of enantiomeric
purity. However, there were a few significant exceptions: the
greatest loss of er was seen in 7b (with an unsubstituted Ph
ring), 7c (whose ring has a 4-Me substituent), and 7d and 7k
(4-F). These all share the feature of lacking a substituent that
may activate the ipso carbon of the N-aryl ring toward
nucleophilic attack. Notably, less π donating groups, such as
4-Cl, or π-donating groups located in the 3-position, such as 3-
OMe, allow rearrangement with full enantiospecificity. We
interpret this as an indication that π donating groups at the 4-
position decelerate the rearrangement to the point where
racemization of the intermediate allyllithium 6Li proceeds at a
comparable rate.18
The product thiocarbamates 7, which carry an acidic NH
proton, were highly succeptible to hydrolysis under mildly basic
conditions, and indeed, a low-temperature acidic quench was
routinely employed to prevent in situ hydrolysis after
rearrangement. Their enantiomerically enriched tertiary thiol
derivatives 10 were most cleanly obtained by treatment of the
thiocarbamates 7 with NaOEt in EtOH/Et2O at 0 °C (Scheme
3 and Table 4). Some of the thiols were highly volatile,
compromising isolated yields. Alkylation of these hindered
thiols was achieved by low-temperature deprotonation with
ASSOCIATED CONTENT
* Supporting Information
Experimental data and characterization for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: clayden@man.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the EPSRC for a studentship (to G.M.) and the RSC
for the Briggs Scholarship (to P.M.).
■
REFERENCES
■
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(17) The R configuration of compounds 6 was assigned initially on
the basis of precedent, given the published enantioselectivity (ref 15)
of related sigmatropic rearrangements using (R,Sp)-COP-Cl, and the R
configuration of compounds 7 on the basis that intramolecular
arylation of related benzylic thiocarbamates proceeds with retention of
configuration (ref 8). Circular dichroism studies of the products arising
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preparation) have since confirmed the assignment of (R)-configuration
to 7.
(18) The enantiomeric ratio did not change as the reaction
proceeded. Attempts to decelerate the racemization in less
coordinating solvents or by using more bulky bases (such as
LiTMP; see ref 8a) were unsuccessful.
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