Enantiomerically enriched atropisomeric N,N′-diaryl ureas by oxidative kinetic resolution of their 2-sulfanyl derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.02.021

Atropisomeric N-methyl-N,N′-diaryl ureas may be obtained in enantiomerically enriched form by oxidative kinetic resolution of their sulfide derivatives. The atropisomeric sulfides may be obtained in up to 97:3 er and display high stability to racemisation

Full text of DOI:10.1016/j.tetlet.2009.02.021

Tetrahedron Letters 50 (2009) 3216–3219
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantiomerically enriched atropisomeric N,N0-diaryl ureas by oxidative
kinetic resolution of their 2-sulfanyl derivatives
*
Jonathan Clayden , Hazel Turner
School of Chemistry, University of Manchester, Oxford Rd., Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Atropisomeric N-methyl-N,N0-diaryl ureas may be obtained in enantiomerically enriched form by oxida-
tive kinetic resolution of their sulfide derivatives. The atropisomeric sulfides may be obtained in up to
97:3 er and display high stability to racemisation (half-lives at 25 °C of up to 500 years). Unlike related
fully alkylated ureas, the product sulfoxides exhibit relatively weak thermodynamic conformational
selectivity.
Article history:
Received 15 January 2009
Revised 23 January 2009
Accepted 2 February 2009
Available online 8 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The last 50 years has seen biaryl atropisomers emerge as a class
of compounds rich in utility for the development of valuable chiral
ligands and chiral catalysts.1 More recently, families of atropisom-
ers based on structures other than biaryls2 have come to the fore as
potential new sources of such structures, and atropisomeric
anilides, benzamides and naphthamides have been used as chiral
ligands, catalysts, auxiliaries and starting materials.3,4
The conformational properties of aryl ureas prompted us to
investigate them as a further potential class of atropisomers, and
we recently reported that hindered ureas not only display atrop-
isomerism,5 but also show high diastereoselectivity in their reac-
tions.6 Moreover, their rich lithiation chemistry makes their
derivatisation and conversion to other related compound classes
particularly straightforward.7,8
This work was all carried out in the racemic series, and in order
to widen the potential utility of atropisomeric ureas, we sought a
method for their asymmetric synthesis. Non-classical resolution
methods have been particularly successful when applied to non-
biaryl atropisomers,9–12 and in this Letter, we report the first asym-
metric synthesis of atropisomeric ureas, using the strategy of ki-
netic resolution.
We have previously made use of dynamic resolution under
thermodynamic control for the asymmetric synthesis of atropiso-
meric amides4,10,13 and ethers,11 and in a preliminary attempt to
extend our methods employing sulfoxide controlling groups to
atropisomeric ureas, we synthesised the sulfoxides syn- and anti-
3a–e by ortholithiation7 of urea 1, either quenching the lithio
derivative directly with a thiosulfinate ester RS(O)SR11 or by first
forming the sulfide 2 then oxidising to the sulfoxide (Scheme 1).
Mixtures of diastereoisomers of 3 were formed in the ratios
indicated.
O
O
1. s-BuLi,
THF, –78 °C
2. R2S2
Me
Me
N
NHPh
N
NHPh
SR
2a R = Me
2b R = c-Hx
2c R = p-Tol
1
route A
route B
1. s-BuLi,
THF, –78 °C
2. RS(O)SR
m-CPBA
NHPh
O
N
O
N
NHPh
Me
Me
+
S
R
S
R
O
O
syn-3
route A
3d R = i-Pr 39%; 85:15
3e R = t-Bu <10%; 90:10
anti-3
route B
3a R = Me 95%; 62:38
3b R = c-Hx 57%; 59:41
3c R = p-Tol 28% 57:43
Scheme 1. Kinetic diastereoselectivity in the formation of sulfinyl-substituted 2-t-
butyl ureas. Yields are from 1.
Diastereoisomeric ratios were greater when 3 was made by
Route A, but yields were low. Ratios obtained by oxidation with
m-CPBA were poor, and remained unchanged on heating in reflux-
ing toluene for extended periods of time (>24 h). We therefore
assume that these product ratios represent selectivity under kinetic
control, with the steric encumbrance of the t-butyl substituent
* Corresponding author.
E-mail address: j.p.clayden@manchester.ac.uk (J. Clayden).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.021

J. Clayden, H. Turner / Tetrahedron Letters 50 (2009) 3216–3219
3217
O
O
O
oxidant,
Ti(Oi-Pr)4 or
VO(acac)2
1. s-BuLi,
THF, –78 °C
2. R2S2
Me
X
Me
X
Me
N
NHPh
N
NHPh
SR
N
NHPh
SR
X
X
X
ligand (10-13)
6a or 7a (R = Me)
6b (R = c-Hx)
6c or 7c (R = p-Tol)
4 (X = Me)
5 (X = SiMe3)
( )-2 or ( )-7
O
O
N
NHPh
NHPh
m-CPBA
Me
Me
N
+
2 or 7
O
O
X
S
O
X
S
R
R
NHPh
NHPh
Me
X
Me
X
O
N
N
+
S
S
R
O
X
X
syn-3 or 9
anti-3 or 9
R
O
tol, Δ
syn-8 (X = Me)
syn-9 (X = SiMe3)
syn-10 (X = H)
anti-8 (X = Me)
anti-9 (X = SiMe3)
anti-10 (X = H)
OH
CsF,
tol, Δ
I
EtO2C
CO2Et
tol, Δ
OH
10
60:40
75:25
80:20
8a (R = Me) 55%; 66:34
8b (R = c-Hx) 53%; 65:35
8c (R = p-Tol) 40% 58:42
N
OH
OH
I
OH
N
OH
13
tol, Δ
N
61:39
9a (R = Me) 51%; 53:47
9c (R = p-Tol) 89%; 75:25
Ph
CsF
Ph
10a (R = Me) 70:30
10b (R = p-Tol) 80:20
12
OH
OH
11
Scheme 2. Kinetic and thermodynamic diastereoselectivity in the formation of
sulfinyl-substituted ureas. Yields are from 4 or 5.
Scheme 3. Kinetic resolution of 2-sulfanyl ureas.1
presenting
a large barrier to Ar–N rotation and consequent
vided the major product diastereoisomer anti-3a in good enan-
tiomeric excess. The remaining sulfide 2a was isolated from this
reaction in 30% yield and with 97:3 er, constituting the first isola-
tion of an enantiomerically enriched atropisomeric urea (entry 5).
From these results, we calculate18 a selectivity factor (S factor) of
>300 for kinetic resolution of 2a.14
A similar kinetic resolution occurred when 2b was used as a
starting material: anti-3b was formed with good diastereoselectiv-
ity and with good er, but it was not possible to determine the er of
the remaining starting material (entry 6). In contrast, p-tolylsulfide
2c (entry 7) oxidised slowly and unselectively under these condi-
tions (S factor = 2). An alternative methylsulfide, 7a, was also oxi-
dised selectively (S factor = 8) to give remaining 7a in good er
when driven to 63% completion (entry 8).
epimerisation.14
Given previous successes with asymmetric synthesis by
dynamic resolution under thermodynamic control,4,9–11,13 we next
investigated oxidation of the less hindered analogues 6a–c and 7a,
c made from the ureas 4 and 5. The structure of 5 was chosen on
the basis that the silyl groups would assist selectivity for ortholith-
iation to yield 7,15 and would also allow simpler methyl substi-
tuted derivatives to be formed later by desilylation. On oxidation
of 6 or 7, mixtures of diastereoisomeric sulfoxides 8a–c and 9a, c
were initially obtained with low selectivity. However, on this occa-
sion heating 8a, 8b and 8c in refluxing toluene led to epimerisation
to a 1.5:1–4:1 mixture of diastereoisomers (Scheme 2), with a clear
dependence of the ratio on the size of R. Desilylation of 9a and 9c
with caesium fluoride in refluxing toluene returned the methyl
substituted sulfoxides 10a and 10c likewise with relatively poor
thermodynamic selectivity.
Incubation of recovered (+)-2a in toluene at 110 °C, resulted in
slow first order loss of enantiomeric purity with time, and an Eyr-
ing analysis16 of the decay allowed us to determine a barrier to rac-
emisation
D
Gzrac ¼ 132 kJmolꢀ1, corresponding to an estimated19
The diastereoisomers of 8a were separated by chromatography,
and an Eyring analysis of the change in anti:syn ratio of 8a with
time at 65 °C in toluene allowed us to deduce a barrier to epimer-
half-life for racemisation at 25 °C of 500 years (Scheme 4).
Similar treatment of (+)-7a led to much faster racemisation: at
65 °C racemisation was almost complete within three days, and
isation by N–Ar rotation
D
Gzepim ¼ 114 kJmolꢀ1 for syn-6a and
117 kJ mol–1 for anti-6a.16 These figures are broadly in accord with
barriers to rotation of related compounds.5
analysis for the decay gave
D
Gzrac ¼ 112 kJmolꢀ1, corresponding to
an estimated half-life for racemisation at 25 °C of 8 weeks. Re-
moval of the silyl groups from (+)-5a with CsF in refluxing toluene
returned a 2-methyl substituted urea but in racemic form, presum-
ably because the barrier to racemisation is even lower.
2-Sulfinyl derivatives 3, 8 and 9 of these N-alkyl-N,N0-diarylu-
reas evidently display relatively poor thermodynamic selectivity,
making dynamic resolution under thermodynamic control using
sulfoxide substituents an unsuitable method for their asymmet-
ric synthesis. Instead, we therefore turned to asymmetric oxida-
tion of 2 or 7 as a potential method for kinetic resolution
(Scheme 3). Trial oxidations of 2a were attempted with perox-
ides in the presence of one of four ligands 10-1317 and the
results are detailed in Table 1, entries 1–5. High diastereo-
selectivity in the oxidation was obtained by vanadium-catalysed
oxidation with the (S)-tert-leucinol derived imine ligand 10,17i
and despite the presence of 1.2 equiv oxidant, this reaction
which reached no further than 50% completion and also pro-
It is interesting that the thermodynamically determined con-
formational selectivities observed for sulfinyl-substituted N-al-
kyl-N,N0-diaryl ureas 3, 8, 9 and 10 are significantly poorer
than those reported previously for (synthetically less versatile)
N,N0-dialkyl-N,N0-diaryl ureas.20 Indeed, when we methylated
the mixture of atropisomers 10b we observed, after equilibra-
tion, an increase in the ratio of conformers from 80:20 to
1
For identity of X, see Table 1.

3218
J. Clayden, H. Turner / Tetrahedron Letters 50 (2009) 3216–3219
Table 1
Kinetic resolution in the oxidation of sulfanyl ureas under the conditions of Scheme 3
Entry
S.M.
X=
R=
Catalyst
Oxidant,
equiv
Extent of
reaction (%)
er remaining
S.M
Product, ratio
syn:anti
er of syn
sulfoxide
Cacld S
factor
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2b
2c
7a
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
(Me3Si)2CH
Me
Me
Me
Me
10 + Ti(Oi-Pr)4
10 + Ti(Oi-Pr)4
11 + Ti(Oi-Pr)4
12 + VO(acac)2
13 + VO(acac)2
13 + VO(acac)2
13 + VO(acac)2
13 + VO(acac)2
t-BuOOH, 2
PhMe2COOH, 2
t-BuOOH, 2
H2O2, 2
H2O2, 1.2
H2O2, 1.2
81
79
41
39
49
43
24
63
—
—
—
—
3a, 33:67
3a, 38:62
3a, 46:54
3a, 58:42
3a, 95:5
3b, 84:13
3c, 55:45
9a, 59:41
—
—
—
—
86:14
89:11
—
—
—
—
–
300
—
2
Me
97:3a
—
c-Hx
p-Tol
Me
H2O2, 2.4
H2O2, 1.2
55:45
93:7b
—
8
a
Isolated in 30% yield.
Isolated in 25% yield.
b
the sulfinyl substituent in a more hindered environment and
thus leads to higher selectivity.
In summary, we present the first method for the asymmetric
synthesis of atropisomeric ureas, employing kinetic resolution
of a sulfide. Stable atropisomeric ureas were obtained in up to
97:3 er.
O
N
NHPh
SMe
e.r. = 97:3; [ α]D22 = +64
ΔG‡rac = 132 kJ mol–1
t1/2(25 °C) = ca. 500 yrs
Me
(+)-2a
Acknowledgements
We are grateful to Organon Laboratories (Lanarkshire, Scotland)
and to the EPSRC for their support, and to Dr. E. Moir for many
helpful discussions.
O
N
NHPh
SMe
Me
e.r. = 93:7; [ α]D22 = +50
ΔG‡rac = 112 kJ mol–1
t1/2(25 °C) = ca. 8 weeks
Me3Si
References and notes
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Ph endo
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3219
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