Achieving conformational control over C-C, C-N and C-O bonds in biaryls, N,N′-diarylureas and diaryl ethers: Advantages of a relay axis

Article abstract of DOI:10.1039/b614618j

The orientation of Ar-C, Ar-N and Ar-O bonds in biaryls, N,N′-diarylureas and diaryl ethers (whose conformers are distinguishable by NMR) may be controlled with a selectivity up to >95: 5 by an adjacent stereogenic centre; the selectivity may be greater when a second stereogenic axis is inserted between the controlling centre and the slowly rotating bond. The Royal Society of Chemistry.

Full text of DOI:10.1039/b614618j

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Achieving conformational control over C–C, C–N and C–O bonds in
biaryls, N,N9-diarylureas and diaryl ethers: advantages of a relay axis{
Mark S. Betson, Ann Bracegirdle, Jonathan Clayden,* Madeleine Helliwell, Andrew Lund, Mark Pickworth,
Timothy J. Snape and Christopher P. Worrall
Received (in Cambridge, UK) 9th October 2006, Accepted 23rd November 2006
First published as an Advance Article on the web 18th December 2006
DOI: 10.1039/b614618j
We used two types of stereogenic centre, X, to control the axial
conformation (Scheme 2), both of which had performed well with
amides:11 the sulfoxides shown as X = x (with the substituent Z
alternatively Me, p-Tol, t-Bu or other alkyl groups) and the
oxazolidine shown as X = y (formed by condensation of (2)-
ephedrine13 with the corresponding aldehydes X = CHO). We also
measured conformational ratios when the bonds under investiga-
tion were located ortho to a rotationally restricted amide group
–CONi-Pr2 (X = z). Biphenyls14 3 (X = Br) were made by a Suzuki
coupling between 2-iodobromobenzene and a range of arylboronic
acids,15 and converted via bromine–lithium exchange to 3x, 3y and
3z. Ureas16 4 were made by the condensation of an appropriate
aniline with phenyl isocyanate, followed by methylation and
conversion to 4x and 4y via bromine–lithium exchange. Diaryl
ethers17 5 were formed by the nucleophilic aromatic substitution of
chloride from 3-bromo-2-chlorobenzonitrile by 2-tert-butylphen-
oxide, reduction to 5 (R = CH2OMe, X = Br) and conversion to
5x and 5y via bromine–lithium exchange. 5z was made by the same
route, with R = CN and X = CONi-Pr2, throughout.
The orientation of Ar–C, Ar–N and Ar–O bonds in biaryls,
N,N9-diarylureas and diaryl ethers (whose conformers are
distinguishable by NMR) may be controlled with a selectivity
up to .95 : 5 by an adjacent stereogenic centre; the selectivity
may be greater when a second stereogenic axis is inserted
between the controlling centre and the slowly rotating bond.
The orientation of functional groups1 has consequences for crystal
engineering,2 for the design of ligands, sensors and other supra-
molecular assemblies,3 for stereoselective synthesis4 via chiral
memory5 and relay,6,7 and for the asymmetric synthesis of atropi-
somers.8,9 Compared to conformational control in rings, rational
conformational control in acyclic systems is in its infancy.10 Using
tertiary aromatic amides (whose conformation can be readily
studied by NMR) as a model, we showed recently that certain
classes of stereogenic centre may exert a remarkably high degree of
conformational control over the orientation of a nearby substi-
tuent.11 For example, amides 1 generally adopt the conformation
1A rather than 1B, with .20 : 1 selectivity, while in amides related
to 2, the conformational selectivity can reach 200 : 1 2A : 2B
(Scheme 1).12 We have used the conformational bias exhibited by
these and other amides as the basis of a strategy for the asym-
metric synthesis of atropisomers under thermodynamic control.9
It seemed reasonable to propose that control of C–C, along with
C–N and C–O bonds, would be achievable in related structures by
locating the bonds adjacent to appropriately chosen stereogenic
centres. Biaryls 3, N,N9-diaryl ureas 4 and diaryl ethers 5 provide
useful model compounds for these studies, and in this commu-
nication we report on the success of this strategy. We show that,
perhaps surprisingly, greater conformational control is sometimes
possible when the centre is located further away from the axis, with
the stereochemical influence being relayed (and amplified) by an
intervening tertiary aromatic amide.
Scheme 2 Synthesis of ortho-substituted biaryls, diaryl ureas and diaryl
ethers. Reagents and conditions a: Pd(PPh3)4, Na2CO3, EtOH, H2O; b:
n-BuLi, THF; c: [for Z = p-Tol] (–)-menthyl para-toluenesulfinate or [for
Z = t-Bu] t-BuS(O)St-Bu or [for Z = Me] (i) Me2S2, (ii) m-CPBA or [for
Z = i-Pr] (i) i-Pr2S2, (ii) m-CPBA or [for Z = c-Hex] cyclohexylsulfinyl
diacetonyl glucose or [for Z = a-Me-c-Hex] (i) LiTMP, (ii) MeI; d:
Me2NCHO; e: (2)-ephedrine, Tol, D; f: ClCONi-Pr2; g: PhNCO, CH2Cl2;
h: NaH, MeI; i: (COCl)2, Me2NCHO, CH2Cl2; j: HNi-Pr2, Et3N, CH2Cl2;
k: H2, Pd/C; l: LiTMP, THF, 290 uC; m: C2Cl6; n: DIBAL; o: NaBH4.
Scheme 1 Conformational control in amides.
School of Chemistry, University of Manchester, Oxford Road,
Manchester, UK M13 9PL. E-mail: clayden@man.ac.uk;
Fax: +44 (0)161 275 4939
{ Electronic supplementary information (ESI) available: ball-and-stick
representations of the X-ray crystal structures reported. See DOI: 10.1039/
b614618j
754 | Chem. Commun., 2007, 754–756
This journal is ß The Royal Society of Chemistry 2007

View Article Online
Slow C–C, C–N or C–O bond rotation yields two sets of peaks
in the NMR spectra of many of these compounds at ambient
temperature. We assign these to conformers A (major) and B
(minor), as shown (for 3x–5x) in Scheme 3 and as indicated in the
footnotes of Table 1. In several cases, the interconvertibility of the
species giving rise to the paired peaks was confirmed by dynamic
NMR analysis or by separation and re-equilibration: the ratios in
Table 1 are governed thermodynamically.
Table 1 Conformational ratios in biaryls, ureas and diaryl ethers
Entry Compound R
Z
Ratio A : B Solventa
1
2
3
4
5
6
7
3x
3y
Me
OMe
Me
t-Bu
t-Bu
—
—
—
28 : 72b,b CDCl3
59 : 41b
50 : 50
50 : 50
50 : 50
50 : 50
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
c
Et
Benzod
OMe
Me
—
—
3z
75 : 25e,f CDCl3
Sulfoxides (X = x) in general gave good control over bond
orientation. Increasing the steric bulk of the sulfoxide substituent Z
significantly increased conformational selectivity (Table 1, entries
18–22 and 26–38). Low ratios were observed for biaryls 3x, with
biaryl ethers 5x performing better and N,N9-diarylureas 4x being
the most effectively controlled. With Z = t-Bu or Z = p-Tol, single
sets of peaks were observed in the NMR spectra of 4x. This high
level of control led us to suppose that the conformer 4xA, seen in
the X-ray crystal structure (Fig. 1(a)),21 is also the unique
conformer in solution. Control in 5x depended heavily on Z, with
only t-Bu and a-methylcyclohexyl sulfoxides giving good con-
formational selectivity (Table 1, entries 34–38). We again assign
the major conformer as structure 5xA on the basis of the X-ray
crystal structure of 5x (Z = t-Bu, R = CH2OMe) (Fig. 1(b)).21
Much less effective conformational control was provided by the
oxazolidines X = y (Table 1, entries 3–6, 23, 24 and 39), in stark
contrast to the control they achieve over amides 1 (Scheme 1).
We propose a common origin for the conformational control in
4x and 5x, arising from the sum of the steric and electronic effects
illustrated in Scheme 3. Fig. 1(a) and 1(b) show the powerful
dipole of the sulfoxide S–O bond more or less opposing the dipole
associated with the Ar–N or Ar–O bond, with this electronic
interaction fixing the orientation of the sulfoxide group by
populating essentially just one Ar–S rotamer. Control over the
orientation of the Ar–N or Ar–O bond is then supplied by steric
interactions between the sulfoxide substituent Z and the rest of
the diaryl urea or diaryl ether moiety, explaining the dependence
on the size of Z. Solvent effects appear to be weak (Table 1,
entries 35–38).
8
9
Et
i-Pr
—
—
—
—
—
—
—
—
75 : 25g
75 : 25g
80 : 20g
.94 : 6e,h
.94 : 6i
.94 : 6i
.94 : 6i
.94 : 6j
.94 : 6j
.94 : 6j
50 : 50
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
d8-THFl
d8-Toluene
d8-THFn
d8-THFn
CDCl3
d8-THFp
d8-Toluene
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
a
Benzoa
OMe
OEt
Oi-Pr
Cl
CO2H
CO2Me
CHO
—
—
4x
4y
H (p-Me)k Me
Br
Me
50 : 50
H (p-Me)k p-Tol
H (p-Me)k t-Bu
.95 : 5m
.95 : 5o
.95 : 5o
50 : 50
Br
H (p-Me)k
Br
p-Tol
—
—
—
Me
p-Tol
i-Pr
c-Hex
50 : 50
.95 : 5q
50 : 50
4z
5x
H
CN
CN
CN
CN
60 : 40b
57 : 43r
60 : 40r
57 : 43r
60 : 40r
CH2OMe Me
CH2OMe p-Tol
CH2OMe i-Pr
CH2OMe c-Hex
CH2OMe a-Me-c-Hex
CH2OMe t-Bu
CH2OMe t-Bu
CH2OMe t-Bu
CH2OMe t-Bu
Ac
CN
Me
OMe
Me
66 : 34r.s CDCl3
57 : 43r
80 : 20r
86 : 14t
86 : 14t
88 : 12u
88 : 12u
66 : 34b
57 : 43b
75 : 25u
.94 : 6u
80 : 20v
93 : 7v
CDCl3
CDCl3
CDCl3
C6D6
d8-THF
CD3OD
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
5y
5z
6x
—
—
p-Tol
p-Tol
—
6y
OMe
H (p-Me)
—
—
Dipoles also appear to govern the selectivities observed in the
amido substituted 3z, 4z and 5z structures (Table 1, entries 7–17,
25 and 40). For diaryl ethers 5z or biaryls 3z (R = alkyl), levels of
control are relatively low, but replacing the R = alkyl substituent
of 3z with a polar group R = OR9, Cl or COR9 raises the control
markedly. Single conformers are likewise observed for ureas 4z,
and we propose that 4zA is also the conformer evident in the X-ray
crystal structure of 4z.21 The control in these compounds seems to
arise from an electronic interaction between the dipole of the
amide’s CLO group and, in the case of 3z, the induced dipole in the
second ring, or in the case of 4z, the urea carbonyl group
(Scheme 4). A steric effect may also be at work in 4z.
10y
.95 : 5w
b
Ratio measured at +25 uC unless otherwise stated. Major isomer
assigned arbitrarily. c NMR recorded at 0 uC. d Upper ring is 1-naphthyl.
Preferred conformer assigned by molecular modelling (Monte Carlo
e
f
search, 5000 steps, MM2*, Macromodel). Conformer A favoured by
3.0 kJ mol21
.
.
g
h
By analogy with entry 7. Conformer A favoured by
By analogy with entry 11. By analogy with the Ar–Ar
7.8 kJ mol21
conformational preference of other 29-carbonyl substituted
i
j
2-phenylbenzamides.6,18 k These compounds carry, in addition, a methyl
l
m
group para to the urea N. NMR recorded at –90 uC. Assumed
preference for the conformation displayed in the crystalline state: see
Fig. 1(a). NMR spectra recorded at +25 and at –90 uC. By analogy
n
o
p
q
with entry 20. NMR spectrum recorded at –50 uC. Assumed
preference for the conformation displayed in the crystalline state: see ref.
r
s
21. By analogy with entry 35. 2-D TLC indicates interconversion of
t
the conformers on a timescale of minutes. Assumed preference for the
u
conformation displayed in the crystalline state: see Fig. 1(b). On the
basis of the conformational preference of 2-amidosulfoxides8,11,12 and of
2-amido biaryls (entries 7 and 11). On the basis of the known
v
conformational preference of 2-amidophenyl oxazolines9,11,19,20 and of
2-amido biaryls (entry 7). Assumed preference for the conformation
displayed in the crystalline state: see ref. 21.
w
The coupling of axial conformations, evident in 3z and 4z, raises
the possibility of using an amide axis to amplify the effect of a
stereocontrolling centre by interposing it between that centre and
Scheme 3 Conformational control with a sulfoxide substituent.
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Chem. Commun., 2007, 754–756 | 755

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and biaryl conformations in these compounds is less secure
(compare Table 1 pairs of entries 41/42 and 43/44 with the pair of
entries 7/11).
These results indicate that rational control over C–C, C–N and
C–O bond conformation is possible by judicious exploitation of
dipolar interactions. We are currently extending this work to the
study of stereochemical relay effects,8 and to the stereoselective
synthesis of new classes of atropisomers.
We are grateful to the Leverhulme Trust, EPSRC,
GlaxoSmithKline and Pfizer for supporting this work.
Notes and references
Fig. 1 (a) X-Ray crystal structure of 4x (R = H, Z = p-Tol); (b) X-Ray
crystal structure of 5x (R = CH2OMe; Z = t-Bu).21,22
1 M. S. Betson, J. Clayden, H. K. Lam and M. Helliwell, Angew. Chem.,
Int. Ed., 2005, 44, 1241.
2 M. L. Bushey, T.-Q. Nguyen, W. Zhang, D. Horoszewski and
C. Nuckolls, Angew. Chem., Int. Ed., 2004, 43, 5446.
3 L. O. Abouderbala, W. J. Belcher, M. G. Boutelle, P. J. Cragg,
J. W. Steed, D. R. Turner and K. J. Wallace, Proc. Natl. Acad. Sci.
U. S. A., 2002, 99, 5001; K. J. Wallace, W. J. Belcher, D. R. Turner,
K. F. Syed and J. W. Steed, J. Am. Chem. Soc., 2003, 125, 9699;
G. Hennrich and E. V. Anslyn, Chem.–Eur. J., 2002, 8, 2219;
K. V. Kilway and J. S. Siegel, Tetrahedron, 2001, 57, 3615.
4 J. Clayden, Chem. Commun., 2004, 127.
5 J. Clayden, C. C. Stimson and M. Keenan, Synlett, 2005, 1716; M. Petit,
A. J. B. Lapierre and D. P. Curran, J. Am. Chem. Soc., 2005, 127,
14994.
6 J. Clayden, A. Lund, L. Vallverdu´ and M. Helliwell, Nature, 2004, 431,
966.
Scheme 4 Conformational communication with amides.
7 J. Clayden and N. Vassiliou, Org. Biomol. Chem., 2006, 4, 2667.
8 J. Clayden, D. Mitjans and L. H. Youssef, J. Am. Chem. Soc., 2002,
124, 5266.
9 J. Clayden, L. W. Lai and M. Helliwell, Tetrahedron, 2004, 60, 4399.
10 R. W. Hoffmann, Angew. Chem., Int. Ed., 2000, 39, 2054.
11 M. S. Betson, J. Clayden, M. Helliwell, P. Johnson, L. W. Lai, J. H. Pink,
C. C. Stimson, N. Vassiliou, N. Westlund, S. A. Yasin and
L. H. Youssef, Org. Biomol. Chem., 2006, 4, 424.
12 M. S. Betson, J. Clayden, M. Helliwell and D. Mitjans, Org. Biomol.
Chem., 2005, 3, 3898.
13 C. Agami and T. Rizk, Tetrahedron, 1985, 41, 537.
14 Biaryls bearing only two ortho-substituents are not usually atropisomeric
(however, see: W. B. Jennings, B. M. Farrell and J. F. Malone, J. Org.
Chem., 2006, 71, 2277; A. Herrbach, A. Marinetti, O. Baudoin,
D. Gue´nard and F. Gue´ritte, J. Org. Chem., 2003, 68, 4897; O. Desponds
and M. Schlosser, Tetrahedron Lett., 1996, 37, 47), but have C–C
conformers that are distinguishable by NMR: see G. Bott, L. D. Field
and S. Sternhell, J. Am. Chem. Soc., 1980, 102, 5618; A. Mazzanti,
L. Lunazzi, M. Minzoni and J. E. Anderson, J. Org. Chem., 2006, 71,
5474.
Scheme 5 Amplification and relay of conformational control. Reagents
and conditions a: sec-BuLi, THF, 278 uC; b: (2)-menthyl toluenesulfi-
nate; c: Me2NCHO; d: (2)-ephedrine, toluene, D; e: KMnO4; f: (COCl)2,
Me2NCHO, CH2Cl2; g: HNi-Pr2, Et3N, CH2Cl2; h: SnCl2?2H2O, HCl; i:
PhNCO, CH2Cl2; j: NaH, MeI; k: n-BuLi, THF, 278 uC.
an otherwise poorly controlled axis. To test this hypothesis, we
made biaryls 6x and 6y (R = Me and OMe) by the ortho-lithiation
of 3z (Scheme 5). We also made diaryl urea 10y from 7. Oxidation
and amide formation gave 8, which was shown to be chiral by
HPLC on a chiral stationary phase. Reduction and urea formation
gave 9, which, like 4z, was conformationally uniform. Halogen
metal exchange and conversion via the aldehyde to the oxazolidine
gave 10y whose X-ray crystal structure is shown in the
supplementary information.{21
15 G. Karig, M.-T. Moon, N. Thasana and T. Gallagher, Org. Lett., 2002,
4, 3115.
16 C–N bond rotation in N,N9-diarylureas may be slow on the NMR
timescale, though N,N9-diarylureas are not generally atropisomeric. See:
T. Adler, J. Bonjoch, J. Clayden, M. Font-Bard´ıa, M. Pickworth,
X. Solans, D. Sole´ and L. Vallverdu´, Org. Biomol. Chem., 2005, 3, 3173.
17 Tri-ortho-substituted diaryl ethers 5 exhibit conformers that are not
atropisomers but are distinguishable by NMR. See: M. S. Betson,
J. Clayden, C. P. Worrall and S. Peace, Angew. Chem., Int. Ed., 2006,
45, 5803.
The NMR spectra of 6x (R = OMe), 6y (R = OMe) and 10y
indicated that these compounds exist almost entirely as single
conformers about their Ar–Ar or Ar–N bonds (Table 1, entries 42,
44 and 45), despite the fact that their congeners 3x (R = OMe), 3y
(R = OMe) and 4y, in which the oxazolidine lies directly adjacent
to the axis, exhibit only poor conformational control (Table 1,
entries 2, 6, 23 and 24). The amide successfully picks up the
stereocontrolling influence of the oxazolidine, amplifies and inverts
it (suggesting projection19 as an apt analogy), and hence induces
control over an adjacent C–C or C–N bond. Control in 6x and 6y
(R = Me) is unsurprisingly less good, since the coupling of amide
18 J. Clayden, A. Lund and L. H. Youssef, Org. Lett., 2001, 3, 4133.
19 J. Clayden and L. W. Lai, Tetrahedron Lett., 2001, 42, 3163.
20 J. Clayden, L. W. Lai and M. Helliwell, Tetrahedron: Asymmetry, 2001,
12, 695.
21 X-ray crystallographic data and ball-and-stick figures of crystal
structures reported in this paper may be found in the Electronic
Supporting Information. CCDC 623108 (4x, R = H, Z = p-Tol), 623109
(5x, R = CH2OMe, Z = t-Bu), 623110 (4z, R = H) and 623110 (10y).
For crystallographic data in CIF or other electronic format see DOI:
10.1039/b614618j.
22 For clarity and consistency of conformational representation, Fig. 1(b)
shows a molecule enantiomeric with that described in the accompanying
crystallographic data.
756 | Chem. Commun., 2007, 754–756
This journal is ß The Royal Society of Chemistry 2007