Conformational preference and remote (1,10) stereocontrol in biphenyl-2,2′-dicarboxamides

Article abstract of DOI:10.1021/ol0167457

(Matrix Presented) The double ortholithiation and electrophilic quench of N,N,N′N′-tetraisopropylbiphenyl-2,2′-dicarboxamide 1 is diastereoselective, giving the chiral C₂-symmetric atropisomers of the 3,3′-disubstituted products 3. These chiral

Full text of DOI:10.1021/ol0167457

ORGANIC
LETTERS
2001
Vol. 3, No. 26
4133-4136
Conformational Preference and Remote
(1,10) Stereocontrol in
Biphenyl-2,2′-dicarboxamides
Jonathan Clayden,* Andrew Lund, and Latifa H. Youssef
Department of Chemistry, UniVersity of Manchester, Oxford Road,
Manchester M13 9PL, U.K.
j.p.clayden@man.ac.uk
Received September 12, 2001
ABSTRACT
The double ortholithiation and electrophilic quench of N,N,N′N′-tetraisopropylbiphenyl-2,2′-dicarboxamide 1 is diastereoselective, giving the
chiral, C -symmetric atropisomers of the 3,3′-disubstituted products 3. These chiral atropisomers can be converted with moderate to good
2
stereoselectivity to their achiral, centrosymmetric epimers by heating. The stereoselectivity of the double lithiation-quench reaction is determined
by the stereochemistry of the intermediate doubly lithiated species 2, either diastereoisomer of which may be formed stereospecfically from
the corresponding atropisomeric dibromo compounds.
Tertiary amide groups in substituted benzamides do not lie
coplanar with the aromatic ring and adopt a more-or-less
perpendicular conformation1 whose stereochemistry depends
on the influence of other stereogenic centers and axes within
the molecule.2 This feature allows tertiary amide groups to
relay stereochemistry, and we have used them in the control
of remote relationships between new stereogenic centers3 or
axes.4 In this paper we show that despite conformational
freedom about the biaryl axis the tertiary amide substituents
of a biphenyl-2,2′-dicarboxamide remain in stereochemical
communication and that they direct the atroposelective
formation of a range of products from 3,3′-diortholithiation
and electrophilic quench.
N,N,N′,N′-Tetraisopropylbiphenyl-2,2′-dicarboxamide 1
was made from 2,2′-biphenic acid by a standard method (3
equiv of (COCl)2, cat. DMF, then 10 equiv of i-Pr2NH). The
1H NMR spectrum of 1 showed a single set of four methyl
doublets down to -20 °C, suggesting that 1 exists in solution
as a single Ar-CO conformer.5 Its X-ray crystal structure
is shown in Figure 1.
Amide 1 was resistant to double ortholithiation,6 but
treatment with 6-10 equiv of s-BuLi in the presence of
TMEDA gave the dilithio species 2, which reacted with
electrophiles (MeI, EtI, DMF, or Me3SiCl) to give the
3,3′-disubstituted products 3a, 3b, 3c, and 3e, as shown in
Scheme 1.
(1) (a) Bowles, P.; Clayden, J.; Helliwell, M.; McCarthy, C.; Tomkinson,
M.; Westlund, N. J. Chem. Soc., Perkin Trans. 1 1997, 2607. (b) Ahmed,
A.; Bragg, R. A.; Clayden, J.; Lai, L. W.; McCarthy, C.; Pink, J. H.;
Westlund, N.; Yasin, S. A. Tetrahedron 1998, 54, 13277.
(2) (a) Clayden, J.; Lai, L. W. Angew. Chem., Int. Ed. 1999, 38, 2556.
(b) Clayden, J.; Johnson, P.; Pink, J. H.; Helliwell, M. J. Org. Chem. 2000,
65, 7033. (c) Clayden, J.; Lai, L. W. Tetrahedron Lett. 2001, 42, 3163.
(3) (a) Clayden, J.; Pink, J. H.; Yasin, S. A. Tetrahedron Lett. 1998, 39,
105. (b) Clayden, J.; Kenworthy, M. N.; Youssef, L. H. Tetrahedron Lett.
2000, 41, 5171. (c) Clayden, J.; Lai, L. W.; Helliwell, M. Tetrahedron:
Asymmetry 2001, 12, 695.
(5) Below -20 °C, decoalescences occur as a result of slow Ar-Ar
rotation. Rotation of the conformer shown in Figure 1 about the Ar-Ar
axis is an enantiomerization and would interconvert the signals of the two
rings.
(4) Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1999,
40, 3331.
(6) (a) Mills, R. J.; Horvath, R. F.; Sibi, M. P.; Snieckus, V. Tetrahedron
Lett. 1985, 26, 1145. (b) Snieckus, V. Chem. ReV. 1990, 90, 879.
10.1021/ol0167457 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/27/2001

atropisomers,8 the Ar-Ar axes of 3 are not expected to be
stereogenic, though the aryl rings will not lie coplanar. On
average, therefore, the atropisomers of 3 will be either chiral
and C2 symmetric (C2-3) or achiral and S2-symmetric )
centrosymmetric (S2-3).
Analytical HPLC on a chiral stationary phase9 showed that
the major products of methylation and ethylation of 1 are
chiral and confirmed the assignments of these compounds
as C2-3a and C2-3b. However, on heating (toluene, reflux,
1 h) both C2-3a and C2-3b epimerized to give, with moderate
to good selectivity, atropisomers that could no longer be
resolved by HPLC on a chiral stationary phase and must
therefore be S2-3a and S2-3b (Figure 2). The kinetic products
Figure 1. X-ray crystal structure of 1.
Because the tertiary amide groups of 3 are each flanked
by two ortho substituents, they possess stereogenic Ar-CO
axes,1 in principle allowing compounds 3 to exist as either
of two atropisomers.7 Since a biphenyl axis usually requires
at least three ortho substituents for its conformers to become
Scheme 1. Atropisomers of Biphenyl-2,2′-dicarboxamidesa
Figure 2. Analytical HPLC traces (chiral stationary phase)9 of (a)
C2-3a; (b) equilibrated mixture of S2-3a and C2-3a.
of the lithiation-quench of 1 are therefore C2-3, while the
more stable atropisomers are S2-3.
By contrast, the products of bis-formylation and bis-
silylation of 1 (3c and 3e) were isolated as a mixture of
atropisomers that displayed no change in stereochemistry on
heating. This is presumably because the -CHO and -SiMe3
substituents provide typically poor barriers to bond rotation,1b
and the isolated products contain an already-equilibrated
mixture of atropisomers. The major isomer of 3c in this
mixture was apparently the achiral S2-3c since neither it nor
its reduction product, the diol S2-3d, could be resolved by
HPLC on a chiral stationary phase.10 Surprisingly, however,
the major isomer of 3e in the equilibrated mixture appeared
to be C2-3e, since double ipso bromo-desilylation with Br2
11
in CCl4 gave mainly the chiral dibromide C2-3f. Heating
this C2-3f-rich mixture in refluxing toluene for 1 h epimerized
it to the achiral atropisomer S2-3f.
Since C2-3a and C2-3b are formed selectively under kinetic
control, either the intermediate 3,3-dilithio species 2 has C2
symmetry (maybe C2-2 is more stable than S2-2 or perhaps
(7) For a related case, see ref 4.
(8) (a) Adams, R.; Yuan, H. C. Chem. ReV. 1933, 12, 261. (b) Eliel, E.
L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley: New York,
1994.
(9) Whelk-O1 from Regis.
(10) Consistent differences between the 1H NMR spectra of C2-3 and
S2-3 confirmed this assignment. In the compounds assigned as C2-3a-f
the highest field methyl doublet lies between δ 0.20 and 0.35; in the
compounds assigned as S2-3a-f the highest field methyl doublet lies
between δ 0.80 and 0.90.
a Reagents: (i) 6-10 equiv of s-BuLi, TMEDA, THF, -78 °C,
30 min; (ii) MeI or EtI or Me2NCHO or Me3SiCl; (iii) toluene,
reflux, 1 h; (iv) NaBH4, EtOH, 0 °C, 30 min; (v) 10 equiv of Br2,
CCl4, reflux, 12 h; (vi) 4 equiv of t-BuLi, THF, -78 °C, 5 min;
(vii) +10 °C, 1 h; (viii) excess MeI, -78 °C.
(11) Mills, R. J.; Taylor, N. J.; Snieckus, V. J. Org. Chem. 1989, 54,
4372.
4134
Org. Lett., Vol. 3, No. 26, 2001

over nucleophilic addition to nearby carbonyl groups.13 The
fact that the two amide groups of 3 are in stereochemical
communication therefore offers the prospect of using bi-
phenyl-2,2′-dicarboxamides to mediate the remote control
of stereochemistry.14 C2-3b and C2-3a were doubly laterally
lithiated (s-BuLi, THF, -78 °C) and treated with phenyldi-
methylsilyl chloride and N-methylbenzaldimine as electro-
philes. Yields were poor, but in both cases a single
diastereoisomer 4 or 5 was produced. Silane 4 carries 1,8-
related and amine 5 1,10-related stereogenic centers.
Scheme 2. Remote Stereocontrol with a
Biphenyl-2,2′-dicarboxamidea
It was also possible to use the amide pair to relay (or
“project”3c) stereochemistry from an auxiliary [(-)-ephedrine
7] attached to one ring to a new stereogenic center attached
to the other. Amide 1 was monolithiated (3 equiv of n-BuLi,
TMEDA, -78 °C, THF) and formylated to give 6, which
condensed with (-)-ephedrine 7 to form the oxazolidine 8.
A second formylation gave 9, apparently as a single
conformer by NMR, presumably (given the S2 conformational
preference of symmetrical 3,3′-disubstituted compounds 3)
as shown in Scheme 3. The addition of aryl Grignard reagents
gave excellent yields of the alcohol 10 as a single diastereo-
isomer.15 The stereoselectivity of the reaction demonstrates
the ability of the amides to project the stereochemistry at
the (-)-ephedrine-derived stereogenic center of 9 to a
prochiral center nine bond lengths away.
a Reagents: (i) 6-10 equiv of s-BuLi, TMEDA, THF, -78 °C;
(ii) PhMe2SiCl, -78 °C (19%); (iii) PhCHdNMe, -78 °C (12%).
the C2 conformer of 1 is lithiated faster than the S2 conformer
of 1) or 2 exists as an interconverting mixture of C2 and S2
conformers and C2-2 reacts faster. We managed to make both
C2-2 and S2-2 selectively by treating each of the two
atropisomeric dibromo compounds C2-3f and S2-3f with
t-BuLi. On quenching with MeI, a different atropisomer was
obtained in each case: C2-3a from C2-3f and S2-3a from
S2-3f. The bromine-lithium exchange of 3f and the alkyl-
ation of 2 are therefore stereospecific: the atropisomers of
2 do not interconvert under the conditions of the reaction
(THF, -78 °C) and hence stereoselectivity in the conversion
1 f 2 f 3 must arise by selective formation of C2-2 under
kinetic control. At higher temperatures, though, C2-2 and S2-2
do interconvert: if the addition of MeI to the organolithium
derived from S2-3f is delayed until after the solution of S2-2
has been raised to +10 °C for 1 h, only C2-3a is obtained.
The relative stabilities of the atropisomers of 2 and of 3 are
therefore opposite, with S2-2 epimerizing to the more stable
C2-2 at temperatures between -78 and +10 °C.
A brief investigation of the lithiation and alkylation of the
biphenyl ether 12 suggests that it behaves similarly to 1.
Ullman coupling of o-cresol with 2-chlorobenzoic acid gave
the carboxylic acid 11,16 which was oxidized (KMnO4)17 and
converted to the amide 12. Double lithiation of 12 (6-10
equiv of s-BuLi, TMEDA, -78 °C, THF) and electrophilic
quench with MeI or EtI gave the chiral (by HPLC8)
atropisomers dl-13a and dl-13b with >10:1 atroposelectivity
(Scheme 4). On heating 13a, some of the epimeric meso-
13a was formed, but dl-13a remained the major component
of the equilibrium mixture. As with 3c, 13c was formed as
a mixture of atropisomers.
We have demonstrated that molecules such as 3, 9, and
13 have a well-defined conformational preference, and it is
possible to exploit that preference for the long-range
transmission of stereochemical information. The ability of
the conformation of a small molecule to transmit information
Rotationally restricted amide substituents exert powerful
stereochemical control over lateral lithiation reactions12 and
Scheme 3. Relaying Stereochemistry from an Auxiliary to a Remote Stereogenic Centera
a Reagents: (i) 3-4 equiv of n- or s-BuLi, TMEDA, THF, -78 °C; (ii) DMF, -78 f 0 °C (81% 6; 91% 9); (iii) 2 equiv of (-)-
ephedrine, cat. TsOH, toluene, ∆, 12 h (81%); (iv) ArMgBr, -78 °C, 2 h.
Org. Lett., Vol. 3, No. 26, 2001
4135

Scheme 4. Atropisomers of a 2,2′-Dicarboxamidobiphenyl Ethera
a Reagents: (i) Cu, CuI, pyridine, H2O, 100 °C (ref 16); (ii) KMnO4, K2CO3, H2O, 100 °C, 20 min (ref 17, 90%); (iii) (COCl)2, DMF
(cat.); (iv) i-Pr2NH, DMAP (71%); (v) 10 equiv of s-BuLi, TMEDA, THF, -78 °C; (vi) MeI (76%) or EtI (31%) or Me2NCHO (61%);
(vii) toluene, reflux, 1 h.
from a “binding site” (for example, the formyl group of 6,
which covalently binds (-)-ephedrine) to an “effector” site
(the formyl group of 9, to which nucleophiles add stereo-
selectively) is reminiscent of biological allostery, and we are
currently working to develop new chemical models of
allosteric systems.
Acknowledgment. We are grateful to the EPSRC for
support and to Dr. Madeleine Helliwell for determining the
X-ray crystal structure of 1.
Supporting Information Available: 1H and 13C NMR
spectra and physical data for 1, C2-3a, S2-3a, C2-3b, S2-3b,
3c, S2-3d, C2-3f, S2-3f, 6, 8-10 (R ) Ph, p-MeOC6H4), dl-
13a, dl-13b, and 13c; crystallographic data for 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Clayden, J.; Pink, J. H. Tetrahedron Lett. 1997, 38, 2565. (b)
Clayden, J.; Pink, J. H. Tetrahedron Lett. 1997, 38, 2565. (c) Clayden, J.;
Helliwell, M.; Pink, J. H.; Westlund, N. J. Am. Chem. Soc. in press. (d)
Clayden, J.; Darbyshire, M.; Pink, J. H.; Westlund, N.; Wilson, F. X.
Tetrahedron Lett. 1997, 38, 8587.
OL0167457
(13) (a) Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1996,
37, 5577. (b) Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron Lett.
1999, 40, 7883. (c) Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron
Lett. 1999, 40, 3329. (d) Clayden, J.; Westlund, N.; Beddoes, R. L.;
Helliwell, M. J. Chem. Soc., Perkin Trans. 1 2000, 1351. (e) Clayden, J.;
McCarthy, C.; Westlund, N.; Frampton, C. S. J. Chem. Soc., Perkin Trans.
1 2000, 1363. (f) Clayden, J.; Westlund, N.; Frampton, C. S. J. Chem. Soc.,
Perkin Trans. 1 2000, 1379.
(15) Comparison of the 1H NMR spectrum of the crude product from
9and PhMgBr with that from the reaction of 9 with PhLi (which gives a
2:1 ratio of diastereoisomers in 94% yield) indicated a stereoselectivity of
>20:1. The stereochemistry of 10 is assigned tentatively by analogy
additions to 2-formyl naphthamides (see ref 13a,e).
(16) Pello´n, R. F.; Carrasco, R.; Milia´n, V.; Rode´s, L. Synth. Commun.
1995, 25, 1077.
(17) Shapiro, R.; Slobodin, D. J. Org. Chem. 1969, 34, 1165.
(14) For an example of remote stereochemical control around rigid ring-
systems mediated by amides, see ref 3.
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Org. Lett., Vol. 3, No. 26, 2001