Contra-Friedel-Crafts tert-butylation of substituted aromatic rings via directed metallation and sulfinylation

Article abstract of DOI:10.1039/b600181e

Directed metallation and sulfinylation yields sulfoxides which undergo ipso nucleophilic aromatic substitution with tertiary and secondary alkyllithiums, giving aromatic rings bearing alkyl groups generally incompatible with directed metallation methods and with regioselectivity complementary with classical Friedel-Crafts substitution. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b600181e

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COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Contra-Friedel–Crafts tert-butylation of substituted aromatic rings via
directed metallation and sulfinylation{
Jonathan Clayden,*a Christopher C. Stimsonab and Martine Keenanb
Received (in Cambridge, UK) 6th January 2006, Accepted 2nd February 2006
First published as an Advance Article on the web 21st February 2006
DOI: 10.1039/b600181e
Directed metallation and sulfinylation yields sulfoxides which
undergo ipso nucleophilic aromatic substitution with tertiary
and secondary alkyllithiums, giving aromatic rings bearing
alkyl groups generally incompatible with directed metallation
methods and with regioselectivity complementary with classical
Friedel–Crafts substitution.
Table 1 ortho-t-Butylation via sulfinylation
Entry
1
X =
2 yield (%)
2a 56
3 yield (%)
3a 73
2
3
4
5
6
7
8
a
CONEt2
CONi-Pr2
CONMet-Bu
CONHMe
CONHi-Pr
OMe
2b 63
2c 43
2d 89
—
2f 69
2g 40
2h 32b
b
3b 100
3c 73
3d 82
3e 95a
0
The combination of electrophilic aromatic substitution,1 nucleo-
philic aromatic substitution,2 and directed metallation3–5 provides
chemists with the tools to elaborate aromatic rings with almost any
pattern of substitution. Nonetheless, some limitations remain, and
the one we address in this paper is the introduction of t-butyl
groups. As part of a programme of research into sterically
hindered atropisomers,6 we needed to construct a variety of
molecules carrying a t-butyl group ortho to pre-existing function-
ality: it is striking that no directed metallation-based method exists
for t-butylation ortho to electron-withdrawing groups. t-Butyl
electrophiles are of course too hindered to undergo substitution
with most organometallics and elimination invariably competes.
Commercially unavailable 2-t-butylbenzoic acid is currently best
made via nucleophilic aromatic substitution of methoxide directed
by an oxazoline substituent.7
3g 75
0
NMe2
From 3d by treatment with acid. Lithiation carried out with
n-BuLi/TMEDA at reflux.
acid (entry 5).11 Remarkably, even 2-sulfinylanisole 2g undergoes
substitution with t-BuLi to yield 2-t-butylanisole 3g in excellent
yield (entry 7). 2-Sulfinylaniline 2h is however apparently too
electron-rich to undergo the substitution.
Because they combine acidification with powerful complexa-
tion-induced proximity effects,12 electron-withdrawing groups such
as amides and oxazolines are more powerful directors of
metallation than electron-donating amino and alkoxy groups,3,13
so our new t-butylation method inverts the usual electronic
dependence of direct Friedel–Crafts alkylations.14 Amides 4
substituted in various positions with electron-donating MeO,
Me2N and t-Bu2P substituents were t-butylated via t-butylsulf-
oxides 5 (Scheme 2). In some hindered cases, yields in either the
sulfinylation or t-butylation steps were low, but t-butylated
products 6 were always formed with regioselectivity expected3
for metallation of arenes carrying a strong (CONR2) and a weak
(MeO etc.) directing group (Table 2).
In this Communication we describe a generally applicable
method for the synthesis of t-butylated products via directed
metallation, allowing the introduction of t-butyl groups ortho to
either electron-withdrawing or -donating metallation directing
groups (‘‘DMG’s’’4). The reaction tolerates both electron-deficient
and moderately electron-rich aryl ring functionality, and differs
markedly from ‘‘classical’’ SNAr reactions in not requiring the ring
to carry an additional anion-stabilising substituent.8
A range of arenes 1 carrying metallation-directing groups X
were t-butylsulfinylated by ortholithiation followed by trapping
with t-butyl t-butylthiosulfinate.9 (Table 1). The t-butylsulfoxides 2
were treated with an excess of t-butyllithium and underwent
substitution to yield t-butylated anisoles, benzamides and phenyl-
oxazolines 3 (Scheme 1).10 With electron-withdrawing tertiary
amide and oxazoline substituents, excellent yields of ortho-
t-butylated products 3a–3d are obtained (entries 1–4).
Substitution adjacent to the (anionic) secondary amide fails
(entry 6), but 2-t-butyl secondary amide 3e can be made by
treatment of 3d, which does undergo successful substitution, with
Scheme 1 t-Butylation by substitution of a sulfinyl group.
aSchool of Chemistry, University of Manchester, Oxford Road,
Manchester, UK M13 9PL. E-mail: clayden@man.ac.uk
bEli Lilly and Co. Ltd., Erl Wood Manor, Windlesham, Surrey, UK
GU20 6PH
{ Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data for all new compounds. See DOI:
10.1039/b600181e
Scheme 2 Contra-Friedel–Crafts t-butylation.
Chem. Commun., 2006, 1393–1394 | 1393
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We expect that this new t-butylation method will find broad
applicability in the synthesis of sterically constrained arenes, not
least in the synthesis of potential atropisomeric systems, an area we
are actively pursuing.
Table 2 t-Butylation of substituted benzamides
Entry
R =
X =
5 yield (%)
Nu =
6 yield (%)
1
2
3
i-Pr
i-Pr
i-Pr
6-OMe
3-OMe
4-OMe
5a 72
5b 88
5c 85
t-Bu
t-Bu
t-Bu
i-Pr
t-Bu
t-Bu
t-Bu
t-Bu
s-Bu
n-Bu
6a 46
6b 15
6c 79
6c9 50
6d 58
6e 77
6f 9
6g 59
6g9 51
0
We thank the EPSRC and Eli Lilly for support.
4
5
6
7
i-Pr
i-Pr
Et
5,6-benzoa
3,6-(OMe)2
6-Pt-Bu2
5d 64
5e 15
5f 49
5g 83
Notes and references
1 R. J. K. Taylor, Electrophilic Aromatic Substitution, Wiley, New York,
1990.
2 J. A. Zoltewicz, Top. Curr. Chem., 1975, 59, 33.
3 J. Clayden, Directed metallation of aromatic compounds, in Chemistry
of Organolithium Compounds, ed. Z. Rappoport and I. Marek, Wiley,
Chichester, 2004, vol. 1, pp. 495–646.
8
Et
6-NMe2
9
10
a
1-Naphthamide.
4 V. Snieckus, Chem. Rev., 1990, 90, 879.
5 H. W. Gschwend and H. R. Rodriguez, Org. React., 1979, 26, 1.
6 For recent progress, 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; J. Clayden, A. Lund, L. Vallverdu´ and
M. Helliwell, Nature, 2004, 431, 966.
7 A. I. Meyers and E. D. Mihelich, J. Am. Chem. Soc., 1975, 97, 7383;
A. I. Meyers, R. Gabel and E. D. Mihelich, J. Org. Chem., 1978, 43,
1372; P. Beak, S. T. Kerrick and D. J. Gallagher, J. Am. Chem. Soc.,
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223.
8 Comparable aromatic substitution reactions of 2-substituted imines,
sulfones etc., have been reported, but in common with most SNAr
reactions they succeed only with electron-withdrawing groups ortho to
the leaving group. See L. A. Flippin, D. S. Darter and N. J. P. Dubree,
Tetrahedron Lett., 1993, 34, 3255; J. Clayden, J. J. A. Cooney and
M. Julia, J. Chem. Soc., Perkin Trans. 1, 1995, 7.
9 The t-butyl t-butylthiosulfinate was made and used in enantiomerically
enriched form, but this is of course inessential to the method. See:
D. J. Weix and J. A. Ellman, Org. Lett., 2003, 5, 1317.
Scheme 3 Substitution by attack at C.
10 Previous substitutions of sulfoxides from aromatic rings are confined to
those leaving electron deficient rings, namely naphthalenes and
pyridines. See ref. 16, ref. 17 and T. Shibutani, H. Fujihara and
N. Furukawa, Tetrahedron Lett., 1991, 32, 2943; N. Furukawa,
S. Ogawa, K. Matsumura and H. Fujihara, J. Org. Chem., 1991, 56,
6341; T. Kawai, Y. Kodera, N. Furukawa, S. Oae, M. Ishida, T. Takeda
and S. Wakabayashi, Phosphorus, Sulfur Relat. Elem., 1987, 34, 139–148
and references therein.
11 D. B. Reitz and S. M. Massey, J. Org. Chem., 1990, 1375.
12 M. C. Whisler, M. MacNeil, V. Snieckus and P. Beak, Angew. Chem.,
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13 J. Clayden, Organolithiums: Selectivity for Synthesis, Pergamon, Oxford,
2002.
14 R. M. Roberts and A. A. Khalaf, Friedel Crafts Alkylation Chemistry,
Marcel Dekker, New York, 1984.
15 The successful substitution to form 6d makes benzyne mechanisms
unlikely.
16 R. W. Baker, S. O. Rea, M. V. Sargent, E. M. C. Schenkelaars,
T. S. Tjahjandarie and A. Totaro, Tetrahedron, 2005, 61, 3733.
17 S. Oae, T. Kawai and N. Furukawa, Phosphorus, Sulfur Relat. Elem.,
1987, 34, 123–132.
18 Such ‘‘ligand exchange’’ reactions with diarylsulfoxides provide the
mechanism for synthetically useful sulfoxide metal exchange reactions.
For recent examples, see: H. L. Pedersen and M. Johanssen, Chem.
Commun., 1999, 2517; G. Argouarch, O. Samuel, O. Riant, J.-C. Daran
and H. B. Kagan, Eur. J. Org. Chem., 2000, 2893; R. W. Hoffmann,
P. G. Nell, R. Leo and K. Harms, Chem.–Eur. J., 2000, 3359;
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Tetrahedron, 2004, 60, 4387; P. B. Hitchcock, G. J. Rowlands and
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Two sulfoxides 5c and 5g were treated with other organo-
lithiums (s-BuLi, i-PrLi, n-BuLi). The substitution was successful
with the secondary organolithiums, but not the primary, providing
complementarity with alkylation via direct trapping of ortholithia-
tion, which works only with primary alkylating agents.
Two reasonable mechanisms can be envisaged for this
reaction.15 Substitution reactions of sulfoxides have generally been
accounted for by assuming the formation of a s-sulfurane
intermediate which collapses either by ‘‘ligand coupling’’ (see
Scheme 3 route a) or by loss of an anionic leaving group – ‘‘ligand
exchange’’.16–18 However, with t-butyl sulfoxides, attack on the
sulfur centre is known to be slow,17 and direct nucleophilic
aromatic substitution of the t-butylsulfinyl group by attack of the
alkyllithium at C (to yield intermediate 9) may compete (Scheme 3
route b). The result of an isotopic labelling experiment leads us to
favour the latter interpretation. Sulfoxide 5d labelled with C-13 in
one of the t-butyl’s methyl groups was made by lithiation of
naphthamide 4d, quenching with diisopropyl disulfide, oxidizing to
the sulfoxide and alkylating with 13CH3I. 13C-5d undergoes
substitution to yield 6d devoid of a 13C label, suggesting the
mechanism follows route b. Substitution via route a is consistent
with this result only in the unlikely event that both formation and
collapse of sulfurane 8 are fully stereospecific. It is remarkable
nonetheless that neither sulfoxide–lithium exchange18 nor ortho-
lithiation19 competes with the substitution, but presumably the
combination of steric hindrance in both the nucleophile and
electrophile is at the root of this unusual and valuable
chemoselectivity.
19 C. Quesnelle, T. Iihama, T. Aubert, H. Perrier and V. Snieckus,
Tetrahedron Lett., 1992, 33, 2625–2628.
1394 | Chem. Commun., 2006, 1393–1394
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