Radical-carbanion cyclo-coupling in armed aromatics: Overriding steric hindrance to ring closure

Article abstract of DOI:10.1039/b506391d

ω-(2-Halophenyl)alkyl-2-oxazolines were prepared and reacted via base promoted intramolecular coupling of radical with carbanionic centres to yield 1-phenyl-1-oxazolino-indan and -tetralin derivatives containing quaternary C-atoms. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b506391d

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Radical-carbanion cyclo-coupling in armed aromatics: overriding steric
hindrance to ring closure
Mark D. Roydhouse and John C. Walton*
Received (in Cambridge, UK) 6th May 2005, Accepted 12th July 2005
First published as an Advance Article on the web 4th August 2005
DOI: 10.1039/b506391d
aromatic and heteroaromatic radicals, giving coupled products in
moderate to high yields.10 Reactions were photoassisted and
involved the use of KNH2 in liquid NH3. 2-Oxazoline units are
synthetically useful and may readily be transformed to amides,
acids, aldehydes etc.11 Furthermore, suitably functionalised
2-oxazolines are useful as chiral auxiliaries.12
v-(2-Halophenyl)alkyl-2-oxazolines were prepared and reacted
via base promoted intramolecular coupling of radical
with carbanionic centres to yield 1-phenyl-1-oxazolino-indan
and -tetralin derivatives containing quaternary C-atoms.
Conventional free radical based ring closures are accomplished by
means of intramolecular additions to alkene and related acceptors
that favour the 5-exo cyclisation mode. A wealth of detail is
available in the literature on such cyclizations.1 Reports of ring
closures proceeding by intramolecular radical–carbanion coupling
(SRN1) are comparatively scant in number.2,3 Potentially, cyclisa-
tion by radical–carbanion coupling is an efficient chain process,
applicable for a different range of functionality, with several latent
advantages. First, for aryl type radicals, cyclo-coupling with
carbanions is expected to be extremely rapid, even when this results
in the formation of a quaternary centre. Second, it can be
anticipated that 6-member ring production by this means should
proceed as readily as 5-member ring formation.2b,2d Conventional
radical cyclizations onto a-substituted alkenes giving quaternary
centres are comparatively slow4 and the substituent on the double
bond often diverts the regioselectivity to the endo mode.5,6
6-Member ring formation by 6-exo or 6-endo processes is also
relatively slow and both modes require particular substituent
patterns if product mixtures are to be avoided.4–6
2-Haloaryl-2-oxazolines of type 5 were chosen as precursors and
prepared from commercially available 2-halophenylacetic acids (3)
as shown in Scheme 2. In reductions of 3 with LiAlH4 it was
necessary to carefully control the amount of metal hydride, and the
reaction conditions, in order to avoid dehalogenation of the ring.
Similarly, during n-BuLi mediated alkylation of the 2-oxazolines
with phenethyl iodides 4, solvent polarity was found to be crucial.
By using a 3 : 2 mixture of THF : hexane, loss of halogen from the
ring was essentially completely suppressed and the 3-(2-haloaryl)-
propyl-2-oxazolines 5 were obtained in satisfactory yields.
The planned intramolecular radical–anion coupling process is
shown in Scheme 3. Treatment of precursor 5 with base should
produce the azaenolate ion present in 6. An electron is also
transferred to 5 in the initiation process giving the aromatic radical
anion shown in 6. Rapid loss of halide from 6 was expected to
yield the aryl radical–carbanion-containing intermediate 7. These
events do not necessarily take place in the order described. The
subsequent intramolecular reaction was expected to cyclo-couple
together the reactive centres in 7 producing indan-type radical
anion 8. SET from 8 to another precursor molecule would then
yield functionalised indan 9 and simultaneously propagate the
chain (Scheme 3).
Anticonvulsant activity has been reported for the benzo-
caramiphen analogue 1.7 Other aryl-substuted indan derivatives
are also precursors for pharmaceuticals.8 Our initial aim was to
develop a new radical-carbanion coupling route to compounds of
type 1 containing quaternary C-atoms. We also investigated the
applicability of similar methodology to preparations of tetralin
analogues 2, containing 6-member rings with quaternary C-atoms,
which are also precursors to pharmaceuticals.9
Several different sets of conditions for promoting the radical–
carbanion coupling reaction were investigated (Table 1).
Potassium tert-butoxide (pKa 5 19) was probably not a strong
In 1997 Wolfe and co-workers reported that carbanions derived
from 2-oxazolines took part in intermolecular reactions with
Scheme 1 Biologically active 1-aryl-indan and -tetralin derivatives.
University of St. Andrews, School of Chemistry, EaStCHEM, St.
Andrews, Fife, KY16 9ST, UK. E-mail: jcw@st-and.ac.uk;
Fax: 44 (0)1334 463808; Tel: 44 (0)1334 463864
Scheme 2 Preparation of 2-halophenylpropyl-2-oxazolines.
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1 equiv) depressed the yield of 9b and made work-up more
difficult. This may be due to the formation of stable complexes
between Fe(II) and the oxazoline. The similar yields of 9a and 9b,
obtained under matching conditions in the LDA promoted
reactions, demonstrated that ring closure to give the quaternary
centre in 9b took place just as readily as formation of the tertiary
centre in 9a.
The analogous radical–carbanion coupling reaction to afford a
6-member ring was next examined. 3-(2-Bromophenyl)propionic
acid (homologue of 3) was obtained by treatment of a mixture of
2-bromobenzaldehyde and Meldrum’s acid with formic acid and
triethylamine,15 and converted to 4-(2-bromophenyl)butyl-2-
oxazoline precursor 11 by an analogous route to that shown in
Scheme 1. Treatment of 11 with 3 equivalents of LDA in THF at
rt for 48 h gave a 55% yield of tetralin derivative 12. This yield was
comparable to that of 9b under similar reaction conditions (yield
of 12 was 50% in a 6 h reaction illuminated with UV light) and
hence our expectation, that 6-member ring closure with generation
of a quaternary centre would be facile, was fulfilled.
Scheme 3 Chain reaction of 2-haloarylpropyl-2-oxazolines yielding
functionalised indanes.
The indan (9) and tetralin derivatives (12) were obtained as
racemates and analogous reactions directed by a chiral 2-oxazoline
were next examined to see if stereoselectivity in the ring closure
step could be achieved with the oxazoline acting as a chiral
auxiliary. (S)-Valinol was condensed with ethyl 2-phenylacetimi-
date hydrochloride 13 to provide (S)-4-isopropyl-2-oxazoline 14.
This was alkylated with 2-bromophenethyl iodide 4 (X 5 Br) to
afford the precursor 15 as a 2 : 1 mixture of diastereoisomers at the
a-position. Oxazoline 15 was treated with three equivalents of
LDA using the best conditions for radical–carbanion coupling
developed for 5b. It was expected that azaenolate 16 would be
generated and that the chiral oxazoline would favour production
of either the (S,S)-indane radical anion 17 or the (R,S)
diastereomer. A 6 h reaction at rt with UV irradiation gave a
55% yield of the substituted indane diastereoisomer mixture 18
which was readily separable by conventional column chromato-
graphy. The d.e. was found to be 18% by comparison of the
1H NMR signals of the two diastereomers. None of the reduced,
de-brominated product was detected. The indane yield was lower
in a reaction carried out over 48 h without UV irradiation but the
d.e. (20%) was virtually unchanged. A reaction carried out at 0 uC
without UV irradiation yielded 50% indane 18 with an improved
d.e. of 48%. The isopropyl group is a comparatively small
substituent so the fact that some stereoselectivity was obtained was
encouraging. Work with other chiral oxazolines, designed to
improve selectivity is in progress.
Table 1 Radical–carbanion coupling reactions (SRN1) of 3-(2-halo-
aryl)propyl-2-oxazolines 5a
Indane Reduced
9 (%) 10 (%)
Precursor
Conditions
5b (X 5 Br) t-BuOK, Et3N, DMSO, UV, rt 4h
5a (X 5 Cl) t-BuOK, Et3N, DMSO, UV, rt 3h
5b (X 5 Br) NaH, DMSO, UV, 100u, 4h
5b (X 5 Br) KNH2, liq. NH3, UV, 233u, 1h
5b (X 5 Br) LDA (3 eq.), THF, rt, 48h
5b (X 5 Br) LDA (3 eq.), THF, UV, rt, 6h
5b (X 5 Br) LDA (3 eq.), THF, FeCl2, rt, 1h
5a (X 5 Br) LDA (3 eq.), THF, UV, rt, 6h
a
0
0
2
0
66
16
75
57b
23
58b
—
31
—
15b
16
—
Yields (mol%) determined by NMR except as indicated otherwise.
In most reactions small amount (,8%) of 2-halostyrene
accompanied the reported products. Isolated yields.
a
b
enough base to deprotonate the oxazolines (pKay20–25) and no
reaction took place, even in the presence of added Et3N as a
PET agent.
DMSO (pKa 5 35) is considered a good solvent for SRN
1
reactions and therefore use of DMSO with NaH (pKa 5 36)
should afford a clean solution of the sulfoxide sodium salt.
However, the cyclization was not spontaneous with this system.
Results suggested anion formation did not take place except at
higher temperatures. However, a satisfactory yield of 9b was
obtained in a reaction at 100 uC with UV irradiation. Promotion
of the reaction with alkali metal amides in liquid ammonia using
conditions similar to those advocated by Wolfe et al.10 resulted in
some indane formation (Table 1) but de-halogenative reduction to
10 accounted for the majority of product. Best results were
obtained in reactions promoted by LDA in THF at rt. Three
equivalents of LDA were required; less base led to slower reactions
with greater amounts of 10. In the reaction irradiated with UV
light, the precursor was all consumed in 6 h and a satisfactory yield
of 9b was obtained, accompanied by some 10b.13 The cleanest
reaction, giving 75% of 9b with negligible 10b, took place without
UV irradiation over 48 h. It has been reported that Fe(II) salts
significantly enhance the rates of some SRN1 reactions.14 We found
however, that for 2-oxazoline precursors, addition of FeCl2 (0.1 to
The SRN1 type chain mechanism of Scheme 3 accounts for
product formation, although obviously the illustrated timing of the
electron transfer and halide loss steps to give the anion-radical 7
is only tentative. An alternative mechanism involving aryne
Scheme 4 Preparation of a tetralin derivative.
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Notes and references
1 For reviews of conventional radical cyclizations see: P. Renaud and
M. P. Sibi, ed., Radicals in Organic Synthesis, vols. 1 & 2, Wiley-VCH,
Weinheim, 2001; S. Z. Zard, Radical Reactions in Organic Synthesis,
Oxford, 2003.
2 (a) J. F. Wolfe, M. C. Sleevi and R. R. Goehring, J. Am. Chem. Soc.,
1980, 102, 3646; (b) R. R. Goehring, Y. P. Sachdeva, J. S. Pisipati,
M. C. Sleevi and J. F. Wolfe, J. Am. Chem. Soc., 1985, 107, 435; (c)
R. R. Goehring, Tetrahedron Lett., 1992, 33, 6045; (d) R. R. Goehring,
Tetrahedron Lett., 1994, 35, 8145; (e) S. A. Dandekar, S. N. Greenwood,
T. D. Greenwood, S. Mabic, J. S. Merola, J. M. Tanko and J. F. Wolfe.,
J. Org. Chem., 1999, 64, 1543.
3 For a review of intramolcular SRN1 reactions see: R. A. Rossi,
A. B. Pierini and A. B. Pen˜e´n˜ory, Chem. Rev., 2003, 103, 71.
4 (a) A. L. J. Beckwith and K. U. Ingold, in Rearrangemements in Ground
and Excited States, ed., P. de Mayo, Academic, New York, 1980, Vol. 1,
p. 161; (b) A. G. Fallis and I. M. Brinza, Tetrahedron, 1997, 53, 17543.
5 (a) D. P. Curran, N. A. Porter and B. Giese, Stereochemistry of Radical
Reactions, VCH, Weinheim, 1996; (b) D. C. Spellmeyer and K. N. Houk,
J. Org. Chem., 1987, 52, 959.
6 (a) A. J. McCarroll and J. C. Walton, Angew. Chem. Int. Ed., 2001, 40,
2224; (b) A. J. McCarroll and J. C. Walton, Chem. Soc. Rev., 2001, 30,
3215.
7 D. L. DeHaven-Hudkins, J. T. Allen, R. L. Hudkins, J. F. Stubbins and
F. C. Tortella, Life Sci., 1995, 56, 1571.
8 M. B. Sommer, M. Begtrup and K. P. Bøgesø, J. Org. Chem., 1990, 55,
4822.
Scheme 5 Preparation of diastereomeric indane derivatives.
9 G. N. Walker and D. Alkalay, J. Org. Chem., 1971, 36, 491;
R. G. Gentles, D. Middlemiss, G. R. Proctor and A. H. Sneddon,
J. Chem. Soc., Perkin Trans. 1, 1991, 1423.
10 J.-W. Wong, K. J. Natalie, G. C. Nwokogu, J. S. Pisipati, P. T. Flaherty,
T. D. Greenwood and J. F. Wolfe, J. Org. Chem., 1997, 62, 6152.
11 D. J. Ager, I. Prakash and D. R. Schaad, Chem. Rev., 1996, 96, 835.
12 K. A. Lutomski and A. I. Myers, in Asymmetric Synthesis, Vol. 3, J. D.
Morrison ed., Academic Press, Orlando, 1984, Chapter 3; R. A. Aitken
and S. N. Kile´nyi, Asymmetric Synthesis, Blackie, London, 1992,
Chapter 5, p. 83.
formation, followed by intramolecular nucleophilic attack, could
be written to account for the products. Wolfe and co-workers
studied in detail the mechanisms of related inter- and intra-
molecular photo-stimulated, base-promoted coupling reactions of
nucleophiles with haloarenes.12e,10 Their evidence that the
mechanism proceeds via the chain anion–radical coupling process
includes the following: (i) the reactions were strongly inhibited
when either of the radical traps di-tert-butyl nitroxide or
p-dinitrobenzene was added, (ii) the reactions were extremely
sensitive to oxygen (just as ours were), (iii) reaction efficiency
increased with photolysis (just as ours did), (iv) most importantly,
substrates incapable of affording arynes (because they lacked
H-atoms adjacent to the halogen on the aromatic ring) never-
theless gave the coupled product in reactions mediated by LDA
(and metal amides in ammonia). We examined the reaction of
precursor 5b with LDA in THF solution, in a quartz capillary
tube, directly in the resonant cavity of a 9 GHz EPR spectrometer.
In the complete absence of oxygen and on illumination with UV
light a strong spectrum was obtained that increased in intensity at
lower temperatures. The EPR parameters, viz: g 5 2.0030,
a(1H) 5 5.7, a(4H) 5 4.2, a(4H) 5 1.5 G, were similar to those
of the radical anions of models diphenylmethane and indane,16
and indicate that the spectrum is due to radical-anion 8b. These
observations provide strong evidence in favour of the SRN1
mechanism of Scheme 3.
13 To a solution of LDA (2.25 mmol) in THF (3.1 cm3) at 278 uC was
added over 10 min a solution of 2-oxazoline 5b (X 5 Br) (279 mg,
0.75 mmol) in THF (1.5 cm3). After a further 10 min stirring, the yellow
solution was allowed to warm to rt over 30 min. THF (4.5 cm3) was
added and the resultant deep red/black solution stirred for 6 h with UV
irradiation. After this time a saturated solution of NH4Cl (7.5 cm3) was
added and the aqueous layer extracted with ether (3 6 4 cm3). The
combined organic layers were washed with water (7.5 cm3) dried
(MgSO4) and evaporated. Purification via column chromatography
(SiO2, 9 : 1 hexane : EtOAc) yielded the pure indane 9b as a clear oil
(126 mg, 57%), Rf (SiO2, 9 : 1 hexanes : EtOAc) 0.35; nmax(film)/cm21
1649 (CLN); dH 1.24 (3H, s, CH3), 1.40 (3H, s, CH3), 2.30 (1H, ddd,
J 5 12.6, 7.7, 5.1, CHAHB), 2.82 (1H, ddd, J 5 15.6, 7.7, 7.4,
ArCHCHD), 3.00 (1H, ddd, J 5 15.6, 7.9, 5.1, ArCHCHD), 3.18 (1H,
ddd, J 5 12.6, 7.9, 7.4, CHAHB), 3.90 (1H, AB Jy7.9, CHEHFO), 3.97
(1H, AB Jy7.9, CHEHFO), 7.06–7.11 (2H, m, ArH), 7.18–7.31 (6H, m,
ArH) and 7.48–7.51 (1H, m, ArH); dC 28.0 (CH3), 28.3 (CH3), 30.3
(CH2), 41.3 (ArCH2), 58.2 ((CH3)2C), 66.8 (PhC), 79.4 (CH2O), 124.7
(CHAr), 126.4 (CHAr), 126.5 (CHAr), 126.6 (CHAr), 126.7 (CHAr), 127.7
(CHAr), 128.3 (CHAr), 143.6 (Cq), 144.3 (Cq), 144.8 (Cq) and 167.6
(CLN); m/z (CI) 292 [100%, (M + H)+] [Found: (MH)+ 292.1708.
C20H22ON requires 292.1701] and 2-[1,3-diphenylpropyl]-4,4-dimethyl-
2-oxazoline 10b, clear oil, (24 mg, 15%) dH 1.25 (3H, s, CH3), 1.26 (3H,
s, CH3) 2.09–2.18 (1H, m, CHACHB), 2.37–2.44 (1H, m, CHACHB),
2.59 (2H, t, J 5 7.7), 3.54 (1H, t, J 5 7.7), 3.81 (1H, s, CHCHDO), 3.82
(1H, s, CHCHDO) and 7.11–7.34 (10H, m, ArH); dC 27.0 (CH3), 28.1
(CH3), 33.3, 35.2, 44.4, 66.6, 78.6, 125.6, 126.8, 127.6, 128.1, 128.3, 128.4,
139.8, 141.2 and 166.4, plus 2-bromostyrene, clear oil (7%).
14 C. Calli and P. Gentili, J. Chem. Soc., Perkin Trans. 2, 1993, 1135;
M. T. Baumgartner, R. A. Rossi and A. B. Pierini, J. Org. Chem., 1999,
64, 6487.
We have established that v-(2-bromophenyl)alkyl-2-oxazolines
readily undergo base-promoted de-brominative-cyclisations that
proceed even when quaternary centres are formed. In this way
1-phenyl-indane and -tetralin derivatives can be accessed, contain-
ing easily manipulated oxazoline moieties, ready for transforma-
tion to biologically active compounds. Modest stereoselectivity
was realized by incorporating a 4-(S)-isopropyl-2-oxazoline unit in
the precursor.
15 G. Toth and K. E. Kover, Synth. Commun., 1995, 25, 3067.
16 F. Gerson and W. B. Martin, Jr., J. Am. Chem. Soc., 1969, 91, 1883;
N. L. Bauld and F. R. Farr, J. Am. Chem. Soc., 1974, 96, 5633.
The authors thank the EPSRC for financial support and Dr
R. A. Aitken for helpful discussions.
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Chem. Commun., 2005, 4453–4455 | 4455